Background People with Parkinson's disease (PD) can develop multidomain cognitive impairments; however, it is unclear whether different pathologies underlie domain‐specific cognitive dysfunction. Objectives We investigated the contribution of vascular copathology severity and location, as measured by MRI white matter hyperintensities (WMHs), to domain‐specific cognitive impairment in PD. Methods We studied 85 PD (66.6 ± 9.2 years) and 18 control (65.9 ± 6.6) participants. Using the Fazekas scale for rating the severity of WMH, we subdivided PD into 14 PD–WMH+ and 71 PD–WMH–. Participants underwent global, executive, visuospatial, episodic memory, and language testing. We performed nonparametric permutation testing to create WMH probability maps based on PD‐WMH group and cognitive test performance. Results The PD–WMH+ group showed worse global and executive cognitive performance than the PD–WMH– group. On individual tests, the PD–WMH+ group showed worse Montreal Cognitive Assessment (MoCA), Stroop, Symbol Digit Modalities Test (SDMT), and Digit Span scores. WMH probability maps showed that in the PD–WMH+ group, worse Stroop was associated with lesions centered around the corticospinal tract (CST), forceps major, inferior‐fronto‐occipital fasciculus, and superior longitudinal fasciculus; worse SDMT with lesions around the CST, forceps major, and posterior corona radiata; worse Digit Span with lesions around the posterior corona radiata; and worse MoCA with lesions around the CST. Conclusions We found that WMH severity was associated with PD executive dysfunction, including worse attention, working memory, and processing speed. Disruption of key white matter tracts in proximity to vascular lesions could contribute to these specific cognitive impairments. Early treatment of vascular disease might mitigate some executive dysfunction in a subset of patients with PD.

Neuroimaging studies in animal models and human subjects have each revealed that relatively low striatal dopamine D2-like receptor binding potential is associated with poor impulse control and with vulnerability for addiction-related behaviors. These studies cannot, however, disambiguate the roles for various pools of D2 receptors found in the striatum (e.g., those expressed on medium spiny striato-pallidal neurons vs on dopamine-releasing nerve terminals) in these behavioral outcomes. To clarify the role of the latter pool, namely, D2 autoreceptors, we studied mice carrying a conditional DRD2 gene, with or without Cre-recombinase expressed under the transcriptional control of the dopamine transporter gene locus (autoDrd2-KO, n = 19 and controls, n = 21). These mice were tested for locomotor response to cocaine, and spatial reversal learning was assessed in operant conditioning chambers. As predicted, compared to control mice, autoDrd2-KO animals demonstrated heightened sensitivity to the locomotor stimulating effect of cocaine (10 mg/kg, i.p.), confirming previous research using a similar genetic model. In the spatial reversal learning task, autoDrd2-KO mice were slower to reach a learning criterion and had difficulty sustaining a prolonged nose poke response, measurements conceptually related to impaired response inhibition. Rate of learning of the initial discrimination and latencies to collect rewards, to initiate trials and to produce a response were unaffected by genetic deletion of D2 autoreceptors, discarding possible motor and motivational factors. Together, these findings confirm the role of D2 autoreceptors in reversal learning and suggest a broader involvement in behavioral inhibition mechanisms.

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Introduction Parkinson's disease (PD) patients commonly experience episodic memory impairments, which are associated with an increased risk of dementia. The Mnemonic Similarity Task (MST) is a well-validated test to investigate episodic memory changes in healthy aging and in neurodegenerative diseases but has not been studied in PD patients. Methods In the MST task, participants respond during a testing phase whether visualized images are “repeat”, “similar”, or “new”, compared to images previously shown during an encoding phase. We tested 17 PD without cognitive impairment (level-II criteria), both off (PD-OFF) and on (PD-ON) dopaminergic medications; and compared PD-OFF with 17 age- and education-matched healthy controls (HC). Results We found no influence of dopaminergic medications nor of disease on MST reaction time for any responses (“repeat”, “similar”, and “new”) during the test phase. However, response probabilities showed that the MST is sensitive to subtle PD-related memory impairments. Specifically, PD-OFF responded more frequently with ‘repeat’, instead of ‘similar’ during lure trials, compared to HC ( p = 0.030). This finding was still significant after correcting for response bias using the Recognition Index ( p = 0.005). Conclusions PD patients perform the MST without interference from bradykinesia or other PD-related motor symptoms. Our findings suggest that PD patients who do not meet criteria for mild cognitive impairment can have subtle recall or recognition impairments, which can be identified using the MST. We propose the MST as a well-tolerated and sensitive cognitive task in future studies of episodic memory impairment and progressive memory dysfunction in people with PD.