INTRODUCTION — The concept of mild cognitive impairment (MCI) as an intermediate state between normal cognition and dementia has been long recognized. While a gradual decline in cognition is a characteristic of normal aging, there is increasing evidence that some forms of cognitive impairment are recognizable as an early manifestation of dementia [1].
This topic review will discuss MCI. Topics related to dementia, including diagnosis, treatment, risk factors, and prevention of dementia, are discussed separately. (See "Dementia syndromes" and see "Treatment of dementia" and see "Risk factors for dementia" and see "Prevention of dementia").
DEFINITIONS — Mild cognitive impairment (MCI) refers to cognitive impairment that does not meet the criteria for dementia. Various researchers have proposed several criteria for and subtypes of MCI [1-3]. These criteria and subtypes differ somewhat, although there is considerable overlap. The Mayo criteria are the ones most commonly applied in the literature [4]:
Memory complaint, preferably corroborated by an informant
Objective memory impairment (for age and education)
Preserved general cognitive function
Intact activities of daily living
Not demented
It is important to emphasize that these criteria are imprecise. Considerable judgment is involved in making the distinction between impairments that are normal for the elderly population and, on the other extreme, that do not represent dementia. Also, some investigators challenge the inclusion of intact activities of daily living as a criterion [5,6]. These and other judgments likely differ between assessors and account for some of the conflicting results in studies of this disorder.
MCI is heterogeneous in terms of clinical presentation, etiology, and prognosis [3,7,8]. There are now accepted definitions for subclasses of MCI: amnestic MCI, multiple-domain MCI, and the single non-memory domain MCI [4,9]. The amnestic type of MCI is generally thought to represent prodromal Alzheimer's disease (AD) [10]. Other subclasses may have different underlying mechanisms of cognitive impairment, and may be associated with other non-AD disease processes (eg, vascular dementia, dementia with Lewy bodies), but there is little supporting evidence for this paradigm [11]. Studies of parkinsonian signs among patients with MCI have conflicted as to their greater association with amnestic versus nonamnestic MCI [12,13].
The term MCI, without qualification, was traditionally and is still often used to refer to the amnestic type; however, using MCI without qualification is somewhat ambiguous.
Amnestic MCI — Amnestic MCI refers to those individuals with significantly impaired memory who do not meet criteria for dementia. The criteria outlined above were initially developed to define MCI in general but subsequently have been understood to identify only this type [1,4].
Memory impairments that qualify for MCI are generally represented by defects that are 1.5 standard deviations (SD) or more below age-corrected norms. While this seems straightforward, different tests of memory likely have different sensitivity and specificity, and norms are not available for all populations [7]. (See "Screening cognitive examinations" below).
Many individuals with amnestic MCI complain only of memory loss; however, they may have additional subtle impairments in other cognitive domains that are revealed with careful neuropsychological testing [9,14-16]. Some would interpret the latter finding as excluding patients from this subtype of MCI according to the criteria listed above [7]. This highlights operational difficulties with the application of the criteria.
Amnestic MCI is often thought of as a precursor to AD [10]. Although memory performances are often similar in patients with amnestic MCI and AD, impairments in multiple cognitive domains are also prominent in patients with AD [1].
Multiple-domain MCI — Individuals with multiple-domain MCI have cognitive performances and complaints that reflect slight deficiencies in multiple domains of cognitive and behavioral functioning. Their cognitive complaints and objective performances do not reflect a circumscribed impairment. Such persons may manifest subtle problems with activities of daily living, but they do not meet criteria for a formal diagnosis of dementia [8]. The multiple domains are, by definition, only slightly impaired (ie, less than 0.5 SD below age and education-matched normal subjects).
Often these individuals progress to meet criteria for AD or vascular dementia; in a minority of cases, the cognitive profile may simply reflect normal aging [8]. The multiple-domain form of MCI may be a particularly unstable condition, with some individuals even returning to a baseline level of functioning over time [9].
Single non-memory domain MCI — The concept of single non-memory domain MCI is similar to amnestic MCI, except that this form of MCI is characterized by a relatively isolated impairment in a single non-memory domain, such as executive functioning, language, or visual spatial skills [8]. Depending upon the domain, individuals with this subtype of MCI may progress to other syndromes, such as frontotemporal dementia, primary progressive aphasia, or dementia with Lewy bodies.
Related terminology — There are a multitude of loosely related terms that have been used to describe constructs that are similar to or perhaps even the same as MCI, eg, incipient dementia, isolated memory impairment, dementia prodrome, minimal AD, predementia AD, prodromal AD, and early AD [1,2,4,8,17,18]. In a glossary of these and other terms that describe cognitive impairment in elderly people without dementia, most of these definitions do not fully overlap with the definition of MCI [19].
The concept of MCI perhaps reflects most closely the idea of "cognitive impairment, no dementia" (CIND) [20]. However, in contrast to the definition for the amnestic form of MCI, CIND less heavily relies on the presence of prominent memory deficits and includes in its definition the presence of a functional disability. It is a more inclusive definition than MCI, as is reflected by its higher prevalence. (See "Epidemiology" below).
"Age-associated memory impairment" and "age-associated cognitive decline" are also widely used and fairly well known terms. However, these terms differ from MCI in that they refer to the memory impairments in older adults as referenced to young normal adult individuals [1,21,22]. In MCI, memory impairments are referenced to age-adjusted norms.
Studies of "preclinical AD" should be distinguished from studies of MCI [23]. In MCI studies, patients meet cognitive criteria for diagnosis, and are then followed prospectively to assess for conversion to AD. In contrast, "preclinical AD" studies examine information retrospectively, following the diagnosis of AD.
EPIDEMIOLOGY — Findings from epidemiological studies vary significantly, partially due to the differing diagnostic criteria, measuring instruments, and definitions.
In cohorts and treatment trials that more strictly apply the criteria for amnestic mild cognitive impairment (MCI), prevalence rates in elderly populations are estimated between 2 and 4 percent [5,7,24].
Studies using different measures, such as "age-associated cognitive decline," "cognitive impairment, no dementia," and "minimal dementia," estimate higher prevalences of 16 to 19 percent [2,5,20,25].
Gender, race, increased age, and lower education are inconsistently associated with MCI in various studies [5,7,25-27,91,92]. Elevated blood pressure and diabetes (even in the absence of symptomatic cerebrovascular disease) and apolipoprotein E epsilon 4 genotype have also been associated with the risk of MCI, particularly amnestic MCI [26-30,91,92].
CONVERSION TO DEMENTIA — It is generally accepted that individuals with mild cognitive impairment (MCI) are at increased risk of developing Alzheimer's disease (AD). In a prospective study of 798 older Catholic clergy without dementia, participants were categorized at baseline as having MCI (n = 211) or no cognitive impairment (n = 587) and were followed for an average of 4.5 years with cognitive tests [31]. The group with MCI developed AD at a rate 3.1 (CI 2.1-4.5) times higher than the group with no cognitive impairment.
However, not all studies have agreed that MCI is an important predictor of conversion to AD. In one retrospective study, a diagnosis of age-associated cognitive decline was a better predictor of conversion to AD than MCI [5]. One criticism of this study is that the MCI criteria were applied retrospectively to neuropsychological test scores [32]. These findings also highlight the general difficulty in defining MCI.
In various studies, a substantial percentage (11 to 40 percent) of patients with MCI improve, even to normal, over a one to three-year follow-up time [5,7,24,33,34]. This finding emphasizes the clinical heterogeneity of MCI. In one study, patients who improved did not appear to be at a higher risk of dementia compared with controls [33].
Rates — Rates of conversion from MCI to dementia have been estimated from treatment trials and population cohorts. In elderly populations, annual rates range from 8 to 16 percent [1,7,11,24,29,33,35-40]. This contrasts with incidence rates for AD in the general population of 1 to 3 percent per year [1,24,36]. The cumulative incidence of dementia in patients with MCI may be as high as 80 percent at six years [1]. The interval between MCI diagnosis and conversion may be as long as eight years in some cases [17].
Predictors — Given the heterogeneity of outcomes among individuals with MCI, many studies have investigated factors that might further identify those with MCI who will develop dementia. Risk factors for dementia in the general population are discussed separately. (See "Risk factors for dementia").
Some studies suggest that socioeconomic variables are equivocal predictors. Gender and education level are not predictors [41].
Age — Aging is a primary predictor of progression of MCI to AD [7,27,38,42,43,92]. With every year of age increase, MCI is slightly more likely to convert to AD. MCI is relatively unlikely to represent a predementia condition in patients less than 50 years [38].
Neuropsychological testing — A variety of observational studies suggest that neuropsychological testing may be helpful in defining individuals at risk for dementia.
Prospective cohort studies of patients with MCI or "cognitive impairment, no dementia" have shown that within this group, more severely affected patients are at greater risk for dementia than those who are less affected [33,44,45]. This was seen as early as nine years prior to diagnosis. A number of specific test measures, such as short delayed verbal recall, visual recognition memory, and other cued memory tasks, as well as measures of instrumental activities of daily living, have been found to have high predictive value for dementia in some studies [42,45-51]. However, these have not been independently and prospectively validated in a manner that allows application to individual cases.
Follow-up neuropsychological testing provides more helpful information, in that intraindividual change in cognitive function is more sensitive than comparison with group norms [52]. In one cohort study, acceleration of cognitive decline occurred approximately three years prior to the diagnosis of AD [44]. Educational level was an important modulator of test performance and rate of decline. These findings have been corroborated in other cohort studies [10,53-55]. One of these studies emphasized that a decline in cognitive measures is a necessary but not sufficient predictor of dementia, having good negative predictive value (as high as 90 percent), but poor positive predictive value (30 percent) in their cohort [54].
ApoE epsilon 4 — Apolipoprotein E (APOE) epsilon 4 (e4) genotype has been associated with the risk of AD in the general population but has had mixed association with conversion to AD among individuals with MCI. In one study, MCI patients carrying the APOE e4 allele had a greater degree of cognitive impairments and hippocampal atrophy on MRI compared with noncarriers [56]. Some studies have found that APOE e4 is a strong risk factor for conversion from MCI to AD [29,43,45,57], but others have found only a marginal or even no association [27,41,42,58-60].
CSF biomarkers — Because the pathological process of AD and other degenerative dementias is likely well underway before clinical symptoms manifest, biomarkers would seem to have potential utility in the early diagnosis of dementia. A number of small studies have examined the use of cerebrospinal fluid (CSF) markers for predicting conversion from MCI to dementia [48,61]. Associations have been suggested for:
Increased levels of tau or phosphorylated tau protein [37,43,62,63]
Lower activity of neprilysin, an amyloid beta peptide degrading enzyme [64]
Lower levels of amyloid beta 42 (Aß42) peptide, a low ratio of Aß42 to Aß40 levels, and a low ratio of Aß42 to tau levels [37,65-67,94]
The applicability of these findings to large populations is unclear, and these tests do not have an established role in the evaluation of patients with MCI. Moreover, the absence of a clinical treatment imperative for MCI makes this relatively invasive test less appealing.
Neuroimaging — Pathologic studies find that the earliest and most severe manifestations of AD are found in the medial temporal lobe. Neuroimaging studies have focused attention to these areas to define abnormalities that may predict conversion from MCI to AD as this appears to be more closely associated with MCI than other findings, such as white matter abnormalities [93].
MRI studies — Volume loss or brain atrophy can be identified on magnetic resonance imaging (MRI) in patients at risk for AD [68]. Temporal lobe atrophy may be an early specific marker for preclinical AD; similar patterns of temporal lobe atrophy are seen in patients with amnestic MCI and AD, which are not seen in individuals with multiple cognitive domain MCI, whose scans are similar to healthy controls [69]. While most studies use a specialized technique for volumetric measurements, visual assessment using a standardized rating scale seems to perform nearly as well [70-72].
Both the degree and progression of medial temporal lobe atrophy on MRI are associated with conversion to dementia in patients with MCI as well as in people with normal baseline cognition [41,42,60,70-79]. These changes can be observed one to two years prior to cognitive decline. Similarly, higher baseline apparent diffusion coefficient (ADC) values in the hippocampus on diffusion-weighted MRI (DWI) may predict conversion to dementia in patients with amnestic MCI [80,81]. However, there is overlap in the degree of atrophy for patients who do and do not progress to dementia, and the same is true for ADC values. Thus, these findings are not a practical way to predict progression to dementia for individual patients. While some investigations suggest that these MRI changes may be useful in combination with other risk factors in predicting risk of AD, such multivariate models require independent validation [79].
PET and SPECT studies — Preliminary data suggest that identification of regional patterns of cortical hypometabolism using fluorodeoxyglucose (FDG) positron emission tomography (PET) may be useful for predicting conversion from MCI to AD, especially in the presence of the APOE e4 allele [82-86]. However, it is unclear as to whether this method will have sufficient predictive value in non-APOE e4 carriers, and the limited availability of PET in most medical centers is an additional obstacle.
One study suggested that a subset of patients with amnestic MCI who perform poorly on a test of visual recognition memory also exhibit patterns of temporomesial and temporoparietal hypoperfusion on single photon emission CT (SPECT), a pattern seen in early AD [87]. However, there were no follow-up data on these patients assessing their risk of developing AD. Another study followed 105 patients with MCI; the 24 who developed AD within four years had reduced perfusion on baseline SPECT in specific brain areas compared with those who remained stable [88]. However, in the brain area most sensitive for early changes, the posterior cingulate, the average perfusion reduction was just 8 percent, which had limited ability to discriminate converters from nonconverters with a sensitivity and specificity of 79 and 67 percent.
Others — One study has found that impaired motor performance, in particular a parkinsonian gait and bradykinesia, was associated with conversion from MCI to AD [89]. In addition, individuals with MCI had levels of motor performance significantly inferior to those with normal cognition and superior to those with AD.
In another small cohort study of 139 individuals with MCI, less than one drink of alcohol per day was associated with decreased progression to dementia compared with those who abstained (HR = 0.15) [90]. Higher amounts of alcohol intake were not associated with increased or decreased risk of dementia.
PATHOLOGY — Support for the idea that mild cognitive impairment (MCI) represents an early clinical expression of age-related neurologic disease comes from neuropathological studies:
Among 180 Catholic clergy who had died at a mean age of 76 years, 37 subjects had MCI, 83 had dementia, and 60 did not have cognitive impairment at a time proximate to their death. [95]. Although there was marked overlap of Alzheimer's disease (AD) pathology among the groups, the MCI group had an intermediate level of AD pathology, compared with individuals with dementia (more AD pathology) and those without cognitive impairment (less AD pathology). Additional age-related neurologic diseases were also identified; about a third of the MCI group had one or more cerebral infarctions, and 8 percent had Lewy body disease. The neuropathologist was blinded to the clinical data.
