Background: Quantitative electroencephalography (qEEG) has been suggested as a biomarker for cognitive decline in Parkinson’s disease (PD).Objective: Determine if applying a wavelet-based qEEG algorithm to 21-electrode, resting-state EEG recordings obtained in a routine clinical setting has utility for predicting cognitive impairment in PD.Methods: PD subjects, evaluated by disease stage and motor score, were compared to healthy controls (N = 20 each). PD subjects with normal (PDN, MoCA 26–30, N = 6) and impaired (PDD, MoCA ≤ 25, N = 14) cognition were compared. The wavelet-transform based time-frequency algorithm assessed the instantaneous predominant frequency (IPF) at 60 ms intervals throughout entire recordings. We then determined the relative time spent by the IPF in the four standard EEG frequency bands (RTF) at each scalp location. The resting occipital rhythm (ROR) was assessed using standard power spectral analysis.Results: Comparing PD subjects to healthy controls, mean values are decreased for ROR and RTF-Beta, greater for RTF-Theta and similar for RTF-Delta and RTF-Alpha. In logistic regression models, arithmetic combinations of RTF values [e.g., (RTF-Alpha) + (RTF-Beta)/(RTF-Delta + RTF-Theta)] and RTF-Alpha values at occipital or parietal locations are most able to discriminate between PD and controls. A principal component (PC) from principal component analysis (PCA) using RTF-band values in all subjects is associated with PD status (p = 0.004, β = 0.31, AUC = 0.780). Its loadings show positive contribution from RTF-Theta at all scalp locations, and negative contributions from RTF-Beta at occipital, parietal, central, and temporal locations. Compared to cognitively normal PD subjects, cognitively impaired PD subjects have lower median RTF-Alpha and RTF-Beta values, greater RTF-Theta values and similar RTF-Delta values. A PC from PCA using RTF-band values in PD subjects is associated with cognitive status (p = 0.002, β = 0.922, AUC = 0.89). Its loadings show positive contributions from RTF-Theta at all scalp locations, negative contributions from RTF-Beta at central locations, and negative contributions from RTF-Delta at central, frontal and temporal locations. Age, disease duration and/or sex are not significant covariates. No PC was associated with motor score or disease stage.Significance: Analyzing standard EEG recordings obtained in a community practice setting using a wavelet-based qEEG algorithm shows promise as a PD biomarker and for predicting cognitive impairment in PD.

ObjectiveMyotonia is caused by involuntary firing of skeletal muscle action potentials and causes debilitating stiffness. Current treatments are insufficiently efficacious and associated with side effects. Myotonia can be triggered by voluntary movement (electrically induced myotonia) or percussion (mechanically induced myotonia). Whether distinct molecular mechanisms underlie these triggers is unknown. Our goal was to identify ion channels involved in mechanically induced myotonia and to evaluate block of the channels involved as a novel approach to therapy.MethodsWe developed a novel system to enable study of mechanically induced myotonia using both genetic and pharmacologic mouse models of myotonia congenita. We extended ex vivo studies of excitability to in vivo studies of muscle stiffness.ResultsAs previous work suggests activation of transient receptor potential vanilloid 4 (TRPV4) channels by mechanical stimuli in muscle, we examined the role of this cation channel. Mechanically induced myotonia was markedly suppressed in TRPV4‐null muscles and in muscles treated with TRPV4 small molecule antagonists. The suppression of mechanically induced myotonia occurred without altering intrinsic muscle excitability, such that myotonia triggered by firing of action potentials (electrically induced myotonia) was unaffected. When injected intraperitoneally, TRPV4 antagonists lessened the severity of myotonia in vivo by approximately 80%.InterpretationThese data demonstrate that there are distinct molecular mechanisms triggering electrically induced and mechanically induced myotonia. Our data indicates that activation of TRPV4 during muscle contraction plays an important role in triggering myotonia in vivo. Elimination of mechanically induced myotonia by TRPV4 inhibition offers a new approach to treating myotonia. ANN NEUROL 2020;88:297–308.

