Optimizing rehabilitation strategies in Parkinson's disease: a comparison of dual cognitive-walking treadmill training and single treadmill training.

Dual cognitive-walking treadmill training (DTT), designed to replicate real-life walking conditions, has shown promise effect in individuals with Parkinson's disease (PD). This study aims to compare the effects of DTT versus single treadmill training (STT) on cognitive and walking performance under both single and dual task conditions, as well as on fall, patients' subjective feeling, and quality of life. Sixteen individuals with PD were randomly assigned to DTT or STT group and underwent 8 weeks of training. The DTT group received treadmill training with cognitive loads, while the STT group received treadmill training without cognitive load. Outcome measures included gait parameters (speed, step length) and cognitive performance (reaction time, accuracy, composite score) under both single and dual task conditions. Unified Parkinson's Disease Rating Scale-part III (UPDRS-III), Falls Efficacy Scale (FES), Patient Global Impression of Change (PGIC), and Parkinson's Disease Questionnaire (PDQ-39) were also measured. Both DTT and STT groups showed increased comfortable walking speed and step length. Only the DTT group demonstrated significant improvements in cognitive composite score under both single and dual task conditions, as well as UPDRS-III, FES, and PDQ-39(p < 0.05). DTT can enhance cognitive function without compromising walking ability and also have real-world transferability.

Dominance of Tau Burden in Cortical Over Subcortical Regions Mediates Glymphatic Activity and Clinical Severity in PSP.

BACKGROUND: Progressive supranuclear palsy (PSP) is a tauopathy that involves subcortical regions but also extends to cortical areas. The clinical impact of different tau protein sites and their influence on glymphatic dysfunction have not been investigated. PATIENTS AND METHODS: Participants (n = 55; 65.6 ± 7.1 years; 29 women) with PSP (n = 32) and age-matched normal controls (NCs; n = 23) underwent 18 F-Florzolotau tau PET, MRI, PSP Rating Scale (PSPRS), and Mini-Mental State Examination. Cerebellar gray matter (GM) and parametric estimation of reference signal intensity were used as references for tau burden measured by SUV ratios. Glymphatic activity was measured by diffusion tensor image analysis along the perivascular space (DTI-ALPS). RESULTS: Parametric estimation of reference signal intensity is a better reference than cerebellar GM to distinguish tau burden between PSP and NCs. PSP patients showed higher cortical and subcortical tau SUV ratios than NCs ( P < 0.001 and <0.001). Cortical and subcortical tau deposition correlated with PSPRS, UPDRS, and Mini-Mental State Examination scores (all P 's < 0.05). Cortical tau deposition was further associated with the DTI-ALPS index and frontal-temporal-parietal GM atrophy. The DTI-ALPS indexes showed a significantly negative correlation with the PSPRS total scores ( P < 0.01). Finally, parietal and occipital lobe tau depositions showed mediating effects between the DTI-ALPS index and PSPRS score. CONCLUSIONS: Cortical tau deposition is associated with glymphatic dysfunction and plays a role in mediating glymphatic dysfunction and clinical severity. Our results provide a possible explanation for the worsening of clinical severity in patients with PSP.

The Executive-Function-Related Cognitive-Motor Dual Task Walking Performance and Task Prioritizing Effect on People with Parkinson's Disease.

To safely walk in a community environment requires dual cognitive-walking ambulation ability for people with Parkinson's disease (PD). A past study showed inconsistent results on cognitive-walking performance for PD patients, possibly due to the various cognitive tasks used and task priority assignment. This study designed cognitive-walking tests that used executive-related cognitive tasks to evaluate patients with early-stage Parkinson's disease who did not have obvious cognitive deficits. The effect of assigning task prioritization was also evaluated. Sixteen individuals with PD (PD group) and 16 individuals without PD (control group) underwent single cognitive tests, single walking tests, dual walking tests, and prioritizing task tests. Three types of cognitive, spatial memory, Stroops, and calculation tasks were employed. The cognitive performance was evaluated by response time, accuracy, and speed-accuracy trade off composite score. The walking performance was evaluated by the temporal spatial gait characteristics and variation in gait. The results showed that the walking performance of the PD group was significantly worse than the control group in both single and dual walking conditions. The group difference in cognitive performance was shown in composite score under the dual calculation walking task but not under the single task. While assigning priority to walking, no group difference in walking was observed but the response accuracy rate of PD groups declined. This study concluded that the dual task walking test could sharpen the cognitive deficits for early-stage PD patients. The task priority assignment might not be recommended while testing gait deficits since it decreased the ability to discriminate group differences.