Similarly, the neuropathologic features in 15 patients classified as amnestic MCI at the time of death were found to be intermediate between the neurofibrillary changes of aging, seen in 28 individuals free of dementia, and early AD, as identified in 23 age-matched patients with a premortem diagnosis of probable AD [96]. These findings were corroborated in a similar study [97].
In a series of 25 patients with MCI, 21 had pathology consistent with AD, three had diffuse Lewy body disease, and 14 had cerebrovascular disease; only one patient had no clear neuropathologic diagnosis [10].
Among 34 patients identified in a community-based study as having MCI and who then developed dementia, pathology at postmortem was consistent with AD in most (71 percent); other diagnoses included vascular dementia, dementia with Lewy bodies, frontotemporal dementia, and progressive supranuclear palsy [98]. Amnestic versus multi-domain MCI did not distinguish those patients who developed AD versus another dementia diagnosis.
SYMPTOMS — Patients with MCI, particularly the amnestic subtype, complain primarily of impaired memory. In contrast to the impaired awareness of deficits commonly present in patients with Alzheimer's disease (AD), patients with MCI are often particularly troubled by their symptoms [99]. However, over time, patients with MCI who convert to AD shift to a relatively greater preponderance of informant- over self-reported symptoms [100]. This phenomenon may be helpful in following an individual patient's progression to dementia.
As with dementia, behavioral symptoms are common in patients with MCI. In a clinical trial of 1010 patients with MCI, 59 percent had behavioral problems [101]. Depression was most prevalent (in almost half) followed by irritability, anxiety, aggression, and apathy. Patients with behavioral symptoms were significantly more impaired on cognitive measures than those without behavioral symptoms.
Population-based studies comparing MCI and AD patients find a similar range of neuropsychiatric symptoms, with AD patients having them in somewhat higher frequency and severity [102,103]. (See "Treatment of behavioral symptoms related to dementia").
The relationship between depression and cognitive impairment is complicated. Cognitive impairment may be a presenting symptom of depression, so-called pseudodementia. Depression may also be an early manifestation of cognitive impairment. A number of population-based studies have studies have found an association between various measure of depression and the presence of MCI [104-106]. However, follow-up data has yielded somewhat mixed results:
Among 500 85-year-old persons, impaired cognition at baseline was associated with increasing depressive symptoms over four years of follow-up, but baseline depression was not associated with accelerated cognitive decline [104].
In contrast, other large cohort studies have found that depressed mood and/or anxiety is associated with increased risk of MCI in patients with normal cognition, and with progression to dementia in patients with MCI [105,106].
Finally, an analysis of MCI diagnostic criteria used in six clinical trials found that excluding patients with depression significantly reduced the sensitivity rates of MCI diagnosis for future AD diagnosis [107].
In the aggregate, these results suggest that depression is more likely to be an early manifestation of cognitive decline rather than an independent risk factor for MCI or progression to dementia.
DIFFERENTIAL DIAGNOSIS — Psychiatric disease, particularly depression, may present with cognitive rather than mood complaints. Adverse effects of medications (eg, antihistamine use) and sleep disturbances are also common causes of cognitive complaints, particularly in elderly populations [114]. Metabolic disturbances, particularly vitamin B12 deficiency and hypothyroidism, should be considered in the differential diagnosis of mild cognitive impairment (MCI). Structural brain disease is an uncommon cause of MCI in the absence of focal neurologic findings.
In one community sample, patients with "cognitive impairment, no dementia" were diagnosed with depression and other psychiatric disease (10.2 percent), alcohol and drug related causes (6.9 percent), and delirium (1 percent) [20]. Approximately one-quarter of cases had neurologic disease (brain tumor, Parkinson's disease, multiple sclerosis, cerebrovascular disease, and epilepsy). Among the remaining 57.5 percent, most (31.7 percent) had circumscribed memory impairment.
EVALUATION — The evaluation in patients who present with cognitive complaints is focused on ruling out treatable conditions as well as establishing the severity of the impairments and providing a baseline for follow-up. These goals overlap in the specific tests that might be ordered. In general, the evaluation of patients with mild cognitive impairment (MCI) should be similar to that performed in patients presenting with dementia and include a neuroimaging study (brain CT or MRI) and screening for B12 deficiency and hypothyroidism. (See "Evaluation of cognitive impairment and dementia").
Despite the high rate of progression from MCI to dementia, the absence of an established treatment limits the value of early detection and routine monitoring for progression to dementia. Nonetheless, this can be valuable for proactive decision making on the part of individual patients and family members.
Screening cognitive examinations — The Quality Standards Subcommittee of the American Academy of Neurology has provided practice parameters, including evaluation guidelines for MCI [4]. Neuropsychological testing and screening cognitive evaluations (eg, mini mental status examination) are recommended to evaluate patients with suspected cognitive impairment.
Neuropsychological testing includes an objective measure of memory impairment [8]. It may also have additional value in the detection of contributing or causative depression. Once a patient meets criteria for MCI, it is recommended that the patient return for neuropsychological reassessment in approximately one year to monitor cognitive and functional decline [4,102]. Improved performance on the examination argues against neurodegenerative disease, while declining performance supports that diagnosis.
Neuropsychological testing should not be used in isolation; clinical judgment is critical to diagnosing both Alzheimer's disease (AD) and MCI [99]. There are no uniformly accepted criteria for the diagnosis of MCI using neuropsychological testing. Some suggest a 1.5 standard deviation (SD) threshold value for tests of memory impairment; others have used 1 SD [1,7,35,108]. In amnestic MCI, other cognitive domains may be impaired, but test abnormalities are generally milder and are usually within 0.5 SD of appropriate comparison groups. In multiple-domain MCI, several cognitive domains may be impaired in the 0.5 to 1.0 SD range. These ranges are not used as cutoff scores, but they provide a sense of the impairments seen in MCI.
Other rating scales have been used to define MCI but not with uniform acceptance. These include the Clinical Dementia Rating Scale (CDRS) (show table 1) and the Mini-Mental Sate Examination (MMSE). (See "Evaluation of cognitive impairment and dementia", section on Mini-Mental State Examination). A CDRS of 0.5 and a score of 24/30 on the MMSE have been used by some investigators to define MCI or CIND. An informant-based questionnaire of cognitive decline may also provide relevant information regarding the diagnosis and prognosis of MCI, but this needs further validation [109].
TREATMENT — This section covers studies that have evaluated treatments for mild cognitive impairment (MCI) specifically. Treatment of dementia is discussed separately. (See "Treatment of dementia").
Acetylcholinesterase inhibitors — Vitamin E and donepezil were evaluated for treatment of patients with the amnestic subtype of MCI in a double-blind study in 769 participants [35]. Vitamin E had no benefit in patients with MCI. Donepezil therapy was associated with a lower rate of progression to Alzheimer's disease (AD) during the first year. However, the cumulative rate of progression of AD after three years was not lower among patients treated with donepezil than among those given placebo. Another randomized controlled trial in 270 patients examined the effects on cognitive function after 24 weeks of treatment and found no significant treatment effect of donepezil for MCI in the primary efficacy measures [110]. Some secondary measures suggested benefit. Withdrawals due to adverse events (mostly gastrointestinal) were higher in the treatment group (32 versus 17 percent) [111].
In April 2005, the US Food and Drug Administration (FDA) and the manufacturer of galantamine reported data from two randomized controlled trials; each was of two years duration and involved a total of 2048 subjects with MCI. Death in patients receiving galantamine was significantly higher than in those receiving placebo (13 patients versus 1 patient). About half of the deaths in the galantamine group appeared to result from vascular causes, such as myocardial infarction, stroke, and sudden death [112].
Based on these results, cholinesterase inhibitors are not routinely recommended for patients with MCI [111]. However, if memory difficulties are particularly troublesome to an individual patient, a trial of donepezil for symptomatic benefit may be warranted. (See "Cholinesterase inhibitors in dementia").
Vascular risk factor modification — Some feel that the association of MCI and vascular dementia has been underappreciated relative to AD:
Patients with MCI and AD have a higher than expected prevalence of atherosclerosis risk factors. (See "Epidemiology" above).
Patients with MCI are likely to have cerebrovascular as well as AD pathology on postmortem examination. (See "Pathology" above).
Cerebrovascular disease may play a prominent pathogenic role in dementia in many patients with AD. (See "Etiology, clinical manifestations, and diagnosis of vascular dementia", section on "Mixed dementia").
These observations suggest that atherosclerosis risk factors should be aggressively treated in patients with MCI. There have been no randomized controlled clinical trials to support this; however, treatment of hypertension has been shown to reduce the incidence of dementia in the general population. There is less compelling evidence for the efficacy of antiplatelet therapy, statin therapy, and diabetes management in the treatment or prevention of dementia. (See "Treatment and prevention of vascular dementia").
Elevated homocysteine levels have been associated with risk of vascular disease, dementia, and decreased cognitive performance. (See "Risk factors for dementia", section on Homocysteine and see "Overview of homocysteine"). However, a systematic review of clinical trials concluded that supplementation with either vitamin B6, B12, and/or folate has not been shown to improve cognition in individuals with MCI or normal cognition [113].
SUMMARY AND RECOMMENDATIONS — Mild cognitive impairment (MCI) represents a state between normal aging and dementia.
MCI includes patients with cognitive deficits that are insufficiently severe to meet criteria for dementia. There are not well defined clinical criteria for diagnosis. Subtypes of MCI based on the affected cognitive domains (amnestic MCI, multiple domain MCI, and single nonmemory domain MCI) are individually recognized. (See "Definitions" above).
Patients with MCI, particularly amnestic MCI, appear to be at risk for dementia. (See "Conversion to dementia" above).
Neuropsychological test measures, cerebrospinal fluid (CSF) biomarkers, and neuroimaging studies are being evaluated as predictive tools for assessing patients' risk for conversion to dementia. These lack standardization, and there is no clinical imperative for general use. (See "Predictors" above).
Patients with cognitive complaints should be evaluated for treatable causes of dementia. (See "Evaluation of cognitive impairment and dementia"). Follow-up evaluations of cognitive complaints are recommended to monitor a patient's progression to dementia. (See "Evaluation" above).
Based on the available clinical trial data and lack of convincing benefit, we recommend NOT routinely treating MCI with cholinesterase inhibitors (Grade 1B). For an individual patient with troublesome memory difficulties, a trial of donepezil for symptomatic benefit may be warranted. Patients and families should be informed of the potential risk. (See "Treatment" above).
Patients with MCI and clinical or radiologic evidence of cerebrovascular pathology should be screened and treated for vascular risk factors, especially hypertension, although this has been shown to be helpful in preventing dementia in the general rather than the MCI population. (See "Treatment and prevention of vascular dementia").
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Parkinson's disease dementia
INTRODUCTION — Cognitive dysfunction is common in Parkinson's disease (PD). When severe, dementia often surpasses the motor features of PD as a major cause of disability and mortality.
While PD can coexist with other common causes of dementia, such as Alzheimer's disease and vascular dementia, dementia is increasingly recognized as a common feature of Parkinson's disease itself. The clinical characteristics and course of dementia, its pathological features, and the most appropriate treatment are areas of current investigation. Clinical features can generally distinguish between PD and other movement disorders associated with dementia. However, whether PD dementia (PDD) and dementia with Lewy bodies (DLB) are distinct disorders, or whether they represent different presentations of the same disease, is an area of debate and investigation [1].
This topic will discuss Parkinson's disease dementia. Other aspects of Parkinson's disease and dementia with Lewy bodies are discussed separately. (See "Clinical manifestations of Parkinson's disease", see "Management of comorbid problems associated with Parkinson's disease", see "Pharmacologic treatment of Parkinson's disease", see "Epidemiology; pathology; and pathogenesis of dementia with Lewy bodies", see "Clinical features and diagnosis of dementia with Lewy bodies" and see "Prognosis and treatment of dementia with Lewy bodies").
EPIDEMIOLOGY — Dementia is a common feature of Parkinson's disease (PD). In community-based studies of PD, the prevalence of dementia has been found to be as high as 41 percent [2]. A meta-analysis of 27 studies largely drawn from academic centers found a mean prevalence of 40 percent; however, this study did not distinguish Parkinson's disease dementia (PDD) from dementia with Lewy bodies (DLB) [3]. In a review, using exacting criteria to identify 24 studies from the literature, 31 percent of 1767 PD patients were found to have dementia [4]. In the same study, PD dementia was found to account for 3.6 percent of all cases of dementia in the population.
Incidence rates may better describe the association of PD and dementia. In prospective cohort studies, incidence rates for dementia in patients with PD are consistently estimated at 95 to 107 per 1000 patient years, a rate almost five- to sixfold higher than controls [5,6]. In one eight-year follow-up study, the cumulative incidence of dementia in PD was found to be as high as 78 percent [7].
Older age, age at onset of PD 60 years, duration of PD, and severity of parkinsonism may impact the incidence of dementia in PD [2,5-10]:
In a community-based study, the prevalence of PD with dementia (PDD) in the general population was 787 per 100,000 for those 80 years, while the prevalence for those <50 years was zero [2].
In a population-based study, 37 percent of patients whose PD began after the age 70 years were demented, compared with 9 percent of patients whose symptoms had begun before 70 years [10]. After 5 years of follow-up, the prevalences had risen to 62 and 17 percent, respectively.
In a prospective follow-up study evaluating the effect of disease duration, a 26 percent prevalence of dementia was noted at baseline in 224 patients with a mean disease duration of 11.5 years [7]. The prevalence of dementia was 52 percent four years later, and 78 percent eight years later. The mean PD duration at the onset of dementia in this study was 14 years.
In a population-based study, the relative risk (RR) for dementia was 9.7 in elderly (72 years), high-severity (Unified Parkinson's Disease Rating Scale, UPDRS >24) PD patients, compared with young, low-severity patients [11]. Young, high-severity patients and elderly, low-severity patients were not at higher risk of dementia compared with the reference population, suggesting that age and PD severity interact to increase the risk of dementia.
However, even patients with mild PD may suffer from cognitive impairment that does not meet criteria for dementia (see "Cognitive features" below) [12-14]. Patients with subtle parkinsonian signs such as rigidity, but without a clinical diagnoses of PD, have been found to exhibit signs of amnestic mild cognitive impairment (MCI) [12]. In two studies of patients with a new diagnosis of PD, MCI was common, in 24 and 36 percent, respectively [13,14]. Older age and severity of motor parkinsonism correlated with cognitive impairment. The prognostic significance of these findings is not yet known.
There may also be genetic risk factors for the development of dementia in PD.
Siblings, but not parents, of patients with PDD were three times as likely to develop AD compared with normal subjects [15].
