Clinical diagnosis of dementia

Alzheimer’s & Dementia 3 (2007) 292–298

Clinical diagnosis of dementia Alain Robillard* Division of Neurology, Department of Medicine, Hôpital Maisonneuve-Rosemont & Université de Montréal, Montréal, Quebec, Canada

Abstract

This paper presents recommendations deriving from the Third Canadian Consensus Conference on the Diagnosis and Treatment of Dementia, concerning the clinical diagnosis of dementia. There are currently no universally accepted biological or radiological markers of dementia. In the absence of these, the diagnosis of dementia remains a clinical exercise aiming to integrate all available clinical and laboratory information. It is proposed that the currently used National Institute of Neurological and Communicative Disorders and Stroke/Alzheimer’s Disease and Related Disorders Association (NINCDS/ADRA) criteria for diagnosis of Alzheimer’s disease (AD) be retained. The currently available vascular dementia (VaD) diagnostic criteria have variable accuracy. An integrative approach to VaD diagnosis based on all the available evidence (history, vascular risk factors, physical exam, clinical course, neuroimaging, cognitive impairment pattern) is recommended. The separation of Lewy body dementia (DLB) from Parkinson’s disease dementia (PDD) is based on the dominant clinical presenting feature of each syndrome, and relies on the duration of this feature: long duration of parkinsonian “motor” syndrome preceding dementia for PDD versus early/initial dementia accompanied by extrapyramidal symptoms for DLB. It is recognized that it is impossible clinically to characterize DLB with (pathologically) coexisting AD changes. The Frontotemporal group of dementia syndromes are discussed in regards to their typical clinical pictures, recognizing that their neuropathological substrate are not predictable from their mode of presentation. Finally, the particular rapid time sequence of evolution of the dementias due to prior disease is recognized as the clinically most useful distinguishing feature of these syndromes. © 2007 The Alzheimer’s Association. All rights reserved.

Keywords:

Dementia; Diagnosis; Alzheimer; Lewy body; Frontotemporal; Vascular; Behavior

1. Introduction This paper presents recommendations deriving from the Third Canadian Consensus Conference on the Diagnosis and Treatment of Dementia, concerning the clinical diagnosis of dementia. These recommendations are the result of a standardized literature review (see series Introduction [1] for methods) and all of the recommendations were supported by at least 80% of the participants at the national meeting held in Montreal in March, 2006. Our focus was on whether there were clearly agreed upon clinical diagnostic criteria for different dementia entities, and if so, what those recommended criteria were. Note that there is a later paper (in this issue) by Rockwood et al [1a], which addresses the

*Corresponding author. Tel.: (514) 252-3528; Fax: (514) 252-3529. E-mail address: [email protected]

question of clinical criteria from a different perspective. That paper critically reviews the literature and proposes changes in the current criteria. The recommendations of this paper pertain to how physicians should apply the current criteria as presently understood. The purpose of the Rockwood et al paper [1a] is to propose changes which might lead in the future to more cogent or coherent conceptualization of the dementias. These are complementary goals. The diagnosis of dementia and of its various etiologies remain at its core a clinical exercise based on the presenting and dominant symptoms, their order of appearance and the evolution of symptoms and signs over time. A number of classification criteria based on this procedure have been proposed through the years for Alzheimer’s disease (AD) and vascular dementia (VaD), with various precision when compared with diagnosis based on pathological outcome. The same applies to the Frontotemporal group of dementias,

