Reorganization of intrinsic functional connectivity in early-stage Parkinson's disease patients with probable REM sleep behavior disorder.

REM sleep behavior disorder (RBD) symptoms in Parkinson's disease (PD) suggest both a clinically and pathologically malignant subtype. However, whether RBD symptoms are associated with alterations in the organization of whole-brain intrinsic functional networks in PD, especially at early disease stages, remains unclear. Here we use resting-state functional MRI, coupled with graph-theoretical approaches and network-based statistics analyses, and validated with large-scale network analyses, to characterize functional brain networks and their relationship with clinical measures in early PD patients with probable RBD (PD+pRBD), early PD patients without probable RBD (PD-pRBD) and healthy controls. Thirty-six PD+pRBD, 57 PD-pRBD and 71 healthy controls were included in the final analyses. The PD+pRBD group demonstrated decreased global efficiency (t = -2.036, P = 0.0432) compared to PD-pRBD, and decreased network efficiency, as well as comprehensively disrupted nodal efficiency and whole-brain networks (all eight networks, but especially in the sensorimotor, default mode and visual networks) compared to healthy controls. The PD-pRBD group showed decreased nodal degree in right ventral frontal cortex and more affected edges in the frontoparietal and ventral attention networks compared to healthy controls. Furthermore, the assortativity coefficient was negatively correlated with Montreal cognitive assessment scores in the PD+pRBD group (r = -0.365, P = 0.026, d = 0.154). The observation of altered whole-brain functional networks and its correlation with cognitive function in PD+pRBD suggest reorganization of the intrinsic functional connectivity to maintain the brain function in the early stage of the disease. Future longitudinal studies following these alterations along disease progression are warranted.

Altered Cerebellar Resting-State Functional Connectivity in Early-Stage Parkinson's Disease Patients With Cognitive Impairment.

Background: Cognitive impairment is one of the most prominent non-motor symptoms in Parkinson's disease (PD), due in part to known cerebellar dysfunctions. Furthermore, previous studies have reported altered cerebellar functional connectivity (FC) in PD patients. Yet whether these changes are also due to the cognitive deficits in PD remain unclear. Methods: A total of 122 non-dementia participants, including 64 patients with early PD and 58 age- and gender-matched elderly controls were stratified into four groups based on their cognitive status (normal cognition vs. cognitive impairment). Cerebellar volumetry and FC were investigated by analyzing, respectively, structural and resting-state functional MRI data among groups using quality control and quantitative measures. Correlation analysis between MRI metrics and clinical features (motor and cognitive scores) were performed. Results: Compared to healthy control subjects with no cognitive deficits, altered cerebellar FC were observed in early PD participants with both motor and cognitive deficits, but not in PD patients with normal cognition, nor elderly subjects showing signs of a cognitive impairment. Moreover, connectivity between the "motor" cerebellum and SMA was positively correlated with motor scores, while intracerebellar connectivity was positively correlated with cognitive scores in PD patients with cognitive impairment. No cerebellar volumetric difference was observed between groups. Conclusions: These findings show that altered cerebellar FC during resting state in early PD patients may be driven not solely by the motor deficits, but by cognitive deficits as well, hence highlighting the interplay between motor and cognitive functioning, and possibly reflecting compensatory mechanisms, in the early PD.

Brain-derived neurotrophic factor Val66Met polymorphism is associated with mild cognitive impairment in elderly patients with type 2 diabetes: a case-controlled study.

BACKGROUND: Brain-derived neurotrophic factor (BDNF) Val66Met polymorphism is reported to be associated with cognitive dysfunction, an important comorbidity factor in patients with type 2 diabetes mellitus (T2DM), especially in elderly populations, however, the underlying pathophysiological mechanisms are unclear. AIM: This study was performed to investigate the association between BDNF Val66Met polymorphism and mild cognitive impairment (MCI) in elderly patients with T2DM. METHODS: In total, 105 MCI and 105 normal cognition controls of T2DM patients were enrolled; all of the patients underwent neuropsychological assessments. BDNF Val66Met polymorphism was genotyped via TaqMan SNP genotyping assay. Data from clinical and laboratory-based examinations were collected. RESULTS: The frequency of the BDNF Met allele was significantly higher in the MCI group than in the controls. Multiple regression analysis indicated an association of the Met allele with MCI in patients with T2DM (OR = 2.54; 95% CI 1.33-4.84; p = 0.005). Stratified by educational level, the BDNF Met allele was significantly associated with MCI in elderly T2DM patients (OR = 3.29; 95% CI 1.26-8.57; p = 0.015) among the group of low educational levels (< 12 years); however, the association was insignificant among those with higher educational levels. DISCUSSION: BDNF Met allele carriers showed a higher frequency of MCI than Val/Val homozygotes in elderly T2DM patients. However, this association was only significant in patients with low education levels. CONCLUSION: BDNF Val66Met polymorphism may have a potential role in MCI in elderly T2DM patients, especially those with low educational levels.