A rare hereditary syndrome of juvenile parkinsonism with dementia has been linked to a region on chromosome 1p and to a mutation in an ATPase gene [16].
Both the epsilon 2 (e2) and epsilon 4 (e4) alleles of the apolipoprotein gene have been implicated as possible risk factors for PDD [17-19]. However, a meta-analysis of studies examining this association found a significant association of PDD and apolipoprotein e4 but not e2 [20]. The investigators cautioned against firm conclusions regarding the association because of potential publication bias and heterogeneity of source data. A subsequent publication reported that in a population in which strict criteria were used to exclude comorbid AD and other dementia types, there was no association between PDD and APOE genotype [21].
NEUROPATHOPHYSIOLOGY
Neuropathology — The anatomic and pathologic basis of Parkinson's disease dementia (PDD) is not fully understood. Magnetic resonance imaging (MRI) and neuropathologic studies demonstrate more prominent global brain atrophy in PD patients with dementia than those without [22-24]. Patients with PD without dementia have similar rates of brain atrophy as do controls. One MRI study found that these changes are most prominent in limbic and paralimbic structures, especially the anterior cingulate gyrus [23].
Neuropathologic staging in PD uses the observation that there is to some extent a relatively predictable neuroanatomic spread of Lewy body pathology. This is initially most prominent in the olfactory system and lower brainstem, then progresses to involve the midbrain structures. In later stages, other brain structures are involved, including the cortex. The neuropathologic stage of PD correlates with the severity of both motor parkinsonism and dementia [25].
In the past, dementia in PDD has been attributed to coexisting Alzheimer and vascular pathology. However, neuropathologic studies have found that the degree of Lewy body pathology (Lewy bodies and Lewy neurites) correlates better with cognitive decline and dementia than does the degree of Alzheimer pathology, which is relatively modest in these patients [26-28]. Studies correlating dementia with neuropathology in PD note a potential critical role for nuclei, which project diffusely to cortical and subcortical areas, limbic structures, and the neocortex [28]. Important exceptions are noted; some individuals have significant cognitive decline in the absence of cortical Lewy pathology, while others have normal cognitive function in the presence of widespread cortical pathology [25,29].
Whether the neuropathology of PDD differs from that seen in dementia with Lewy bodies (DLB), or whether both conditions exist on a continuum is not clear; there are few comparative neuropathologic studies [30,31]. Cortical Lewy bodies and Lewy neurites appear to substantially contribute to the pathologic substrate for dementia in both conditions [30,32,33]. One small study did find that neuronal loss in the substantia nigra was more significant in PDD than in DLB; other features including cortical Lewy pathology and Alzheimer pathology did not differ in PDD and DLB [34]. In contrast, an evaluation of brain pathology in 57 patients with DLB or PDD found that a longer duration of parkinsonism prior to dementia was associated with more pronounced cortical cholinergic deficits and less severe cortical Lewy body pathology [35].
Neurotransmitter systems — Cognitive dysfunction in PD is less a function of dopaminergic loss than are the motor symptoms [36]. Dopaminergic medication has mild, heterogeneous effects on cognitive performance and may improve short-term memory early in the disease but not in more advanced patients [37,38].
Cholinergic systems may be more important in the cognitive decline in PDD:
Loss of cholinergic neurons in the nucleus basalis of Meynert and decreased cholinergic activity in the cortex appears to be at least as significant in PDD as in AD [39-42]
Anticholinergic drugs often exacerbate cognitive deficits in PD patients
Cholinesterase inhibitors modestly improve cognitive function in PDD (see "Cholinesterase inhibitors" below)
CLINICAL FEATURES
Cognitive features — Early signs of cognitive impairment in patients with Parkinson's disease (PD) include executive dysfunction and visuospatial impairments [13]. Tests of face recognition, in particular, are impaired early in the course of PD [43]. Other measures of visuospatial function become impaired in more severe PD and are more impaired in those with, rather than without, dementia. All of these deficits may impair higher-level functioning well before patients meet criteria for dementia [44,45].
The prognostic significance of these early findings has not been as well defined for PD dementia (PDD) as they have for mild cognitive impairment (MCI) and Alzheimer's disease (AD) [46]. However, some studies suggest that early evidence of cognitive impairment in PD identifies a higher risk of future dementia [5,6].
Executive dysfunction is a hallmark feature of PDD. This syndrome consists of deficiencies in set shifting, attention, and planning [47]. In addition, visuospatial function appears disproportionately impaired in PDD compared with AD [43,48]. Memory deficits, while less prominent than in AD, do occur in PDD but appear to be related to retrieval of learned information, which is improved by cuing. Conspicuously absent in PDD is aphasia, apraxia, and severe memory loss, features that are more common in AD.
Comparison of neuropsychologic test profiles among patients with DLB, AD, and PDD revealed no differences between DLB and PDD [49,50]. AD patients were more likely to have significant impairment on memory testing, while patients with PDD and DLB were more likely to have visuoperceptive, visuoconstructive, and attentional deficits [49].
Neuropsychiatric features — Visual hallucinations are common in PD with and without dementia and can be identified in as many as 50 percent of patients [51,52]. The presence of visual hallucinations is strongly associated with cognitive dysfunction and to a lesser extent with rigidity and autonomic dysfunction [53]. A variety of antiparkinson's drugs, most notably anticholinergic agents, dopaminergic agents, and amantadine, can exacerbate visual hallucinations. In nondemented PD patients, those with hallucinations are more likely to develop dementia than are patients without this symptom [5,7,8,54].
Other manifestations of psychosis in PD include delusions, often paranoid and related to spousal infidelity and persecution. These also may be exacerbated by antiparkinsonian drugs. The neuropsychiatric features of PD are discussed in more detail separately. (See "Management of comorbid problems associated with Parkinson's disease", section on Psychosis and hallucinations).
PD patients with and without dementia are also subject to depression, anxiety, and sleep disorders [52]. Depression occurs in 30 to 40 percent and correlates poorly with degree of motor impairment [31]. Sleep disorders include sleep fragmentation, nightmares, and REM sleep behavior disorder. The latter is a parasomnia characterized by vivid dreams in REM sleep without the usual accompanying muscle atonia. This causes individuals to "act out" their dreams, especially when they are vivid or frightening. REM sleep behavior disorder occurs in 15 percent of patients with PD and may be even more common in patients with DLB [55]. (See "Clinical features and diagnosis of dementia with Lewy bodies", section on REM sleep disorder).
Cardinal motor features — Core motor features of Parkinson's disease include:
Brady- and akinesia
Rigidity
Resting tremor
Postural instability
Resting tremor is more specific to PD than are other parkinsonian features; however, PD patients with tremor as their predominant motor symptom are less likely to develop cognitive impairment than are those with more prominent postural instability and gait impairment [56,57]. Another characteristic of PD is the asymmetry of motor features early in the disease. (See "Clinical manifestations of Parkinson's disease").
Other features — Other signs of neurologic impairment are prevalent in patients with Parkinson's disease. These are summarized in the tables (show table 1 and show table 2) and discussed in more detail separately. (See "Clinical manifestations of Parkinson's disease").
Clinical course — Dementia typically occurs in the last half of the clinical course of PD, whereas it is often one of the presenting features of DLB. Similarly, hallucinations are a late-appearing consequence of PD or PDD but are seen early in the course of DLB and may be among the presenting features of the illness.
DIFFERENTIAL DIAGNOSIS — Parkinson's disease dementia (PDD) is one of a number of conditions that include dementia and parkinsonism as prominent features.
Dementia with Lewy bodies — The differentiation of PDD and Dementia with Lewy bodies (DLB) is somewhat arbitrary. In PDD, dementia occurs in the setting of well-established parkinsonism, while in DLB, dementia usually occurs before, at the same time, or very shortly after the development of parkinsonian signs. If parkinsonism is present for more than one year before the onset of dementia, it is officially classified as PDD. This arbitrary "one year rule" may be an artificial distinction; the length of time that parkinsonism precedes other symptoms in otherwise similar patients does not correlate with pathologic differences [58].
Other features that may help distinguish between PDD and DLB are a faster clinical decline and decreased levodopa responsivity for DLB compared with PDD [59]. Parkinsonian features are more likely to be bilaterally asymmetric and more severe in PDD according to most, although not all, studies [60]. Tremor is more common in PDD than DLB [61]. Significant fluctuations in cognition are common in DLB, but rarely occur in PDD.
In one study, volumetric analysis of MRI scans found that patients with DLB had more pronounced cortical atrophy than did patients with Parkinson's disease dementia (PDD) despite having a similar severity of clinical dementia [89]. However, it seems unlikely that this observation is sufficiently sensitive and specific to aid in diagnosis of DLB versus PDD in individual patients [90].
Despite these observed clinical trends, no individual symptom characteristic or test finding reliably distinguishes the motor parkinsonism of PD versus DLB. It remains uncertain even whether these are distinct disorders. (See "Clinical features and diagnosis of dementia with Lewy bodies").
Progressive supranuclear palsy — Progressive supranuclear palsy (PSP) is a rare syndrome that can mimic PDD early on. Distinctive early features of this disorder include a vertical supranuclear gaze palsy and prominent postural instability with falls [62,63]. The response to levodopa is typically poor, but about 20 percent of patients may have some improvement with L-dopa in early stages of the disease [62]. Bradykinesia and rigidity are typically symmetric in onset [64]. Behavioral changes: apathy, disinhibition, dysphoria, and anxiety are common [65]. (See "Dementia syndromes", section on Progressive supranuclear palsy).
Multiple systems atrophy — An umbrella term for olivopontocerebellar atrophy, striatonigral degeneration, and Shy-Drager syndrome, multiple systems atrophy (MSA) commonly presents with parkinsonism. Other features can include dysautonomia, cerebellar ataxia, and corticospinal tract deficits. The prominence of these manifestations and the symmetry of onset, absence of tremor, and poor response to levodopa suggest this diagnosis rather than PDD [66]. The dementia of MSA is much milder than that seen in PSP or CBD, probably reflecting less cortical involvement in that condition [67].
Corticobasal degeneration — Patients with this condition (CBD) can have asymmetric parkinsonism including bradykinesia, rigidity, and postural instability. More distinctive features can include ideomotor apraxia, alien limb phenomenon, aphasia, and loss of cortical sensory function [66]. Absence of tremor and lack of levodopa response are typical for CBD and help to distinguish it from PDD.
Alzheimer's disease — Parkinsonism may develop in late stages of Alzheimer's disease (AD). However, the relative timing of the appearance of dementia and parkinsonism is usually obvious, such that this feature, in itself, does not confuse AD and PDD.
Alternatively, AD may develop in a patient with PD, as the two disorders are not rare. This might be hard to distinguish from PDD early on, but the ultimate appearance of cortical dysfunction, such as aphasia or apraxia, or a profound amnesic syndrome usually suggests the presence of the second dementing condition. Prominent neuropsychiatric symptoms, however, suggest that the dementia is due to PDD rather than AD [54].
Cerebrovascular disease — Infarctions in multiple vascular territories affecting periventricular and subcortical white matter, basal ganglia, and brainstem can produce dementia and a vascular parkinsonism. An abrupt onset of symptoms, predominant involvement of the lower extremities, a stepwise course, vascular risk factors, focal neurologic signs, pseudobulbar palsy, and evidence of vascular disease on neuroimaging suggest this diagnosis. (See "Etiology; clinical manifestations; and diagnosis of vascular dementia").
Other considerations — When cognitive impairment occurs in the setting of Parkinson's disease, clinicians should consider possibilities other than dementia. Depression and other neuropsychiatric symptoms are common in PD and may contribute to cognitive impairment. Motor impairments of PD, particularly physical inactivity and bradyphrenia, may lead to the appearance of dementia. Similarly, patients with PD should be screened for causes of delirium that can lead to superimposed cognitive impairment, usually presenting more acutely and with altered sensorium.
Patients with Alzheimer's disease or other dementias may be treated with neuroleptic drugs associated with extrapyramidal side effects. Valproate also has been associated with a syndrome of reversible parkinsonism and cognitive decline. (See "Pharmacology of antiepileptic drugs", section on Valproate). Because medication effects can be prolonged, even for a year or more, after medication discontinuation, a complete history of medication use should be elicited [66].
DIAGNOSIS — The evaluation of a patient with dementia first establishes the presence of cognitive impairment and provides a measure of its severity. The mini mental state exam (MMSE) cannot be solely relied upon to detect disabling cognitive impairment in Parkinson's disease dementia (PDD) because it is not very sensitive to executive dysfunction, a key feature of PDD (see "Cognitive features" above). Neuropsychologic testing is more sensitive for defining cognitive impairments.
Treatable causes of cognitive impairment and dementia should be excluded. In general, this evaluation includes a neuroimaging study (usually magnetic resonance imaging), and laboratory evaluations (eg, vitamin B12 level and thyroid function tests). This topic is discussed in more detail elsewhere. (See "Evaluation of cognitive impairment and dementia").
Because of the frequent comorbidity of depression in PD, screening for depression as an alternative cause or a contributor to cognitive impairment is recommended. The Beck Depression Inventory, Hamilton Depression Rating Scale, and the Montgomery Asberg Depression Rating scale have all had demonstrated utility in this setting [68-71].
There are no published clinical criteria for PDD as there are for dementia with Lewy bodies (DLB). The diagnosis of PDD is primarily based upon clinical history and examination, in which the diagnosis of dementia is made in the setting of established parkinsonism (of at least one year), and other diagnoses are excluded. There are no specific findings on either neuroimaging, neuropsychologic testing, or laboratory results that are useful in the positive diagnosis of PDD. While some neuropsychologic test features are more suggestive of PDD versus AD, their sensitivity and specificity is not defined, and at present there is little clinical imperative to make this distinction [67].
PROGNOSIS — Dementia in Parkinson's disease is associated with reduced patient and caregiver quality of life, reduced survival, increased risks of nursing home admission, and other neuropsychiatric symptoms [5,10,17,68,72-75]. Among a cohort of 180 patients with PD not demented at baseline, incident dementia was associated with a twofold increase in mortality over a mean four-year follow-up, even after controlling for severity of motor symptoms [73].
TREATMENT — The treatment of Parkinson's disease dementia (PDD) is symptomatic. No therapies have been shown to modify the course of the disease or influence prognosis.
Cholinesterase inhibitors — The treatment of dementia in PD centers on the use of cholinesterase inhibitors. Most studies of cholinesterase inhibitors in PDD have noted a mild to moderate benefit:
Rivastigmine was evaluated in a 24-week, double-blind, placebo-controlled study of 501 patients with mild to moderate PDD and was found to result in moderate improvement in dementia, mean improvement of 2.1 points on the Alzheimer's disease Assessment Scale-Cognitive Subscale (ADAS-cog) score compared with 0.7 point decline in the placebo-treated group [76]. Clinically meaningful improvements were seen in 20 and 14.5 percent in the treatment and placebo groups, respectively, while clinically meaningful worsening was observed in 13 and 23 percent. This suggests that overall, 15 percent of patients benefited from treatment [77].