ABSTRACT Background Few studies have systematically investigated the association between PARKIN genotype and psychiatric co‐morbidities of Parkison's disease (PD). PARKIN ‐associated PD is characterized by severe nigral dopaminergic neuronal loss, a finding that may have implications for behaviors rooted in dopaminergic circuits such as obsessive‐compulsive symptoms (OCS). Methods The Schedule of Compulsions and Obsessions Patient Inventory (SCOPI) was administered to 104 patients with early‐onset PD and 257 asymptomatic first‐degree relatives. Carriers of one and two PARKIN mutations were compared with noncarriers. Results Among patients, carriers scored lower than noncarriers in adjusted models (one‐mutation: 13.9 point difference, P = 0.03; two‐mutation: 24.1, P = 0.001), where lower scores indicate less OCS. Among asymptomatic relatives, a trend toward the opposite was seen: mutation carriers scored higher than noncarriers (one mutation, P = 0.05; two mutations, P = 0.13). Conclusions First, a significant association was found between PARKIN mutation status and obsessive‐compulsive symptom level in both PD and asymptomatic patients, suggesting that OCS might represent an early non‐motor dopamine‐dependent feature. Second, irrespective of disease status, heterozygotes were significantly different from noncarriers, suggesting that PARKIN heterozygosity may contribute to phenotype. © 2014 International Parkinson and Movement Disorder Society

IMPORTANCE:Data on the long-term cognitive outcomes of patients with PARKIN-associated Parkinson disease (PD) are unknown but may be useful when counseling these patients. OBJECTIVE:Among patients with early-onset PD of long duration, we assessed cognitive and motor performances, comparing homozygotes and compound heterozygotes who carry 2 PARKIN mutations with noncarriers. DESIGN, SETTING, AND PARTICIPANTS:Cross-sectional study of 44 participants at 17 different movement disorder centers who were in the Consortium on Risk for Early-Onset PD study with a duration of PD greater than the median duration (>14 years): 4 homozygotes and 17 compound heterozygotes (hereafter referred to as carriers) and 23 noncarriers. MAIN OUTCOMES AND MEASURES:Unified Parkinson Disease Rating Scale Part III (UPDRS-III) and Clinical Dementia Rating scores and neuropsychological performance. Linear regression models were applied to assess the association between PARKIN mutation status and cognitive domain scores and UPDRS-III scores. Models were adjusted for age, education, disease duration, language, and levodopa equivalent daily dose. RESULTS:Carriers had an earlier age at onset of PD (P < .001) and were younger (P = .004) at time of examination than noncarriers. They performed better than noncarriers on the Mini-Mental State Examination (P = .010) and were more likely to receive lower scores on the Clinical Dementia Rating (P = .003). In multivariate analyses, carriers performed better than noncarriers on the UPDRS-III (P = .02) and on tests of attention (P = .03), memory (P = .03), and visuospatial (P = .02) cognitive domains. CONCLUSIONS AND RELEVANCE:In cross-sectional analyses, carriers demonstrated better cognitive and motor performance than did noncarriers with long disease duration, suggesting slower disease progression. A longitudinal follow-up study is required to confirm these findings.

