S. M. Sumi

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.

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

Familial presenile dementia with psychosis associated with cortical neurofibrillary tangles and degeneration of the amygdala

We report a family in which 13 members in three generations had the presenile (age 42 to 66 years) onset of dementia with an autosomal dominant pattern of inheritance. An early symptom in eight individuals was prominent antisocial psychotic or belligerent behavior, often leading to the initial clinical diagnosis of paranoid schizophrenia. Duration of illness was longer than is usual in Alzheimers disease (AD), ranging from 14 to 26 years in six members. Three affected siblings and a cousin have come to autopsy, and all had neurofibrillary tangles without senile plaques in several regions of the neocortex, amygdala, and parahippocampal gyrus. The hippocampus was free of both neurofibrillary tangles and senile plaques in all four, but in three there was neuronal loss with gliosis in the CA1 region of Ammons horn bilaterally. There also was neuronal loss and neurofibrillary tangles in the nucleus basalis. The neurofibrillary tangles were tau-2 and Alz-50 positive and were composed of paired helical filaments ultrastructurally. The disease in this kindred appears to be a unique hereditary disorder that is distinct from familial AD.

Chromosome 17 and hereditary dementia : Linkage studies in three non-Alzheimer families and kindreds with late-onset FAD

Several previous families with differing clinical and pathologic characteristics have demonstrated linkage to the 17q21–22 region. We have performed a linkage analysis with chromosome 17 markers on three families showing autosomal dominant inheritance of non-Alzheimer dementia and 60 kindreds with late-onset familial Alzheimers disease (FAD). Family A shows unequivocal evidence of linkage with a maximum lod score of 5.0 for marker D17S934 (𝛉 = 0.001). This family has an unusual syndrome of a schizophrenia-like psychosis beginning in the fifth or sixth decade followed by severe dementia with an average disease duration of 13.8 years. Neuropathology from five autopsies in this family has shown marked neurofibrillary tangle formation (NFT), degeneration of the amygdala, and no amyloid plaques. This confirms the presence of a gene associated with dementia on 17q and extends the related phenotype to include schizophrenia-like symptoms and classic NFT pathology. A second family with early aphasia progressing to dementia and cortical-basal ganglion-like degeneration also has suggestive evidence for linkage to 17q. A third family with very early-onset dementia (mean, 31 years) and nonspecific pathology can be excluded from the 17q region and emphasizes additional genetic heterogeneity in non-Alzheimer hereditary dementia. Finally, we also present evidence against linkage to D17S579 in the set of 60 families with late-onset FAD, providing further evidence that the chromosome 17 gene is unlikely to be involved in the pathogenesis of typical AD.

Myoclonus, Seizures, and Paratonia in Alzheimer Disease

Twenty-eight patients with the clinical diagnosis of probable Alzheimer disease (AD) were followed longitudinally until death. The presence of myoclonus, seizures, and paratonia was monitored as part of this process. At autopsy, 22 of the patients met pathologic criteria for AD and 6 had other degenerative neurologic diseases. Myoclonus was present in 55% of the AD patients and none of the non-AD patients. Seizures were present in 64% of the AD patients, and only 17% of the non-AD patients. Paratonia was found frequently in all patient groups. In most patients, symptoms developed late in the course of their illness. The incidence of myoclonus, seizures, and paratonia in our patients was higher than in most previous studies. The reasons for this finding are discussed.

Cerebrospinal fluid creatine kinase activity and neurologic recovery after cardiac arrest

We evaluated prospectively the relation between cerebrospinal fluid creatine kinase activity (CSF CK) and neurologic recovery after out-of-hospital cardiac arrest. Without knowledge of the enzyme results, we determined whether patients awoke, followed commands, or had comprehensible speech. CSF CK was significantly higher in never-awakening than in awakening patients. After cardiac arrest, elevation of CSF CK predicts poor neurologic recovery.

The Mean Aβ Load in the Hippocampus Correlates with Duration and Severity of Dementia in Subgroups of Alzheimer Disease

Using image analysis techniques to quantify the percentage area covered by the immunopositive marker for amyloid β-peptide (Aβ), we examined subjects with combinations of either early-onset or late-onset Alzheimer disease (AD) and either familial Alzheimer disease (FAD) or sporadic Alzheimer disease (SAD). We measured the mean and maximum Aβ loads, in the hippocampus of each subject. There were no statistically significant differences in the mean Aβ load between familial and sporadic AD subjects. Although sample sizes were too small for statistical testing, subjects with the ϵ4/ϵ4 allele of the apolipoprotein E (ApoE) gene had higher mean Aβ loads than those with the ϵ3/ϵ3 or ϵ3/ϵ4 alleles. Members of the Volga Gennan families (recently linked to chromosome 1) all had high mean Aβ loads, and one of the chromosome 14-linked subjects had the highest mean Aβ load while the other had a relatively small load, but the sample was too small for statistical comparisons. The duration of dementia and neuropsychological test scores showed a statistically significant correlation with the mean Aβ load in the hippocampus, but not with the maximum Aβ load. This difference indicates that the mean Aβ load may be a more useful feature than the maximum Aβ load as an objective neuropathological measure for cognitive status. This finding may help to improve the established methods for quantitative assessment of the neuropathological changes in AD.

A case of persistent cortical deafness Clinical, neuro‐physiologic, and neuropathologic observations

A 61-year-old man became deaf after the second of two cerebral infarctions which successively involved the temporal and adjacent cortices. He remained completely deaf until death 27 months later. Click stimulation demonstrated normal short-latency potentials, middle-latency responses better developed to stimulation of the right than of the left ear, and absent long-latency potentials. Neuropathologic examination showed cystic infarctions involving both transverse temporal gyri and adjacent cortical areas with preservation of the brainstem auditory nuclei. Persistent deafness can result from bilateral lesions involving the auditory and adjoining cortices.

Mathematical Morphology Techniques For Image Processing Applications In Biomedical Imaging

Mathematical morphology operations allow object identification based on shape and are useful for grouping a cluster of small objects into one object. Because of these capabilities, we have implemented and evaluated this technique for our study of Alzheimers disease. The microscopic hallmark of Alzheimers disease is the presence of brain lesions known as neurofibrillary tangles and senile plaques. These lesions have distinct shapes compared to normal brain tissue. Neurofibrillary tangles appear as flame-shaped structures, whereas senile plaques appear as circular clusters of small objects. In order to quantitatively analyze the distribution of these lesions, we have developed and applied the tools of mathematical morphology on the Pixar Image Computer. As a preliminary test of the accuracy of the automatic detection algorithm, a study comparing computer and human detection of senile plaques was performed by evaluating 50 images from 5 different patients. The results of this comparison demonstrates that the computer counts correlate very well with the human counts (correlation coefficient = .81). Now that the basic algorithm has been shown to work, optimization of the software will be performed to improve its speed. Also future improvements such as local adaptive thresholding will be made to the image analysis routine to further improve the systems accuracy.

A proposed classification of familial Alzheimer’s disease based on analysis of 32 multigeneration pedigrees

We propose a classification of familial Alzheimer’s disease (FAD) based on our clinical and pathological analysis of 32 kindreds with multigeneration dementia. The classification can briefly be stated as follows I. Early onset FAD with mean age of onset before 50 years; II. Late onset FAD with mean age of onset after 60 years; III. Intermediate/variable onset FAD; IV. Familial dementia with atypical Alzheimer changes; V. FAD without multigeneration involvement.