A small double-blind crossover study of donepezil in 22 patients revealed only a nonsignificant trend toward improvement on the ADAS-cog in treated patients after 10 weeks of treatment; mini mental state exam (MMSE) scores were significantly better on treatment compared with placebo [78]. Another 14-patient, 10-week, double-blind crossover study also found improvement with treatment on MMSE [79]. An open-label study of donepezil that specifically utilized measures of executive function did note benefit in PDD [80].
Among other cholinesterase inhibitors, an open-label study suggested that galantamine is useful in treating PDD [81].
An additional potential benefit of cholinesterase inhibitor therapy in PDD is improvement in neuropsychiatric symptoms, such as hallucinations. This was seen in one trial and one open-label study [76,81]. However, increased dropouts due to worsened tremor, nausea, and vomiting were also reported [76,81]. (See "Treatment of behavioral symptoms related to dementia", section on Cholinesterase inhibitors).
Because of the presence of a modest benefit for acetylcholinesterase inhibitors, we suggest their use in PDD if the patient does not experience intolerable side effects. A more detailed discussion of the use of cholinesterase inhibitors in dementia is found separately. (See "Cholinesterase inhibitors in dementia"). When cholinesterase inhibitors are discontinued, they should not be abruptly terminated, if at all possible, but rather tapered to avoid sudden cognitive and behavioral worsening [82].
Psychosis — Visual hallucinations and other psychotic features can be treated with atypical antipsychotic agents. Some caution should be employed with these agents because of the risk of motor side effects in this population. Severe side effects, while not as common as in dementia with Lewy bodies, do occur in a substantial portion of patients with PDD [83]. (See "Clinical features and diagnosis of dementia with Lewy bodies", section on Neuroleptic sensitivity). Doses should be started at the lowest possible and titrated upward gradually.
Among the atypical antipsychotic agents, clozapine has the best established utility, with an extremely low risk of exacerbating parkinsonism, but has a risk of fatal agranulocytosis, requiring rigorous monitoring of the white blood cell count [68,69]. Quetiapine is also effective and has a more acceptable side effect profile [84,85]. Olanzapine doesn't clearly improve psychosis and may worsen motor symptoms [68]. Older, so-called conventional antipsychotic agents are much more likely to exacerbate motor parkinsonism and should be avoided in PDD. This topic is discussed separately. (See "Management of comorbid problems associated with Parkinson's disease", section on Psychosis and hallucinations and see "Treatment of behavioral symptoms related to dementia").
Motor parkinsonism — Treatment of motor parkinsonian symptoms is similar in PD with and without dementia. However, patients with PDD may be particularly susceptible to the neuropsychiatric side effects of dopaminergic medications; these may be dose limiting and/or require concomitant use of antipsychotic agents. Anticholinergic agents frequently exacerbate cognitive impairment and are generally avoided in patients with PDD. Observational studies suggest that L-dopa does not adversely affect cognition [86]. (See "Pharmacologic treatment of Parkinson's disease", section on Symptomatic therapy).
Patients with PDD are generally excluded from consideration for deep brain stimulation (DBS) therapy because of poor outcomes. As an example, in a study of 41 patients evaluated after suboptimal response to DBS, 20 percent of these patients had preoperative dementia [87]. On the other hand, in PD patients with mild or no dementia, accumulated evidence suggests that bilateral subthalamic DBS can result in small declines in measures of executive function and a moderate decline in verbal fluency [88].
SUMMARY AND RECOMMENDATIONS — Cognitive dysfunction and dementia are common in Parkinson's disease (PD).
The risk of dementia in patients with PD increases with age of onset, age of the patient, duration, and severity of the illness. (See "Epidemiology" above).
Neuropathologic studies suggest that Lewy body pathology rather than coincident Alzheimer's or cerebrovascular disease is responsible for dementia in most patients with PDD (PD dementia). (See "Neuropathophysiology" above).
The cognitive dysfunction of PDD is distinct from Alzheimer's disease. With PDD, memory impairment is less prominent early on, while executive dysfunction and visual spatial impairments are features that may be apparent and functionally limiting before the patient meets criteria for dementia. (See "Cognitive features" above).
Other disorders that produce dementia and parkinsonism include dementia with Lewy bodies (DLB), progressive supranuclear palsy, multiple systems atrophy, and corticobasal degeneration. PDD is distinguished from DLB by the onset of dementia in the setting of well-established parkinsonism of at least one year's duration. (See "Differential diagnosis" above).
The diagnosis of PDD is made by the determination of dementia in a patient with typical, well-established PD of at least one year's duration. Neuropsychological testing may aid in the diagnosis of dementia; laboratory studies and neuroimaging are performed to exclude other conditions. The mini mental state exam (MMSE) cannot be solely relied upon to detect disabling cognitive impairment in PDD because it is not very sensitive to executive dysfunction. (See "Diagnosis" above).
We suggest the use of cholinesterase inhibitors in patients with PDD (Grade 2B). These appear to confer a modest benefit for cognition in patients with PDD; evidence for improved neuropsychiatric symptoms is less convincing. (See "Cholinesterase inhibitors" above).
Patients with PDD may be more susceptible to neuropsychiatric side effects of antiparkinson medications. This may be dose limiting. We suggest avoiding anticholinergic medications in patients with PDD. We recommend using low-dose quetiapine or clozapine for treatment of psychosis when necessary (Grade 1B). Clozapine requires rigorous white blood cell monitoring. We recommend avoiding the use of older, conventional antipsychotics, which are known to exacerbate motor parkinsonism. (See "Psychosis" above).
The treatment of motor parkinsonism is similar to that for the patient with PD without dementia. An exception is that dementia is a relative contraindication for deep brain stimulation therapy. (See "Treatment" above).
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While PD can coexist with other common causes of dementia, such as Alzheimer's disease and vascular dementia, dementia is increasingly recognized as a common feature of Parkinson's disease itself. The clinical characteristics and course of dementia, its pathological features, and the most appropriate treatment are areas of current investigation. Clinical features can generally distinguish between PD and other movement disorders associated with dementia. However, whether PD dementia (PDD) and dementia with Lewy bodies (DLB) are distinct disorders, or whether they represent different presentations of the same disease, is an area of debate and investigation [1].
This topic will discuss Parkinson's disease dementia. Other aspects of Parkinson's disease and dementia with Lewy bodies are discussed separately. (See "Clinical manifestations of Parkinson's disease", see "Management of comorbid problems associated with Parkinson's disease", see "Pharmacologic treatment of Parkinson's disease", see "Epidemiology; pathology; and pathogenesis of dementia with Lewy bodies", see "Clinical features and diagnosis of dementia with Lewy bodies" and see "Prognosis and treatment of dementia with Lewy bodies").
EPIDEMIOLOGY — Dementia is a common feature of Parkinson's disease (PD). In community-based studies of PD, the prevalence of dementia has been found to be as high as 41 percent [2]. A meta-analysis of 27 studies largely drawn from academic centers found a mean prevalence of 40 percent; however, this study did not distinguish Parkinson's disease dementia (PDD) from dementia with Lewy bodies (DLB) [3]. In a review, using exacting criteria to identify 24 studies from the literature, 31 percent of 1767 PD patients were found to have dementia [4]. In the same study, PD dementia was found to account for 3.6 percent of all cases of dementia in the population.
Incidence rates may better describe the association of PD and dementia. In prospective cohort studies, incidence rates for dementia in patients with PD are consistently estimated at 95 to 107 per 1000 patient years, a rate almost five- to sixfold higher than controls [5,6]. In one eight-year follow-up study, the cumulative incidence of dementia in PD was found to be as high as 78 percent [7].
Older age, age at onset of PD 60 years, duration of PD, and severity of parkinsonism may impact the incidence of dementia in PD [2,5-10]:
In a community-based study, the prevalence of PD with dementia (PDD) in the general population was 787 per 100,000 for those 80 years, while the prevalence for those <50 years was zero [2].
In a population-based study, 37 percent of patients whose PD began after the age 70 years were demented, compared with 9 percent of patients whose symptoms had begun before 70 years [10]. After 5 years of follow-up, the prevalences had risen to 62 and 17 percent, respectively.
In a prospective follow-up study evaluating the effect of disease duration, a 26 percent prevalence of dementia was noted at baseline in 224 patients with a mean disease duration of 11.5 years [7]. The prevalence of dementia was 52 percent four years later, and 78 percent eight years later. The mean PD duration at the onset of dementia in this study was 14 years.
In a population-based study, the relative risk (RR) for dementia was 9.7 in elderly (72 years), high-severity (Unified Parkinson's Disease Rating Scale, UPDRS >24) PD patients, compared with young, low-severity patients [11]. Young, high-severity patients and elderly, low-severity patients were not at higher risk of dementia compared with the reference population, suggesting that age and PD severity interact to increase the risk of dementia.
However, even patients with mild PD may suffer from cognitive impairment that does not meet criteria for dementia (see "Cognitive features" below) [12-14]. Patients with subtle parkinsonian signs such as rigidity, but without a clinical diagnoses of PD, have been found to exhibit signs of amnestic mild cognitive impairment (MCI) [12]. In two studies of patients with a new diagnosis of PD, MCI was common, in 24 and 36 percent, respectively [13,14]. Older age and severity of motor parkinsonism correlated with cognitive impairment. The prognostic significance of these findings is not yet known.
There may also be genetic risk factors for the development of dementia in PD.
Siblings, but not parents, of patients with PDD were three times as likely to develop AD compared with normal subjects [15].
A rare hereditary syndrome of juvenile parkinsonism with dementia has been linked to a region on chromosome 1p and to a mutation in an ATPase gene [16].
Both the epsilon 2 (e2) and epsilon 4 (e4) alleles of the apolipoprotein gene have been implicated as possible risk factors for PDD [17-19]. However, a meta-analysis of studies examining this association found a significant association of PDD and apolipoprotein e4 but not e2 [20]. The investigators cautioned against firm conclusions regarding the association because of potential publication bias and heterogeneity of source data. A subsequent publication reported that in a population in which strict criteria were used to exclude comorbid AD and other dementia types, there was no association between PDD and APOE genotype [21].
NEUROPATHOPHYSIOLOGY
Neuropathology — The anatomic and pathologic basis of Parkinson's disease dementia (PDD) is not fully understood. Magnetic resonance imaging (MRI) and neuropathologic studies demonstrate more prominent global brain atrophy in PD patients with dementia than those without [22-24]. Patients with PD without dementia have similar rates of brain atrophy as do controls. One MRI study found that these changes are most prominent in limbic and paralimbic structures, especially the anterior cingulate gyrus [23].
Neuropathologic staging in PD uses the observation that there is to some extent a relatively predictable neuroanatomic spread of Lewy body pathology. This is initially most prominent in the olfactory system and lower brainstem, then progresses to involve the midbrain structures. In later stages, other brain structures are involved, including the cortex. The neuropathologic stage of PD correlates with the severity of both motor parkinsonism and dementia [25].
In the past, dementia in PDD has been attributed to coexisting Alzheimer and vascular pathology. However, neuropathologic studies have found that the degree of Lewy body pathology (Lewy bodies and Lewy neurites) correlates better with cognitive decline and dementia than does the degree of Alzheimer pathology, which is relatively modest in these patients [26-28]. Studies correlating dementia with neuropathology in PD note a potential critical role for nuclei, which project diffusely to cortical and subcortical areas, limbic structures, and the neocortex [28]. Important exceptions are noted; some individuals have significant cognitive decline in the absence of cortical Lewy pathology, while others have normal cognitive function in the presence of widespread cortical pathology [25,29].
Whether the neuropathology of PDD differs from that seen in dementia with Lewy bodies (DLB), or whether both conditions exist on a continuum is not clear; there are few comparative neuropathologic studies [30,31]. Cortical Lewy bodies and Lewy neurites appear to substantially contribute to the pathologic substrate for dementia in both conditions [30,32,33]. One small study did find that neuronal loss in the substantia nigra was more significant in PDD than in DLB; other features including cortical Lewy pathology and Alzheimer pathology did not differ in PDD and DLB [34]. In contrast, an evaluation of brain pathology in 57 patients with DLB or PDD found that a longer duration of parkinsonism prior to dementia was associated with more pronounced cortical cholinergic deficits and less severe cortical Lewy body pathology [35].
Neurotransmitter systems — Cognitive dysfunction in PD is less a function of dopaminergic loss than are the motor symptoms [36]. Dopaminergic medication has mild, heterogeneous effects on cognitive performance and may improve short-term memory early in the disease but not in more advanced patients [37,38].
Cholinergic systems may be more important in the cognitive decline in PDD:
Loss of cholinergic neurons in the nucleus basalis of Meynert and decreased cholinergic activity in the cortex appears to be at least as significant in PDD as in AD [39-42]
Anticholinergic drugs often exacerbate cognitive deficits in PD patients
Cholinesterase inhibitors modestly improve cognitive function in PDD (see "Cholinesterase inhibitors" below)
CLINICAL FEATURES
Cognitive features — Early signs of cognitive impairment in patients with Parkinson's disease (PD) include executive dysfunction and visuospatial impairments [13]. Tests of face recognition, in particular, are impaired early in the course of PD [43]. Other measures of visuospatial function become impaired in more severe PD and are more impaired in those with, rather than without, dementia. All of these deficits may impair higher-level functioning well before patients meet criteria for dementia [44,45].
The prognostic significance of these early findings has not been as well defined for PD dementia (PDD) as they have for mild cognitive impairment (MCI) and Alzheimer's disease (AD) [46]. However, some studies suggest that early evidence of cognitive impairment in PD identifies a higher risk of future dementia [5,6].
Executive dysfunction is a hallmark feature of PDD. This syndrome consists of deficiencies in set shifting, attention, and planning [47]. In addition, visuospatial function appears disproportionately impaired in PDD compared with AD [43,48]. Memory deficits, while less prominent than in AD, do occur in PDD but appear to be related to retrieval of learned information, which is improved by cuing. Conspicuously absent in PDD is aphasia, apraxia, and severe memory loss, features that are more common in AD.
Comparison of neuropsychologic test profiles among patients with DLB, AD, and PDD revealed no differences between DLB and PDD [49,50]. AD patients were more likely to have significant impairment on memory testing, while patients with PDD and DLB were more likely to have visuoperceptive, visuoconstructive, and attentional deficits [49].