Diffusion tensor imaging for the differential diagnosis of Parkinsonism by machine learning.

BACKGROUND: There are currently no specific tests for either idiopathic Parkinson's disease or Parkinson-plus syndromes. The study aimed to investigate the diagnostic performance of features extracted from the whole brain using diffusion tensor imaging concerning parkinsonian disorders. METHODS: The retrospective data yielded 625 participants (average age: 61.4 ± 8.2, men/women: 313/312; healthy controls/idiopathic Parkinson's disease/multiple system atrophy/progressive supranuclear palsy: 219/286/51/69) between 2008 and 2017. Diffusion-weighted images were obtained using a 3T MR scanner. The 90th, 50th, and 10th percentiles of fractional anisotropy and mean/axial/radial diffusivity from each parcellated brain area were recorded. Statistical analysis was evaluated based on the features extracted from the whole brain, as determined using discriminant function analysis and support vector machine. 20% of the participants were used as an independent blind dataset with 5 times cross-verification. Diagnostic performance was evaluated by the sensitivity and the F1 score. RESULTS: Diagnoses were accurate for distinguishing idiopathic Parkinson's disease from healthy control and Parkinson-plus syndromes (87.4 ± 2.1% and 82.5 ± 3.9%, respectively). Diagnostic F1 scores varied for Parkinson-plus syndromes with 67.2 ± 3.8% for multiple system atrophy and 71.6 ± 3.5% for progressive supranuclear palsy. For early and late detection of idiopathic Parkinson's disease, the diagnostic performance was 79.2 ± 7.4% and 84.4 ± 6.9%, respectively. The diagnostic performance was 68.8 ± 11.0% and 52.5 ± 8.9% in early and late detection to distinguish different Parkinson-plus syndromes. CONCLUSIONS: Features extracted from diffusion tensor imaging of the whole brain can provide objective evidence for the diagnosis of healthy control, idiopathic Parkinson's disease, and Parkinson-plus syndromes with fair to very good diagnostic performance.

Clinical and genetic characterization of a Taiwanese cohort with spastic paraparesis combined with cerebellar involvement.

Hereditary spastic paraplegias (HSPs) are a heterogeneous group of neurodegenerative disorders clinically characterized by progressive lower-limb spasticity. Cerebellar ataxia commonly co-occurs with complicated HSPs. HSP with concurrent cerebellar ataxia has significant clinical and genetic overlaps with hereditary cerebellar ataxia (HCA) and other inherited neurological diseases, adding to the challenge of planning genetic testing for the disease. In this study, we characterized clinical features of a cohort of 24 patients (male/female: 15/9) from 22 families who presented spastic paraparesis combined with cerebellar involvement, with a median disease onset age 20.5 (range 5-53) years. Aside from the core phenotype, 18 (75%) patients had additional neuropsychiatric and systemic manifestations. A stepwise genetic testing strategy stratified by mode of inheritance, distinct neuroimaging features (e.g., thin corpus callosum), population-specific prevalence and whole-exome sequencing was utilized to investigate the genetic etiology. Causative mutations in up to 10 genes traditionally related to HSP, HCA and other neurogenetic diseases (autosomal recessive spastic ataxia of Charlevoix-Saguenay, neurodegeneration with brain iron accumulation, and progressive encephalopathy with brain atrophy and thin corpus callosum) were detected in 16 (73%) of the 22 pedigrees. Our study revealed the genetic complexity of HSP combined with cerebellar involvement. In contrast to the marked genetic diversity, the functions of the causative genes are restricted to a limited number of physiological themes. The functional overlap might reflect common underlying pathogenic mechanisms, to which the corticospinal tract and cerebellar neuron circuits may be especially vulnerable.

Subthalamic high-beta oscillation informs the outcome of deep brain stimulation in patients with Parkinson's disease.

