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October 01, 1999; 53 (6) Articles

Accuracy of four clinical diagnostic criteria for the diagnosis of neurodegenerative dementias

O.L. Lopez, I. Litvan, K.E. Catt, R. Stowe, W. Klunk, D.I. Kaufer, J.T. Becker, S.T. DeKosky
First published October 1, 1999, DOI: https://doi.org/10.1212/WNL.53.6.1292
O.L. Lopez
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I. Litvan
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K.E. Catt
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R. Stowe
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W. Klunk
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D.I. Kaufer
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J.T. Becker
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S.T. DeKosky
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Accuracy of four clinical diagnostic criteria for the diagnosis of neurodegenerative dementias
O.L. Lopez, I. Litvan, K.E. Catt, R. Stowe, W. Klunk, D.I. Kaufer, J.T. Becker, S.T. DeKosky
Neurology Oct 1999, 53 (6) 1292; DOI: 10.1212/WNL.53.6.1292

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Abstract

Objective: To evaluate the inter-rater reliability and validity of clinical diagnostic criteria for neurodegenerative dementias.

Background: Inter-rater accuracy of the diagnosis of AD has been explored, but there are few accuracy studies for progressive supranuclear palsy (PSP) and frontotemporal lobe dementia (FTD). Furthermore, there have been no simultaneous accuracy studies in a mixed sample of patients with cortical and subcortical neurodegenerative processes.

Methods: Four experienced clinicians reviewed first-visit clinical data abstracted from the records of 40 pathologically diagnosed demented subjects. They were asked to apply the NINCDS-ADRDA criteria for AD, the NINDS-SPSP clinical criteria for PSP, the Lund and Manchester criteria for FTD, and the Consensus Guidelines for the Clinical Diagnosis of Dementia with Lewy Bodies (DLB).

Results: The generalized κ for AD was 0.73, for PSP 0.82, for FTD 0.75, and for DLB 0.37. The κ pool test showed a statistically significant difference between DLB and the other disease processes, and no differences were observed among AD, FTD, and PSP. The mean sensitivity for AD was 95%, for PSP 75%, for FTD 97%, and for DLB 34%. The mean specificity for AD was 79%, for PSP 98.5%, for FTD 97%, and for DLB 94%.

Conclusions: We found improved inter-rater reliability for the diagnosis of AD among clinicians compared with earlier studies. Similarly, there was a near-perfect and substantial inter-rater agreement for the diagnosis of PSP and FTD. The sensitivity for the diagnosis of AD was high, although clinicians overdiagnosed this condition. However, there was a reasonable accuracy for the diagnosis of PSP and FTD. Heterogeneity of the clinical presentation of DLB significantly affected inter-rater agreement and accuracy. The use of multiple diagnostic criteria for cortical and subcortical dementia increases the level of clinical diagnostic accuracy.

The development of clinical criteria for their accurate diagnosis has improved the study of neurodegenerative diseases that cause dementia. Clinicopathologic studies conducted in AD found accuracies of less than 50% before the development of clinical criteria1 and of 80 to 100% after they became available.2-6 Researchers have also developed criteria to diagnose less frequent forms of dementia, such as frontotemporal lobe dementia (FTD)7 and progressive supranuclear palsy (PSP).8-11 More recently, neuropathologic series have found that up to 25% of the patients with dementia have cerebral Lewy bodies (LB), sometimes alone and sometimes associated with AD.12,13 This led investigators to develop clinical and pathologic criteria for dementia with LB (DLB).14-16

As our knowledge of the degenerative dementias increases, clinicians and researchers have available several sets of diagnostic clinical criteria for the different dementia disorders. Therefore, it is of both practical and theoretical importance to examine the accuracy of these different diagnostic criteria in a group of patients with cortical (e.g., AD, FTD) and subcortical (e.g., PSP) dementia or in those who can present both syndromes (e.g., DLB).

