Neural Substrates of Cognitive Subtypes in Parkinson’s Disease: A 3-Year Longitudinal Study Yumiko Shoji 1 , Yoshiyuki Nishio 1 *, Toru Baba 1 , Makoto Uchiyama 1,2 , Kayoko Yokoi 1 , Toshiyuki Ishioka 3 , Yoshiyuki Hosokai 4 , Kazumi Hirayama 1,5 , Hiroshi Fukuda 6 , Masashi Aoki 7 , Takafumi Hasegawa 7 , Atsushi Takeda 8 , Etsuro Mori 1 1 Department of Behavioral Neurology and Cognitive Neuroscience, Tohoku University School of Medicine, Sendai, Japan, 2 Department of Speech, Language and Hearing Sciences, Niigata University of Health and Welfare, Niigata, Japan, 3 Department of Occupational Therapy, Saitama Prefectural University, Koshigaya, Japan, 4 Department of Diagnostic Image Analysis, Tohoku University School of Medicine, Sendai, Japan, 5 Department of Occupational Therapy, Yamagata Prefectural University of Health Science, Yamagata, Japan, 6 Department of Radiology and Nuclear Medicine, Institute of Development, Aging, and Cancer, Tohoku University, Sendai, Japan, 7 Department of Neurology, Tohoku University School of Medicine, Sendai, Japan, 8 Department of Neurology, Sendai Nishitaga Hospital, Sendai, Japan Abstract Background: The neuropsychological features and neuropathological progression patterns associated with rapidly evolving cognitive decline or dementia in Parkinson’s disease (PD) remain to be elucidated. Methods: Fifty-three PD patients without dementia were recruited to participate in a 3-year longitudinal cohort study. The patients were grouped according to the Clinical Dementia Rating (CDR). Group-wise comparisons were made with regard to demographic characteristics, motor symptoms, neuropsychological performances and 18F-fluorodeoxyglucose positron emission tomography. Results: Patients who had memory-plus cognitive impairment (patients whose CDR was 0 at baseline and 0.5 in memory and other domains at follow-up, and those whose baseline CDR was 0.5 in memory and other domains) exhibited higher age at onset, visuoperceptual impairment, non-tremor-dominant motor disturbance, rapid symptomatic progression and posterior neocortical hypometabolism. In patients who were cognitively unimpaired and those who had memory-dominant cognitive impairment (patients whose CDR was 0 at baseline and 0.5 only in memory domain at follow-up, and those whose baseline CDR was 0.5 only in memory domain), the posterior neocortex was relatively unaffected until a later stage of the disease. Conclusions: These results suggest that visuoperceptual impairment and the early involvement of the posterior neocortex may be risk factors for rapid symptomatic progression and dementia in PD. Citation: Shoji Y, Nishio Y, Baba T, Uchiyama M, Yokoi K, et al. (2014) Neural Substrates of Cognitive Subtypes in Parkinson’s Disease: A 3-Year Longitudinal Study. PLoS ONE 9(10): e110547. doi:10.1371/journal.pone.0110547 Editor: Stephen D. Ginsberg, Nathan Kline Institute and New York University School of Medicine, United States of America Received July 7, 2014; Accepted September 15, 2014; Published October 20, 2014 Copyright: ß 2014 Shoji et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Data Availability: The authors confirm that all data underlying the findings are fully available without restriction. All relevant data are within the paper. Funding: This work was supported by a Grant-in-Aid for Scientific Research (B) (24390278 to EM) and a Grant-in-Aid for Scientific Research for Young Scientists (90451591 to YN). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * Email: nishiou@med.tohoku.ac.jp Introduction The cognitive features of Parkinson’s disease (PD) are hetero- geneous and can be categorized into several major subtypes. [1,2] However, the neural substrates underlying the cognitive subtypes remain to be elucidated. Recent studies have demonstrated that there are correlations between cognitive impairment and non- cognitive features in PD: patients who develop dementia have a higher age of onset, rapid symptomatic progression, anosmia and a non-tremor-dominant motor subtype. [3,4,5,6] Consistent with these observations, neuropathological studies have suggested that the anatomical distribution of Lewy-related pathology differs depending on the clinical subtypes. The pathology rapidly evolves from the brainstem into the cerebral cortex in patients with the non-tremor-dominant motor subtype and/or dementia, whereas it is relatively confined to the brainstem for a longer period of time in patients with a tremor-dominant motor subtype and no cognitive impairment. [7] If such provisional clinico-pathological relation- ships are genuine and if specific subtypes of cognitive impairment are associated with the future development of dementia, these cognitive subtypes may be associated with specific clinico- pathological subtypes. Previous morphometric MRI and 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) studies have demon- strated greater frontal, temporal and occipital gray matter volume reduction and greater frontal and parietal cortical hypometabo- lism in PD patients with dementia or mild cognitive impairment (MCI) compared with cognitively unimpaired patients. [8,9,10,11,12] In agreement with these neuroimaging findings, several neuropathological studies demonstrated the relationship PLOS ONE | www.plosone.org 1 October 2014 | Volume 9 | Issue 10 | e110547