Neuropsychiatric features — Visual hallucinations are common in PD with and without dementia and can be identified in as many as 50 percent of patients [51,52]. The presence of visual hallucinations is strongly associated with cognitive dysfunction and to a lesser extent with rigidity and autonomic dysfunction [53]. A variety of antiparkinson's drugs, most notably anticholinergic agents, dopaminergic agents, and amantadine, can exacerbate visual hallucinations. In nondemented PD patients, those with hallucinations are more likely to develop dementia than are patients without this symptom [5,7,8,54].
Other manifestations of psychosis in PD include delusions, often paranoid and related to spousal infidelity and persecution. These also may be exacerbated by antiparkinsonian drugs. The neuropsychiatric features of PD are discussed in more detail separately. (See "Management of comorbid problems associated with Parkinson's disease", section on Psychosis and hallucinations).
PD patients with and without dementia are also subject to depression, anxiety, and sleep disorders [52]. Depression occurs in 30 to 40 percent and correlates poorly with degree of motor impairment [31]. Sleep disorders include sleep fragmentation, nightmares, and REM sleep behavior disorder. The latter is a parasomnia characterized by vivid dreams in REM sleep without the usual accompanying muscle atonia. This causes individuals to "act out" their dreams, especially when they are vivid or frightening. REM sleep behavior disorder occurs in 15 percent of patients with PD and may be even more common in patients with DLB [55]. (See "Clinical features and diagnosis of dementia with Lewy bodies", section on REM sleep disorder).
Cardinal motor features — Core motor features of Parkinson's disease include:
Brady- and akinesia
Rigidity
Resting tremor
Postural instability
Resting tremor is more specific to PD than are other parkinsonian features; however, PD patients with tremor as their predominant motor symptom are less likely to develop cognitive impairment than are those with more prominent postural instability and gait impairment [56,57]. Another characteristic of PD is the asymmetry of motor features early in the disease. (See "Clinical manifestations of Parkinson's disease").
Other features — Other signs of neurologic impairment are prevalent in patients with Parkinson's disease. These are summarized in the tables (show table 1 and show table 2) and discussed in more detail separately. (See "Clinical manifestations of Parkinson's disease").
Clinical course — Dementia typically occurs in the last half of the clinical course of PD, whereas it is often one of the presenting features of DLB. Similarly, hallucinations are a late-appearing consequence of PD or PDD but are seen early in the course of DLB and may be among the presenting features of the illness.
DIFFERENTIAL DIAGNOSIS — Parkinson's disease dementia (PDD) is one of a number of conditions that include dementia and parkinsonism as prominent features.
Dementia with Lewy bodies — The differentiation of PDD and Dementia with Lewy bodies (DLB) is somewhat arbitrary. In PDD, dementia occurs in the setting of well-established parkinsonism, while in DLB, dementia usually occurs before, at the same time, or very shortly after the development of parkinsonian signs. If parkinsonism is present for more than one year before the onset of dementia, it is officially classified as PDD. This arbitrary "one year rule" may be an artificial distinction; the length of time that parkinsonism precedes other symptoms in otherwise similar patients does not correlate with pathologic differences [58].
Other features that may help distinguish between PDD and DLB are a faster clinical decline and decreased levodopa responsivity for DLB compared with PDD [59]. Parkinsonian features are more likely to be bilaterally asymmetric and more severe in PDD according to most, although not all, studies [60]. Tremor is more common in PDD than DLB [61]. Significant fluctuations in cognition are common in DLB, but rarely occur in PDD.
In one study, volumetric analysis of MRI scans found that patients with DLB had more pronounced cortical atrophy than did patients with Parkinson's disease dementia (PDD) despite having a similar severity of clinical dementia [89]. However, it seems unlikely that this observation is sufficiently sensitive and specific to aid in diagnosis of DLB versus PDD in individual patients [90].
Despite these observed clinical trends, no individual symptom characteristic or test finding reliably distinguishes the motor parkinsonism of PD versus DLB. It remains uncertain even whether these are distinct disorders. (See "Clinical features and diagnosis of dementia with Lewy bodies").
Progressive supranuclear palsy — Progressive supranuclear palsy (PSP) is a rare syndrome that can mimic PDD early on. Distinctive early features of this disorder include a vertical supranuclear gaze palsy and prominent postural instability with falls [62,63]. The response to levodopa is typically poor, but about 20 percent of patients may have some improvement with L-dopa in early stages of the disease [62]. Bradykinesia and rigidity are typically symmetric in onset [64]. Behavioral changes: apathy, disinhibition, dysphoria, and anxiety are common [65]. (See "Dementia syndromes", section on Progressive supranuclear palsy).
Multiple systems atrophy — An umbrella term for olivopontocerebellar atrophy, striatonigral degeneration, and Shy-Drager syndrome, multiple systems atrophy (MSA) commonly presents with parkinsonism. Other features can include dysautonomia, cerebellar ataxia, and corticospinal tract deficits. The prominence of these manifestations and the symmetry of onset, absence of tremor, and poor response to levodopa suggest this diagnosis rather than PDD [66]. The dementia of MSA is much milder than that seen in PSP or CBD, probably reflecting less cortical involvement in that condition [67].
Corticobasal degeneration — Patients with this condition (CBD) can have asymmetric parkinsonism including bradykinesia, rigidity, and postural instability. More distinctive features can include ideomotor apraxia, alien limb phenomenon, aphasia, and loss of cortical sensory function [66]. Absence of tremor and lack of levodopa response are typical for CBD and help to distinguish it from PDD.
Alzheimer's disease — Parkinsonism may develop in late stages of Alzheimer's disease (AD). However, the relative timing of the appearance of dementia and parkinsonism is usually obvious, such that this feature, in itself, does not confuse AD and PDD.
Alternatively, AD may develop in a patient with PD, as the two disorders are not rare. This might be hard to distinguish from PDD early on, but the ultimate appearance of cortical dysfunction, such as aphasia or apraxia, or a profound amnesic syndrome usually suggests the presence of the second dementing condition. Prominent neuropsychiatric symptoms, however, suggest that the dementia is due to PDD rather than AD [54].
Cerebrovascular disease — Infarctions in multiple vascular territories affecting periventricular and subcortical white matter, basal ganglia, and brainstem can produce dementia and a vascular parkinsonism. An abrupt onset of symptoms, predominant involvement of the lower extremities, a stepwise course, vascular risk factors, focal neurologic signs, pseudobulbar palsy, and evidence of vascular disease on neuroimaging suggest this diagnosis. (See "Etiology; clinical manifestations; and diagnosis of vascular dementia").
Other considerations — When cognitive impairment occurs in the setting of Parkinson's disease, clinicians should consider possibilities other than dementia. Depression and other neuropsychiatric symptoms are common in PD and may contribute to cognitive impairment. Motor impairments of PD, particularly physical inactivity and bradyphrenia, may lead to the appearance of dementia. Similarly, patients with PD should be screened for causes of delirium that can lead to superimposed cognitive impairment, usually presenting more acutely and with altered sensorium.
Patients with Alzheimer's disease or other dementias may be treated with neuroleptic drugs associated with extrapyramidal side effects. Valproate also has been associated with a syndrome of reversible parkinsonism and cognitive decline. (See "Pharmacology of antiepileptic drugs", section on Valproate). Because medication effects can be prolonged, even for a year or more, after medication discontinuation, a complete history of medication use should be elicited [66].
DIAGNOSIS — The evaluation of a patient with dementia first establishes the presence of cognitive impairment and provides a measure of its severity. The mini mental state exam (MMSE) cannot be solely relied upon to detect disabling cognitive impairment in Parkinson's disease dementia (PDD) because it is not very sensitive to executive dysfunction, a key feature of PDD (see "Cognitive features" above). Neuropsychologic testing is more sensitive for defining cognitive impairments.
Treatable causes of cognitive impairment and dementia should be excluded. In general, this evaluation includes a neuroimaging study (usually magnetic resonance imaging), and laboratory evaluations (eg, vitamin B12 level and thyroid function tests). This topic is discussed in more detail elsewhere. (See "Evaluation of cognitive impairment and dementia").
Because of the frequent comorbidity of depression in PD, screening for depression as an alternative cause or a contributor to cognitive impairment is recommended. The Beck Depression Inventory, Hamilton Depression Rating Scale, and the Montgomery Asberg Depression Rating scale have all had demonstrated utility in this setting [68-71].
There are no published clinical criteria for PDD as there are for dementia with Lewy bodies (DLB). The diagnosis of PDD is primarily based upon clinical history and examination, in which the diagnosis of dementia is made in the setting of established parkinsonism (of at least one year), and other diagnoses are excluded. There are no specific findings on either neuroimaging, neuropsychologic testing, or laboratory results that are useful in the positive diagnosis of PDD. While some neuropsychologic test features are more suggestive of PDD versus AD, their sensitivity and specificity is not defined, and at present there is little clinical imperative to make this distinction [67].
PROGNOSIS — Dementia in Parkinson's disease is associated with reduced patient and caregiver quality of life, reduced survival, increased risks of nursing home admission, and other neuropsychiatric symptoms [5,10,17,68,72-75]. Among a cohort of 180 patients with PD not demented at baseline, incident dementia was associated with a twofold increase in mortality over a mean four-year follow-up, even after controlling for severity of motor symptoms [73].
TREATMENT — The treatment of Parkinson's disease dementia (PDD) is symptomatic. No therapies have been shown to modify the course of the disease or influence prognosis.
Cholinesterase inhibitors — The treatment of dementia in PD centers on the use of cholinesterase inhibitors. Most studies of cholinesterase inhibitors in PDD have noted a mild to moderate benefit:
Rivastigmine was evaluated in a 24-week, double-blind, placebo-controlled study of 501 patients with mild to moderate PDD and was found to result in moderate improvement in dementia, mean improvement of 2.1 points on the Alzheimer's disease Assessment Scale-Cognitive Subscale (ADAS-cog) score compared with 0.7 point decline in the placebo-treated group [76]. Clinically meaningful improvements were seen in 20 and 14.5 percent in the treatment and placebo groups, respectively, while clinically meaningful worsening was observed in 13 and 23 percent. This suggests that overall, 15 percent of patients benefited from treatment [77].
A small double-blind crossover study of donepezil in 22 patients revealed only a nonsignificant trend toward improvement on the ADAS-cog in treated patients after 10 weeks of treatment; mini mental state exam (MMSE) scores were significantly better on treatment compared with placebo [78]. Another 14-patient, 10-week, double-blind crossover study also found improvement with treatment on MMSE [79]. An open-label study of donepezil that specifically utilized measures of executive function did note benefit in PDD [80].
Among other cholinesterase inhibitors, an open-label study suggested that galantamine is useful in treating PDD [81].
An additional potential benefit of cholinesterase inhibitor therapy in PDD is improvement in neuropsychiatric symptoms, such as hallucinations. This was seen in one trial and one open-label study [76,81]. However, increased dropouts due to worsened tremor, nausea, and vomiting were also reported [76,81]. (See "Treatment of behavioral symptoms related to dementia", section on Cholinesterase inhibitors).
Because of the presence of a modest benefit for acetylcholinesterase inhibitors, we suggest their use in PDD if the patient does not experience intolerable side effects. A more detailed discussion of the use of cholinesterase inhibitors in dementia is found separately. (See "Cholinesterase inhibitors in dementia"). When cholinesterase inhibitors are discontinued, they should not be abruptly terminated, if at all possible, but rather tapered to avoid sudden cognitive and behavioral worsening [82].
Psychosis — Visual hallucinations and other psychotic features can be treated with atypical antipsychotic agents. Some caution should be employed with these agents because of the risk of motor side effects in this population. Severe side effects, while not as common as in dementia with Lewy bodies, do occur in a substantial portion of patients with PDD [83]. (See "Clinical features and diagnosis of dementia with Lewy bodies", section on Neuroleptic sensitivity). Doses should be started at the lowest possible and titrated upward gradually.
Among the atypical antipsychotic agents, clozapine has the best established utility, with an extremely low risk of exacerbating parkinsonism, but has a risk of fatal agranulocytosis, requiring rigorous monitoring of the white blood cell count [68,69]. Quetiapine is also effective and has a more acceptable side effect profile [84,85]. Olanzapine doesn't clearly improve psychosis and may worsen motor symptoms [68]. Older, so-called conventional antipsychotic agents are much more likely to exacerbate motor parkinsonism and should be avoided in PDD. This topic is discussed separately. (See "Management of comorbid problems associated with Parkinson's disease", section on Psychosis and hallucinations and see "Treatment of behavioral symptoms related to dementia").
Motor parkinsonism — Treatment of motor parkinsonian symptoms is similar in PD with and without dementia. However, patients with PDD may be particularly susceptible to the neuropsychiatric side effects of dopaminergic medications; these may be dose limiting and/or require concomitant use of antipsychotic agents. Anticholinergic agents frequently exacerbate cognitive impairment and are generally avoided in patients with PDD. Observational studies suggest that L-dopa does not adversely affect cognition [86]. (See "Pharmacologic treatment of Parkinson's disease", section on Symptomatic therapy).
Patients with PDD are generally excluded from consideration for deep brain stimulation (DBS) therapy because of poor outcomes. As an example, in a study of 41 patients evaluated after suboptimal response to DBS, 20 percent of these patients had preoperative dementia [87]. On the other hand, in PD patients with mild or no dementia, accumulated evidence suggests that bilateral subthalamic DBS can result in small declines in measures of executive function and a moderate decline in verbal fluency [88].
SUMMARY AND RECOMMENDATIONS — Cognitive dysfunction and dementia are common in Parkinson's disease (PD).
The risk of dementia in patients with PD increases with age of onset, age of the patient, duration, and severity of the illness. (See "Epidemiology" above).
Neuropathologic studies suggest that Lewy body pathology rather than coincident Alzheimer's or cerebrovascular disease is responsible for dementia in most patients with PDD (PD dementia). (See "Neuropathophysiology" above).
The cognitive dysfunction of PDD is distinct from Alzheimer's disease. With PDD, memory impairment is less prominent early on, while executive dysfunction and visual spatial impairments are features that may be apparent and functionally limiting before the patient meets criteria for dementia. (See "Cognitive features" above).
Other disorders that produce dementia and parkinsonism include dementia with Lewy bodies (DLB), progressive supranuclear palsy, multiple systems atrophy, and corticobasal degeneration. PDD is distinguished from DLB by the onset of dementia in the setting of well-established parkinsonism of at least one year's duration. (See "Differential diagnosis" above).
The diagnosis of PDD is made by the determination of dementia in a patient with typical, well-established PD of at least one year's duration. Neuropsychological testing may aid in the diagnosis of dementia; laboratory studies and neuroimaging are performed to exclude other conditions. The mini mental state exam (MMSE) cannot be solely relied upon to detect disabling cognitive impairment in PDD because it is not very sensitive to executive dysfunction. (See "Diagnosis" above).