Background: The therapeutic effect of deep brain stimulation (DBS) of the subthalamic nucleus (STN) for Parkinson's disease (PD) is related to the modulation of pathological neural activities, particularly the synchronization in the ß band (13-35 Hz). However, whether the local ß activity in the STN region can directly predict the stimulation outcome remains unclear. Objective: We tested the hypothesis that low-ß (13-20 Hz) and/or high-ß (20-35 Hz) band activities recorded from the STN region can predict DBS efficacy. Methods: Local field potentials (LFPs) were recorded in 26 patients undergoing deep brain stimulation surgery in the subthalamic nucleus area. Recordings were made after the implantation of the DBS electrode prior to its connection to a stimulator. The maximum normalized powers in the theta (4-7 Hz), alpha (7-13 Hz), low-ß (13-20 Hz), high-ß (20-35 Hz), and low-γ (40-55 Hz) subbands in the postoperatively recorded LFP were correlated with the stimulation-induced improvement in contralateral tremor or bradykinesia-rigidity. The distance between the contact selected for stimulation and the contact with the maximum subband power was correlated with the stimulation efficacy. Following the identification of the potential predictors by the significant correlations, a multiple regression analysis was performed to evaluate their effect on the outcome. Results: The maximum high-ß power was positively correlated with bradykinesia-rigidity improvement (r s = 0.549, p < 0.0001). The distance to the contact with maximum high-ß power was negatively correlated with bradykinesia-rigidity improvement (r s = -0.452, p < 0.001). No significant correlation was observed with low-ß power. The maximum high-ß power and the distance to the contact with maximum high-ß power were both significant predictors for bradykinesia-rigidity improvement in the multiple regression analysis, explaining 37.4% of the variance altogether. Tremor improvement was not significantly correlated with any frequency. Conclusion: High-ß oscillations, but not low-ß oscillations, recorded from the STN region with the DBS lead can inform stimulation-induced improvement in contralateral bradykinesia-rigidity in patients with PD. High-ß oscillations can help refine electrode targeting and inform contact selection for DBS therapy.

Comparisons of vesicular monoamine transporter type 2 signals in Parkinson's disease and parkinsonism secondary to carbon monoxide poisoning.

Parkinson's disease (PD) and carbon monoxide (CO) poisoning demonstrate parkinsonian features related to presynaptic dopaminergic deficits. However, their clinical features and treatment responses are different, indicating other roles of neurotransmitters in symptomatic modulation. In this study, we used 18F-FP-(+)-DTBZ PET to explore vesicular monoamine transporter type 2 (VMAT2) distributions in 31 patients with PD, 39 patients with CO poisoning and parkinsonian features (n = 39), and 24 age-matched controls. In addition to the disease-specific VMAT2 topographies in PD and CO poisoning, we also constructed feature-specific functional networks. The cardinal features included tremor, rigidity, akinesia, and rapid alternating movements (RAM), and the overall motor severity was scored using Unified Parkinson Disease Rating Scale (UPDRS) and modified Hoehn-Yahr (mH-Y) Scale scores. Our results suggested that a reduction in VMAT2 signals in the caudate, amygdala, and hippocampus were more specific to CO poisoning, while low uptake in the putamen and substantia nigra was more specific to PD. UPDRS and mH-Y scores were related to striatum signals in both groups and hippocampus and raphe in the CO poisoning group. With regards to the cardinal features, the putamen was related to akinesia in both groups. The substantia nigra was related to rigidity in PD, and the caudate and nucleus accumbens were related to akinesia, RAM and rigidity in CO poisoning. Our study enhances the current understanding of different patterns of monoaminergic terminal deficits in patients with CO poisoning and PD.

PLA2G6 mutations cause motor dysfunction phenotypes of young-onset dystonia-parkinsonism type 14 and can be relieved by DHA treatment in animal models.