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where pathological diagnosis is more difficult to predict on clinical grounds alone. The problem is similar in the Lewy Body dementias (Parkinson’s disease dementia and Lewy Body dementia) where there exist a considerable overlap in the presenting symptoms, and where again neuropathology cannot always be relied on to “confirm” a clinical diagnosis. Here the sequence of appearance of the cardinal symptoms in both syndromes is central to a clinical diagnosis. In all of these dementias, a descriptive and “integrative” approach to diagnosis is proposed in the following discussions. The essential symptoms of dementia are “. . . an acquired impairment in short and long-term memory, associated with impairment in abstract thinking, impaired judgment, other disturbances of higher cortical function, or personality changes. The disturbance is severe enough to interfere with work or usual social activities or relationships with others. The diagnosis of dementia is not made if these symptoms occur in the presence of Delirium.” This definition is the most widely used in practice and is based on the Diagnostic and Statistical Manual [of Mental Disorders], Third Edition, Revised (DSM-IIIR), DSM-IV, and the National Institute of Neurological and Communicative Disorders and Stroke/ Alzheimer’s Disease and Related Disorders Association (NINCDS/ADRDA) [1b–3]. This DSM III-R definition of dementia has good reliability particularly with respect to Alzheimer’s disease. The DSM-IV version has not been validated, although it is identical to the former definition [2,4,5]. After identifying the presence of a dementia syndrome, the specific causes can be recognized by using clinical criteria for the various clinical profiles. 2. AD AD is characterized by gradual onset and continued decline of memory and at least one additional cognitive domain that is not explained by another systemic or neurologic disorder [3]. Both the reliability of the clinical diagnosis and interrater reliability have been subjected to review, with more than 14 studies addressing these concerns [6 –23]. The general consensus is that on the basis of Class I and Class II studies and with neuropathologic data as confirming evidence of clinical diagnosis, there is very good sensitivity of clinical criteria (average, 81%; range, 49% to 100%), at the expense of specificity (average, 70%; range, 47% to 100%), with the NINCDS/ADRDA definition of “probable” AD. “Possible” AD, as a diagnostic category, achieves higher sensitivity (average, 93%) but much lower specificity (average, 48%); this reflects the fact that there are many common features between different types of dementia. “Mild” AD (as defined by a Mini Mental State Examination [MMSE] score of ⱖ24) can also be diagnosed according to clinical criteria, with a high degree of certainty (89%, compared with pathology) (Class II, one trial). The

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diagnostic accuracy is enhanced in this group of patients by the use of a more comprehensive neuropsychological test battery [24]. Patients with mild cognitive impairment (MCI), as defined by Petersen et al [25], have a memory impairment beyond that expected for age and education, yet they are not demented. These subjects have become the focus of many prediction studies and are diagnosed according to clinical criteria. Debate is still ongoing regarding the specific subtypes of MCI (amnestic and non-amnestic, single or multiple domains), with definitions used on the basis of a presumed etiology. With the criteria of Petersen et al for amnestic MCI, it has been shown that a high proportion of these patients go on to AD [25–28]. The definition of MCI is difficult to apply in a clinical setting, and the available diagnostic instruments used for diagnosing dementia lack sensitivity to MCI. A new tool, the Montreal Cognitive Assessment (MoCA), has been proposed and validated in one trial [29], demonstrating a higher sensitivity for MCI (100% when judged against the MMSE, with a cutoff score of 26), with good specificity (87%). A separate paper by Chertkow et al in this issue further pursues the concept of MCI and derives evidence-based recommendations for MCI diagnosis [29a]. 3. VaD VaD is a dementia syndrome resulting from cerebrovascular damage. This syndrome can occur as the result of a single strategically placed brain infarct or as the result of numerous discrete smaller (and most often subcortical) lesions. The progression is classically in a stepwise fashion, but increasingly a slow insidious progress is recognized. The clinical hallmark of VaD is dysexecutive syndrome. Four consensus criteria for VaD are in use: the State of California AD Diagnostic and Treatment Centers criteria (the California criteria), the National Institute of Neurologic Disorders and Stroke and the Association Internationale pour la Recherche et l’Enseignement en Neurosciences (NINDS-AIREN) criteria, the Hachinski Ischemic Score (HIS) modified by Rosen, and those found in the DSM-IV. They all have poor sensitivity at the cost of high specificity, when judged against the best clinical judgment (including neuroimaging) of trained clinicians [30] (Class II evidence). In studies that compared clinical diagnoses and neuropathologic findings, the NINDS-AIREN and the California criteria (as well as DSM-IIIR) had very low sensitivity but higher specificity. One Class I study [31] reported the sensitivity (43%) and specificity (95%) of the NINDS-AIREN criteria for VaD. Five Class II studies [32–36] reported sensitivity and specificity of the diagnosis of VaD with any criteria. The results showed low sensitivity (average of 5 studies, 50%; range, 20% to 89%) but high specificity (average across 5 studies, 87%; range, 64% to 98%) for the HIS, DSM-IIIR, NINDS-AIREN, or California clinical cri-