Inter-rater reliability is a necessary precondition for validity. Reliability studies are important to clarify discrepancies in the interpretation of clinical criteria that lead to diagnostic disagreement. Validity studies provide information about factors that lead to inaccurate pathologic diagnosis. Of the current clinical criteria for AD (e.g., DSM-IV,17 CAMDEX18), the NINCDS-ADRDA criteria19 have shown a better degree of inter-rater reliability (and validity) among clinicians compared with other criteria.5,20-24 However, inter-rater reliability has not been tested in the less frequent forms of dementia, especially in the context of multiple disease processes that cause cognitive impairment.

In this study, we examined the inter-rater reliability and validity of four clinical diagnostic criteria: NINCDS-ADRDA criteria for AD,19 Lund and Manchester criteria for FTD,7 NINDS-SPSP criteria for PSP,8 and the Consensus Guidelines for the Clinical Diagnosis of Dementia with Lewy Bodies.14 The NINDS-SPSP criteria for PSP and the Consensus Guidelines for the Clinical Diagnosis of DLB classify patients as “probable” and “possible” based on the degree of diagnostic certainty of the presence of each condition. By contrast, the diagnosis of “possible” AD according to NINCDS-ADRDA criteria is made when the typical clinical syndrome is present, but there are variations in the onset or clinical course, or when other systemic or brain illnesses that can affect cognitive function are present. The Lund and Manchester criteria for FTD do not establish any degree of certainty and present a list of core and supportive diagnostic features associated with FTD.25 Furthermore, the presence of dementia is essential for the diagnosis of DLB, AD, and FTD, but this is not the case for the diagnosis of PSP because these patients do not always have dementia at the initial presentation. However, more than 50% of PSP patients have frontal lobe features within 1 year of symptom onset.26,27

Methods.

Clinical data obtained from 40 pathologically confirmed demented patients were reviewed by four experienced clinicians unaware of the patients’ initial classification or pathologic diagnosis. The clinicians were three behavioral neurologists and one psychiatrist currently engaged in both research and clinical practice with patients with dementia and other age-associated neuropsychiatric disorders. Each patient underwent extensive screening, including general medical, neurologic, psychiatric, social work/nursing, and neuropsychological evaluation. Thirty-three patients were part of a longitudinal study of dementia at the University of Pittsburgh,20,28 and 7 were from the National Institute of Degenerative Diseases and Stroke.29 None of the clinicians participated in the evaluation of the subjects.

The information available concerning each subject was abstracted from the clinical record onto a standardized form by one neurologist (K.E.C.) and the coding verified by another (O.L.L.); neither took part in the accuracy study itself. Age, sex, handedness, level of education, presenting complaints, medical history, current medications, EEG report, and the results of the MRI were recorded for each patient. Results of physical, psychiatric, and neurologic examinations as well as blood and other laboratory tests relevant to the cognitive impairment were also noted. For the purpose of this study, we provided the raters with information obtained at the first clinical examination.

Each form included the scores of the Mini-Mental State Examination (MMSE),30 the Mattis Dementia Rating Scale (MDRS),31 the Clinical Dementia Rating,32 and the Blessed Rating Scale for activities of daily living.33 In addition, the form contained a list of the cognitive domains impaired in each subject (e.g., memory, language, judgment/abstract thinking, attention/concentration, visuospatial, and visuoconstructional functions) based on the neuropsychological examination.

The psychiatric information included the DSM-III-R criteria Axis I disorders34 and the Hamilton Depression Rating Scale.35 The neurologic information included detailed information about cranial nerves, motor tone (e.g., gegenhalten, cogwheel, lead-pipe, spasticity), abnormal movements (e.g., tremors, dyskinesia, dystonia, myoclonus), alien hand syndrome, strength, deep tendon reflexes, plantar response, cerebellar testing, gait, sensory testing (e.g., pinprick, vibration, stereognosis, graphesthesia), postural instability, bradykinesia, release signs, abnormal speech, buccolingual praxis, limb praxis, dysautonomia (e.g., orthostatic hypotension, sphincter incontinence), and history of frequent falls. Severity of extrapyramidal signs was measured with the New York University Scale for Parkinsonism36 and severity of cerebrovascular disease (CVD) with the Hachinski Ischemic Scale.37

The study sample included 10 patients with AD, 8 with DLB, 8 with FTD (7 frontotemporal lobe degeneration type and one Pick’s disease), 8 with PSP, 2 with corticobasal degeneration (CBD), 3 with PD, and 1 with multiple system atrophy (MSA). The patients with DLB also had neuropathologic evidence of AD.