Parkinson's disease (PD), the most common neurodegenerative motor disorder, is currently incurable. Although many studies have provided insights on the substantial influence of genetic factors on the occurrence and development of PD, the molecular mechanism underlying the disease is largely unclear. Previous studies have shown that point mutations in the phospholipase A2 group VI gene (PLA2G6) correlate with young-onset dystonia-parkinsonism type 14 (PARK14). However, limited information is available regarding the pathogenic role of this gene and the mechanism underlying its function. To study the role of PLA2G6 mutations, we first used zebrafish larvae to screen six PLA2G6 mutations and revealed that injection of D331Y, T572I, and R741Q mutation constructs induced phenotypes such as motility defects and reduction in dopaminergic neurons. The motility defects could be alleviated by treatment with L-3, 4-dihydroxyphenylalanine (L-dopa), indicating that these mutations are pathological for PARK14 symptoms. Furthermore, the injection of D331Y and T572I mutation constructs reduced phospholipase activity of PLA2G6 and its lipid metabolites, which confirmed that these two mutations are loss-of-function mutations. Metabolomic analysis revealed that D331Y or T572I mutation led to higher phospholipid and lower docosahexaenoic acid (DHA) levels, indicating that reduced DHA levels are pathological for defective motor functions. Further, a dietary DHA supplement relieved the motility defects in PLA2G6D331Y/D331Y knock-in mice. This result revealed that the D331Y mutation caused defective PLA2G6 phospholipase activity and consequently reduced the DHA level, which is the pathogenic factor responsible for PARK14. The results of this study will facilitate the development of therapeutic strategies for PARK14.

Functional variant rs17525453 within RAB35 gene promoter is possibly associated with increased risk of Parkinson's disease in Taiwanese population.

Our previous study suggests that upregulated RAB35 is implicated in etiology of Parkinson's disease (PD). We hypothesized that upregulated RAB35 results from single nucleotide polymorphisms (SNPs) in RAB35 gene promoter. We identified SNPs within RAB35 gene promoter by analyzing DNA samples of discovery cohort and validation cohort. SNP rs17525453 within RAB35 gene promoter (T>C at position of -66) was significantly associated with idiopathic PD patients. Compared to normal controls, sporadic PD patients had higher C allele frequency. CC and CT genotype significantly increased risk of PD compared with TT genotype. SNP rs17525453 within RAB35 gene promoter leads to formation of transcription factor TFII-I binding site. Results of EMSA and supershift assay indicated that TFII-I binds to rs17525453 sequence of RAB35 gene promoter. Luciferase reporter assays showed that rs17525453 variant of RAB35 gene promoter possesses an augmented transcriptional activity. Our results suggest that functional variant rs17525453 within RAB35 gene promoter is likely to enhance transcriptional activity and upregulate RAB35 protein, which could lead to increased risk of PD in Taiwanese population.

The Add-On Effect of Lactobacillus plantarum PS128 in Patients With Parkinson's Disease: A Pilot Study.

Background: Lactobacillus plantarum PS128 (PS128) is a specific probiotic, known as a psychobiotic, which has been demonstrated to alleviate motor deficits and inhibit neurodegenerative processes in Parkinson's disease (PD)-model mice. We hypothesize that it may also be beneficial to patients with PD based on the possible mechanism via the microbiome-gut-brain axis. Methods: This is an open-label, single-arm, baseline-controlled trial. The eligible participants were scheduled to take 60 billion colony-forming units of PS128 once per night for 12 weeks. Clinical assessments were conducted using the Unified Parkinson's Disease Rating Scale (UPDRS), modified Hoehn and Yahr scale, and change in patient "ON-OFF" diary recording as primary outcome measures. The non-motor symptoms questionnaire, Beck depression inventory-II, patient assessment of constipation symptom, 39-item Parkinson's Disease Questionnaire (PDQ-39), and Patient Global Impression of Change (PGI-C) were assessed as secondary outcome measures. Results: Twenty-five eligible patients (32% women) completed the study. The mean age was 61.84 ± 5.74 years (range, 52-72), mean disease duration was 10.12 ± 2.3 years (range, 5-14), and levodopa equivalent daily dosage was 1063.4 ± 209.5 mg/daily (range, 675-1,560). All patients remained on the same dosage of anti-parkinsonian and other drugs throughout the study. After 12 weeks of PS128 supplementation, the UPDRS motor scores improved significantly in both the OFF and ON states (p = 0.004 and p = 0.007, respectively). In addition, PS128 intervention significantly improved the duration of the ON period and OFF period as well as PDQ-39 values. However, no obvious effect of PS128 on non-motor symptoms of patients with PD was observed. Notably, the PGI-C scores improved in 17 patients (68%). PS128 intervention was also found to significantly reduce plasma myeloperoxidase and urine creatinine levels. Conclusion: The present study demonstrated that PS128 supplementation for 12 weeks with constant anti-parkinsonian medication improved the UPDRS motor score and quality of life of PD patients. We suggest that PS128 could serve as a therapeutic adjuvant for the treatment of PD. In the future, placebo-controlled studies are needed to further support the efficacy of PS128 supplementation. Clinical Trial Registration: https://clinicaltrials.gov/, identifier: NCT04389762.