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teria. Only one retrospective (Class II) study [35] showed better sensitivity and specificity (both 89%) with the HIS. This lack of sensitivity in the available diagnostic criteria is confounded by the presence on neuropathologic examination of considerable overlap between vascular and degenerative (AD) pathology (some vascular pathology exists in 29% to 41% of dementia cases coming to autopsy), whereas pure vascular pathology accounts for dementia in only 9% to 10% [12,14], leading some to propose that pure VaD or AD is rare [12–17]. A descriptive approach to the diagnosis of VaD is proposed, which would take into account the neuropsychological profile of the dementia syndrome, neuroimaging, and vascular risk factors [37,38]. 4. Lewy body disease The third report of the Dementia with Lewy Bodies (DLB) consortium was published in December 2005 [39]. The central feature of DLB remains the presence of a dementia syndrome of sufficient intensity to interfere with social or occupational function, although memory impairment might not be prominent at diagnosis, whereas deficits on tests of attention, visuospatial ability, and executive function might be more prominent. The core features include spontaneous parkinsonian symptoms, fluctuating cognition with pronounced variations in attention and alertness, and recurrent well-formed and detailed visual hallucinations. The consensus report also details suggestive as well as supportive features that add a degree of probability to the diagnosis. Clinically the most important supportive symptoms remain rapid eye movement sleep behavior disorder and severe neuroleptic sensitivity. The time sequence in which symptoms of DLB appear is key to differentiation from Parkinson’s disease dementia (PDD); typically dementia appears after a number of years in PD (10 years usually), whereas parkinsonian symptoms are central to the initial diagnosis of DLB. There are no distinguishing clinical features that can discriminate between PDD and DLB at any given point in time [40]. The sensitivity of the DLB diagnosis based on pathology has been subject to controversy [41] due in large part to the original pathologic reports stating that the presence of any LBs in whatever distribution was sufficient for diagnosis [42,43]. One Class I study [12] investigated the diagnostic accuracy of DLB criteria against neuropathologic findings; sensitivity was low at 22%, but specificity was high (100%). Six Class II studies also showed low sensitivities (average across 5 studies, 58%; range, 30% to 75%) but higher specificities (average across 5 studies, 87%; range, 71% to 100%) for the Consortium diagnostic criteria of DLB [10,44 – 48]. New pathologic criteria have been proposed by the DLB Consortium that will take into account the concomitant presence of AD pathology in the future [39]. The recognition that AD and DLB neuropathology can

coexist to various degrees in patients presenting initially with either AD or DLB symptomatology has lead to attempts at clinical differentiation. In a Class II study, Lopez et al [49] reported that in patients with pathologically diagnosed AD and DLB, sensitivity of the clinical diagnostic criteria improved as dementia worsened, at the expense of specificity. There were no distinguishing features between AD and AD with DLB in mild dementia. In moderate dementia, the presence of extrapyramidal signs (EPS) and major depression were associated with AD ⫹ DLB, and in severe dementia, EPS and diurnal hypersomnia were indicators of AD ⫹ DLB. Del Ser et al [50] noted in a Class II study that the clinical features of AD ⫹ DLB patients were similar to those of AD patients except for more frequent acute-subacute onset and a fluctuating evolution. Differentiation between three groups of patients (pure DLB, AD ⫹ LB, and AD) or between both groups with LB (DLB) from AD could only be attained in 70% of cases. Accuracy was excellent for the diagnosis of pure DLB but only mediocre for separating AD ⫹ LB as well as the pure DLB and DLB ⫹ AD groups from AD. In a Class II retrospective study of 90 patients with autopsy-proven DLB, Merdes et al [51] noted that only 27% of these demonstrated both visual hallucinations and spontaneous EPS. Subjects with lower tangle burden on Braak staging had a higher frequency of visual hallucinations (65%) than did subjects with DLB with higher Braak stages (33%) and showed a slightly greater but not significant degree of EPS. Although clinical diagnostic accuracy for DLB was relatively low (49%), it was higher for subjects with low (75%) compared with high (39%) Braak stages. The degree of concomitant AD tangle pathology had an important influence on the clinical characteristics and the accuracy of clinical diagnosis of DLB. 5. Frontotemporal dementia The clinical presentation in frontotemporal dementia (FTD) reflects the distribution of the pathologic changes rather than the exact histologic subtype of the disease. Three clinical syndromes are recognized, all of insidious onset. 5.1. Frontal variant FTD Frontal variant FTD (dementia of frontal type), in which changes in social behavior and personality predominate, reflects the orbitobasal frontal lobe focus of the pathology. 5.2. Semantic dementia In semantic dementia (progressive fluent aphasia) there is a breakdown in the conceptual database that underlies language production and comprehension. Patients with semantic dementia have asymmetric anterolateral temporal atrophy with relative sparing of the hippocampal formation, typically worse on the left side.