Poor self-perceived health is associated with frailty and prefrailty in urban living older adults: A cross-sectional analysis.

In this study, we investigated the cross-sectional association of Self-perceived health (SPH) with frailty phenotype. A total of 4632 participants of the Beijing Longitudinal Study of Aging II (mean age 75.4 ± 6.8years) were categorized into having good, fair, and poor SPH. Individuals were compared according to their frailty status (i.e., frail and prefrail vs robust) with SPH rating. The association of SPH with respect to the five components of frailty phenotype was further investigated. Older adults who were frail had lower odds of having good SPH (OR=0.64). Whereas frail and prefrail individuals had higher odds of having poor SPH (OR=6.26,OR=2.09 respectively). Having low education, polypharmacy, ADL and IADL disability, cognitive impairment, and depression was associated with a higher likelihood of having poor SPH. All components of frailty except weight loss was associated with poor SPH. SPH may serve as a tool to identify frail or prefrail individuals in the community.

ABCG2 rs2231142 variant in hyperuricemia is modified by SLC2A9 and SLC22A12 polymorphisms and cardiovascular risk factors in an elderly community-dwelling population.

BACKGROUND: The ABCG2 rs2231142 single nucleotide polymorphism (SNP) is one of the most significant genetic variants associated with hyperuricemia (HUA) in Asian populations. However, the risk of ABCG2 rs2231142 variants for HUA could interact with other important HUA risk variants and cardiovascular factors. This study investigated the effects of the combined association among ABCG2 rs2231142 and multiple HUA genetic variants or cardiovascular risk factors on HUA risk and serum uric acid (sUA) levels in an elderly Chinese population. METHODS: A total of 1206 participants over 65 years old were enrolled in this study. Physical and laboratory examinations were performed for all participants. The ABCG2 rs2231142, SLC2A9 rs3733591, and SLC22A12 rs893006 SNPs were assayed using a standardized protocol. Logistic regression analysis and liner regression were adjusted respectively to account for the association between ABCG2 rs2231142 and other genetic variants, as well as between cardiovascular risk factors and HUA risk and sUA levels. RESULTS: The prevalence of HUA was 14.71% in the elderly community-dwelling population. The ABCG2 rs2231142 risk T allele was associated with HUA risk (odds ratio (OR) = 1.63, 95% confidence interval (CI): 1.27-2.11; p = 1.65 × 10- 4) and with increased sUA levels (Beta = 0.16, p = 6.75 × 10- 9) in the whole study population. Linear regression analysis showed that the mean sUA level increased linearly with the number of risk alleles of the three candidate genetic variants (Beta = 0.18, p = 1.94 × 10- 12) The joint effect of the ABCG2 rs2231142 T allele and cardiovascular risk factors (obesity, hypertension and dyslipidemia) was also associated with increased HUA risk and sUA levels. Each copy of the risk T allele was significantly associated with enhanced HUA risk in patients with hypertriglyceridemia (OR = 2.52, 95% CI: 1.33-4.60; p = 0.003) compared to controls. CONCLUSION: Our findings reinforce the importance of the ABCG2 rs2231143 variant as a crucial genetic locus for HUA in Chinese populations and demonstrated the combined effects of multiple genetic risk variants and cardiovascular risk exposures on HUA risk and increased sUA level.

High-frequency rTMS over the supplementary motor area improves freezing of gait in Parkinson's disease: a randomized controlled trial.

