Encephalopathy, Hypoglycemia, and Flailing Extremities: A Case of Bilateral Chorea““Ballism Associated with Diabetic Ketoacidosis

Background: Hypo/hyperglycemia is a known cause of chorea and hemiballism. The temporallobes, hippocampus, basal ganglia, and substantia nigra are most susceptible to hypoglycemic changes. Methods: We present a caseof bilateral chorea and bi-ballism accompanied by encephalopathyin the setting of severe hypoglycemia and diabetic ketoacidosis. The patient had brain MRI changes involving both caudate nuclei, temporal lobes, and hippocampi. Discussion: This case demonstrates the basal ganglia's vulnerability to hypoglycemia and the need for cautious evaluation of involuntary movements when they occur in the setting of encephalopathy

Driving Errors in Parkinson’s Disease: Moving Closer to Predicting On-Road Outcomes

Age-related medical conditions such as Parkinson’s disease (PD) compromise driver fitness. Results from studies are unclear on the specific driving errors that underlie passing or failing an on-road assessment. In this study, we determined the between-group differences and quantified the on-road driving errors that predicted pass or fail on-road outcomes in 101 drivers with PD (mean age 5 69.38 ± 7.43) and 138 healthy control (HC) drivers (mean age 5 71.76 ± 5.08). Participants with PD had minor differences in demographics and driving habits and history but made more and different driving errors than HC participants. Drivers with PD failed the on-road test to a greater extent than HC drivers (41% vs. 9%), x2(1) 5 35.54, HC N 5 138, PD N 5 99, p \u3c .001. The driving errors predicting on-road pass or fail outcomes (95% confidence interval, Nagelkerke R2 5.771) were made in visual scanning, signaling, vehicle positioning, speeding (mainly underspeeding, t (61) 5 7.004, p \u3c .001, and total errors. Although it is difficult to predict on-road outcomes, this study provides a foundation for doing so

Direct detection of alpha synuclein oligomers in vivo

Background: Rat models of Parkinson’s disease are widely used to elucidate the mechanisms underlying disease etiology or to investigate therapeutic approaches. Models were developed using toxins such as MPTP or 6-OHDA to specifically target dopaminergic neurons resulting in acute neuronal loss in the substantia nigra or by using viral vectors to induce the specific and gradual expression of alpha synuclein in the substantia nigra. The detection of alpha- synuclein oligomers, the presumed toxic species, in these models and others has been possible using only indirect biochemical approaches to date. Here we coinjected AAVs encoding alpha-synuclein fused to the N- or C-terminal half of VenusYFP in rat substantia nigra pars compacta and describe for the first time a novel viral vector rodent model with the unique ability to directly detect and track alpha synuclein oligomers ex vivo and in vivo. Results: Viral coinjection resulted in widespread VenusYFP signal within the nigrostriatal pathway, including cell bodies in the substantia nigra and synaptic accumulation in striatal terminals, suggestive of in vivo alpha-synuclein oligomers formation. Transduced rats showed alpha-synuclein induced dopaminergic neuron loss in the substantia nigra, the appearance of dystrophic neurites, and gliosis in the striatum. Moreover, we have applied in vivo imaging techniques in the living mouse to directly image alpha-synuclein oligomers in the cortex. Conclusion: We have developed a unique animal model that provides a tool for the Parkinson’s disease research community with which to directly detect alpha- synuclein oligomers in vivo and screen therapeutic approaches targeting alpha-synuclein oligomers

A randomized, double-blind, placebo-controlled trial of coenzyme Q10 in Huntington disease

Objective: To test the hypothesis that chronic treatment of early-stage Huntington disease (HD) with high-dose coenzyme Q10 (CoQ) will slow the progressive functional decline of HD. Methods: We performed a multicenter randomized, double-blind, placebo-controlled trial. Patients with early-stage HD (n = 609) were enrolled at 48 sites in the United States, Canada, and Australia from 2008 to 2012. Patients were randomized to receive either CoQ 2,400 mg/d or matching placebo, then followed for 60 months. The primary outcome variable was the change from baseline to month 60 in Total Functional Capacity score (for patients who survived) combined with time to death (for patients who died) analyzed using a joint-rank analysis approach. Results: An interim analysis for futility revealed a conditional power of <5% for the primary analysis, prompting premature conclusion in July 2014. No statistically significant differences were seen between treatment groups for the primary or secondary outcome measures. CoQ was generally safe and well-tolerated throughout the study. Conclusions: These data do not justify use of CoQ as a treatment to slow functional decline in HD