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5.3. Progressive nonfluent aphasia In progressive nonfluent aphasia the phonologic and syntactic components of language are affected in association with left perisylvian atrophy [52]. The original Lund-Manchester criteria [53] and the Consensus revision [54] have been tested against pathology, with low specificity; an autopsy-based Class II study (based on retrospective clinical diagnoses) showed that most patients with FTD fulfill diagnostic criteria for AD [55]. In contrast, a Class II study without autopsy confirmation [56] found that the Lund-Manchester criteria differentiated 100% of FTD and AD patients. A recent Class II retrospective study concluded that FTD, corticobasal degeneration, and progressive supranuclear palsy have overlapping clinical features, with FTD being an unpredictable disease in terms of its tau-positive biochemistry [57]. 6. Normal pressure hydrocephalus The classic clinical presentation of normal pressure hydrocephalus (NPH) is one of progressive gait apraxia, urinary incontinence, and ultimately dementia [58 – 60]. There have been a number of reports of amelioration of the clinical picture through ventriculoperitoneal shunting but no positive predictive test to differentiate those patients who might benefit from the procedure from those who will not. One trial of temporary external lumbar cerebrospinal fluid (CSF) drainage proved negative because of a high rate of falsenegative results [61] (Class II); although the predictive value of a positive external lumbar drainage was high, the costs and invasiveness of the test and the possibility of serious test-related complications limit its usefulness in managing patients with presumed NPH. Lately there has been interest for low-flow CSF drainage as a treatment for AD. Advancing age is the key risk factor for developing AD. With aging, abnormal metabolism and clearance of amyloid beta proteins (A␤) can lead to accumulation of these proteins in brain parenchyma, resulting in plaque formation. It has been postulated that age-associated impairment in the CSF circulation and cerebral vasculature could play a role, through diminished clearance of A␤, in the high incidence of AD in the elderly [62,63]. The result of one pilot trial of low-flow CSF drainage has been reported, indicating a small stabilizing effect on dementia severity rating (Class III) [64]. There is one ongoing trial for which no results have been published. 7. Prion diseases The clinical diagnosis of Creutzfeldt-Jakob disease (CJD) rests on the occurrence of a rapidly progressing dementia syndrome, associated with myoclonus and a characteristic electroencephalogram (EEG) pattern of periodic sharp waves. Probable CJD is diagnosed if patients have rapidly progres-

