Neuropathological Correlates of Dementia in Over-80-Year-Old Brain Donors from the Population-Based Cambridge City over-75s Cohort (CC75C) Study

Abstract

Key neuropathological changes associated with late-onset dementia are not fully understood. Population-based longitudinal studies offer an opportunity to step back and examine which pathological indices best link to clinical state. CC75C is a longitudinal study of the population aged 75 and over at baseline in Cambridge, UK. We report on the first 213 participants coming to autopsy with sufficient information for an end of life dementia diagnosis. Clinical diagnosis was ascertained by examining retrospective informant interviews, survey responses, and death certificates according to DSM-IV criteria. The neuropathological protocol was based on the Consortium to Establish a Registry of Alzheimer's Disease (CERAD). Clinical dementia was present in 113 participants (53%): 67% with Alzheimer's disease, 4% vascular dementia, 22% mixed dementia, and 1% dementia with Lewy bodies. As Alzheimer-type pathology was common, the mutually blinded clinical and neuropathological diagnoses were not strongly related. Multivariable analysis identified associations between dementia during life and entorhinal cortex neuritic plaques, hippocampal diffuse plaques, neocortical neurofibrillary tangles, white matter pallor, Lewy bodies, and hippocampal atrophy. These results were consistent in those with clinical Alzheimer's disease. Vascular pathologies, especially microinfarcts, were more common in those with clinical diagnoses including vascular dementia. Alzheimer-type and cerebrovascular pathology are both common in the very old. A greater burden of these pathologies, Lewy bodies, and hippocampal atrophy, are associated with a higher risk of, but do not define, clinical dementia in old age.

Cerebral Microinfarcts: A Systematic Review of Neuropathological Studies

“…The greater part (63%) concerned hospital-based cohorts, mostly patients admitted to geriatric hospitals or dementia clinics. Twelve studies (41%) described a population-based cohort (Arvanitakis et al, 2011;Ballard et al, 2000;Rossi et al, 2004;Brayne et al, 2009; Review on cerebral microinfarcts M Brundel et al Xuereb et al, 2000;White et al, 2002;Sonnen et al, 2007;Schneider et al, 2007a, b;Strozyk et al, 2010;Troncoso et al, 2008;White, 2009;Wang et al, 2009), mostly of elderly, that is, the ACT Study (Sonnen et al, 2007;Wang et al, 2009) or the Baltimore Longitudinal Study on Aging (Troncoso et al, 2008). Two of these population-based studies involved specific groups of individuals: that is, only men (HAAS) (White et al, 2002;White, 2009) or people from religious orders (Religious Orders Study (Arvanitakis et al, 2011)) ( Table 1).…”

“…The most commonly used neuropathological criteria for AD were the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) (Mirra et al, 1991) and the Braak criteria (Braak and Braak, 1991). Fifteen studies (41%) primarily classified the patients on clinical criteria (Erkinjuntti et al, 1988;Vinters et al, 2000;Xuereb et al, 2000;White et al, 2002;Gold et al, 2007;Sonnen et al, 2007;Schneider et al, 2007a, b;Strozyk et al, 2010;Troncoso et al, 2008;White, 2009;Wang et al, 2009;Brayne et al, 2009;Ghebremedhin et al, 2010;Sinka et al, 2010;Arvanitakis et al, 2011). The Diagnostic and Statistical Manual of Mental Disorders (American Psychiatric Association, 2000) was used most frequently, followed by the Cognitive Assessment Screening Instrument (Teng et al, 1994).…”

“…In five of these papers, the frequency could be extracted. The summed sample size was 553, and the weighted frequency was 33% (Olichney et al, 1997;Lee et al, 2000;Ballard et al, 2000;Del Ser et al, 2005;Brayne et al, 2009;De Reuck et al, 2011a).…”

Chronic traumatic encephalopathy: A paradigm in search of evidence?

“…83 Blinded neuropathologic examination, for example, cannot distinguish intact cognition from dementia in the very old. 84 Discerning clinical presentation among the FTD subtypes, or initial presentation in Lewy body diseases (cortical signs versus parkinsonism), 74,[85][86][87] also cannot be carried out accurately with available methodology and consensus criteria. With this in mind, drawing mechanistic associations between tauopathy at autopsy, and psychiatric signs or complex behaviors such as suicide, explosive anger, impulse control, or posttraumatic stress disorder, 88 appears beyond the scope of neuropathological interpretation.…”

Current Pathogenetic Concepts of Vascular Cognitive Impairment

“…The prevalence studies must be interpreted cautiously since aged subjects with and without dementia show a high frequency of mixed pathologies [18][19][20][21][22].…”