Early‐Motor Phenotype Relates to Neuropsychiatric and Cognitive Disorders in Huntington's Disease

OBJECTIVE: To determine the relationships between the motor phenotype and the presence of specific neuropsychiatric and neuropsychological disorders in patients with early motor-manifest Huntington\u27s disease (HD). METHODS: From the Enroll-HD study, 3,505 individuals with HD who had ≤5 years of motor symptoms were classified based on the predefined parkinsonism/chorea index into chorea-dominant (n = 1125), parkinsonism-dominant (n = 867), and mixed-motor phenotype (n = 1513) groups. An analysis was performed on the results of the short Problem Behaviors Assessment. This test assesses patients for neuropsychiatric disorders such as depression, irritability/aggression, apathy, obsessive-compulsive behaviors, and psychosis as well as cognitive disorders by using neuropsychological tests such as the Stroop Interference test, Trail Making Test Part A and B, letter fluency, Symbol Digit Modality test, and animal fluency test. RESULTS: In these early motor-manifest HD individuals, motor phenotype was associated with neuropsychiatric and cognitive changes. Independent of the age of motor onset, motor duration and severity, CAG repeat expansion, and medication use, the parkinsonism-dominant group had more severe neuropsychiatric disorders (depression, apathy, obsessive-compulsive behaviors, and psychosis) and poorer performance on all cognitive tests than those patients in the mixed-motor phenotype and chorea-dominant groups. The patients in the chorea-dominant group had less apathy and depression than those in the mixed-motor phenotype group. CONCLUSIONS: In the early stage of motor-manifest HD, parkinsonism-dominant patients appear to have more severe neuropsychiatric disturbances and more cognitive impairments than those HD patients with chorea-dominant and mixed-motor phenotypes. Future studies should explore the brain mechanisms of these disorders and the possible treatments. © 2020 International Parkinson and Movement Disorder Society

Early-Motor Phenotype Relates to Neuropsychiatric and Cognitive Disorders in Huntington\u27s Disease

OBJECTIVE: To determine the relationships between the motor phenotype and the presence of specific neuropsychiatric and neuropsychological disorders in patients with early motor-manifest Huntington\u27s disease (HD). METHODS: From the Enroll-HD study, 3,505 individuals with HD who had ≤5 years of motor symptoms were classified based on the predefined parkinsonism/chorea index into chorea-dominant (n = 1125), parkinsonism-dominant (n = 867), and mixed-motor phenotype (n = 1513) groups. An analysis was performed on the results of the short Problem Behaviors Assessment. This test assesses patients for neuropsychiatric disorders such as depression, irritability/aggression, apathy, obsessive-compulsive behaviors, and psychosis as well as cognitive disorders by using neuropsychological tests such as the Stroop Interference test, Trail Making Test Part A and B, letter fluency, Symbol Digit Modality test, and animal fluency test. RESULTS: In these early motor-manifest HD individuals, motor phenotype was associated with neuropsychiatric and cognitive changes. Independent of the age of motor onset, motor duration and severity, CAG repeat expansion, and medication use, the parkinsonism-dominant group had more severe neuropsychiatric disorders (depression, apathy, obsessive-compulsive behaviors, and psychosis) and poorer performance on all cognitive tests than those patients in the mixed-motor phenotype and chorea-dominant groups. The patients in the chorea-dominant group had less apathy and depression than those in the mixed-motor phenotype group. CONCLUSIONS: In the early stage of motor-manifest HD, parkinsonism-dominant patients appear to have more severe neuropsychiatric disturbances and more cognitive impairments than those HD patients with chorea-dominant and mixed-motor phenotypes. Future studies should explore the brain mechanisms of these disorders and the possible treatments. © 2020 International Parkinson and Movement Disorder Society

Mild cognitive impairment and dementia in motor manifest Huntington\u27s disease: Classification and prevalence