We suggest the use of cholinesterase inhibitors in patients with PDD (Grade 2B). These appear to confer a modest benefit for cognition in patients with PDD; evidence for improved neuropsychiatric symptoms is less convincing. (See "Cholinesterase inhibitors" above).
Patients with PDD may be more susceptible to neuropsychiatric side effects of antiparkinson medications. This may be dose limiting. We suggest avoiding anticholinergic medications in patients with PDD. We recommend using low-dose quetiapine or clozapine for treatment of psychosis when necessary (Grade 1B). Clozapine requires rigorous white blood cell monitoring. We recommend avoiding the use of older, conventional antipsychotics, which are known to exacerbate motor parkinsonism. (See "Psychosis" above).
The treatment of motor parkinsonism is similar to that for the patient with PD without dementia. An exception is that dementia is a relative contraindication for deep brain stimulation therapy. (See "Treatment" above).
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Evaluation of cognitive impairment and dementia
INTRODUCTION — Dementia is a disorder that is characterized by impairment of memory and at least one other cognitive domain (aphasia, apraxia, agnosia, executive function). These must represent a decline from previous level of function and be severe enough to interfere with daily function and independence [1].
Alzheimer's disease (AD) is the most common form of dementia in the elderly, accounting for 60 to 80 percent of cases, and it is estimated to affect more than 4 million Americans [2-5]. Between 2.4 and 3.1 million spouses, relatives, and friends take care of people with AD [6]. The cost of caring for one person with this disorder at home or in a nursing home is more than $47,000 per year [7]. Clinicians will need to accurately diagnose and manage the early cognitive manifestations of AD, particularly as new pharmacological agents are developed.
This topic will discuss the evaluation of cognitive impairment and dementia. The clinical, diagnostic, and pathologic aspects of specific dementia syndromes are discussed separately. (See "Dementia syndromes").
The treatment, risk factors, and prevention of dementia are also discussed separately. (See "Treatment of dementia", see "Risk factors for dementia" and see "Prevention of dementia"). The risk factors, treatment, and prevention of vascular dementia are specifically discussed separately. (See "Etiology, clinical manifestations, and diagnosis of vascular dementia" and see "Treatment and prevention of vascular dementia").
DEFINITION OF DEMENTIA — Although a number of definitions exist for dementia, the DSM-IV definition is widely accepted and includes the following [1]:
Evidence from the history and mental status examination that indicates major impairment in learning and memory as well as at least one of the following:
- Impairment in handling complex tasks
- Impairment in reasoning ability
- Impaired spatial ability and orientation
- Impaired language
The cognitive symptoms must significantly interfere with the individual's work performance, usual social activities, or relationships with other people
This must represent a significant decline from a previous level of functioning
The disturbances are of insidious onset and are progressive, based on evidence from the history or serial mental-status examinations
The disturbances are not occurring exclusively during the course of
delirium
The disturbances are not better accounted for by a major psychiatric diagnosis
The disturbances are not better accounted for by a systemic disease or another brain disease
In a practice guideline published by the American Academy of Neurology (AAN), the DSM-IIIR definition of dementia (identical to the DSM-IV definition) was reported to have good to very good reliability and was recommended for routine use [8].
IDENTIFICATION OF DEMENTIA — Detecting dementia is a problem in routine, day-to-day medical practice [9]. One study found that the diagnosis was missed in 21 percent of demented or delirious patients on a general medical ward, while 20 percent of nondemented patients were misjudged as demented [10]. Nonetheless, the clinical diagnosis of dementia is reasonably accurate for those with experience in the evaluation of this disorder (show table 1) [11].
Most patients with dementia do not present with a complaint of memory loss; it is often a spouse or other informant who brings the problem to the physician's attention. Self-reported memory loss does not appear to correlate with the subsequent development of dementia, while informant-reported memory loss is a much better predictor of the current presence and future development of dementia [12,13]. Nevertheless, family members are often delayed in recognizing the signs of dementia, many of which are inaccurately ascribed to "aging."
The normal cognitive decline associated with aging consists primarily of mild changes in memory and the rate of information processing, which are not progressive and do not affect daily function. In a study of 161 community-dwelling, cognitively normal individuals ages 62 to 100 years, learning or acquisition performance declined uniformly with increasing age [14]. In contrast, delayed recall or forgetting remained relatively stable. Similarly, a second report found that aging was associated with a decline in the acquisition and early retrieval of new information but not in memory retention [15].
Patients with dementia may have difficulty with one or more of the following [16]:
Learning and retaining new information (eg, trouble remembering events)
Handling complex tasks (eg, balancing a checkbook)
Reasoning (eg, unable to cope with unexpected events)
Spatial ability and orientation (eg, getting lost in familiar places)
Language (eg, word finding)
Behavior
Patients and informants are often uncertain about the onset of symptoms since the appearance of dementia is insidious. The physician can usually date the onset of dementia by identifying when the patient stopped driving or managing finances. Useful questions for the patient and informant are, "When did you first notice the memory loss?" and "How has the memory loss progressed since then?"
The diagnosis of dementia must be distinguished from delirium and depression (show table 2) [17]. (See "Diagnosis of delirium and confusional states" and see "Depression: Clinical manifestations and diagnosis"):
Delirium is usually acute in onset and is associated with a clouding of the sensorium. Patients with delirium may have fluctuations in their level of consciousness and have difficulty with attention and concentration. Delirium and dementia can overlap, making the distinction difficult and sometimes impossible.
Patients with depression are more likely to complain about memory loss than those with dementia; the latter are frequently brought to physicians by their families, while depressed patients often present by themselves. Patients with depression may have signs of psychomotor slowing and produce a poor effort on testing, while those with dementia often try hard but respond with incorrect answers. Depression and dementia may occur in the same patient.
The pretest probability of dementia and of various causes of dementia depends upon patient characteristics such as age and race. Realizing that 5 percent of individuals over age 65 years and 35 to 50 percent of persons over age 85 years have dementia, the pretest probability of dementia in an older person with reported memory loss is estimated to be at least 60 percent.
The US Preventive Services Task Force has concluded that there is insufficient evidence to recommend for or against routine screening for dementia in older adults [18,19]. (See "USPSTF Guidelines: Screening for dementia: Recommendations and rationale").
Mild cognitive impairment — Mild cognitive impairment (MCI) is generally defined by the presence of memory difficulty and objective memory impairment but preserved ability to function in daily life. Patients with MCI appear to be at increased risk of dementia. This topic is discussed separately. (See "Mild cognitive impairment").
Dementia syndromes — The major dementia syndromes include [20-22]: (see "Dementia syndromes")
Alzheimer's disease (AD)
Dementia with Lewy bodies (DLB)
Frontotemporal dementia (FTD)
Vascular (multi-infarct) dementia (VaD)
Parkinson's disease with dementia (PDD)
Less common disorders such as progressive supranuclear palsy (PSP) can also be associated with dementia. Non-neurodegenerative dementias may be reversible, if the underlying cause can be identified and adequately treated [23].
Most elderly patients with chronic dementia have AD (approximately 60 to 80 percent). The vascular dementias account for 10 to 20 percent, and PD for 5 percent. The prevalence of VaD is relatively high in blacks, hypertensive persons, and patients with diabetes; some of the reversible dementias (eg, metabolic dementias) tend to occur in younger individuals. DLB may be as prevalent as VaD in older cohorts of patients [24]. FTD is much less common than AD, VaD, or DLB.
Alcohol-related dementia, medication side effects (eg, antihistamine use), depression, and other central nervous system illnesses are responsible for the remainder of the chronic dementias.
Dementia frequently has more than one cause, particularly as the condition progresses. In addition, medical illnesses exacerbating poor cognition are common in patients with dementia. The bedside evaluation combined with historical information from a reliable informant provides most of the information needed to ascertain the cause of dementia [17]. However, even with the addition of information from imaging studies, clinical criteria for VaD have relatively poor sensitivity [25].
DIAGNOSTIC APPROACH — The initial appointment in a patient with suspected dementia should focus upon the history. Preferably, family members are available to give an adequate history of cognitive and behavioral changes [21]. A drug history is particularly important; use of drugs that impair cognition (eg, analgesics, anticholinergics, psychotropic medications, and sedative-hypnotics) should be sought.
A full dementia evaluation can probably not be completed in a routine 30-minute visit; adequate time should be arranged as a follow-up appointment. The initial step at the follow-up visit is an assessment of cognitive function. This should be followed by a complete physical examination, including neurologic examination. The subsequent work-up may include laboratory and imaging studies (show algorithm 1) [26,27]. The DSM-IV criteria for the diagnosis of dementia are shown in Table three (show table 3).
Cognitive testing — Agreement between the history and the mental status examination is strongly suggestive of the diagnosis of dementia. When the history suggests cognitive impairment but the mental status examination is normal, possible explanations include mild dementia, high intelligence or education, depression, or rarely, misrepresentation on the part of the informants [28]. Conversely, when the mental status examination suggests cognitive impairment but the family and patient deny any problems, possible explanations include an acute confusional state, very low intelligence or education, or inadequate recognition by the family [28]. Neuropsychological assessment (psychometric testing) may be useful in difficult situations; re-evaluation at a later time is often helpful.
Mini-Mental State Examination — The Mini-Mental State Exam (MMSE) is the most widely used cognitive test for dementia in US clinical practice [29,30]. The examination takes approximately seven minutes to complete. It tests a broad range of cognitive functions including orientation, recall, attention, calculation, language manipulation, and constructional praxis.
The MMSE includes the following tasks [29]:
Orientation:
What is the date: (year)(season)(date)(day)(month) - 5 points
Where are we: (state)(county)(town)(hospital)(floor) - 5 points
Registration:
Name three objects: one second to say each. Ask the patient all three after you have said them. Give one point for each correct answer. Then repeat them until he/she learns all three. Count trials and record. The first repetition determines the score, but if the patient cannot learn the words after six trials then recall cannot be meaningfully tested. Maximum score - 3 points.
Attention and calculation:
Serial 7s, beginning with 100 and counting backward: one point for each correct; stop after five answers. Alternatively, spell WORLD backwards: one point for each letter that is in correct order. Maximum score - 5 points.
Ask for the three objects repeated above: one point for each correct. Maximum score - 3 points.
Show and ask patient to name a pencil and wrist watch - 2 points.
Repeat the following, "No ifs ands or buts." Allow only one trial - 1 point.
Follow a three stage command, "Take a paper in your right hand, fold it in half, and put it on the floor." Score one point for each task executed. Maximum score - 3 points.
On a blank piece of paper write "close your eyes," and ask the patient to read and do what it says - 1 point.
Give the patient a blank piece of paper and ask him/her to write a sentence. The sentence must contain a noun and verb and be sensible - 1 point.
Ask the patient to copy a design (eg, intersecting pentagons). All 10 angles must be present and two must intersect - 1 point.
A total maximal score on the MMSE is 30 points. Generally a score of less than 24 points is suggestive of dementia or delirium. Using a cutoff of 24 points, the MMSE had a sensitivity of 87 percent and a specificity of 82 percent in a large population based sample (show table 1) [31]. However, the test is not sensitive for mild dementia, and scores may be influenced by age and education, as well as language, motor, and visual impairments [32]. In one study, for example, the median MMSE score was 29 for individuals with at least nine years of schooling, 26 for those with five to eight years of schooling, and 22 for those with four years of schooling or less [31].
The use of higher cutoff scores on the MMSE improves sensitivity but lowers specificity. For research purposes, some investigators use a cutoff score of 26 or 27 in symptomatic populations in order to miss few true cases, while lower cutoffs would be necessary in populations where the expected prevalence is low [33]. Age-specific norms also have been established [31]; some groups have developed tools that incorporate age, gender, and education level (show figure 1) [34,35].
The MMSE also has utility in assessing competency in decision making. Studies suggest that high scores, 23, and low scores, <19, can be highly predictive in discriminating competency from incompetency. Intermediate scores warrant more detailed competency evaluation [36,37].
Other brief cognitive assessments — An ideal test for mental status screening should be brief and have good performance in populations with different cultural, linguistic, and educational backgrounds.
Mini-Cog. One such test is the "Mini-Cog," which consists of a clock drawing task (CDT) and an uncued recall of three unrelated words [38].
Scoring of the Mini-Cog is based on a simple decision tree with the following three rules:
Subjects recalling none of the words are classified as demented
Subjects recalling all three words are classified as non-demented
Subjects with intermediate (one to two) word recall are classified based on the CDT (abnormal = demented; normal = non-demented)
The CDT is considered normal if all numbers are present in the correct sequence and the hands readably display the correct time.
The advantages of the Mini-Cog include high sensitivity for predicting dementia status, short testing time relative to the MMSE, ease of administration, and diagnostic value not limited by the subject's education or language [38].
In a retrospective analysis of data from a random sample of 1119 older adults, the Mini-Cog was compared with the MMSE (at a cut point of 25); the Mini-Cog had similar sensitivity (76 versus 79 percent) and specificity (89 versus 88 percent) for dementia [39]. Although these results are promising, the Mini-Cog requires further validation with prospective data. These tests are also not appropriate for patients with aphasic or anomic disorders.
Informant interview — A brief, eight-item questionnaire for informants appears to be sensitive for detecting dementia and cognitive impairment [40]. Informants are asked whether the patient has exhibited any increase in the following deficits or behaviors:
- Problems with judgment
- Reduced interest in hobbies/activities
- Repeats questions, stories, or statements
- Trouble learning how to use a tool or appliance
- Forgetting the correct month or year
- Difficulty handling financial affairs (bill-paying, taxes)
- Difficulty remembering appointments
- Consistent problems with thinking and/or memory
A positive response to two or more questions had a sensitivity of 93 percent and a specificity of 46 percent. Increasing the cutoff score to three positive responses decreased the sensitivity to 90 percent and increased the specificity to 68 percent.
Short portable mental status questionnaire. The short portable mental status questionnaire is another popular test of cognitive function [41]. It can be performed in approximately five minutes. This test contains items that test orientation, attention, immediate recall, arithmetic, abstraction, construction, information, and delayed (approximately three minutes) recall. It is reasonably sensitive and specific for the diagnosis of moderate to severe dementia, but similar to the MMSE, it is relatively insensitive in cases of mild dementia (show table 1).
Clock drawing. Asking the patient to draw a clock with a specific time is a quick examination that appears to correlate well with the MMSE score, although it has not undergone as rigorous an evaluation as the MMSE [42]. It is not a sensitive test for identifying very mild dementia [43,44].
Neuropsychologic testing — Neuropsychologic testing usually involves extensive evaluation of multiple cognitive domains (eg, attention, orientation, executive function, verbal memory, spatial memory, language, calculations, mental flexibility and conceptualization).