Table 1 shows the demographic and neuropsychiatric characteristics of the patients. Patients with FTD had an earlier age at study entry and age at symptom onset. Patients with AD and DLB had lower MMSE scores than patients with PSP, FTD, and other disease processes. The New York University Scale for Parkinsonism scores were higher in patients with PSP and other disease processes relative to AD, DLB, and FTD.

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Table 1.

Characteristics of the study sample, mean ± SD

Diagnosis of dementia.

The diagnosis of dementia was based on a progressive deterioration of the cognitive function, in the absence of reversible causes of dementia, and history of normal intellectual function before the onset of cognitive abnormalities. Patients had impairment in at least two cognitive domains, which did not necessarily include memory.38

Statistical analysis.

Generalized κ statistics were used to examine the inter-rater reliability among the four clinicians. Strength of the agreement was designed as poor (κ < 0), slight (κ = 0 to 0.20), fair (κ = 0.21 to 0.40), moderate (κ = 0.41 to 0.60), substantial (κ = 0.61 to 0.80), and near-perfect to perfect (κ = 0.81 to 1.0). The pooled test determined the significance between κ values. Chi-square and one-way ANOVA with post hoc comparisons were used to analyze contingency tables.

Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were ascertained by comparing the clinicians’ diagnoses with the pathologic diagnoses. Sensitivity refers to the probability of having a clinical diagnosis of a disease given the neuropathologic presence of the disease. PPV refers to the probability of having the disease given the clinical diagnosis of having the disease. Specificity refers to the probability of not having a clinical diagnosis of a disease given the neuropathologic absence of the disease. NPV refers to the probability of not having the disease given the clinical diagnosis of not having it.39 These indices were calculated twice. First, we classified a patient if there was any mention of the condition in the diagnosis (i.e., probable, possible). Second, we applied more stringent criteria and considered a patient to have a condition only if the clinician used a “probable” diagnosis.

Results.

Table 2 shows a summary of the clinicians’ individual diagnoses. The generalized κ for the clinical diagnosis of AD was 0.73 (range 0.58 to 0.83), for PSP 0.82 (range 0.72 to 0.91), for FTD 0.75 (range 0.54 to 0.90), and for DLB 0.37 (range 0.10 to 0.55). The κ pool test showed a statistically significant difference between the agreement for the diagnosis of DLB and the other dementias, and no differences were observed among AD, FTD, and PSP. The generalized κ for probable AD was 0.59, for probable PSP 0.75, and for probable DLB 0. The sensitivity and specificity as well as the PPV and NPV for the clinical diagnostic criteria are shown in table 3.

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Table 2.

Raters’ diagnoses

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Table 3.

Sensitivity and specificity

Discussion.

This study reveals high inter-rater diagnostic agreement using the most recently developed clinical criteria for the diagnosis of PSP and FTD. In addition, clinicians achieved a higher level of agreement for the diagnosis of AD compared with previous studies.20-22,28 In early studies, the kappa value ranged from 0.36 to 0.65,20-22 and more recently the level of agreement increased to 0.72.23,28 However, the reliability of the diagnosis of some dementia disorders is still not perfect, even among experienced clinicians. The maximum level of agreement was 0.91 (almost perfect reliability) for PSP, and the lowest was 0.10 (almost no agreement) for DLB. Even so, however, the high level of inter-rater agreement does not necessarily ensure the validity of the diagnosis.

Factors that commonly affect reliability can also affect validity. First, clinical experience of the raters and their medical speciality may alter the diagnosis.3,20,40 For example, psychiatrists may weight their diagnosis more likely on behavioral symptoms, whereas neurologists may do so on motor signs. Furthermore, the familiarity that clinicians have with the diagnostic criteria may increase the level of agreement and validity. Although the NINCDS-ADRDA criteria for AD have been in use since 1984, criteria for FTD, PSP, and DLB are more recent, and none of the clinicians had previously used the NINDS-SPSP criteria.

