Risk Factors and Pathological Substrates Associated with Agitation/Aggression in Alzheimer’s Disease: A Preliminary Study using NACC Data

Article type: Research Article

Authors: Sennik, Simrin^a | Schweizer, Tom A.^{a; b; c; d; e} | Fischer, Corinne E.^{a; f} | Munoz, David G.^{a; g; h; *}

Affiliations: [a] Keenan Biomedical Research Centre, the Li Ka Shing Knowledge Institute, St. Michael’s Hospital, Toronto, ON, Canada | [b] Institute of Medical Sciences, University of Toronto, Toronto, ON, Canada | [c] Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, ON, Canada | [d] Department of Surgery, Division of Neurosurgery, Faculty of Medicine, University of Toronto, ON, Canada | [e] Division of Neurosurgery, St. Michael’s Hospital, Toronto, ON, Canada | [f] Department of Psychiatry, Faculty of Medicine, University of Toronto, ON, Canada | [g] Department of Laboratory Medicine and Pathobiology, University of Toronto, ON, Canada | [h] Department of Laboratory Medicine, St. Michael’s Hospital, Toronto, ON, Canada

Correspondence: [*] Correspondence to: Dr. David G. Munoz, Department of Laboratory Medicine, Room 2-097 CC Wing, St. Michael’s Hospital, 30 Bond Street. Toronto, M5B 1W8. ON, Canada. Tel.: +1 416 864 5858; Fax: +1 416 864 5648; E-mail: [email protected].

Abstract: Background: Neuropsychiatric symptoms are common manifestations of Alzheimer’s disease (AD). A number of studies have targeted psychosis, i.e., hallucinations and delusions in AD, but few have assessed agitation/aggression in AD. Objective: To investigate the risk factors and pathological substrates associated with presence [A(+)] and absence [A(–)] of agitation/aggression (A) in autopsy-confirmed AD. Methods: Data was collected from the UDS data as of 2015 on the NACC database. Patients were stratified as intermediate (IAD) or high (HAD) pathological load of AD. Clinical diagnoses were not considered; additional pathological diagnoses were treated as variables. Analysis of data did not include a control group or corrections for multiple comparisons. Results: 1,716 patients met the eligibility criteria; 31.2% of the IAD and 47.8% of the HAD patients were A(+), indicating an association with severity of pathology (p = 0.001). Risk factors for A(+) included: age at initial visit, age at death, years of education, smoking (in females), recent cardiac events (in males), and clinical history of traumatic brain injury (TBI) (in males). A history of hypertension was not related to A(+). In terms of comorbidity, clinical diagnosis of Lewy body dementia syndrome was associated with A(+) but the association was not confirmed when pathological diagnosis based on demonstration of Lewy bodies was used as the criterion. The additional presence of phosphorylated TDP-43, but not tau pathologies, was associated with A(+)HAD. Vascular lesions, including lacunes, large arterial infarcts, and severity of atherosclerosis were negatively associated with A(+). Associated symptoms included delusions, hallucinations, and depression, but not irritability, aberrant motor behavior, sleep and night time behavioral changes, or changes in appetite and eating habits. Conclusions: Smoking, TBI, and phosphorylated TDP-43 are associated with A(+)AD in specific groups, respectively. A(+) is directly associated with AD pathology load and inversely with vascular lesions.

Keywords: Alzheimer’s disease, agitation, aggression, neuropathology, (p)-TDP-43, traumatic brain injury, vascular lesions, vascular risk factors

DOI: 10.3233/JAD-160780

Journal: Journal of Alzheimer's Disease, vol. 55, no. 4, pp. 1519-1528, 2017