Fixel-Based Analysis of White Matter Degeneration in Patients With Progressive Supranuclear Palsy or Multiple System Atrophy, as Compared to Parkinson's Disease.

Introduction: White matter degeneration may contribute to clinical symptoms of parkinsonism. Objective: We used fixel-based analysis (FBA) to compare the extent and patterns of white matter degeneration in different parkinsonian syndromes-including idiopathic Parkinson's disease (PD), multiple system atrophy (MSA), and progressive supranuclear palsy (PSP). Methods: This is a retrospective interpretation of prospectively acquired data of patients recruited in previous studies during 2008 and 2019. Diffusion-weighted images were acquired on a 3-Tesla scanner (diffusion weighting b = 1000 s/mm2-applied along either 64 or 30 non-collinear directions) from 53 patients with PD (men/women: 29/24; mean age: 65.06 ± 5.51 years), 47 with MSA (men/women: 20/27; mean age: 63.00 ± 7.19 years), and 50 with PSP men/women: 20/30; mean age: 65.96 ± 3.14 years). Non-parametric permutation tests were used to detect intergroup differences in fixel-related indices-including fiber density, fiber cross-section, and their combination. Results: Patterns of white matter degeneration were significantly different between PD and atypical parkinsonisms (MSA and PSP). Compared with patients with PD, those with MSA and PSP showed a more extensive white matter involvement-noticeably descending tracts from primary motor cortex to corona radiata and cerebral peduncle. Lesions of corpus callosum were specific to PSP and absent in both MSA and PD. Discussion: FBA identified specific patterns of white matter changes in MSA and PSP patients compared to PD. Our results proved the utility of FBA in evaluation of implied biological processes of white matter changes in parkinsonism. Our study set the stage for future applications of this technique in patients with parkinsonian syndromes.

Theta Oscillations at Subthalamic Region Predicts Hypomania State After Deep Brain Stimulation in Parkinson's Disease.

Subthalamic nucleus (STN) deep brain stimulation (DBS) is an effective treatment for the motor impairments of patients with advanced Parkinson's disease. However, mood or behavioral changes, such as mania, hypomania, and impulsive disorders, can occur postoperatively. It has been suggested that these symptoms are associated with the stimulation of the limbic subregion of the STN. Electrophysiological studies demonstrate that the low-frequency activities in ventral STN are modulated during emotional processing. In this study, we report 22 patients with Parkinson's disease who underwent STN DBS for treatment of motor impairment and presented stimulation-induced mood elevation during initial postoperative programming. The contact at which a euphoric state was elicited by stimulation was termed as the hypomania-inducing contact (HIC) and was further correlated with intraoperative local field potential recorded during the descending of DBS electrodes. The power of four frequency bands, namely, θ (4-7 Hz), α (7-10 Hz), ß (13-35 Hz), and γ (40-60 Hz), were determined by a non-linear variation of the spectrogram using the concentration of frequency of time (conceFT). The depth of maximum θ power is located approximately 2 mm below HIC on average and has significant correlation with the location of contacts (r = 0.676, p < 0.001), even after partializing the effect of α and ß, respectively (r = 0.474, p = 0.022; r = 0.461, p = 0.027). The occurrence of HIC was not associated with patient-specific characteristics such as age, gender, disease duration, motor or non-motor symptoms before the operation, or improvement after stimulation. Taken together, these data suggest that the location of maximum θ power is associated with the stimulation-induced hypomania and the prediction of θ power is frequency specific. Our results provide further information to refine targeting intraoperatively and select stimulation contacts in programming.

EIF2AK2 Missense Variants Associated with Early Onset Generalized Dystonia.

