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Psychiatric symptoms, including changes in emotional processing, are a common feature of many neurodegenerative disorders, such as Alzheimer's disease, dementia with Lewy Bodies, frontotemporal dementia, and Huntington's disease. However, the neuroanatomical basis of emotional symptoms is not well defined; this stands in contrast to the relatively well-understood neuroanatomical correlates of cognitive and motor symptoms in neurodegenerative disorders. Furthermore, psychiatric diagnostic categories, as defined by the Diagnostic and Statistical Manual of Mental Disorders (DSM) and International Statistical Classification of Diseases and Related Health Problems (ICD), may have limited applicability in patients with late-onset psychiatric symptoms in the context of neurodegenerative disorders. In this clinical review, we suggest that early-onset and late-onset psychiatric symptoms have distinct etiologies, and that late-onset changes in emotional processing are likely underpinned by neurodegenerative disease. Furthermore, we suggest that an improved understanding of the neuroanatomical correlates of emotional changes in neurodegenerative disease may facilitate diagnosis and future treatment development. Finally, we propose a novel clinical approach, in a preliminary attempt to incorporate late-onset emotional symptoms alongside cognitive and motor symptoms into a clinical "algorithm," with a focus on the neuroanatomy implicated when particular combinations of emotional, cognitive, and motor features are present. We anticipate that this clinical approach will assist with the diagnosis of neurodegenerative disorders, and our proposed schema represents a move towards integrating neurologic and psychiatric classification systems.

Importance: Understanding associations of Alzheimer disease (AD) and related dementias (ADRD) pathologies with common neuropsychiatric symptoms (NPS) may have implications for diagnosis and management., Objective: To evaluate ADRD neuropathological diagnoses and NPS without consideration of clinical diagnosis., Design, Setting, and Participants: This retrospective cohort study evaluated 1808 brains from 39 sites in the US National Alzheimer Coordinating Center v. 10 collection for participants among whom the Neuropsychiatric Inventory Questionnaire (NPIQ) was administered annually. Brain autopsy diagnoses of AD, Lewy body disease (LBD), cerebral amyloid angiopathy, frontotemporal lobar degeneration, cerebrovascular disease, hippocampal sclerosis, and no known pathology were examined. Autopsy data collected from January 2012 to January 2018 were deidentified and compiled into the publicly available v. 10 database. Data were analyzed from February 2021 to August 2021., Main Outcomes and Measures: The primary outcome was NPIQ domain score, if present at any time point, and mean NPIQ domain score during follow-up was secondary. Associations of ADRD diagnoses with 12 NPIQ symptom domains were examined in regression analyses, correcting for multiple comparisons., Results: The study sample of 1808 adults had a mean (SD) age of 80.0 (11.0) years, and 987 participants (54.6%) were male. Apathy was the most prevalent NPS, reaching 80% (203 of 254 individuals) in those with hippocampal sclerosis. Cerebrovascular disease showed few NPS associations. Frontotemporal lobar degeneration was associated with increased apathy, increased disinhibition, and decreased psychosis and agitation compared with AD. Hippocampal sclerosis was associated with increased apathy (odds ratio, 2.60; 95% CI; 1.86-3.66, false discovery rate controlled P < .001) and disinhibition (odds ratio, 2.15; 95% CI, 1.63-2.84; false discovery rate controlled P < .001). In multiple regression analyses that included concomitant neuropathologies, the main findings remained. More severe pathology was consistently associated with increased NPS (eg, LBD was associated with an increase in hallucinations from brain stem [β, 0.23; 95% CI, 0.07-0.76; P = .02] to limbic [β, 1.69; 95% CI, 1.27-2.27; P < .001] to neocortical [β, 4.49; 95% CI, 3.27-6.16; P < .001] pathology). Hallucinations were more common in participants with AD and LBD (168 of 534 [31.5%]) compared with those with AD without LBD (152 of 704 [21.6%]) and those with LBD without AD (23 of 119 [19.6%])., Conclusions and Relevance: In this cohort study of 1808 brains from the US National Alzheimer Coordinating Center, patients with LBD and AD showed a higher prevalence of hallucinations compared with those with LBD without AD. Neuropsychiatric symptom criteria of apathy and disinhibition in behavioral variant frontotemporal lobar degeneration were supported in this study. In hippocampal sclerosis, the findings of increased apathy and disinhibition merit further investigation. Severity of neuropathology was associated with NPS severity, indicating that NPS may reflect underlying ADRD pathology and highlighting the importance of diagnosing and treating NPS.

Background: Apathy is a common and problematic symptom of several neurodegenerative illnesses, but its neuroanatomical bases are not understood., Objective: To determine the regions associated with apathy in subjects with mild Alzheimer's disease (AD) using a method that accounts for the significant co-linearity of regional atrophy and neuropsychiatric symptoms., Methods: We identified 57 subjects with mild AD (CDR = 1) and neuropsychiatric symptoms in the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. We performed a multivariate multiple regression with LASSO regularization on all symptom subscales of the Neuropsychiatric Inventory and the whole-brain ROI volumes calculated from their baseline MRIs with FreeSurfer. We compared our results to those from a previous study using the same method in patients with frontotemporal dementia (FTD) and corticobasal syndrome (CBS)., Results: Of neuropsychiatric symptoms, apathy showed the most robust neuroanatomical associations in the AD subjects. Atrophy of the following regions were independently associated with apathy: the ventromedial prefrontal cortex; ventrolateral prefrontal cortex; posterior cingulate cortex and adjacent lateral cortex; and the bank of the superior temporal sulcus. These results replicate previous studies using FTD and CBS patients, mostly agree with the previous literature on apathy in AD, and correspond to the Medial and Orbital Prefrontal Cortex networks identified in non-human primates., Conclusion: The current study, previous studies from our laboratory, and the previous literature suggest that impairment of the same brain networks involved in arousal, threat response, and reward processing are associated with apathy in AD and FTD.