Objective: We describe all Juvenile Parkinson9s Disease (JPD) probands who were recruited through the CORE-PD study. Background JPD is exceptionally rare, seldom reported, and defined as disease age at onset (AAO) Design/Methods: Eleven hundred and three individuals with early-onset PD (defined as AAO SNCA , PRKN , PINK1 , DJ1 , LRRK2 and GBA . Results: Twenty probands (1.8%) reported AAO PRKN carriers, two were PRKN heterozygotes, two carried heterozygous GBA mutations (one L444P and one N370S) and one carried the LRRK2 G2019S mutation. Only four (20%) reported a family history of PD in a first degree relative, all of whom carried PRKN mutations (two compound heterozygotes and two heterozygotes). Of these four probands, two had a family history of JPD in siblings (one heterozygote with AAO=16 and one compound heterozygote with AAO=12), each with a similar genotype to proband. None of the 66 PRKN mutation carriers with disease onset>20 had a sibling with JPD. Conclusions: JPD is extremely rare among EOPD. While identifiable genetic risk factors are common, first degree family history of PD is present in a minority. Supported by: Funded by NIH NS36630, UL1 RR024156 (K.S.M.), NS050487, NS060113 (L.N.C.), the Parkinson9s Disease Foundation (K.S.M., S.F., and L.N.C.), P50 NS039764 (W.K.S) and NS36960 (H.P). RNA is a Brookdale Foundation Leadership in Aging Fellow. Disclosure: Dr. Alcalay has nothing to disclose. Dr. Rosado has nothing to disclose. Dr. Mejia-Santana has nothing to disclose. Dr. Orbe-Reilly has nothing to disclose. Dr. Caccappolo has nothing to disclose. Dr. Tang has nothing to disclose. Dr. Ruiz has nothing to disclose. Dr. Ross has nothing to disclose. Dr. Verbitsky has nothing to disclose. Dr. Kisselev has nothing to disclose. Dr. Louis has nothing to disclose. Dr. Comella has received personal compensation for activities with Ipsen, Merz Pharma, Allergan, Inc., and NuPathe. Dr. Comella has received research support from Ipsen, Merz Pharma, Allergan, Inc., the National Institutes of Health, and the Dystonia Study Group. Dr. Colcher has nothing to disclose. Dr. Jennings has received personal compensation for activities with Lundbeck Research USA as a speaker. Dr. Nance has received research support from Medivation, Santhera, Juvantia, Neurosearch Sweden, Pfizer Inc, Neuraltus, Impax, and Schwarz Biosciences. Dr. Bressman has received license fee payments from Beth Israel/Mount Sinai/Athena. Dr. Scott has nothing to disclose. Dr. Tanner has received personal compensation for activities with Impax Pharmaceuticals, Allergan, Inc. & Genentech, Inc. as a consultant. Dr. Tanner has received research support from Michael J. Fox Foundation, Department of Defense, Parkinson9s Disease Foundation, Parkinson9s Institute, Unity Walk and Brin Foundation. Dr. Andrews has nothing to disclose. Dr. Waters has received personal compensation for activities with Boehringer Ingelheim Pharmaceuticals, Inc., Novartis, and Teva Neuroscience as a speaker. Dr. Fahn has received personal compensation for activities with Intec Pharma, Merz Pharma, Oxford Biomedica, RJG Foundation, IMPAX Pharmaceuticals, and Lundbeck as a consultant. Dr. Fahn has received personal compensation in an editorial capacity for Elsevier and Springer. Dr. Cote has nothing to disclose. Dr. Frucht has received personal compensation for activities with UCB Pharma. Dr. Ford has received personal compensation for activities with Novartis and Medtronic, Inc. Dr. Rezak has received personal compensation for activities with Medtronic, Teva, Novartis, Allergan, Smih-Klein, Boehringer-Ingleheim, and UBC as a speaker. Dr. Novak has nothing to disclose. Dr. Friedman has received personal compensation for activities with Teva Neuroscience, Boehringer Ingelheim Pharmaceuticals, Inc., Genzyme Corporation, Adix, Roche Diagnostics Corporation. Dr. Friedman has received research support from Teva Neuroscience, Merck & Co., Inc., EMD Serono, Schering-Plough Corporation, National Institutes of Health, Michael J. Fox Foundation, GE Healthcare and Acadia. Dr. Pfeiffer has received personal compensation for activities with UCB Pharmaceuticals, Teva Neurosciences, Novartis, Glaxo-Smith-Kline, and Boehringer Ingelheim.Dr. Pfeiffer has received personal compensation in an editorial capacity for Parkinsonism and Related Disorders.Dr. Pfeiffer has received (royalty or license fee or contractual rights) payments from Butterworth Heinemann, Elsevier, CRC Press, Taylor & Francis, and Humana Press.Dr. Pfeiffer has received research support from Boehringer Ingelheim, UCB Pharmaceuticals, and Schwarz Biosciences. Dr. Marsh has received research support from Eli Lilly & Company, Forest Pharmaceuticals, Acadia, Ovation, and National Institutes of Health. Dr. Hiner has received personal compensation for activities with Teva Neuroscience. Dr. Siderowf has received personal compensation for activities with Teva Neuroscience, Supernus Pharmaceuticals, Schering-Plough, and Merck Serono. Dr. Siderowf has received research support from the NINDS, the Department of Health of the Commonwealth of Pennsylvania, and Avid Radiopharmaceuticals. Dr. Payami has nothing to disclose. Dr. Molho has received personal compensation for activities with Allergan, Teva, Merz, Ipsen, and Boehringer Ingelheim. Dr. Molho has received research support from Teva, Allergan, Merz, IPsen, Parkinson9s Study Group, and Huntington9s Study Group. Dr. Nutt has received personal compensation for activities with XenPort, Impax Laboratories, Neurogen, Synosia, Neuroderm, Merck, Lily/Medtronic, Elan Pharmaceuticals, Lundbeck, Merz Pharmaceuticals, Synagile, and the National Parkinson Foundation. Dr. Nutt has received research support from Merck. Dr. Factor has received personal compensation for activities with Merz and Ipsen as a consultant. Dr. Factor has received personal compensation in an editorial capacity for Current Neurology and Neuroscience. Dr. Factor has received research support from Ceregene, Teva Neuroscience, Ipsen, and EMD Serono. Dr. Ottman has received personal compensation for activities with Ortho-McNeil Janssen Scientific Affairs, LLC. Dr. Clark has nothing to disclose. Dr. Marder has received personal compensation in an editorial capacity for Current Neuroscience. Dr. Marder has received research support from the NIH, Michael J. Fox Parkinson Disease Foundation, CHDI, and the Huntington9s Disease Society of America.

