Neuropathologic Correlates of Psychiatric Symptoms in Alzheimer’s Disease

Abstract

Clarifying the relationships between neuropsychiatric symptoms and Alzheimer's disease (AD)-related pathology may open avenues for effective treatments. Here, we investigate the odds of developing neuropsychiatric symptoms across increasing burdens of neurofibrillary tangle and amyloid-β pathology. Participants who passed away between 2004 and 2014 underwent comprehensive neuropathologic evaluation at the Biobank for Aging Studies from the Faculty of Medicine at the University of São Paulo. Postmortem interviews with reliable informants were used to collect information regarding neuropsychiatric and cognitive status. Of 1,092 cases collected, those with any non-Alzheimer pathology were excluded, bringing the cohort to 455 cases. Braak staging was used to evaluate neurofibrillary tangle burden, and the CERAD neuropathology score was used to evaluate amyloid-β burden. The 12-item neuropsychiatric inventory was used to evaluate neuropsychiatric symptoms and CDR-SOB score was used to evaluate dementia status. In Braak I/II, significantly increased odds were detected for agitation, anxiety, appetite changes, depression, and sleep disturbances, compared to controls. Increased odds of agitation continue into Braak III/IV. Braak V/VI is associated with higher odds for delusions. No increased odds for neuropsychiatric symptoms were found to correlate with amyloid-β pathology. Increased odds of neuropsychiatric symptoms are associated with early neurofibrillary tangle pathology, suggesting that subcortical neurofibrillary tangle accumulation with minimal cortical pathology is sufficient to impact quality of life and that neuropsychiatric symptoms are a manifestation of AD biological processes.

Sleep and neurocognitive decline in the Hispanic Community Health Study/Study of Latinos

“…For example, history of sleep disruption was associated with increased neurofibrillary tangles in the brainstem nuclei known to regulate sleep‐wake process in a postmortem sample of patients with early AD (Braak stage I/II). In a different study, older adults with MCI had increased sleep symptoms, as well as decreased objectively measured sleep continuity and more fragmented sleep independent of neurocognitive performance, suggesting that sleep disruption could be an early marker of neurodegeneration …”

White matter hyperintensities and neuropsychiatric symptoms in Alzheimer’s disease and mild cognitive impairment

“…Anor et al reported greater delusions with right frontal WMH volume in AD. Delusions have been associated with later Braak staging V/VI (Ehrenberg et al, 2018) suggesting that these symptoms are more likely to present in the late stages of AD. GM atrophy and WMH burden in these regions may contribute to the disruption of connectivity in frontotemporal networks.…”

What’s That (Blue) Spot on my MRI? Multimodal Neuroimaging of the Locus Coeruleus in Neurodegenerative Disease

“…Interestingly, while protein aggregates are thought to trigger neural degeneration in other brain regions, the LC appears to be spared from frank cell death until mid to late stages of disease, when up to 80% of its cell bodies are lost ( German et al, 1992 ; Busch et al, 1997 ; Zarow et al, 2003 ; Theofilas et al, 2017 ). Furthermore, AD and PD share many comorbidities associated with LC dysfunction, such as exaggerated stress response and anxiety ( Teri et al, 1999 ; Pietrzak et al, 2015 ; Schrag and Taddei, 2017 ), attentional deficits ( Rizzo et al, 2000 ; Berardi et al, 2005 ; Dujardin et al, 2013 ), fatigue and reduced arousal ( Hamann et al, 2000 ; Kelberman and Vazey, 2016 ) and sleep disturbances ( Yesavage et al, 2004 ; Ju et al, 2013 ) that appear time-locked with development of LC pathology ( Busch et al, 1997 ; Grinberg et al, 2010 ; Ehrenberg et al, 2018 ).…”