Suzanne S. Mirra

The Consortium to Establish a Registry for Alzheimer's Disease (CERAD). Part II. Standardization of the neuropathologic assessment of Alzheimer's disease

The Neuropathology Task Force of the Consortium to Establish a Registry for Alzheimers Disease (CERAD) has developed a practical and standardized neuropathology protocol for the postmortem assessment of dementia and control subjects. The protocol provides neuropathologic definitions of such terms as “definite Alzheimers disease” (AD), “probable AD,” “possible AD,” and “normal brain” to indicate levels of diagnostic certainty, reduce subjective interpretation, and assure common language. To pretest the protocol, neuropathologists from 15 participating centers entered information on autopsy brains from 142 demented patients clinically diagnosed as probable AD and on eight nondemented patients. Eighty-four percent of the dementia cases fulfilled CERAD neuropathologic criteria for definite AD. As increasingly large numbers of prospectively studied dementia and control subjects are autopsied, the CERAD neuropathology protocol will help to refine diagnostic criteria, assess overlapping pathology, and lead to a better understanding of early subclinical changes of AD and normal aging.

Consensus guidelines for the clinical and pathologic diagnosis of dementia with Lewy bodies (DLB) Report of the consortium on DLB international workshop

Recent neuropathologic autopsy studies found that 15 to 25% of elderly demented patients have Lewy bodies (LB) in their brainstem and cortex, and in hospital series this may constitute the most common pathologic subgroup after pure Alzheimers disease (AD).The Consortium on Dementia with Lewy bodies met to establish consensus guidelines for the clinical diagnosis of dementia with Lewy bodies (DLB) and to establish a common framework for the assessment and characterization of pathologic lesions at autopsy. The importance of accurate antemortem diagnosis of DLB includes a characteristic and often rapidly progressive clinical syndrome, a need for particular caution with neuroleptic medication, and the possibility that DLB patients may be particularly responsive to cholinesterase inhibitors. We identified progressive disabling mental impairment progressing to dementia as the central feature of DLB. Attentional impairments and disproportionate problem solving and visuospatial difficulties are often early and prominent. Fluctuation in cognitive function, persistent well-formed visual hallucinations, and spontaneous motor features of parkinsonism are core features with diagnostic significance in discriminating DLB from AD and other dementias. Appropriate clinical methods for eliciting these key symptoms are described. Brainstem or cortical LB are the only features considered essential for a pathologic diagnosis of DLB, although Lewy-related neurites, Alzheimer pathology, and spongiform change may also be seen. We identified optimal staining methods for each of these and devised a protocol for the evaluation of cortical LB frequency based on a brain sampling procedure consistent with CERAD. This allows cases to be classified into brainstem predominant, limbic (transitional), and neocortical subtypes, using a simple scoring system based on the relative distribution of semiquantitative LB counts. Alzheimer pathology is also frequently present in DLB, usually as diffuse or neuritic plaques, neocortical neurofibrillary tangles being much less common. The precise nosological relationship between DLB and AD remains uncertain, as does that between DLB and patients with Parkinsons disease who subsequently develop neuropsychiatric features. Finally, we recommend procedures for the selective sampling and storage of frozen tissue for a variety of neurochemical assays, which together with developments in molecular genetics, should assist future refinements of diagnosis and classification. NEUROLOGY 1996;47: 1113-1124

National Institute on Aging–Alzheimer's Association guidelines for the neuropathologic assessment of Alzheimer's disease

A consensus panel from the United States and Europe was convened recently to update and revise the 1997 consensus guidelines for the neuropathologic evaluation of Alzheimers disease (AD) and other diseases of brain that are common in the elderly. The new guidelines recognize the pre‐clinical stage of AD, enhance the assessment of AD to include amyloid accumulation as well as neurofibrillary change and neuritic plaques, establish protocols for the neuropathologic assessment of Lewy body disease, vascular brain injury, hippocampal sclerosis, and TDP‐43 inclusions, and recommend standard approaches for the workup of cases and their clinico‐pathologic correlation.