The modifications of electrophysiological activities of subthalamic nucleus (STN) by non-motor tasks, i.e. movement observation, emotional stimuli and impulse control, were reported repeatedly.Despite being a small structure, STN is apparently involved in a variety of functions.Based on our own electrophysiological recordings and results of other groups we believe that it acts as an indirect modulator which may be involved in tuning the functional systems. STN may modulate specific cognitive activities via contextual modulation of certain cortical areas. Our findings support the hypothesis of a cortical-STN bypass (via hyperdirect pathway) of “classical” basal ganglia-thalamocortical circuitry, at least during the processing of certain cognitive functions. The modulation of cognitive functions appears to be selective, probably determined by the involvement of cortical neuronal populations interconnected with STN. There could also exist a spatial overlap of areas within STN regulating various functions. That may explain the fact that some non-motor symptoms of Parkinson’s disease may improve after deep brain stimulation of STN. These improvements are likely caused by combination of direct stimulation effect on non-motor function and overall beneficial effect of motor improvement on quality of life.

Background Mutations in theparkingene are the most common genetic cause of early-onset Parkinson disease (PD). Results from a multicenter study of patients with PD systematically sampled by age at onset have not been reported to date. Objective To determine risk factors associated with carryingparkinmutations. Design Cross-sectional observational study. Setting Thirteen movement disorders centers. Participants A total of 956 patients with early-onset PD, defined as age at onset younger than 51 years. Main Outcome Measures Presence of heterozygous, homozygous, or compound heterozygousparkinmutations. Results Using a previously validated interview, 14.7% of patients reported a family history of PD in a first-degree relative. Sixty-four patients (6.7%) hadparkinmutations (3.9% heterozygous, 0.6% homozygous, and 2.2% compound heterozygous). Copy number variation was present in 52.3% of mutation carriers (31.6% of heterozygous, 83.3% of homozygous, and 81.0% of compound heterozygous). Deletions in exons 3 and 4 and 255delA were common among Hispanics (specifically Puerto Ricans). Younger age at onset (<40 years) (odds ratio [OR], 5.0; 95% confidence interval [CI], 2.8-8.8;P = .001), Hispanic race/ethnicity (OR compared with white non-Hispanic race/ethnicity, 2.7; 95% CI, 1.3-5.7;P = .009), and family history of PD in a first-degree relative (OR compared with noncarriers, 2.8; 95% CI, 1.5-5.3;P = .002) were associated with carrying anyparkinmutation (heterozygous, homozygous, or compound heterozygous). Hispanic race/ethnicity was associated with carrying a heterozygous mutation (OR compared with white non-Hispanic race/ethnicity, 2.8; 95% CI, 1.1-7.2;P = .03) after adjustment for covariates. Conclusions Age at onset, Hispanic race/ethnicity, and family history of PD are associated with carrying anyparkinmutation (heterozygous, homozygous, or compound heterozygous) and heterozygous mutations alone. The increased odds of carrying aparkinmutation among Hispanics warrants further study.

