Association between male gender and cortical Lewy body pathology in large autopsy series

Abstract

Sex-linked factors may alter risk for neurodegenerative diseases. Definitive diagnoses are not established until autopsy, so neuropathological studies are critical. There have not been reported gender-related differences in neocortical Lewy bodies (LBs) using large multi-center autopsy series. We evaluated the associations between gender and pathologically characterized neurodegenerative diseases. Cases with Alzheimer's disease (AD), neocortical LBs, AD + neocortical LBs, or neither pathology were evaluated as separate groups. Results were corrected for possible confounders including age at death, smoking history, and education. The settings were the University of Kentucky Alzheimer's Disease Center and the National Alzheimer's Coordinating Center (NACC) Registry autopsy series; 3,830 subjects met inclusion criteria. Patients with neocortical ("diffuse") or intermediate ("limbic") LB pathologies tended to be male (male:female odds ratios ~2.9 with 95% CI 2.02-4.18). The preponderance of males dying with neocortical LB pathology was seen consistently across age groups and was not due to the potential confounders evaluated. By contrast, individuals dying with AD pathology were more likely to be female if dying over 80 (male:female odds ratio 0.66, 95% CI 0.50-0.88), but that tendency was not seen in individuals dying with AD pathology prior to age 80. Increased understanding of the male predominance in neocortical LB pathology may help guide clinicians, because males are more likely to be "undercalled" for neocortical LBs clinically, and females are more likely to be "overcalled" (P < 0.05 for both). Males are far more likely than females to die with neocortical LB pathology. This phenomenon may help guide medical practice including clinical trial study design.

Fig. 1

NACC Registry data was analyzed to test the effects of age and neocortical Lewy body (LB) pathology subtype. a Percent male by age at death cohort: AD, DLB, AD + DLB or neither pathology. The association between gender and pathologically-verified neurodegenerative disease diagnoses across different cohorts stratified by age at death. In each cohort, males are far more likely to die with neocortical LBs. By contrast, Alzheimer's disease is not skewed to women when death occurs before age 80. Shown are NACC Registry data with autopsy-verified neurodegenerative disease diagnoses (N = 2,718 in these age ranges). b Male:female risk ratio by subgroup of cases with Lewy body (LB) pathology. The more the pathology is concentrated in the neocortex instead of the brainstem, the higher is the odds ratio that the patient is male, indicating neuropathological subtype of LB disease is important in male preponderence

Fig. 2

Clinical misdiagnoses in DLB: males versus females. Gender differences in neocortical Lewy body (LB) pathology is directly relevant to clinical diagnoses in neurodegenerative diseases and appears to be under-appreciated by clinicians. The presence of LB pathology in males is relatively likely to be missed by clinicians, whereas in females the diagnosis tends to be “overcalled”, according to NACC Registry data tabulated since 2000 (total N = 2,862). These data involve only cases where the clinical (N = 99) and/or pathological (N = 162) diagnoses of pure dementia with Lewy bodies (DLB) were documented. For individuals where cortical LB pathology was observed upon autopsy (left bars), a false-negative “undercall” was indicated if the diagnosis of DLB was not made during life. In the case of patients where DLB was suspected clinically (right bars), a false-positive “overcall” meant that cortical LB pathology was not judged to neuropathologically contribute to the dementia. Results were compared using the Chi-square statistic. These data indicate that an appreciation of the relative tendency for males to have cortical LB pathology may help prevent clinical diagnostic misdiagnoses