The AAN practice parameter for the early detection of dementia was published in 2001 [45]. The AAN reviewed a number of studies of neuropsychological testing for dementia; some were well designed observational controlled studies [46-49], and others were case series [50-52]. Most studies demonstrated a relatively high sensitivity (range 80 to 98 percent) and specificity (from 44 to 98 percent) for detection of dementia.
The AAN concluded that neuropsychologic batteries are useful instruments in identifying patients with dementia, particularly when administered to those at higher risk by virtue of memory impairment [45]. The neuropsychologic instruments that emphasize memory function were considered most useful. In particular, five subtests (Animal naming, Modified Boston Naming Test, MMSE, Constructional Praxis, and Word List Memory) were identified by a consortium of experts to be a valid, reliable measure of cognition in normal aging and AD. An aggregate total score accurately differentiated normals from those with MCI and AD [53]. However, it is important to recognize that scores can also be influenced by education and age and apply only to individuals whose primary language is English [54].
Assessment of premorbid ability — Estimating the premorbid mental ability is vital in order to assess the extent of dementia present. The National Adult Reading Test (NART) involves pronunciation of 50 irregular English words such as "ache" and "thyme" [55]. The more words a patient can read, the higher the estimate of premorbid functioning. The use of NART as an estimator of premorbid ability was validated in a case-control study of subjects about 80 years old; mean NART scores did not differ in those with and without mild to moderate dementia after controlling for actual premorbid IQ scores recorded at age 11 [56].
Physical examination — A thorough general physical examination to rule out an atypical presentation of a medical illness should be combined with a neurologic examination. The latter should focus upon focal neurologic deficits that may be consistent with prior strokes, signs of Parkinson's disease (PD) (eg, cogwheel rigidity and tremors), gait, and eye movements. In comparison, patients with Alzheimer's disease (AD) generally have no motor deficits at presentation. This examination, along with the medical and neurologic history, will allow tailoring of laboratory tests.
Laboratory testing — The American Academy of Neurology (AAN) recommends screening for B12 deficiency and hypothyroidism in patients with dementia [8]. (See "Neurologic manifestations of hypothyroidism" section on Screening for hypothyroidism in cognitive impairment). There are no clear data to support or refute ordering "routine" laboratory studies such as a complete blood count, electrolytes, calcium, glucose, blood urea nitrogen, creatinine, and liver function tests. Screening for neurosyphilis is not recommended unless there is a high clinical suspicion of neurosyphilis.
The cost-effectiveness of obtaining multiple laboratory studies in all patients has been questioned because the yield is low [57]. The prevalence of reversible dementia has fallen since 1972. In a 1994 study, this was less than one percent, and in a 2006 community-based series, none of the 560 patients with dementia screened had a treatable metabolic cause [57,58]. Some tests can be tailored to patients with a compatible history (eg, red blood cell folate in a patient with ethanol dependence, or ionized serum calcium in a patient with multiple myeloma, prostate cancer, or breast cancer).
The value of genetic testing for AD in patients with dementia is controversial. The apolipoprotein E epsilon 4 allele has been considered for use as a diagnostic test. As previously mentioned, however, many patients who are homozygotes for this allele will not develop AD [59]; thus, application of this test to large populations would lead to the overdiagnosis of AD, a practice with obvious potentially damaging consequences. For these reasons, genetic testing for the apolipoprotein E epsilon 4 allele is not currently recommended [60], nor is genetic testing for other potential causes of dementia [8].
While some studies suggest that increased levels of tau protein and decreased levels of beta-amyloid protein ending at amino acid 42 in cerebrospinal fluid may have predictive value for AD in nondemented patients and in patients with MCI, and may also distinguish AD from other forms of dementia [61-68], a role for these measurements in clinical practice has not been established [69,70].
Neuroimaging — The use of neuroimaging in patients with dementia is controversial. A number of guidelines on the clinical evaluation of dementia have been published, many of which do not recommend imaging studies routinely, but include clinical prediction rules to identify patients who might have reversible causes of dementia that can be diagnosed with imaging studies (eg, subdural hematoma, normal pressure hydrocephalus, treatable cancer) [8,58,71-77]. The prediction rules vary, including factors such as young age (<60), focal signs, short duration of symptoms (less than two years), among others. However, the sensitivity and specificity of these prediction rules is low [78]. The AAN recommends structural neuroimaging with either a noncontrast head CT or MRI in the routine initial evaluation of all patients with dementia [8].
MRI findings in AD include both generalized and focal atrophy as well as white matter lesions [79]. In general, these findings are nonspecific. However, a number of investigators have correlated changes in hippocampal volume with cognitive decline in patients with and without preexisting dementia [80-82]. Because hippocampal volumes decline in normal aging, age-specific criteria are needed; however, both young and old patients with AD have abnormal hippocampal atrophy for age [83]. In the future, if found to have sufficient specificity, these findings may be useful in detecting AD at an early or even preclinical stage and in following the course of the disease, thereby guiding treatment decisions [80,84].
Demented patients with significant atherosclerotic risk factors may harbor silent cerebrovascular disease. Obtaining a head CT in these selected cases may lead to more aggressive management of the patient's hypertension, diabetes, lipid disorders, alcohol consumption, and smoking cessation, and may prompt one to prescribe aspirin. A head CT scan is important for patients with acute onset of cognitive impairment and rapid neurologic deterioration. Neuroimaging is also indicated when there are historical features or findings on physical examination suggestive of a subdural hematoma, thrombotic stroke, or cerebral hemorrhage.
AD and other neurodegenerative diseases can cause serious alterations in brain metabolism, providing the rationale for the use of positron emission tomography (PET) to assist in the diagnosis of dementia. In one of the largest studies of PET for this purpose to date, PET studies in 146 patients presenting with cognitive symptoms of dementia were sensitive indicators of the presence of AD and of neurodegenerative disease in general [85]. A negative PET scan indicated that pathologic progression of cognitive impairment was unlikely to occur over the next three years. The clinical application of PET scanning remains to be determined [86]. New techniques, such as the use of 11C-labeled Pittsburgh compound-B tracer, which binds to fibrillar amyloid beta plaques, are under investigation [87,88].
Brain biopsy — Brain biopsy has a very limited role in the diagnosis of dementia; the diagnostic yield is low, and the test is invasive with a significant risk of serious complications. Typically, it is used in younger patients and those with atypical clinical presentations in which a treatable cause of dementia (eg, inflammatory disorders such as vasculitis or multiple sclerosis) is considered plausible. In one series of 90 consecutive biopsies undertaken for the investigation of dementia, 57 percent were diagnostic, although biopsy obtained information led to specific treatment interventions in only 11 percent [89]. Only a raised cerebrospinal fluid cell count predicted the finding of a potentially treatable disease. In another series of similar size, the diagnostic yield was 47 percent [90].
SUMMARY AND RECOMMENDATIONS — Recommendations for the evaluation of cognitive impairment and dementia are derived from our clinical experience as well as from the American Academy of Neurology (AAN) practice guidelines [8,45].
The initial step in the evaluation of a patient with suspected dementia should focus upon the history. Family members or other informants who know the patient well are invaluable resources for providing an adequate history of cognitive and behavioral changes.
Adequate time should be arranged for a full assessment of cognitive function, followed by a complete physical examination, including neurologic examination.
The Mini-Mental State Exam is a useful screening test for dementia; a score of less than 24 points is suggestive of dementia or delirium.
Neuropsychologic testing batteries are useful in identifying patients with dementia, particularly when administered to those who may be at increased risk of cognitive impairment.
Screening for B12 deficiency and hypothyroidism is recommended for patients being evaluated for dementia.
Screening for depression in patients with dementia is recommended because depression is a common treatable comorbidity that may also masquerade as dementia.
Genetic testing for the apolipoprotein E epsilon 4 allele is not currently recommended, nor is genetic testing for other potential causes of dementia.
Structural neuroimaging with either a noncontrast head CT or MRI is recommended in the routine initial evaluation of all patients with dementia.
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Alzheimer's disease (AD) is the most common form of dementia in the elderly, accounting for 60 to 80 percent of cases, and it is estimated to affect more than 4 million Americans [2-5]. Between 2.4 and 3.1 million spouses, relatives, and friends take care of people with AD [6]. The cost of caring for one person with this disorder at home or in a nursing home is more than $47,000 per year [7]. Clinicians will need to accurately diagnose and manage the early cognitive manifestations of AD, particularly as new pharmacological agents are developed.
This topic will discuss the evaluation of cognitive impairment and dementia. The clinical, diagnostic, and pathologic aspects of specific dementia syndromes are discussed separately. (See "Dementia syndromes").
The treatment, risk factors, and prevention of dementia are also discussed separately. (See "Treatment of dementia", see "Risk factors for dementia" and see "Prevention of dementia"). The risk factors, treatment, and prevention of vascular dementia are specifically discussed separately. (See "Etiology, clinical manifestations, and diagnosis of vascular dementia" and see "Treatment and prevention of vascular dementia").
DEFINITION OF DEMENTIA — Although a number of definitions exist for dementia, the DSM-IV definition is widely accepted and includes the following [1]:
Evidence from the history and mental status examination that indicates major impairment in learning and memory as well as at least one of the following:
- Impairment in handling complex tasks
- Impairment in reasoning ability
- Impaired spatial ability and orientation
- Impaired language
The cognitive symptoms must significantly interfere with the individual's work performance, usual social activities, or relationships with other people
This must represent a significant decline from a previous level of functioning
The disturbances are of insidious onset and are progressive, based on evidence from the history or serial mental-status examinations
The disturbances are not occurring exclusively during the course of
delirium
The disturbances are not better accounted for by a major psychiatric diagnosis
The disturbances are not better accounted for by a systemic disease or another brain disease
In a practice guideline published by the American Academy of Neurology (AAN), the DSM-IIIR definition of dementia (identical to the DSM-IV definition) was reported to have good to very good reliability and was recommended for routine use [8].
IDENTIFICATION OF DEMENTIA — Detecting dementia is a problem in routine, day-to-day medical practice [9]. One study found that the diagnosis was missed in 21 percent of demented or delirious patients on a general medical ward, while 20 percent of nondemented patients were misjudged as demented [10]. Nonetheless, the clinical diagnosis of dementia is reasonably accurate for those with experience in the evaluation of this disorder (show table 1) [11].
Most patients with dementia do not present with a complaint of memory loss; it is often a spouse or other informant who brings the problem to the physician's attention. Self-reported memory loss does not appear to correlate with the subsequent development of dementia, while informant-reported memory loss is a much better predictor of the current presence and future development of dementia [12,13]. Nevertheless, family members are often delayed in recognizing the signs of dementia, many of which are inaccurately ascribed to "aging."
The normal cognitive decline associated with aging consists primarily of mild changes in memory and the rate of information processing, which are not progressive and do not affect daily function. In a study of 161 community-dwelling, cognitively normal individuals ages 62 to 100 years, learning or acquisition performance declined uniformly with increasing age [14]. In contrast, delayed recall or forgetting remained relatively stable. Similarly, a second report found that aging was associated with a decline in the acquisition and early retrieval of new information but not in memory retention [15].
Patients with dementia may have difficulty with one or more of the following [16]:
Learning and retaining new information (eg, trouble remembering events)
Handling complex tasks (eg, balancing a checkbook)
Reasoning (eg, unable to cope with unexpected events)
Spatial ability and orientation (eg, getting lost in familiar places)
Language (eg, word finding)
Behavior
Patients and informants are often uncertain about the onset of symptoms since the appearance of dementia is insidious. The physician can usually date the onset of dementia by identifying when the patient stopped driving or managing finances. Useful questions for the patient and informant are, "When did you first notice the memory loss?" and "How has the memory loss progressed since then?"
The diagnosis of dementia must be distinguished from delirium and depression (show table 2) [17]. (See "Diagnosis of delirium and confusional states" and see "Depression: Clinical manifestations and diagnosis"):
Delirium is usually acute in onset and is associated with a clouding of the sensorium. Patients with delirium may have fluctuations in their level of consciousness and have difficulty with attention and concentration. Delirium and dementia can overlap, making the distinction difficult and sometimes impossible.
Patients with depression are more likely to complain about memory loss than those with dementia; the latter are frequently brought to physicians by their families, while depressed patients often present by themselves. Patients with depression may have signs of psychomotor slowing and produce a poor effort on testing, while those with dementia often try hard but respond with incorrect answers. Depression and dementia may occur in the same patient.
The pretest probability of dementia and of various causes of dementia depends upon patient characteristics such as age and race. Realizing that 5 percent of individuals over age 65 years and 35 to 50 percent of persons over age 85 years have dementia, the pretest probability of dementia in an older person with reported memory loss is estimated to be at least 60 percent.
The US Preventive Services Task Force has concluded that there is insufficient evidence to recommend for or against routine screening for dementia in older adults [18,19]. (See "USPSTF Guidelines: Screening for dementia: Recommendations and rationale").
Mild cognitive impairment — Mild cognitive impairment (MCI) is generally defined by the presence of memory difficulty and objective memory impairment but preserved ability to function in daily life. Patients with MCI appear to be at increased risk of dementia. This topic is discussed separately. (See "Mild cognitive impairment").
Dementia syndromes — The major dementia syndromes include [20-22]: (see "Dementia syndromes")
Alzheimer's disease (AD)
Dementia with Lewy bodies (DLB)
Frontotemporal dementia (FTD)
Vascular (multi-infarct) dementia (VaD)
Parkinson's disease with dementia (PDD)
Less common disorders such as progressive supranuclear palsy (PSP) can also be associated with dementia. Non-neurodegenerative dementias may be reversible, if the underlying cause can be identified and adequately treated [23].
Most elderly patients with chronic dementia have AD (approximately 60 to 80 percent). The vascular dementias account for 10 to 20 percent, and PD for 5 percent. The prevalence of VaD is relatively high in blacks, hypertensive persons, and patients with diabetes; some of the reversible dementias (eg, metabolic dementias) tend to occur in younger individuals. DLB may be as prevalent as VaD in older cohorts of patients [24]. FTD is much less common than AD, VaD, or DLB.
Alcohol-related dementia, medication side effects (eg, antihistamine use), depression, and other central nervous system illnesses are responsible for the remainder of the chronic dementias.
Dementia frequently has more than one cause, particularly as the condition progresses. In addition, medical illnesses exacerbating poor cognition are common in patients with dementia. The bedside evaluation combined with historical information from a reliable informant provides most of the information needed to ascertain the cause of dementia [17]. However, even with the addition of information from imaging studies, clinical criteria for VaD have relatively poor sensitivity [25].