The cognitive profile of early onset Parkinson's disease (EOPD) has not been clearly defined. Mutations in the parkin gene are the most common genetic risk factor for EOPD and may offer information about the neuropsychological pattern of performance in both symptomatic and asymptomatic mutation carriers. EOPD probands and their first-degree relatives who did not have Parkinson's disease (PD) were genotyped for mutations in the parkin gene and administered a comprehensive neuropsychological battery. Performance was compared between EOPD probands with (N = 43) and without (N = 52) parkin mutations. The same neuropsychological battery was administered to 217 first-degree relatives to assess neuropsychological function in individuals who carry parkin mutations but do not have PD. No significant differences in neuropsychological test performance were found between parkin carrier and noncarrier probands. Performance also did not differ between EOPD noncarriers and carrier subgroups (i.e., heterozygotes, compound heterozygotes/homozygotes). Similarly, no differences were found among unaffected family members across genotypes. Mean neuropsychological test performance was within normal range in all probands and relatives. Carriers of parkin mutations, whether or not they have PD, do not perform differently on neuropsychological measures as compared to noncarriers. The cognitive functioning of parkin carriers over time warrants further study.

OBJECTIVE:To assess the frequency and clinical characteristics of carriers of previously identified mutations in 6 genes associated with early-onset Parkinson disease (PD) and provide empirical data that can be used to inform genetic counseling. DESIGN:Cross-sectional observational study. SETTING:Thirteen movement disorders centers. PATIENTS:Nine hundred fifty-three individuals with early-onset PD defined as age at onset (AAO) younger than 51 years. Participants included 77 and 139 individuals of Hispanic and Jewish ancestry, respectively. Intervention Mutations in SNCA, PRKN, PINK1, DJ1, LRRK2, and GBA were assessed. A validated family history interview and the Unified Parkinson Disease Rating Scale were administered. Demographic and phenotypic characteristics were compared among groups defined by mutation status. Main Outcome Measure Mutation carrier frequency stratified by AAO and ethnic background. RESULTS:One hundred fifty-eight (16.6%) participants had mutations, including 64 (6.7%) PRKN, 35 (3.6%) LRRK2 G2019S, 64 (6.7%) GBA, and 1 (0.2%) DJ1. Mutation carriers were more frequent in those with an AAO of 30 years or younger compared with those with AAO between 31 and 50 years (40.6% vs 14.6%, P < .001), in individuals who reported Jewish ancestry (32.4% vs 13.7%, P < .001), and in those reporting a first-degree family history of PD (23.9% vs 15.1%, P = .01). Hispanic individuals were more likely to be PRKN carriers than non-Hispanic individuals (15.6% vs 5.9%, P = .003). The GBA L444P mutation was associated with a higher mean Unified Parkinson Disease Rating Scale III score after adjustment for covariates. CONCLUSION:Individuals of Jewish or Hispanic ancestry with early-onset PD, those with AAO of 30 years or younger, and those with a history of PD in a first-degree relative may benefit from genetic counseling.