National Institute on Aging-Alzheimer’s Association guidelines for the neuropathologic assessment of Alzheimer’s disease: a practical approach

We present a practical guide for the implementation of recently revised National Institute on Aging–Alzheimer’s Association guidelines for the neuropathologic assessment of Alzheimer’s disease (AD). Major revisions from previous consensus criteria are: (1) recognition that AD neuropathologic changes may occur in the apparent absence of cognitive impairment, (2) an “ABC” score for AD neuropathologic change that incorporates histopathologic assessments of amyloid β deposits (A), staging of neurofibrillary tangles (B), and scoring of neuritic plaques (C), and (3) more detailed approaches for assessing commonly co-morbid conditions such as Lewy body disease, vascular brain injury, hippocampal sclerosis, and TAR DNA binding protein (TDP)-43 immunoreactive inclusions. Recommendations also are made for the minimum sampling of brain, preferred staining methods with acceptable alternatives, reporting of results, and clinico-pathologic correlations.

Utility of the Apolipoprotein E Genotype in the Diagnosis of Alzheimer's Disease

BACKGROUND The epsilon4 allele of the gene encoding apolipoprotein E (APOE) is strongly associated with Alzheimers disease, but its value in the diagnosis remains uncertain. METHODS We reviewed clinical diagnoses and diagnoses obtained at autopsy in 2188 patients referred to 1 of 26 Alzheimers disease centers for evaluation of dementia. The sensitivity and specificity of the clinical diagnosis or the presence of an APOE epsilon4 allele were calculated, with pathologically confirmed Alzheimers disease used as the standard. The added value of the APOE genotype was estimated with pretest and post-test probabilities from multivariate analyses to generate receiver-operating-characteristic curves plotting sensitivity against the false positive rate. RESULTS Of the 2188 patients, 1833 were given a clinical diagnosis of Alzheimers disease, and the diagnosis was confirmed pathologically in 1770 patients at autopsy. Sixty-two percent of patients with clinically diagnosed Alzheimers disease, as compared with 65 percent of those with pathologically confirmed Alzheimers disease, had at least one APOE epsilon4 allele. The sensitivity of the clinical diagnosis was 93 percent, and the specificity was 55 percent, whereas the sensitivity and specificity of the APOE epsilon4 allele were 65 and 68 percent, respectively. The addition of information about the APOE genotype increased the overall specificity to 84 percent in patients who met the clinical criteria for Alzheimers disease, although the sensitivity decreased. The improvement in specificity remained statistically significant in the multivariate analysis after adjustment for differences in age, clinical diagnosis, sex, and center. CONCLUSIONS APOE genotyping does not provide sufficient sensitivity or specificity to be used alone as a diagnostic test for Alzheimers disease, but when used in combination with clinical criteria, it improves the specificity of the diagnosis.

Cerebral amyloid angiopathy in the brains of patients with Alzheimer's disease: The CERAD experience, part XV

We studied the frequency, severity, and clinical correlations of cerebral amyloid angiopathy (CAA) in 117 CERAD subjects with autopsy-confirmed AD. Eighty-three percent showed at least a mild degree of amyloid angiopathy. Thirty of 117 brains (25.6%) showed moderate to severe CAA affecting the cerebral vessels in one or more cortical regions. These brains also showed a significantly higher frequency of hemorrhages or ischemic lesions than those of subjects with little or no amyloid angiopathy (43.3% versus 23.0%; odds ratio = 2.6, 95% CI = 1.1 to 6.2). High CAA scores also correlated with the presence of cerebral arteriosclerosis and with older age at onset of dementia. Our findings suggest that factors contributing to non-AD-related vascular pathology (e.g., atherosclerosis) may play a role in amyloid deposition in cerebral vessels in AD. NEUROLOGY 1996;46: 1592-1596

The Consortium to Establish a Registry for Alzheimer's Disease (CERAD). Part X. Neuropathology Confirmation of the Clinical Diagnosis of Alzheimer's Disease

Article abstract-This report summarizes the neuropathologic findings in the first 106 autopsies of CERAD (Consortium to Establish a Registry for Alzheimers Disease) dementia patients diagnosed clinically as having Alzheimers disease (AD). In 92 (87%) of the 106 cases, neuropathologists confirmed Alzheimers disease (AD) as the primary dementing illness. Coexistent Parkinsons disease (PD) changes were present in 19 (21%) and vascular lesions of varying nature and size in 26 (28%) of these 92 AD cases. The 14 cases in which AD was not interpreted as the primary dementing illness can be divided into four major subgroups based on their neuropathology findings: PD and related pathology (n = 5), hippocampal sclerosis (n = 3), miscellaneous neurodegenerative and other disorders (n = 3), and no significant changes (n = 3). Despite the relatively high level of clinical diagnostic accuracy, further refinement of assessment batteries may facilitate distinction of non-AD dementias from AD. NEUROLOGY 1995;45: 461-466

