Ann Marie Kazee

Clinicopathologic correlates in Alzheimer disease: assessment of clinical and pathologic diagnostic criteria

The neuropathologic findings from a group of 123 patients who have come to autopsy from the Rochester Alzheimer Disease Project (RADP) are presented. Among these 123 cases, there were 94 demented subjects who met the National Institute of Neurological and Communicative Disorders and Stroke–Alzheimer Disease and Related Disorders Association (NINCDS–ADRDA) clinical criteria for the diagnosis of “probable Alzheimer disease,‘’ and 29 normal elderly controls. Autopsy confirmation of Alzheimer disease (AD) was based on the age-graded National Institutes of Health (NIH) consensus conference pathologic criteria. Using the NINCDS–ADRDA clinical criteria and the NIH pathologic criteria, the diagnostic accuracy was 88%, the sensitivity was 98%, and the specificity was 69%. Additional strict clinical and pathologic criteria developed by the RADP were applied in the final review of these cases to exclude all confounding causes of dementia, including cerebral infarcts. After applying these additional criteria, a subset of 62 cases of “pure‘’ AD and “pure‘’ control subjects was identified for a more detailed examination of neuritic plaques (NP) and neurons containing neurofibrillary tangles (NFT). The NP and NFT were counted in three subfields of hippocampus and two areas of association neocortex. The density of diffuse plaques (plaques lacking dystrophic neurites) was estimated on a semi-quantitative basis. Results show that the AD patients and control groups could be distinguished from each other easily on the basis of mean NP and NFT counts, but there was sufficient overlap in the counts to present difficulty in diagnosing any individual case. Abundant diffuse plaque involvement and NFT in the neocortex were, however, seen only in AD cases.

Synaptic loss in the central nucleus of the inferior colliculus correlates with sensorineural hearing loss in the C57BL/6 mouse model of presbycusis

Between 3 and 25 months of age, light and electron microscopic features of principal neurons in the central nucleus of the inferior colliculus of the C57BL/6 mouse were quantitated. This mouse strain has a genetic defect producing progressive sensorineural hearing loss which starts during young adulthood (2 months of age) with high-frequency sounds. During the second year of life, hearing is severely impaired, progressively involving all frequencies. The hearing loss was documented in the present study by auditory brainstem recordings of the mice at various ages. The cochleas from many of the same animals showed massive loss of both inner and outer hair cells beginning at the base (high-frequency region) and progressing with age along the entire length to the apex (low-frequency region). In the inferior colliculi, there was a significant decrease in the size of principal neurons in the central nucleus. There was a dramatic decrease in the number of synapses of all morphologic types on principal neuronal somas. The percentage of somatic membrane covered by synapses decreased by 67%. A ventral (high frequency) to dorsal (low frequency) gradient of synaptic loss could not be identified within the central nucleus. These synaptic changes may be related to the equally dramatic physiologic changes which have been noted in the central nucleus of the inferior colliculus, in which response properties of neurons normally sensitive to high-frequency sounds become more sensitive to low-frequency sounds. The synaptic loss noted in this study may be due to more than the loss of primary afferent pathways. It may represent alterations of the complex synaptic circuitry related to the central deficits of presbycusis.

Reduced GAP-43 message levels are associated with increased neurofibrillary tangle density in the frontal association cortex (area 9) in Alzheimer's disease.

