Low soluble amyloid-ß 42 is associated with smaller brain volume in Parkinson's disease.

INTRODUCTION: We sought to examine whether levels of soluble alpha-synuclein (α-syn), amyloid-beta (Aß42), phosphorylated tau (p-tau), and total tau (t-tau), as measured in cerebrospinal fluid (CSF), are associated with changes in brain volume in Parkinson's disease. METHODS: We assessed the 4-year change in total brain volume (n = 99) and baseline CSF α-syn, Aß42, p-tau, and t-tau of Parkinson Progression Markers Initiative participants. We used linear mixed models to assess the longitudinal effect of baseline CSF biomarkers on total and regional brain volume and thickness as well as linear regression for cross-sectional analyses at baseline and year 2. All models were adjusted for age and gender; brain volume models also adjusted for baseline intracranial volume. Bonferroni correction was applied. RESULTS: The 4-year change in total brain volume was -21.2 mm3 (95% confidence interval, -26.1, -16.3). There were no significant associations between the 4-year change in total brain volume and baseline levels of any CSF biomarker (all p-values > 0.05). On cross-sectional analyses, CSF Aß42 was linearly associated with total brain volume at baseline (R2 = 0.60, p = 0.0004) and at year 2 (R2 = 0.66, p < 0.0001), with CSF Aß42 < 1100 pg/ml, the threshold for brain amyloid pathology, associated with smaller total brain volume at baseline (p = 0.0010) and at year 2 (p = 0.0002). CSF α-syn was linearly associated with total brain volume at baseline (R2 = 0.58, p = 0.0044) but not at year 2 (R2 = 0.58, p = 0.1342). CONCLUSION: Reduction in soluble Aß42 is associated with lower total brain volume in Parkinson's disease.

White Matter Hyperintensities Related to Parkinson's Disease Executive Function.

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.

Mnemonic Similarity Task to study episodic memory in Parkinson's disease.

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.

Dopamine D2 Receptors in Dopaminergic Neurons Modulate Performance in a Reversal Learning Task in Mice.

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.