Relation of Quantitative Indexes of Concurrent ␣-Synuclein Abnormalities to Clinical Outcome in Autopsy-Proven Alzheimer Disease

Holtzer, Roee; Irizarry, Michael C; Sanders, Jody; Hyman, Bradley T; Wegesin, Domonick J; Riba, Aliza; Brandt, Jason; Albert, Marilyn; Stern, Yaakov

Background: Lewy bodies (LBs) and Lewy neurites are frequent concomitant neuropathologic observations in clinical and neuropathologically defined Alzheimer disease (AD), but their relation to clinical features in AD is uncertain. Most studies used semiquantitative measures to determine the presence or absence of LB abnormalities.

Objective: To determine the clinical consequences of LB abnormalities in the setting of AD.

Design: Prospective study.

Setting: Three outpatient research and treatment centers.

Participants: Fourteen autopsy cases with a pathologic diagnosis of AD abnormalities and concomitant LBs followed semiannually for up to 8 years (mean age at intake, 72 years; mean age at death, 77 years; mean education, 15 years; 12 women).

Main Outcome Measures: The modified Mini-Mental State Examination was used to assess cognitive function. The Unified Parkinson Disease Rating Scale was used to rate extrapyramidal motor signs. Hallucinations were evaluated using the Columbia University Scale for Psychopathology in Alzheimer's Disease. Time from the first evaluation in which diagnostic criteria for probable AD were met to death was used to determine illness duration. Quantitative measures of LB abnormalities were obtained for the frontal cortex, entorhinal cortex, substantia nigra, and hippocampus.

Results: Independent-samples t tests were used to assess whether the degree of LB abnormality varied as a function of the presence or absence of hallucinations and extrapyramidal signs. Pearson r correlations were run to examine whether there was a relation among LB abnormalities, cognitive function, and illness duration. There was no relation between quantitative neuropathologic indexes of LB abnormalities and clinical outcome.

Conclusion: The variability of clinical features in AD was not related to the presence or degree of LB abnormalities.

Current consensus guidelines1 for the clinical and pathologic diagnosis of dementia with Lewy bodies (DLB) represent an attempt to synthesize previous studies of dementia associated with LB abnormalities and to develop uniform diagnostic criteria. These guidelines may be relevant to the diagnosis of Alzheimer disease (AD) given that one third to one half of patients with AD have concomitant LB abnormalities when examined at autopsy.2 Previous studies3-17 produced mixed results when examining the relation of LB abnormalities to clinical features such as extrapyramidal signs (EPSs), psychiatric features, changes in cognitive status, and changes in the course or progression of dementia in patients with confirmed AD.

Stern et al2 reported that LB abnormalities were not related to distinct clinical features in 51 autopsy cases with confirmed AD from the Predictors Study cohort.18,19 However, the negative findings might have been due to limitations of the semiquantitative rating method used to determine the presence or absence of LB abnormalities.

The goal of the present study is to extend the previous observations by studying additional brain areas and types of pathologic lesions. The frontal and entorhinal cortices, the hippocampus, and the substantia nigra were examined for LBs and Lewy neurites. Moreover, we used immunostaining to identify these lesions, systematic random sampling to provide quantitative estimates of LB and Lewy neurite numbers, and image analysis approaches to assess amyloid burden, neurofibrillary tangle number, and neuropil thread number. This allowed us to examine the relation of the pathologic lesions to clinical symptoms and to one another.



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February 11, 2022