OBJECTIVES: To identify the characteristics and prevalence of mild cognitive impairment in patients with motor-manifest Huntington\u27s disease (HD) and to propose a new mild cognitive impairment (HD-MCI) classification for HD. METHODS: We included 307 motor-manifest HD participants from the ENROLL-HD study who completed the evaluation in four neurocognitive domains including executive functions, processing speed, language, and memory. Cognitive impairment in each domain was determined by age- and education-adjusted cutoffs (\u3e 1.5 standard deviations below the mean). HD-MCI was defined as an impairment in at least one cognitive domain without a loss of functional independence (Function Independence Scale, FIS ≥85). Dementia (HD-Dem) was defined as at least two domains of cognitive impairment with functional impairment (FIS ≤80). RESULTS: At the onset of motor symptoms, MCI was present in 84% and dementia in 5% of patients. After 5 years of motor symptoms, 24% of participants met the criteria for MCI and 69% for dementia. Executive dysfunction was the most common impairment, being present in 70% of participants, followed by slowed processing speed in 67%. Language impairment was reported in 55% and memory deficits in 53%. MCI subtypes were classified as Executive-predominant (executive impairment and slowed processing speed), Representational-predominant (impaired language and memory) and Mixed Executive-Representational . Executive-predominant MCI comprised 30%, Representational-predominant 15% and Mixed 55% of this cohort. CONCLUSION: MCI is highly prevalent in the early stage of motor-manifest HD. Three MCI subgroups are defined suggesting at the earlier stage of this disease the frontal-striatal-executive and/or the temporoparietal-representational functional network can be impaired

Rab GTPase Protein Expression Changes in alpha-Synucleinopathy and Tauopathy Disorders

Objective: Determine Rab GTPase expression changes in α-synucleinopathy and tauopathy disorders. Background: Alterations in Rab GTPase function are increasingly implicated in neurodegenerative diseases. In Lewy body disorders, Rab proteins interact with α-synuclein, supporting a potential role in Parkinson disease (PD). Expression of specific Rabs (e.g., Rab1, 8a) rescues α-synuclein associated trafficking deficits. Rab proteins have similarly been linked to Alzheimer disease (AD). However, little is known about the role of Rab GTPases in tau disorders and expression patterns in neurodegenerative disease. Design/Methods: We examined expression levels of several Rab GTPase proteins (Rab 3a, 5, 7, 8a, 10, 11a, and 35) in postmortem human brain regions from multiple tauopathy (AD, PSP, CBD), Lewy body (α-Synucleinopathy) disorders (PD, DLB, MSA), and matched controls. Frozen brain samples were homogenized in high salt buffer and analyzed by Western blot with specific Rab antibodies. Results: Rab3a expression was significantly increased in the striatum of DLB and MSA, but not PD. Rab8a levels were decreased in frontal and temporal cortex in atypical parkinsonian disorders (APD) compared to control. Rab11a was similarly decreased in frontal cortex in APD’s but increased in the striatum and white matter of PSP and CBD. Rab35 appeared unchanged in PD but was significantly decreased in the striatum in APD’s. Conclusions: These findings represent the first comprehensive analysis of Rab GTPase expression and demonstrate differential expression patterns for Rab proteins in disease-affected regions of tau and α-synuclein disorders. Grant: Supported by the Allen-Simmons Atypical Parkinsonism Fellowship. Work performed at the University of Florida by Dr. Parmar under the mentorship of Dr. McFarland

The ER retention protein RER1 promotes alpha-synuclein degradation via the proteasome

<div><p>Abnormal accumulation of α-synuclein (αSyn) has been linked to endoplasmic-reticulum (ER) stress, defective intracellular protein/vesicle trafficking, and cytotoxicity. Targeting factors involved in ER-related protein processing and trafficking may, therefore, be a key to modulating αSyn levels and associated toxicity. Recently retention in endoplasmic reticulum 1 (RER1) has been identified as an important ER retrieval/retention factor for Alzheimer’s disease proteins and negatively regulates amyloid-β peptide levels. Here, we hypothesized that RER1 might also play an important role in retention/retrieval of αSyn and mediate levels. We expressed RER1 and a C-terminal mutant RER1Δ25, which lacks the ER retention/retrieval function, in HEK293 and H4 neuroglioma cells. RER1 overexpression significantly decreased levels of both wild type and A30P, A53T, and E46K disease causal mutants of αSyn, whereas the RER1Δ25 mutant had a significantly attenuated effect on αSyn. RER1 effects were specific to αSyn and had little to no effect on either βSyn or the Δ71–82 αSyn mutant, which both lack the NAC domain sequence critical for synuclein fibrillization. Tests with proteasomal and macroautophagy inhibitors further demonstrate that RER1 effects on αSyn are primarily mediated through the ubiquitin-proteasome system. RER1 also appears to interact with the ubiquitin ligase NEDD4. RER1 in human diseased brain tissues co-localizes with αSyn-positive Lewy bodies. Together, these findings provide evidence that RER1 is a novel and potential important mediator of elevated αSyn levels. Further investigation of the mechanism of RER1 and downstream effectors on αSyn may yield novel therapeutic targets for modulation in Parkinson disease and related synucleinopathies.</p></div