White matter hyperintensities and smaller cortical thickness are associated with neuropsychiatric symptoms in neurodegenerative and cerebrovascular diseases
Authors: Ozzoude Miracle , Varriano Brenda , Beaton Derek , Ramirez Joel , Adamo Sabrina , Holmes Melissa F. , Scott Christopher J. M. , Gao Fuqiang , Sunderland Kelly M. , McLaughlin Paula , Goubran Maged , Kwan Donna , Roberts Angela , Bartha Robert , Symons Sean , Tan Brian , Swartz Richard H. , Abrahao Agessandro , Saposnik Gustavo , Masellis Mario , Lang Anthony E. , Marras Connie , Zinman Lorne , Shoesmith Christen , Borrie Michael , Fischer Corinne E. , Frank Andrew , Freedman Morris , Montero-Odasso Manuel , Kumar Sanjeev , Pasternak Stephen , Strother Stephen C. , Pollock Bruce G. , Rajji Tarek K. , Seitz Dallas , Tang-Wai David F. , Turnbull John , Dowlatshahi Dar , Hassan Ayman , Casaubon Leanne , Mandzia Jennifer , Sahlas Demetrios , Breen David P. , Grimes David , Jog Mandar , Steeves Thomas D. L. , Arnott Stephen R. , Black Sandra E. , Finger Elizabeth , Rabin Jennifer ,   ONDRI Investigators, Strong Michael , Kleinstiver Peter , Lawrence-Dewar Jane , Rashkovan Natalie , Bronskil Susan , Fraser Julia , McIlroy Bill , Cornish Ben , Van Ooteghem Karen , Faria Frederico , Sarquis-Adamson Yanina , Black Alanna , Greenberg Barry , Hatch Wendy , Hudson Chris , Leontieva Elena , Margolin Ed , Mandelcorn Efrem , Tayyari Faryan , Defrawy Sherif , Brien Don , Chen Ying , Coe Brian , Munoz Doug , Southwell Alisia , Bulman Dennis , Dilliott Allison Ann , Ghani Mahdi , Hegele Rob , Robinson John , Rogaeva Ekaterina , Farhan Sali , Haddad Seyyed Mohammad Hassan , Nanayakkara Nuwan , Berezuk Courtney , Binns Malcolm , Lou Wendy , Theyers Athena , Uthirakumaran Abiramy , Zou Guangyong , Sujanthan Sujeevini , Zamyadi Mojdeh , Munoz David , Dixon Roger A. , Woulfe John , Levine Brian , Orange J. B. , Peltsch Alicia , Troyer Angela , Chum Marvin , Tartaglia Maria Carmela 
Published: June 2023

Abstract
Background
Neuropsychiatric symptoms (NPS) are a core feature of most neurodegenerative and cerebrovascular diseases. White matter hyperintensities and brain atrophy have been implicated in NPS. We aimed to investigate the relative contribution of white matter hyperintensities and cortical thickness to NPS in participants across neurodegenerative and cerebrovascular diseases.

Methods
Five hundred thirteen participants with one of these conditions, i.e. Alzheimer’s Disease/Mild Cognitive Impairment, Amyotrophic Lateral Sclerosis, Frontotemporal Dementia, Parkinson’s Disease, or Cerebrovascular Disease, were included in the study. NPS were assessed using the Neuropsychiatric Inventory – Questionnaire and grouped into hyperactivity, psychotic, affective, and apathy subsyndromes. White matter hyperintensities were quantified using a semi-automatic segmentation technique and FreeSurfer cortical thickness was used to measure regional grey matter loss.

Results
Although NPS were frequent across the five disease groups, participants with frontotemporal dementia had the highest frequency of hyperactivity, apathy, and affective subsyndromes compared to other groups, whilst psychotic subsyndrome was high in both frontotemporal dementia and Parkinson’s disease. Results from univariate and multivariate results showed that various predictors were associated with neuropsychiatric subsyndromes, especially cortical thickness in the inferior frontal, cingulate, and insula regions, sex(female), global cognition, and basal ganglia-thalamus white matter hyperintensities.

Conclusions
In participants with neurodegenerative and cerebrovascular diseases, our results suggest that smaller cortical thickness and white matter hyperintensity burden in several cortical-subcortical structures may contribute to the development of NPS. Further studies investigating the mechanisms that determine the progression of NPS in various neurodegenerative and cerebrovascular diseases are needed.