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.

Soluble TREM2 is elevated in Parkinson's disease subgroups with increased CSF tau.

Parkinson's disease is the second most common neurodegenerative disease after Alzheimer's disease and affects 1% of the population above 60 years old. Although Parkinson's disease commonly manifests with motor symptoms, a majority of patients with Parkinson's disease subsequently develop cognitive impairment, which often progresses to dementia, a major cause of morbidity and disability. Parkinson's disease is characterized by α-synuclein accumulation that frequently associates with amyloid-ß and tau fibrils, the hallmarks of Alzheimer's disease neuropathological changes; this co-occurrence suggests that onset of cognitive decline in Parkinson's disease may be associated with appearance of pathological amyloid-ß and/or tau. Recent studies have highlighted the appearance of the soluble form of the triggering receptor expressed on myeloid cells 2 (sTREM2) receptor in CSF during development of Alzheimer's disease. Given the known association of microglial activation with advancing Parkinson's disease, we investigated whether CSF and/or plasma sTREM2 differed between CSF biomarker-defined Parkinson's disease participant subgroups. In this cross-sectional study, we examined 165 participants consisting of 17 cognitively normal elderly subjects, 45 patients with Parkinson's disease with no cognitive impairment, 86 with mild cognitive impairment, and 17 with dementia. Stratification of subjects by CSF amyloid-ß and tau levels revealed that CSF sTREM2 concentrations were elevated in Parkinson's disease subgroups with a positive tau CSF biomarker signature, but not in Parkinson's disease subgroups with a positive CSF amyloid-ß biomarker signature. These findings indicate that CSF sTREM2 could serve as a surrogate immune biomarker of neuronal injury in Parkinson's disease.

Hippocampal CA1 subfield predicts episodic memory impairment in Parkinson's disease.

OBJECTIVE: Parkinson's disease (PD) episodic memory impairments are common; however, it is not known whether these impairments are due to hippocampal pathology. Hippocampal Lewy-bodies emerge by Braak stage 4, but are not uniformly distributed. For instance, hippocampal CA1 Lewy-body pathology has been specifically associated with pre-mortem episodic memory performance in demented patients. By contrast, the dentate gyrus (DG) is relatively free of Lewy-body pathology. In this study, we used ultra-high field 7-Tesla to measure hippocampal subfields in vivo and determine if these measures predict episodic memory impairment in PD during life. METHODS: We studied 29 participants with PD (age 65.5 ±â€¯7.8 years; disease duration 4.5 ±â€¯3.0 years) and 8 matched-healthy controls (age 67.9 ±â€¯6.8 years), who completed comprehensive neuropsychological testing and MRI. With 7-Tesla MRI, we used validated segmentation techniques to estimate CA1 stratum pyramidale (CA1-SP) and stratum radiatum lacunosum moleculare (CA1-SRLM) thickness, dentate gyrus/CA3 (DG/CA3) area, and whole hippocampus area. We used linear regression, which included imaging and clinical measures (age, duration, education, gender, and CSF), to determine the best predictors of episodic memory impairment in PD. RESULTS: In our cohort, 62.1% of participants with PD had normal cognition, 27.6% had mild cognitive impairment, and 10.3% had dementia. Using 7-Tesla MRI, we found that smaller CA1-SP thickness was significantly associated with poorer immediate memory, delayed memory, and delayed cued memory; by contrast, whole hippocampus area, DG/CA3 area, and CA1-SRLM thickness did not significantly predict memory. Age-adjusted linear regression models revealed that CA1-SP predicted immediate memory (beta[standard error]10.895[4.215], p < .05), delayed memory (12.740[5.014], p < .05), and delayed cued memory (12.801[3.991], p < .05). In the fully-adjusted models, which included all five clinical measures as covariates, only CA1-SP remained a significant predictor of delayed cued memory (13.436[4.651], p < .05). CONCLUSIONS: In PD, we found hippocampal CA1-SP subfield thickness estimated on 7-Tesla MRI scans was the best predictor of episodic memory impairment, even when controlling for confounding clinical measures. Our results imply that ultra-high field imaging could be a sensitive measure to identify changes in hippocampal subfields and thus probe the neuroanatomical underpinnings of episodic memory impairments in patients with PD.

Aging associated changes in the motor control of ankle movements in the brain.

Although age-related gait changes have been well characterized, little is known regarding potential functional changes in central motor control of distal lower limb movements with age. We hypothesized that there are age-related changes in brain activity associated with the control of repetitive ankle movements, an element of gait feasible for study with functional magnetic resonance imaging. We analyzed standardized functional magnetic resonance imaging data from 102 right-foot dominant healthy participants aged 20-83 years for age-associated effects using FSL and a meta-analysis using coordinate-based activation likelihood estimation. For the first time, we have confirmed age-related changes in brain activity with this gait-related movement of the lower limb in a large population. Increasing age correlated strongly with increased movement-associated activity in the cerebellum and precuneus. Given that task performance did not vary with age, we interpret these changes as potentially compensatory for other age-related changes in the sensorimotor network responsible for control of limb function.