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sive dementia, periodic sharp waves in the EEG, and at least two of the following four findings: myoclonus, visual and/or cerebellar symptoms, pyramidal and/or extrapyramidal signs, and akinetic mutism. Cases that fulfill these criteria but do not have a typical EEG are classified as possible CJD, according to the criteria of Masters et al [65]. Other criteria have been proposed (French [66] and European criteria [67]). In a prospective Class I study Poser et al [68] tested the diagnostic criteria for CJD. Diagnosis was confirmed in 188 autopsy-confirmed cases (97%) of 193 cases diagnosed with probable CJD. In this cohort, among 54 cases diagnosed with possible CJD, the diagnosis was confirmed in 44 (81%). Only two pathologically diagnosed CJD cases were found among 111 patients who had been given other clinical diagnoses. Thus the criteria achieved high sensitivity and specificity. In a Class II retrospective trial Brandel et al [69] compared three sets of clinical diagnostic criteria in a cohort of 428 patients, showing that the three sets of criteria had a high specificity and low sensitivity as judged against neuropathology; all three criteria had poor negative predictive value (average, 44%; range, 29% to 57%). An immunoassay for the detection of the 14-3-3 protein in CSF was described in 1996 [70] that had a reported specificity of 99% and a sensitivity of 96% for the diagnosis of CJD among patients with dementia who had not had a stroke within 1 month of testing. During the ensuing years it has been shown that the 14-3-3 assay is not valid to discriminate between unselected rapidly progressing dementia syndromes. Burkhard et al [71] did a Class I study but validated against clinical diagnosis, showing 14 of 100 positive patients, of whom only two had a final diagnosis of CJD. There is also variation in the sensitivity of the 14-3-3 assay among CJD subtypes. In a Class II study Castellani et al [72] reported sensitivity between 77% and 94%, according to subtypes of CJD; the lower sensitivity was reported in the less frequent atypical subtypes. Magnetic resonance imaging (MRI), especially with diffusion-weighted imaging, in a Class II study but with a small number of subjects [73], showed evidence of a comparable sensitivity to 14-3-3 assay. In a prospective study of 219 patients suspected of having CJD, the presence of basal ganglia high signal on T2-weighted MRI showed a sensitivity of 63% and a specificity of 88% in definite/probable CJD [74].

8. Recommendations approved at the Third Canadian Consensus Conference on the Diagnosis and Treatment of Dementia (1) The diagnosis of dementia remains clinical. There is good evidence to retain the diagnostic criteria currently in use (Grade A, Level 2).

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(2) The sensitivity of clinical diagnosis for possible or probable AD based on the NINCDS-ADRDA criteria remains high. The specificity is lower. The continued use of the NINCDS-ADRDA criteria is recommended (Grade A, Level 1). (3) Mild AD can be diagnosed with a high degree of specificity, when the presenting clinical picture is one of memory impairment (Grade B, Level 1). (4) The currently available VaD diagnostic criteria have variable accuracy. An integrative approach to VaD diagnosis based on all the available evidence (history, vascular risk factors, physical exam, clinical course, neuroimaging, cognitive impairment pattern) is recommended (Grade B, Level 2). (5) The clinical features of DLB and PDD overlap considerably. At present, DLB should be diagnosed when this pattern of dementia occurs before or concurrently with parkinsonism. PDD can be diagnosed when dementia occurs in the context of well-established PD, generally after many years (Grade B, Level 3). (6) There is frequent coexistence of AD and LB neuropathology in subjects presenting with the initial clinical picture of either pathology. At present, it is impossible to propose clinical guidelines that would permit separation of the two diagnoses and AD ⫹ DLB with a high specificity (Grade A, Level 2). (7) In patients presenting primarily with progressive decline in language or praxis or with prominent changes in behavior or personality, Pick complex disease (also known as FTD or frontotemporal lobar degeneration) should be considered. These disorders of Pick complex include semantic dementia, FTD behavioral variant, primary progressive aphasia, corticobasal degeneration, progressive supranuclear palsy, and FTD with motor neuron disease. These disorders have clinical features that are distinctive and are best referred for specialist care (Grade A, Level 2). (8) When gait apraxia or urinary incontinence occurs early in the course of dementia, NPH should be considered and should be supported by computed tomography or MRI. Specialist referral is advised for further assessment. The diagnostic work-up might include the removal of a large CSF volume with documentation of clinical response, if surgical intervention is considered an appropriate option (Grade B, Level 2). (9) Rapidly progressing dementia associated with myoclonus and an EEG with the presence of periodic sharp waves is typical of CJD. There are three clinical criteria sets in use to diagnose CJD, all with some specificity. The recognition of rapid progression in a dementia syndrome should by itself suggest the possibility of CJD (Grade A, Level 2).

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