INTRODUCTION: Freezing of gait (FOG) contributes to falls in Parkinson's disease (PD), but robust, effective treatments remain elusive. There is evidence indicating that the supplementary motor area (SMA) plays an important role in the pathogenesis of FOG and may therefore be a potential neuromodulation target. The present study explored the clinical efficacy of high-frequency repetitive transcranial magnetic stimulation (rTMS) over the SMA on FOG in PD patients. METHODS: A group of 30 PD patients with FOG were enrolled in a randomized, double-blind, sham-controlled trial. Patients were randomly allocated 2:1 to receive ten sessions of either real (N = 20) or sham (N = 10) 10 Hz rTMS over SMA. The patients were assessed at baseline (T0), after the 5th (T1) and 10th (T2) sessions, and then 2 weeks (T3) and 4 weeks (T4) after the last session. The primary clinical outcome was the Freezing of Gait Questionnaire score (FOGQ), with the Movement Disorder Society-Unified Parkinson's Disease Rating Scale motor scores (MDS-UPDRS III) and Timed Up and Go test as secondary clinical outcomes. All the assessments were carried out at the "ON" state. RESULTS: With a four week's follow-up, there were significant interaction effects in the FOGQ (effect of group*time, p = 0.04), MDS-UPDRS III (p = 0.02) and several gait variables (total duration, p < 0.01; cadence, p = 0.04; turn duration, p = 0.01; and turn to sit duration, p = 0.02). Post-hoc analyses revealed a significantly decreased FOGQ score at T2 and T4, and significant improvements of MDS-UPDRS III and gait variables at T1, T2, T3 and T4 in the rTMS group. No significant improvements were found in the sham group. CONCLUSION: High-frequency rTMS over SMA may ultimately serve as an add-on therapy for alleviating FOG in PD patients.

Impaired Fine Motor Function of the Asymptomatic Hand in Unilateral Parkinson's Disease.

The early detection of Parkinson's disease (PD) still remains a challenge to date. Although studies have previously reported subtle motor function abnormalities in early PD patients, it is unclear whether such clinical signs can be better detected while patients are concurrently performing a cognitive task, and whether they can be useful in predicting patients' clinical conversion state. Seventy-two right-handed participants (40 drug-naive patients with idiopathic unilateral PD and 32 age-matched healthy controls) were enrolled in this study. All participants were asked to perform the Purdue Pegboard test (PPT) either alone (single-task condition) or during a concurrent mental subtraction-by-3 task (dual-task condition). A 4-year telephone follow-up was later conducted to determine whether PD patients converted to bilateral signs. We found that PD patients showed a significant reduction in dexterity on the PPT compared to the controls in both single- and dual-task conditions. Yet patients' performance in the dual-task condition revealed a greater interference effect when patients performed the task with their right hand than with their left hand. PPT also revealed reasonable discriminative ability for prediagnosing PD. However, dual-tasking did not have added value in differentiating early patients and controls. At follow-up, the baseline PPT performance of the asymptomatic hands was positively correlated with time to convert from unilaterally to bilaterally affected states (r = 0.62, P = 0.031). Together, these findings suggest that PPT can serve as a useful auxiliary tool in evaluating early PD, and shed light on the neuroplasticity mechanism of fine motor deficit at this very early stage.

Association between common genetic risk variants and depression in Parkinson's disease: A dPD study in Chinese.

INTRODUCTION: Prediction of depression in patients with Parkinson's disease (PD) remains challenging. We investigated whether the common susceptible genetic variants for PD are associated with the risk and improves prediction of development of depression in PD (dPD). METHODS: 1134 individuals with a primary diagnosis of PD were recruited. Demographic information, Unified Parkinson's Disease Rating Scale (UPDRS), and 17-item Hamilton Rating Scale for Depression (HAMD) were obtained. Nine variants located in six susceptible genes for PD were determined in all subjects. Logistic regression analyses were used to identify the study genetic variants that individually and collectively best predicted the presence of depressive disorder (HAMD ≥14). RESULTS: Depression occurred in 19.8% of patients with PD. The GBA L444P variant was associated with an increased risk of depression (odds ratio [OR] = 2.69, 95% confidence interval [CI] = 1.31-5.53, P = 0.007) and SNCA-Rep1 (CA)12/12 showed a decreased risk for the presence of depression (OR = 0.54, 95% CI = 0.29-0.99, P = 0.049) in the PD population after adjusted for demographic and clinical factors. Stepwise logistic regression model found that female sex, UPDRS part II score, motor fluctuation, GBA L1444P and SNCA Rep-1 variants collectively best predict depression in PD. CONCLUSIONS: Besides non PD-specific and PD-specific clinical correlates, we showed that GBA L444P and SNCA Rep-1 were also associated with dPD. Our findings highlight the crucial role of genetic variants for the prediction of dPD in clinical practice and may shed light on the future development of better therapeutic targets for dPD.