White matter hyperintensities alter functional organization of the motor system.

Severe white matter hyperintensities (WMH) represent cerebral small vessel disease and predict functional decline in the elderly. We used fMRI to test if severe WMH impact on functional brain network organization even before clinical dysfunction. Thirty healthy right-handed/footed subjects (mean age, 67.8 ± 7.5 years) underwent clinical testing, structural MRI and fMRI at 3.0T involving repetitive right ankle and finger movements. Data were compared between individuals with absent or punctuate (n = 17) and early confluent or confluent (n = 13) WMH. Both groups did not differ in mobility or cognition data. On fMRI, subjects with severe WMH demonstrated excess activation in the pre-supplementary motor area (SMA), frontal, and occipital regions. Activation differences were noted with ankle movements only. Pre-SMA activation correlated with frontal WMH load for ankle but not finger movements. With simple ankle movements and no behavioral deficits, elderly subjects with severe WMH demonstrated pre-SMA activation, usually noted with complex tasks, as a function of frontal WMH load. This suggests compensatory activation related to disturbance of frontosubcortical circuits.

Driving cessation and dementia: results of the prospective registry on dementia in Austria (PRODEM).

OBJECTIVE: To assess the influence of cognitive, functional and behavioral factors, co-morbidities as well as caregiver characteristics on driving cessation in dementia patients. METHODS: The study cohort consists of those 240 dementia cases of the ongoing prospective registry on dementia in Austria (PRODEM) who were former or current car-drivers (mean age 74.2 (±8.8) years, 39.6% females, 80.8% Alzheimer's disease). Reasons for driving cessation were assessed with the patients' caregivers. Standardized questionnaires were used to evaluate patient- and caregiver characteristics. Cognitive functioning was determined by Mini-Mental State Examination (MMSE), the CERAD neuropsychological test battery and Clinical Dementia Rating (CDR), activities of daily living (ADL) by the Disability Assessment for Dementia, behavior by the Neuropsychiatric Inventory (NPI) and caregiver burden by the Zarit burden scale. RESULTS: Among subjects who had ceased driving, 136 (93.8%) did so because of "Unacceptable risk" according to caregiver's judgment. Car accidents and revocation of the driving license were responsible in 8 (5.5%) and 1(0.7%) participant, respectively. Female gender (OR 5.057; 95%CI 1.803-14.180; p = 0.002), constructional abilities (OR 0.611; 95%CI 0.445-0.839; p = 0.002) and impairment in Activities of Daily Living (OR 0.941; 95%CI 0.911-0.973; p<0.001) were the only significant and independent associates of driving cessation. In multivariate analysis none of the currently proposed screening tools for assessment of fitness to drive in elderly subjects including the MMSE and CDR were significantly associated with driving cessation. CONCLUSION: The risk-estimate of caregivers, but not car accidents or revocation of the driving license determines if dementia patients cease driving. Female gender and increasing impairment in constructional abilities and ADL raise the probability for driving cessation. If any of these factors also relates to undesired traffic situations needs to be determined before recommendations for their inclusion into practice parameters for the assessment of driving abilities in the elderly can be derived from our data.

Self-paced operation of an SSVEP-Based orthosis with and without an imagery-based "brain switch:" a feasibility study towards a hybrid BCI.

This work introduces a hybrid brain-computer interface (BCI) composed of an imagery-based brain switch and a steady-state visual evoked potential (SSVEP)-based BCI. The brain switch (event related synchronization (ERS)-based BCI) was used to activate the four-step SSVEP-based orthosis (via gazing at a 8 Hz LED to open and gazing at a 13 Hz LED to close) only when needed for control, and to deactivate the LEDs during resting periods. Only two EEG channels were required, one over the motor cortex and one over the visual cortex. As a basis for comparison, the orthosis was also operated without using the brain switch. Six subjects participated in this study. This combination of two BCIs operated with different mental strategies is one example of a "hybrid" BCI and revealed a much lower rate of FPs per minute during resting periods or breaks compared to the SSVEP BCI alone ( FP=1.46+/-1.18 versus 5.40 +/- 0.90). Four out of the six subjects succeeded in operating the self-paced hybrid BCI with a good performance (positive prediction value PPVb > 0.70).

Does conscious intention to perform a motor act depend on slow cardiovascular rhythms?

Slow oscillations around 0.1 Hz are characteristic features of both the cardiovascular and central nervous systems. Such oscillation have been reported, e.g. in blood pressure, heart rate, EEG and brain oxygenation. Hence, conscious intention of a motor act may occur only as a result of brain activity changes in frontal and related brain areas, or might be entrained by slow oscillations in the blood pressure. Twenty-six subjects were asked to perform voluntary, self-paced (at free will) brisk finger movements. Some subjects performed self-paced movements in relatively periodic intervals of around 10s at the decreasing slope of the slow 0.1-Hz blood pressure oscillation. Our study reveals the first time that self-paced movements, at least in some subjects, do not stem from "free will" based on brain activity alone, but are influenced by slow blood pressure oscillations.