Neuropathologic and clinical features of Parkinson's disease in Alzheimer's disease patients

While dementia in Parkinsons disease (PD) is well described, PD features in Alzheimers disease (AD) are being increasingly recognized. In 20 neuropathologically confirmed AD brains, 11 cases (55%) showed PD changes (Lewy body formation, neuronal loss, and gliosis of pigmented nuclei), with no significant difference in age or symptom duration between those cases with and without PD pathology. A history of rigidity in the absence of neuroleptic medication was noted in 80% of those with PD pathology but only 14% of those without PD pathology. Tremor was not observed in either group. This suggests that extrapyramidal signs, especially rigidity, noted in many AD patients are related to coexistent PD pathology.

Cerebral infarcts in patients with autopsy-proven Alzheimer's disease CERAD, part XVIII

Objective: To study the relation between cerebral infarction and clinical and neuropsychologic manifestations in patients with autopsy-proven Alzheimers disease (AD) enrolled in the Consortium to Establish a Registry for Alzheimers Disease (CERAD). Background: Prior studies report that subjects with neuropathologic evidence of AD and concomitant brain infarcts had poorer cognitive function and higher frequency of dementia than those with AD alone. Methods: Clinical and neuropsychologic manifestations of dementia were studied in 74 subjects with neuropathologic findings of AD alone and 32 with AD and concomitant cerebral infarcts or lacunar lesions. Results: The 32 patients with both AD and vascular lesions were significantly older at time of death (median age, 81 years) than the 74 patients with AD alone(76 years; p = 0.02). At the final follow-up visit, the severity of the dementia was greater in AD patients with vascular lesions(median Clinical Dementia Rating [CDR] = 3) than in those with AD alone (CDR= 2; p = 0.03). Patients with AD and vascular lesions performed significantly worse on verbal fluency, Boston Naming, and Mini-Mental State Examination (MMSE) tests. No differences between the groups were observed, however, in the semiquantitative measures of frequency of neuritic plaques or neurofibrillary tangles. Conclusions: The clinical-neuropathologic correlations in CERAD patients generally confirm those in prior studies, indicating that the presence of cerebral infarction in patients with AD is associated with greater overall severity of clinical dementia and poorer performance on specific tests of language and cognitive function.

Corticobasal degeneration Neuropathologic and clinical heterogeneity

We investigated clinical and neuropathologic heterogeneity and apolipoprotein E (apoE) genotype in 11 cases of neuropathologically diagnosed corticobasal degeneration (CBD). Although seven of the 11 patients presented with unilateral limb dysfunction, the remaining four patients had less typical presentations including memory loss, behavioral changes, and difficulties with speech or gait. All 11 patients eventually developed extrapyramidal signs as well as cortical features, most commonly apraxia. At autopsy, the brains of seven of the 11 patients exhibited predominant neuronal loss and gliosis of perirolandic cortex; degeneration of more rostral frontal cortex was observed in three of the four patients with atypical clinical presentations. All cases displayed ballooned neurons, tau-positive neuronal and glial inclusions, threads and grains, and nigral degeneration. Six of the 11 cases manifested overlapping neuropathologic features of one or more disorders, including Alzheimers disease (AD), progressive supranuclear palsy (PSP), Parkinsons disease (PD), and hippocampal sclerosis. Interestingly, these six patients all exhibited memory loss early in the course of their illness. The 11 CBD cases exhibited increased frequency (0.32) of the ϵ4 allele of apoE, relative to control populations; the frequency remained elevated (0.25) even when the three cases with concomitant AD were excluded. Beta-amyloid (Ap) deposition in hippocampus or cortex was present in five of the seven cases with an ϵ4 genotype. These observations indicate that CBD is a pathologically and clinically heterogeneous disorder with substantial overlap with other neurodegenerative disorders.