Olfactory Dysfunction in Parkinson's Disease Patients with the LRRK2 G2385R Variant.

Olfactory dysfunction has been reported in Parkinson's disease (PD) patients carrying the LRRK2 G2019S variant in Caucasians but rarely in those with the LRRK2 G2385R variant. In this study, we performed genotyping for the LRRK2 G2385R variant in PD patients recruited from the Movement Disorder Clinic of Xuanwu Hospital in Beijing and in healthy controls randomly selected from the Beijing Longitudinal Study on Aging cohort. The "five-odor olfactory detection array", an olfactory threshold test, was used to assess olfactory function. One hundred and eighty-six participants were enrolled, comprising 43 PD patients without (iPD) and 25 with (LRRK2-PD) the LRRK2 G2385R variant, and 118 healthy controls. Our results showed that the threshold of olfactory identification was significantly worse in PD patients than in controls, but not significantly different between the iPD and LRRK2-PD groups. These findings suggested that although olfactory function in LRRK2-PD patients is impaired, it is similar to that in iPD patients.

Motor Sequence Learning and Consolidation in Unilateral De Novo Patients with Parkinson's Disease.

Previous research investigating motor sequence learning (MSL) and consolidation in patients with Parkinson's disease (PD) has predominantly included heterogeneous participant samples with early and advanced disease stages; thus, little is known about the onset of potential behavioral impairments. We employed a multisession MSL paradigm to investigate whether behavioral deficits in learning and consolidation appear immediately after or prior to the detection of clinical symptoms in the tested (left) hand. Specifically, our patient sample was limited to recently diagnosed patients with pure unilateral PD. The left hand symptomatic (LH-S) patients provided an assessment of performance following the onset of clinical symptoms in the tested hand. Conversely, right hand affected (left hand asymptomatic, LH-A) patients served to investigate whether MSL impairments appear before symptoms in the tested hand. LH-S patients demonstrated impaired learning during the initial training session and both LH-S and LH-A patients demonstrated decreased performance compared to controls during the next-day retest. Critically, the impairments in later learning stages in the LH-A patients were evident even before the appearance of traditional clinical symptoms in the tested hand. Results may be explained by the progression of disease-related alterations in relevant corticostriatal networks.

MAPT IVS1+124 C>G modifies risk of LRRK2 G2385R for Parkinson's disease in Chinese individuals.

Variants of the MAPT gene have been suggested to be associated with Parkinson's disease (PD) and to modify the risk for leucine-rich repeat kinase 2 (LRRK2) Parkinsonism. However, this has not been confirmed in Asians with ethnicity-specific variants of MAPT and LRRK2. In this study, Asian-specific LRRK2 p.G2385R variant and IVS1+124 C>G, a functional single-nucleotide polymorphism located in the MAPT promoter region, were genotyped in 561 Chinese PD patients and 556 control subjects. Allelic and genotypic frequencies of the 2 variants were compared between cases and control subjects independently and in combination. As a result, the LRRK2 p.G2385R variant alone was associated with an increased risk for PD (Odds ratio, 1.86; 95% confidence intervals, 1.08-3.19; p = 0.014), whereas MAPT IVS1+124 C>G was not (p = 0.34). However, the coexistence of MAPT IVS1+124C>G significantly enhanced the LRRK2 G2385R-conferred risk for PD (Odds ratio, 2.30; 95% confidence intervals, 1.14-4.54; p = 0.012). These results provide further evidence supporting the interaction between MAPT and LRRK2 genes, which increases the susceptibility to PD in Chinese individuals.