OBJECTIVE: The study was undertaken to identify a monogenic cause of early onset, generalized dystonia. METHODS: Methods consisted of genome-wide linkage analysis, exome and Sanger sequencing, clinical neurological examination, brain magnetic resonance imaging, and protein expression studies in skin fibroblasts from patients. RESULTS: We identified a heterozygous variant, c.388G>A, p.Gly130Arg, in the eukaryotic translation initiation factor 2 alpha kinase 2 (EIF2AK2) gene, segregating with early onset isolated generalized dystonia in 5 patients of a Taiwanese family. EIF2AK2 sequencing in 191 unrelated patients with unexplained dystonia yielded 2 unrelated Caucasian patients with an identical heterozygous c.388G>A, p.Gly130Arg variant, occurring de novo in one case, another patient carrying a different heterozygous variant, c.413G>C, p.Gly138Ala, and one last patient, born from consanguineous parents, carrying a third, homozygous variant c.95A>C, p.Asn32Thr. These 3 missense variants are absent from gnomAD, and are located in functional domains of the encoded protein. In 3 patients, additional neurological manifestations were present, including intellectual disability and spasticity. EIF2AK2 encodes a kinase (protein kinase R [PKR]) that phosphorylates eukaryotic translation initiation factor 2 alpha (eIF2α), which orchestrates the cellular stress response. Our expression studies showed abnormally enhanced activation of the cellular stress response, monitored by PKR-mediated phosphorylation of eIF2α, in fibroblasts from patients with EIF2AK2 variants. Intriguingly, PKR can also be regulated by PRKRA (protein interferon-inducible double-stranded RNA-dependent protein kinase activator A), the product of another gene causing monogenic dystonia. INTERPRETATION: We identified EIF2AK2 variants implicated in early onset generalized dystonia, which can be dominantly or recessively inherited, or occur de novo. Our findings provide direct evidence for a key role of a dysfunctional eIF2α pathway in the pathogenesis of dystonia. ANN NEUROL 2021;89:485-497.

(D620N) VPS35 causes the impairment of Wnt/ß-catenin signaling cascade and mitochondrial dysfunction in a PARK17 knockin mouse model.

Patients with familial type 17 of Parkinson's disease (PARK17) manifest autosomal dominant pattern and late-onset parkinsonian syndromes. Heterozygous (D620N) mutation of vacuolar protein sorting 35 (VPS35) is genetic cause of PARK17. We prepared heterozygous VPS35D620N/+ knockin mouse, which is an ideal animal model of (D620N) VPS35-induced autosomal dominant PARK17. Late-onset loss of substantia nigra pars compacta (SNpc) dopaminergic (DAergic) neurons and motor deficits of Parkinson's disease were found in 16-month-old VPS35D620N/+ mice. Normal function of VPS35-containing retromer is needed for activity of Wnt/ß-catenin cascade, which participates in protection and survival of SNpc DAergic neurons. It was hypothesized that (D620N) VPS35 mutation causes the malfunction of VPS35 and resulting impaired activity of Wnt/ß-catenin pathway. Protein levels of Wnt1 and nuclear ß-catenin were reduced in SN of 16-month-old VPS35D620N/+ knockin mice. Downregulated protein expression of survivin, which is a target gene of nuclear ß-catenin, and upregulated protein levels of active caspase-8 and active caspase-9 were observed in SN of VPS35D620N/+ mice at age of 16 months. VPS35 is involved in controlling morphology and function of mitochondria. Impaired function of VPS35 caused by (D620N) mutation could lead to abnormal morphology and malfunction of mitochondria. A significant decrease in mitochondrial size and resulting mitochondrial fragmentation was found in tyrosine hydroxylase-positive and neuromelanin-positive SNpc DAergic neurons of 16-month-old VPS35D620N/+ mice. Mitochondrial complex I activity or complex IV activity was reduced in SN of 16-month-old VPS35D620N/+ mice. Increased level of mitochondrial ROS and oxidative stress were found in SN of 16-month-old VPS35D620N/+ mice. Levels of cytosolic cytochrome c and active caspase-3 were increased in SN of VPS35D620N/+ mice aged 16 months. Our results suggest that PARK17 mutant (D620N) VPS35 impairs activity of Wnt/ß-catenin signaling pathway and causes abnormal morphology and dysfunction of mitochondria, which could lead to neurodegeneration of SNpc DAergic cells.