Second, the amount of information provided to the clinicians is critical; we expect to find less agreement and validity among clinicians when the information comes from the first clinic visit when the neurobehavioral syndromes may not have fully developed. By contrast, better agreement is expected when clinicians have a summary of the entire clinical course of the disease. Here, we provided only the information available at the baseline examination, permitting us to test the diagnostic criteria at the first impression that a clinician may have from any patient. In the current clinical environment this may be the only contact that the specialists have with the patient.

The way that clinical information is presented can also affect diagnostic accuracy (i.e., standardized form versus full clinical records). Our raters had access to standardized summaries of the patients’ clinical examinations, which ensured that each patient gave identical clinical information to each clinician and that each clinician used identical measurement procedures in evaluating these patients.

Third, the over-representation of one pathologic condition in a study cohort can affect diagnostic reliability and validity.41 Clinicians who expect to find a cohort with a high proportion of patients with a targeted condition will overdiagnose the disorder, and artificially inflate, or alter, the variability of the reliability of the diagnosis. This is particularly evident in AD, where the majority of the studies have tested accuracy in samples with a disproportionately high number of AD cases (which are the most frequent types in clinical practice) but with a few patients with other conditions. The clinicians in the present study were unaware of the sample composition but were aware that other disorders besides AD were included, probably lessening the impact of the examiner’s base rate expectations on their reliability and validity measures.

Fourth, interpretations of the definition of dementia can cause difficulty in reliability and accuracy studies using different clinical criteria.23,28 The DSM-IV17 clinical criteria for dementia require memory deficits and at least one other area of cognition affected (e.g., apraxia, agnosia, aphasia, executive deficits). By contrast, the NINCDS-ADRDA clinical criteria require that only two areas of cognition be affected, not necessarily memory, although they state that memory deficits must be progressive. Here, we defined dementia as the presence of deficits in two areas of the cognition, not necessarily memory, allowing the clinicians to classify dementia syndromes that included relatively preserved memory functions, such as FTD (Patient 28) or CBD (Patient 35). Furthermore, although the presence of dementia is not necessary for the diagnosis of PSP, and most PSP patients do not have dementia at symptom onset, all PSP patients included in this study did have cognitive deficits, and two had a severe syndrome. In this context, it seems that severity of dementia can affect reliability (Patient 11) and accuracy (Patient 14) of the diagnosis of PSP.

Alzheimer’s disease.

The presence of another potential cause of dementia in a patient who otherwise meets all NINCDS-ADRDA clinical criteria for probable AD produced the greatest diagnostic disagreement. In particular, the presence of CVD produced mixed diagnostic results. In some cases, clinicians felt that AD and CVD contributed independently to the dementia syndrome and classified patients as having possible AD with CVD; in other cases the cerebrovascular factor was minimized, and the patients were classified as having probable AD (Patients 5, 8, 9, and 20). Similarly, they classified a patient with laboratory findings indicating thyroid disease as having probable AD (Patient 7). This use of multiple diagnoses represents a lack of strict adherence to the NINCDS-ADRDA clinical criteria and has been reported in other reliability studies.20 Furthermore, because we did not include mildly demented AD patients, or nondemented individuals with mild cognitive impairment, the NINCDS-ADRDA criteria were not tested in cases where there is a possibility of AD.

There was a high sensitivity for AD (95%) but with a relatively low specificity (79%) and PPV (61%), reflecting a tendency to overdiagnose. Indeed, the specificity (82%) and PPV (61%) remained low, even when we used more stringent criteria for probable AD. The clinicians classified as having AD patients with other cortical (e.g., FTD) (Patients 30, 31, and 34) and subcortical dementias who manifested a cortical neuropsychological dysfunction (Patient 38). Patients with dementia syndromes may appear more similar as they progress, which makes it difficult to differentiate them with only the MMSE or MDRS. To the extent that it is possible to differentiate between dementia syndromes with predominant cortical versus subcortical pathology,42 additional, more sensitive neuropsychological measures might have improved specificity.

Progressive supranuclear palsy.