We previously suggested the hypothesis that defective neuronal plasticity is a major neurobiological deficit causing the dementia of Alzheimers disease (AD). We used message levels of the growth-associated protein, GAP-43, as a marker of axonal plasticity to examine the hypothesis of defective neuronal plasticity in AD. When all AD cases are combined, the average level of GAP-43 message in area 9 of the AD frontal association cortex was not significantly different from the level in the comparably aged control cortex. Differentiation of AD cases on the basis of neurofibrillary tangle (NFT) density revealed that in AD cases with high tangle density average GAP-43 message level was reduced fivefold relative to levels in AD cases with low NFT density. AD cases with low neurofibrillary tangle density had levels of GAP-43 message that were not significantly different from the levels of normal controls. Differentiation of AD cases on the basis of neuritic plaque density did not indicate as strong a relationship to GAP-43 message level. The association between neurofibrillary tangle density and GAP-43 message level suggests the hypothesis that neurofibrillary tangles may reduce GAP-43 expression. Data of others show a relationship between high NFT density and reduced levels of synaptophysin-like immunoreactivity and reduced cerebral glucose metabolism. These data combine to suggest a set of AD cases with high NFT density, reduced axonal plasticity, reduced synaptic density, and reduced cerebral glucose metabolism--all variables that may be directly related to the functioning of the brain.(ABSTRACT TRUNCATED AT 250 WORDS)

Substantia nigra lesions in Alzheimer disease and normal aging

Clinical and pathological overlap between Alzheimer disease (AD) and Parkinsons disease (PD) has been well described; however, the mechanisms of overlap between these two disorders remain unknown. We retrospectively examined clinical and neuropathological features from 66 individuals participating in the Rochester Alzheimer Disease Center to determine the association of AD with substantia nigra (SN) pathology. SN pathology, identified by a loss of pigmented neurons and the presence of gliosis, pigment-laden macrophages, and Lewy bodies, was blindly scored in 48 AD cases and 18 normal elderly controls. We found moderate or severe pathology in the SN in 2 control brains (11%) and 29 AD brains (60%). The numbers of neocortical and hippocampal neurofibrillary tangles (NFTs) and senile plaques (SPs) were not associated with nigral pathology. There was also no significant association of SN pathology with NFTs or SPs in the striatum, the site to which these neurons project. There was no significant association of increasing SN pathology with aging among AD patients, nor with increasing severity and duration of AD. The signs and symptoms of an extrapyramidal movement disorder were, however, associated with increasing SN pathology. We confirm that pathological lesions in the SN are a common feature of AD and an uncommon feature in normal aging. AD is a significant risk factor for SN lesions and PD, but the pathologic severity of AD, as measured by NFTs and SPs, was not associated with SN lesions.

Tardive Dyskinesia in Alzheimer's Disease: Clinical Features and Neuropathologic Correlates:

Medical record review was conducted on 14 patients with neuropathologically confirmed Alzheimers disease, all of whom had been treated with antipsychotic medications, to determine the relationship between neuropathology and the development of tardive dyskinesia. Four cases were found to have chart descriptions of hyperkinetic movement disorders consistent with tardive dyskinesia. When the group with tardive dyskinesia was compared to the group without tardive dyskinesia, there were no statistically significant differences regarding gender, age of onset of dementia, duration of de mentia, age at death, or duration of antipsychotic treatment. Neuropathologic comparisons revealed greater degenerative changes in the substantia nigra in those patients with tardive dyskinesia. These preliminary observations suggest that patients with Alzheimers disease and significant coexisting substantia nigra pathologic changes may be at higher risk for developing tardive dyskinesia when treated with antipsychotic medication (J Geriatr Psychiatry Neurol 1991;4:79-85).

Hair Cell Loss and Synaptic Loss in Inferior Colliculus of C57BL/6 MICE

The C57BL/6 mouse is an extremely popular animal model of presbycusis because of its relatively short life span and genetic pattern of high-frequency sensorineural hearing loss (SNHL) (Henry and Chole, 1980; Willott, 1984; Erway et al., 1993) that resembles the age-related hearing loss seen in humans (Nadol, 1993). Presbycusis and SNHL have traditionally been thought of as peripheral disorders that mainly result in the loss of sensitivity and frequency selectivity (Schmiedt and Schulte, 1992). However, recent studies suggest that peripheral pathologies can lead to functional and anatomical changes in the central nervous system (Hall, 1974, 1976; Wightman, 1982; Morest and Bohne, 1983; Willott, 1984; Salvi and Arehole, 1985; Arehole et al., 1987a; Robertson and Irvine, 1989; Salvi et al., 1990) that may contribute to some of the hearing deficits associated with SNHL and presbycusis.