The efficacy of cognitive-cycling dual-task training in patients with early-stage Parkinson's disease: A pilot study.

BACKGROUND: Recent studies have suggested that cognitive-motor dual-task (DT) training might improve gait performance, locomotion automaticity, balance, and cognition in patients with Parkinson's disease (PD). OBJECTIVE: We aimed to investigate the efficacy of cognitive-cycling DT training in patients with early-stage PD. METHODS: Participants were scheduled to perform cognitive tasks simultaneously with the cycling training twice per week for eight weeks for a total of 16 sessions during their on-states. Clinical assessments were conducted using the unified Parkinson's disease rating scale (UPDRS), modified Hoehn and Yahr stage, Timed Up and Go (TUG) test, gait and cognitive performances under dual-task paradigm, the new freezing of gait questionnaire, Schwab and England Activities of Daily Living scale, 39-item Parkinson's disease questionnaire, and cognitive performance. RESULTS: Thirteen eligible patients were enrolled in the study. The mean age was 60.64±5.32 years, and the mean disease duration was 7.02±3.23 years. Twelve PD patients completed 16 serial cognitive-cycling sessions for two months. After 16 sessions of training (T2), the UPDRS III scores improved significantly in both the off- and on-states, and TUG were significantly less than those at pretraining (T0). During both the single-task and the DT situations, gait performance and spatial memory cognitive performance significantly improved from T0 to T2. CONCLUSION: The present study demonstrated that cognitive-cycling DT training improves the motor functions, gait and cognitive performances of PD patients.

18F-THK5351 PET imaging in patients with progressive supranuclear palsy: associations with core domains and diagnostic certainty.

The associations of 18F-THK5351 tau positron emission tomography (PET) findings with core domains of progressive supranuclear palsy (PSP) and its diagnostic certainty have yet to be fully elucidated. The 18F-THK5351 PET patterns of 17 patients with PSP (68.9 ± 6.5 years; 8 women) were compared with those observed in 28 age-matched and sex-matched (66.2 ± 4.5 years, 18 women) control subjects (CS). Tracer accumulation-as reflected by standardized uptake value ratios (SUVRs) and z-scores-was correlated with core domains of PSP and different levels of diagnostic certainty. Compared with CS, patients with PSP showed an increased 18F-THK5351 uptake in the globus pallidus and red nucleus. Patients with PSP and oculomotor dysfunction had significantly higher SUVRs in the midbrain, red nucleus, and raphe nucleus than those without. In addition, cases who meet criteria for level 1 (highest) certainty in the postural instability domain showed significantly higher SUVRs in the frontal, parietal, precuneus, and sensory-motor cortex. Patients with probable PSP had significantly higher SUVR values than those with possible PSP in multiple cortical (i.e., frontal, parietal, temporal, anterior cingulate gyrus, precuneus, and sensory-motor gyrus) and subcortical (i.e., putamen, thalamus, and raphe nucleus) regions. Patterns of 18F-THK5351 uptake were correlated to core domains of PSP-including oculomotor dysfunction and postural instability. Moreover, the degree of diagnostic certainty for PSP was appreciably associated with 18F-THK5351 PET findings.

A Method for the Prediction of Clinical Outcome Using Diffusion Magnetic Resonance Imaging: Application on Parkinson's Disease.