There was a high level of inter-rater agreement for the NINDS-SPSP criteria for PSP, similar to other tested criteria.29 The most frequent source of disagreement was between probable and possible PSP. In contrast to the way that these modifiers were used in AD diagnosis, probable and possible PSP indicated the degree of certainty of the diagnosis. However, clinicians inappropriately used the term “possible PSP” to indicate that a second disease process was contributing to the patient’s cognitive and neurologic symptomatology, such as CVD (Patient 11) or vitamin B12 deficiency (Patient 13), just as they would for AD. The NINDS-SPSP criteria do not mention how these criteria should be applied in cases with concomitant systemic or CNS conditions that can affect the clinical presentation of PSP, but do specify that the presence of CVD is an exclusionary criterion. The clinicians found a way to acknowledge that the presence of CVD and vitamin B12 deficiency may have affected the cognitive presentation by using the term “possible PSP,” following the current interpretation of the NINCDS-ADRDA criteria for possible AD (when AD coexists with other disease processes). However, in the future it may be better to indicate the association of PSP with other conditions that may affect its presentation and course, as it is commonly seen in clinical practice, by using the term “associated with.”

Despite this, the NINDS-SPSP criteria have an optimal specificity (98.5%) and PPV (96%), even for the category probable PSP alone (specificity and PPV for probable PSP were 100%), with a relatively good sensitivity (50 to 75%). Underdiagnosis is the main concern when using these criteria, and this may be inevitable in some cases. For example, the presence of a dementia syndrome, mild parkinsonism, and normal extraocular movements led clinicians to diagnose these patients as having possible PSP or PD with dementia (Patient 14). Furthermore, the NINDS-SPSP criteria were more accurate than previous ones. Litvan et al.29 examined the accuracy of four clinical criteria for PSP,9-11 and their sensitivity ranged from 13 to 55%.

Dementia with Lewy bodies.

The reliability for the diagnosis of DLB was poor, consistent with Litvan et al.,39 who found only a fair (κ = 0.38) level of reliability for DLB. By contrast, McKeith et al.43 reported a moderate to near-perfect agreement (κ = 0.50 to 0.87) for DLB. It has been noted that sample composition could have accounted, in part, for the differences between these studies, in that McKeith et al. examined patients with AD, DLB, and vascular dementia, whereas Litvan et al. examined patients with multiple cortical and subcortical pathologies (e.g., Pick’s disease, DLB, PSP, MSA, CBD, postencephalic parkinsonism, Creutzfeldt-Jakob disease, Whipple’s disease), but included several AD cases, all with extrapyramidal signs. Furthermore, although Litvan et al. did not use standardized clinical criteria for DLB, our clinicians used the Consensus Guidelines for the Clinical Diagnosis of DLB. However, we did not include patients with “pure” DLB, which may have allowed us only to test reliability of the most difficult cases where DLB is associated with AD pathology.

The low mean sensitivity (34%) and PPV (55%) for the diagnosis of DLB with a high mean specificity (94%) indicated that our clinicians were better at identifying non-DLB cases than DLB cases. The sensitivity for DLB was low compared with previous studies. Indeed, Mega et al.44 found a sensitivity of 79% and a specificity of 100% for DLB, and McKeith et al.43 found a sensitivity of 90% and a specificity of 97%.

The diagnostic boundary between AD and DLB is difficult to identify. In some cases, clinicians used the term “probable AD” and minimized the presence of DLB symptomatology, whereas in other cases, they used the term “possible DLB” to indicate that both AD and DLB were present (Patients 20, 21, 23, and 24). Interestingly, none of the raters used the term “probable DLB.” This could be attributed to the tendency of the clinicians to overdiagnose AD or to the difficulty determining when the core signs and symptoms of DLB are different from those observed in AD.

Although DLB is described as including alterations in the sensorium, this can range from normal function to frank fluctuations in alertness and to delirium. Differentiating episodes of mild fluctuations of consciousness from diurnal hypersomnia (frequently seen in cortical and subcortical dementias) is difficult. However, when overt alteration of alertness occurred with episodes of delirium, all clinicians to agreed with the presence of DLB (Patient 22). Although hallucinations are more frequent in DLB than in AD,43,44 and are a reliable predictor for DLB,39 they can occur in other cortical and subcortical dementias.45 Indeed, the PSP and FTD patients used here did not experience hallucinations, and no statistical differences were observed between the proportion of patients with DLB with hallucinations (37.5%), AD (20%), and other disease processes (20%) (p = 0.18).