While little is known about risk factors for cognitive impairment in early onset Parkinson disease (EOPD), postmortem studies have shown an association between dementia with Lewy bodies (DLB) and glucocerebrosidase (GBA) mutation. We compared Mini-Mental State Examination (MMSE) performance and self-reported cognitive impairment in 699 EOPD participants genotyped for mutations in parkin (PRKN), leucine-rich repeat kinase-2 (LRRK2), and GBA. Logistic regression was used to assess the association between reported cognitive impairment and MMSE score, as well as between GBA group membership and self-reported impairment and MMSE. GBA carriers reported more impairment, but MMSE performance did not differ among genetic groups. Detailed neuropsychological testing is required to explore the association between cognitive impairment and GBA mutations.

Objective To determine the motor phenotype ofLRRK2G2019S mutation carriers.LRRK2mutation carriers were previously reported to manifest the tremor dominant motor phenotype, which has been associated with slower motor progression and less cognitive impairment compared with the postural instability and gait difficulty (PIGD) phenotype. Design Cross-sectional observational study. Setting Thirteen movement disorders centers. Participants Nine hundred twenty-five early-onset Parkinson disease cases defined as age at onset younger than 51 years. Main Outcome Measures LRRK2mutation status and Parkinson disease motor phenotype: tremor dominant or PIGD. Demographic information, family history of Parkinson disease, and the Unified Parkinson's Disease Rating Scale score were collected on all participants. DNA samples were genotyped forLRRK2mutations (G2019S, I2020T, R1441C, and Y1699C). Logistic regression was used to examine associations of G2019S mutation status with motor phenotype adjusting for disease duration, Ashkenazi Jewish ancestry, levodopa dose, and family history of Parkinson disease. Results Thirty-four cases (3.7%) (14 previously reported) were G2019S carriers. No other mutations were found. Carriers were more likely to be Ashkenazi Jewish (55.9% vs 11.9%;P < .001) but did not significantly differ in any other demographic or disease characteristics. Carriers had a lower tremor score (P = .03) and were more likely to have a PIGD phenotype (92.3% vs 58.9%;P = .003). The association of the G2019S mutation with PIGD phenotype remained after controlling for disease duration and Ashkenazi Jewish ancestry (odds ratio, 17.7;P < .001). Conclusion Early-onset Parkinson disease G2019SLRRK2carriers are more likely to manifest the PIGD phenotype, which may have implications for disease course.

BACKGROUND:Several subcortical structures have been targeted for surgical treatment of dystonia, including motor thalamus, internal segment of globus pallidus (GPi), and more recently, the subthalamic nucleus (STN). Deep brain stimulation of GPi is currently the preferred surgical treatment, but it is unclear if targeting other structures would yield better results. Patients who have already had a pallidotomy yet continue to experience dystonic symptoms may be limited in further treatment options.METHODS:A patient with medically intractable, segmental, early-onset, primary torsion dystonia presented for surgical consultation after exhausting nearly all treatment options. Medications, botulinum toxin injections, cervical denervation surgery, and left-sided pallidotomy failed to give adequate relief. The patient was implanted with STN stimulating leads bilaterally according to standard procedures.RESULTS:The patient received a 36% improvement in dystonic symptoms as measured by several dystonia rating scales. These benefits persisted for 2 years after surgery despite several hardware-related complications, and the patient reported being very satisfied with the outcome.CONCLUSION:This result supports the efficacy of STN deep brain stimulation in dystonia patients, even those with prior pallidotomy.

Deep brain stimulation is generally a safe and effective method of alleviating motor impairment in advanced‐stage Parkinson's disease patients. However, adverse events of surgery have been noted, such as hemorrhage, infection, seizures, and device failure. In this report, we describe 2 cases of the unusual adverse event of ischemia associated with subthalamic nucleus stimulator implantation. We present the intraoperative neurological symptoms, microelectrode recording data, imaging findings, and other correlated events. In the first case, the clinical effects of ischemia were evident intraoperatively and coincided with silence during microelectrode recording from the ischemic region. In the second case, the timing of the ischemic event could not be determined precisely but also was associated with a difficult mapping. Subcortical ischemia may be an underrecognized event that confounds neurophysiological mapping of deep brain structures and affects clinical outcomes. © 2006 Movement Disorder Society