Robust early prediction of clinical outcomes in Parkinson's disease (PD) is paramount for implementing appropriate management interventions. We propose a method that uses the baseline MRI, measuring diffusion parameters from multiple parcellated brain regions, to predict the 2-year clinical outcome in Parkinson's disease. Diffusion tensor imaging was obtained from 82 patients (males/females = 45/37, mean age: 60.9 ± 7.3 years, baseline and after 23.7 ± 0.7 months) using a 3T MR scanner, which was normalized and parcellated according to the Automated Anatomical Labelling template. All patients were diagnosed with probable Parkinson's disease by the National Institute of Neurological Disorders and Stroke criteria. Clinical outcome was graded using disease severity (Unified Parkinson's Disease Rating Scale and Modified Hoehn and Yahr staging), drug administration (levodopa equivalent daily dose), and quality of life (39-item PD Questionnaire). Selection and regularization of diffusion parameters, the mean diffusivity and fractional anisotropy, were performed using least absolute shrinkage and selection operator (LASSO) between baseline diffusion index and clinical outcome over 2 years. Identified features were entered into a stepwise multivariate regression model, followed by a leave-one-out/5-fold cross validation and additional blind validation using an independent dataset. The predicted Unified Parkinson's Disease Rating Scale for each individual was consistent with the observed values at blind validation (adjusted R2 0.76) by using 13 features, such as mean diffusivity in lingual, nodule lobule of cerebellum vermis and fractional anisotropy in rolandic operculum, and quadrangular lobule of cerebellum. We conclude that baseline diffusion MRI is potentially capable of predicting 2-year clinical outcomes in patients with Parkinson's disease on an individual basis.

Alda-1, an activator of ALDH2, ameliorates Achilles tendinopathy in cellular and mouse models.

Achilles tendinopathy has a high re-injury rate and poor prognosis. Development of effective therapy for Achilles tendinopathy is important. Excessive accumulation of ROS and resulting oxidative stress are believed to cause tendinopathy. Overproduction of hydrogen peroxide (H2O2), the most common ROS, could lead to the tendinopathy by causing oxidative damage, activation of endoplasmic reticulum (ER) stress and apoptotic death of tenocytes. Activation of mitochondrial aldehyde dehydrogenase 2 (ALDH2) is expected to alleviate oxidative stress and ER stress. Alda-1 is a selective and potent activator of ALDH2. In this study, we examined the cytoprotective benefit of Alda-1, an activator of ALDH2, on H2O2-induced Achilles tendinopathy in cellular and mouse models. We prepared cellular and mouse models of Achilles tendinopathy by treating cultured Achilles tenocytes and Achilles tendons with oxidative stressor H2O2. Subsequently, we studied the protective benefit of Alda-1 on H2O2-induced Achilles tendinopathy. Alda-1 pretreatment attenuated H2O2-induced cell death of cultured Achilles tenocytes. Treatment of Alda-1 prevented H2O2-induced oxidative stress and depolarization of mitochondrial membrane potential in tenocytes. Application of Alda-1 attenuated H2O2-triggered mitochondria- and ER stress-mediated apoptotic cascades in cultured tenocytes. Alda-1 treatment ameliorated the severity of H2O2-induced Achilles tendinopathy in vivo by preventing H2O2-induced pathological histological features of Achilles tendons, apoptotic death of Achilles tenocytes and upregulated expression of inflammatory cytokines IL-1ß and TNF-α. Our results provide the evidence that ALDH2 activator Alda-1 ameliorates H2O2-induced Achilles tendinopathy. Alda-1 could be used for preventing and treating Achilles tendinopathy.

Prediction of the Clinical Severity of Progressive Supranuclear Palsy by Diffusion Tensor Imaging.

Progressive supranuclear palsy (PSP) is characterized by a rapid and progressive clinical course. A timely and objective image-based evaluation of disease severity before standard clinical assessments might increase the diagnostic confidence of the neurologist. We sought to investigate whether features from diffusion tensor imaging of the entire brain with a machine learning algorithm, rather than a few pathogenically involved regions, may predict the clinical severity of PSP. Fifty-three patients who met the diagnostic criteria for probable PSP were subjected to diffusion tensor imaging. Of them, 15 underwent follow-up imaging. Clinical severity was assessed by the neurological examinations. Mean diffusivity and fractional anisotropy maps were spatially co-registered, normalized, and parcellated into 246 brain regions from the human Brainnetome atlas. The predictors of clinical severity from a stepwise linear regression model were determined after feature reduction by the least absolute shrinkage and selection operator. Performance estimates were obtained using bootstrapping, cross-validation, and through application of the model in the patients who underwent repeated imaging. The algorithm confidently predicts the clinical severity of PSP at the individual level (adjusted R2: 0.739 and 0.892, p < 0.001). The machine learning algorithm for selection of diffusion tensor imaging-based features is accurate in predicting motor subscale of unified Parkinson's disease rating scale and postural instability and gait disturbance of PSP.