Extrapyramidal signs may be helpful in differentiating DLB from AD or FTD in early stages, but this is more difficult in advanced cases (Patients 21 and 26). In addition, they cannot discriminate DLB from other dementias associated with parkinsonism. Our findings suggested that DLB is still frequently misdiagnosed and that the Consensus Guidelines for the Clinical Diagnosis of DLB are suboptimal.39,46 Alternatively, one could argue that the difficulty diagnosing DLB is not because of weaknesses in the criteria, but because LB are part of the neuropathologic spectrum of AD and sometimes can exist without clinical manifestations.

Frontotemporal lobe dementia.

The inter-rater agreement for FTD was substantial. The most frequent source of disagreement was between FTD and patients with a frontal lobe syndrome in the context of AD. In addition, the presence of frontal lobe symptoms associated with parkinsonism was another source of disagreement among raters. The Lund and Manchester criteria for FTD do not provide a degree of certainty (e.g., probable, possible), but they provide core diagnostic features that are commonly observed in FTD.25 Because it is difficult to differentiate clinically frontal-temporal lobe degeneration from Pick’s disease,47 these criteria do not attempt to classify these entities independently. Nevertheless, their neuropathologic classification includes frontal-temporal lobe degeneration, Pick’s disease, and frontal lobe degeneration associated with motor neuron disease. In our study, none of the clinicians attempted to classify patients as having Pick’s disease. These results are different from those of Litvan et al.,40 who found a moderate (κ = 0.54) level of agreement in identifying a frontal lobe type dementia in patients with pathologically diagnosed Pick’s disease. However, they did not provide their raters with a set of diagnostic criteria.

The high sensitivity and specificity for the diagnosis of FTD found in this study indicated that the use of the Lund and Manchester criteria can improve diagnostic accuracy. By contrast, Mendez et al.48 found that only 25% of patients with Pick’s disease were correctly diagnosed antemortem, and Litvan et al.40 found a mean sensitivity of 43% for Pick’s disease. However, despite the high degree of accuracy observed in this study, in some cases clinicians diagnosed FTD as AD, and in one case as Creutzfeldt-Jakob disease or normal pressure hydrocephalus (Patient 33). This latter patient had a rapidly progressive motor syndrome (e.g., frequent falls, severe gait problems, dysarthria, urinary incontinence) and a gradual deterioration of his cognitive abilities, with apathy, depressed mood, and social withdrawal.

The presence of early behavioral abnormalities is the hallmark of FTD,38,49 which usually helps clinicians to differentiate FTD from other cortical dementias. However, the behavioral abnormalities of FTD can be heterogeneous and sometimes difficult to differentiate from AD. In this study, clinicians were able to classify as having FTD not only those patients who initially presented with significant disruptive social behavior (e.g., disinhibition, social inappropriateness, stereotype/perseverative behavior) but also those who presented marked apathy, mood lability, or depression.38,49 The availability of neuropsychological measures that indicated a frontal-temporal lobe compromise (e.g., verbal fluency and attention/abstract thinking deficits with a relative preservation of visuospatial and visuoconstructional abilities) in conjunction with the psychiatric information was an important factor that influenced the high accuracy.

We found that the use of multiple diagnostic criteria can increase the level of inter-rater agreement as well as diagnostic accuracy. Nevertheless, these criteria have their limitations, and they sometimes failed to capture cases in a “gray zone.” Although diagnostic criteria for AD have been available for research and clinical practice for the past 15 years,19 clinicians still tend to overdiagnose this disease. By contrast, DLB was underdiagnosed. Consequently, it is necessary to better operationalize both diagnostic criteria. The Lund and Manchester criteria for FTD and the NINDS-SPSP criteria for PSP helped to diagnose these relatively rare disorders.

Acknowledgments

Supported by grants AG 03705 and AG 05133 from the National Institute on Aging. J.T.B. is recipient of a Research Scientist Development Award (Level II) (K02-MH01077).

  • Received December 24, 1998.
  • Accepted April 29, 1999.

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