DIAGNOSTIC APPROACH — The initial appointment in a patient with suspected dementia should focus upon the history. Preferably, family members are available to give an adequate history of cognitive and behavioral changes [21]. A drug history is particularly important; use of drugs that impair cognition (eg, analgesics, anticholinergics, psychotropic medications, and sedative-hypnotics) should be sought.
A full dementia evaluation can probably not be completed in a routine 30-minute visit; adequate time should be arranged as a follow-up appointment. The initial step at the follow-up visit is an assessment of cognitive function. This should be followed by a complete physical examination, including neurologic examination. The subsequent work-up may include laboratory and imaging studies (show algorithm 1) [26,27]. The DSM-IV criteria for the diagnosis of dementia are shown in Table three (show table 3).
Cognitive testing — Agreement between the history and the mental status examination is strongly suggestive of the diagnosis of dementia. When the history suggests cognitive impairment but the mental status examination is normal, possible explanations include mild dementia, high intelligence or education, depression, or rarely, misrepresentation on the part of the informants [28]. Conversely, when the mental status examination suggests cognitive impairment but the family and patient deny any problems, possible explanations include an acute confusional state, very low intelligence or education, or inadequate recognition by the family [28]. Neuropsychological assessment (psychometric testing) may be useful in difficult situations; re-evaluation at a later time is often helpful.
Mini-Mental State Examination — The Mini-Mental State Exam (MMSE) is the most widely used cognitive test for dementia in US clinical practice [29,30]. The examination takes approximately seven minutes to complete. It tests a broad range of cognitive functions including orientation, recall, attention, calculation, language manipulation, and constructional praxis.
The MMSE includes the following tasks [29]:
Orientation:
What is the date: (year)(season)(date)(day)(month) - 5 points
Where are we: (state)(county)(town)(hospital)(floor) - 5 points
Registration:
Name three objects: one second to say each. Ask the patient all three after you have said them. Give one point for each correct answer. Then repeat them until he/she learns all three. Count trials and record. The first repetition determines the score, but if the patient cannot learn the words after six trials then recall cannot be meaningfully tested. Maximum score - 3 points.
Attention and calculation:
Serial 7s, beginning with 100 and counting backward: one point for each correct; stop after five answers. Alternatively, spell WORLD backwards: one point for each letter that is in correct order. Maximum score - 5 points.
Ask for the three objects repeated above: one point for each correct. Maximum score - 3 points.
Show and ask patient to name a pencil and wrist watch - 2 points.
Repeat the following, "No ifs ands or buts." Allow only one trial - 1 point.
Follow a three stage command, "Take a paper in your right hand, fold it in half, and put it on the floor." Score one point for each task executed. Maximum score - 3 points.
On a blank piece of paper write "close your eyes," and ask the patient to read and do what it says - 1 point.
Give the patient a blank piece of paper and ask him/her to write a sentence. The sentence must contain a noun and verb and be sensible - 1 point.
Ask the patient to copy a design (eg, intersecting pentagons). All 10 angles must be present and two must intersect - 1 point.
A total maximal score on the MMSE is 30 points. Generally a score of less than 24 points is suggestive of dementia or delirium. Using a cutoff of 24 points, the MMSE had a sensitivity of 87 percent and a specificity of 82 percent in a large population based sample (show table 1) [31]. However, the test is not sensitive for mild dementia, and scores may be influenced by age and education, as well as language, motor, and visual impairments [32]. In one study, for example, the median MMSE score was 29 for individuals with at least nine years of schooling, 26 for those with five to eight years of schooling, and 22 for those with four years of schooling or less [31].
The use of higher cutoff scores on the MMSE improves sensitivity but lowers specificity. For research purposes, some investigators use a cutoff score of 26 or 27 in symptomatic populations in order to miss few true cases, while lower cutoffs would be necessary in populations where the expected prevalence is low [33]. Age-specific norms also have been established [31]; some groups have developed tools that incorporate age, gender, and education level (show figure 1) [34,35].
The MMSE also has utility in assessing competency in decision making. Studies suggest that high scores, 23, and low scores, <19, can be highly predictive in discriminating competency from incompetency. Intermediate scores warrant more detailed competency evaluation [36,37].
Other brief cognitive assessments — An ideal test for mental status screening should be brief and have good performance in populations with different cultural, linguistic, and educational backgrounds.
Mini-Cog. One such test is the "Mini-Cog," which consists of a clock drawing task (CDT) and an uncued recall of three unrelated words [38].
Scoring of the Mini-Cog is based on a simple decision tree with the following three rules:
Subjects recalling none of the words are classified as demented
Subjects recalling all three words are classified as non-demented
Subjects with intermediate (one to two) word recall are classified based on the CDT (abnormal = demented; normal = non-demented)
The CDT is considered normal if all numbers are present in the correct sequence and the hands readably display the correct time.
The advantages of the Mini-Cog include high sensitivity for predicting dementia status, short testing time relative to the MMSE, ease of administration, and diagnostic value not limited by the subject's education or language [38].
In a retrospective analysis of data from a random sample of 1119 older adults, the Mini-Cog was compared with the MMSE (at a cut point of 25); the Mini-Cog had similar sensitivity (76 versus 79 percent) and specificity (89 versus 88 percent) for dementia [39]. Although these results are promising, the Mini-Cog requires further validation with prospective data. These tests are also not appropriate for patients with aphasic or anomic disorders.
Informant interview — A brief, eight-item questionnaire for informants appears to be sensitive for detecting dementia and cognitive impairment [40]. Informants are asked whether the patient has exhibited any increase in the following deficits or behaviors:
- Problems with judgment
- Reduced interest in hobbies/activities
- Repeats questions, stories, or statements
- Trouble learning how to use a tool or appliance
- Forgetting the correct month or year
- Difficulty handling financial affairs (bill-paying, taxes)
- Difficulty remembering appointments
- Consistent problems with thinking and/or memory
A positive response to two or more questions had a sensitivity of 93 percent and a specificity of 46 percent. Increasing the cutoff score to three positive responses decreased the sensitivity to 90 percent and increased the specificity to 68 percent.
Short portable mental status questionnaire. The short portable mental status questionnaire is another popular test of cognitive function [41]. It can be performed in approximately five minutes. This test contains items that test orientation, attention, immediate recall, arithmetic, abstraction, construction, information, and delayed (approximately three minutes) recall. It is reasonably sensitive and specific for the diagnosis of moderate to severe dementia, but similar to the MMSE, it is relatively insensitive in cases of mild dementia (show table 1).
Clock drawing. Asking the patient to draw a clock with a specific time is a quick examination that appears to correlate well with the MMSE score, although it has not undergone as rigorous an evaluation as the MMSE [42]. It is not a sensitive test for identifying very mild dementia [43,44].
Neuropsychologic testing — Neuropsychologic testing usually involves extensive evaluation of multiple cognitive domains (eg, attention, orientation, executive function, verbal memory, spatial memory, language, calculations, mental flexibility and conceptualization).
The AAN practice parameter for the early detection of dementia was published in 2001 [45]. The AAN reviewed a number of studies of neuropsychological testing for dementia; some were well designed observational controlled studies [46-49], and others were case series [50-52]. Most studies demonstrated a relatively high sensitivity (range 80 to 98 percent) and specificity (from 44 to 98 percent) for detection of dementia.
The AAN concluded that neuropsychologic batteries are useful instruments in identifying patients with dementia, particularly when administered to those at higher risk by virtue of memory impairment [45]. The neuropsychologic instruments that emphasize memory function were considered most useful. In particular, five subtests (Animal naming, Modified Boston Naming Test, MMSE, Constructional Praxis, and Word List Memory) were identified by a consortium of experts to be a valid, reliable measure of cognition in normal aging and AD. An aggregate total score accurately differentiated normals from those with MCI and AD [53]. However, it is important to recognize that scores can also be influenced by education and age and apply only to individuals whose primary language is English [54].
Assessment of premorbid ability — Estimating the premorbid mental ability is vital in order to assess the extent of dementia present. The National Adult Reading Test (NART) involves pronunciation of 50 irregular English words such as "ache" and "thyme" [55]. The more words a patient can read, the higher the estimate of premorbid functioning. The use of NART as an estimator of premorbid ability was validated in a case-control study of subjects about 80 years old; mean NART scores did not differ in those with and without mild to moderate dementia after controlling for actual premorbid IQ scores recorded at age 11 [56].
Physical examination — A thorough general physical examination to rule out an atypical presentation of a medical illness should be combined with a neurologic examination. The latter should focus upon focal neurologic deficits that may be consistent with prior strokes, signs of Parkinson's disease (PD) (eg, cogwheel rigidity and tremors), gait, and eye movements. In comparison, patients with Alzheimer's disease (AD) generally have no motor deficits at presentation. This examination, along with the medical and neurologic history, will allow tailoring of laboratory tests.
Laboratory testing — The American Academy of Neurology (AAN) recommends screening for B12 deficiency and hypothyroidism in patients with dementia [8]. (See "Neurologic manifestations of hypothyroidism" section on Screening for hypothyroidism in cognitive impairment). There are no clear data to support or refute ordering "routine" laboratory studies such as a complete blood count, electrolytes, calcium, glucose, blood urea nitrogen, creatinine, and liver function tests. Screening for neurosyphilis is not recommended unless there is a high clinical suspicion of neurosyphilis.
The cost-effectiveness of obtaining multiple laboratory studies in all patients has been questioned because the yield is low [57]. The prevalence of reversible dementia has fallen since 1972. In a 1994 study, this was less than one percent, and in a 2006 community-based series, none of the 560 patients with dementia screened had a treatable metabolic cause [57,58]. Some tests can be tailored to patients with a compatible history (eg, red blood cell folate in a patient with ethanol dependence, or ionized serum calcium in a patient with multiple myeloma, prostate cancer, or breast cancer).
The value of genetic testing for AD in patients with dementia is controversial. The apolipoprotein E epsilon 4 allele has been considered for use as a diagnostic test. As previously mentioned, however, many patients who are homozygotes for this allele will not develop AD [59]; thus, application of this test to large populations would lead to the overdiagnosis of AD, a practice with obvious potentially damaging consequences. For these reasons, genetic testing for the apolipoprotein E epsilon 4 allele is not currently recommended [60], nor is genetic testing for other potential causes of dementia [8].
While some studies suggest that increased levels of tau protein and decreased levels of beta-amyloid protein ending at amino acid 42 in cerebrospinal fluid may have predictive value for AD in nondemented patients and in patients with MCI, and may also distinguish AD from other forms of dementia [61-68], a role for these measurements in clinical practice has not been established [69,70].
Neuroimaging — The use of neuroimaging in patients with dementia is controversial. A number of guidelines on the clinical evaluation of dementia have been published, many of which do not recommend imaging studies routinely, but include clinical prediction rules to identify patients who might have reversible causes of dementia that can be diagnosed with imaging studies (eg, subdural hematoma, normal pressure hydrocephalus, treatable cancer) [8,58,71-77]. The prediction rules vary, including factors such as young age (<60), focal signs, short duration of symptoms (less than two years), among others. However, the sensitivity and specificity of these prediction rules is low [78]. The AAN recommends structural neuroimaging with either a noncontrast head CT or MRI in the routine initial evaluation of all patients with dementia [8].
MRI findings in AD include both generalized and focal atrophy as well as white matter lesions [79]. In general, these findings are nonspecific. However, a number of investigators have correlated changes in hippocampal volume with cognitive decline in patients with and without preexisting dementia [80-82]. Because hippocampal volumes decline in normal aging, age-specific criteria are needed; however, both young and old patients with AD have abnormal hippocampal atrophy for age [83]. In the future, if found to have sufficient specificity, these findings may be useful in detecting AD at an early or even preclinical stage and in following the course of the disease, thereby guiding treatment decisions [80,84].
Demented patients with significant atherosclerotic risk factors may harbor silent cerebrovascular disease. Obtaining a head CT in these selected cases may lead to more aggressive management of the patient's hypertension, diabetes, lipid disorders, alcohol consumption, and smoking cessation, and may prompt one to prescribe aspirin. A head CT scan is important for patients with acute onset of cognitive impairment and rapid neurologic deterioration. Neuroimaging is also indicated when there are historical features or findings on physical examination suggestive of a subdural hematoma, thrombotic stroke, or cerebral hemorrhage.
AD and other neurodegenerative diseases can cause serious alterations in brain metabolism, providing the rationale for the use of positron emission tomography (PET) to assist in the diagnosis of dementia. In one of the largest studies of PET for this purpose to date, PET studies in 146 patients presenting with cognitive symptoms of dementia were sensitive indicators of the presence of AD and of neurodegenerative disease in general [85]. A negative PET scan indicated that pathologic progression of cognitive impairment was unlikely to occur over the next three years. The clinical application of PET scanning remains to be determined [86]. New techniques, such as the use of 11C-labeled Pittsburgh compound-B tracer, which binds to fibrillar amyloid beta plaques, are under investigation [87,88].
Brain biopsy — Brain biopsy has a very limited role in the diagnosis of dementia; the diagnostic yield is low, and the test is invasive with a significant risk of serious complications. Typically, it is used in younger patients and those with atypical clinical presentations in which a treatable cause of dementia (eg, inflammatory disorders such as vasculitis or multiple sclerosis) is considered plausible. In one series of 90 consecutive biopsies undertaken for the investigation of dementia, 57 percent were diagnostic, although biopsy obtained information led to specific treatment interventions in only 11 percent [89]. Only a raised cerebrospinal fluid cell count predicted the finding of a potentially treatable disease. In another series of similar size, the diagnostic yield was 47 percent [90].
SUMMARY AND RECOMMENDATIONS — Recommendations for the evaluation of cognitive impairment and dementia are derived from our clinical experience as well as from the American Academy of Neurology (AAN) practice guidelines [8,45].
The initial step in the evaluation of a patient with suspected dementia should focus upon the history. Family members or other informants who know the patient well are invaluable resources for providing an adequate history of cognitive and behavioral changes.
Adequate time should be arranged for a full assessment of cognitive function, followed by a complete physical examination, including neurologic examination.
The Mini-Mental State Exam is a useful screening test for dementia; a score of less than 24 points is suggestive of dementia or delirium.
Neuropsychologic testing batteries are useful in identifying patients with dementia, particularly when administered to those who may be at increased risk of cognitive impairment.
Screening for B12 deficiency and hypothyroidism is recommended for patients being evaluated for dementia.
Screening for depression in patients with dementia is recommended because depression is a common treatable comorbidity that may also masquerade as dementia.
Genetic testing for the apolipoprotein E epsilon 4 allele is not currently recommended, nor is genetic testing for other potential causes of dementia.
Structural neuroimaging with either a noncontrast head CT or MRI is recommended in the routine initial evaluation of all patients with dementia.
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