Mark Groves

Parkinson disease phenotype in Ashkenazi jews with and without LRRK2 G2019S mutations

The phenotype of Parkinsons disease (PD) in patients with and without leucine‐rich repeat kinase 2 (LRRK2) G2019S mutations reportedly is similar; however, large, uniformly evaluated series are lacking. The objective of this study was to characterize the clinical phenotype of Ashkenazi Jewish (AJ) PD carriers of the LRRK2 G2019S mutation. We studied 553 AJ PD patients, including 65 patients who were previously reported, from three sites (two in New York and one in Tel‐Aviv). Glucocerebrosidase (GBA) mutation carriers were excluded. Evaluations included the Montreal Cognitive Assessment (MoCA), the Unified Parkinsons Disease Rating Scale (UPDRS), the Geriatric Depression Scale (GDS) and the Non‐Motor Symptoms (NMS) questionnaire. Regression models were constructed to test the association between clinical and demographic features and LRRK2 status (outcome) in 488 newly recruited participants. LRRK2 G2019S carriers (n = 97) and non‐carriers (n = 391) were similar in age and age at onset of PD. Carriers had longer disease duration (8.6 years vs. 6.1 years; P < 0.001), were more likely to be women (51.5% vs. 37.9%; P = 0.015), and more often reported first symptoms in the lower extremities (40.0% vs. 19.2%; P < 0.001). In logistic models that were adjusted for age, disease duration, sex, education, and site, carriers were more likely to have lower extremity onset (P < 0.001), postural instability and gait difficulty (PIGD) (P = 0.043), and a persistent levodopa response for >5 years (P = 0.042). Performance on the UPDRS, MoCA, GDS, and NMS did not differ by mutation status. PD in AJ LRRK2 G2019S mutation carriers is similar to idiopathic PD but is characterized by more frequent lower extremity involvement at onset and PIGD without the associated cognitive impairment.

Mood and Cognition in Leucine-rich Repeat Kinase 2 G2019S Parkinson’s Disease

The behavioral and cognitive features of the leucine‐rich repeat kinase G2019S mutation in Parkinsons disease in the Ashkenazi Jewish population are not well described; therefore, we sought to more systematically characterize these features using a semistructured psychiatric interview and neuropsychological testing. Twenty‐one Ashkenazi Jewish patients having the leucine‐rich repeat kinase G2019S mutation were compared with age‐ and sex‐matched Ashkenazi Jewish patients with Parkinsons disease without mutations. Although overall rates of affective disorders were not greater in mutation carriers, the carriers exhibited a 6‐fold increased risk of premorbid affective disorders (odds ratio, 6.0; P = .10), as determined by the Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders–IV. Of interest, we identified 2 leucine‐rich repeat kinase carriers with bipolar disorder; no mutation‐negative subjects had this diagnosis. Performance on the Hopkins Verbal Learning Test–Revised, Judgment of Line Orientation, and Frontal Assessment Battery was consistent with previous reports and did not differ between groups. Study findings suggest a possible association between premorbid mood disorders and leucine‐rich repeat kinase Parkinsons disease, warranting further evaluation.

Characterization of Depression in Prodromal Huntington Disease in the Neurobiological Predictors of HD (PREDICT-HD) Study

Depression causes significant morbidity and mortality, and this also occurs in Huntington Disease (HD), an inherited neurodegenerative illness with motor, cognitive, and psychiatric symptoms. The presentation of depression in this population remains poorly understood, particularly in the prodromal period before development of significant motor symptoms. In this study, we assessed depressive symptoms in a sample of 803 individuals with the HD mutation in the prodromal stage and 223 mutation-negative participants at the time of entry in the Neurobiological Predictors of HD (PREDICT-HD) study. Clinical and biological HD variables potentially related to severity of depression were analyzed. A factor analysis was conducted to characterize the symptom domains of depression in a subset (n=168) with clinically significant depressive symptoms. Depressive symptoms were found to be more prevalent in HD mutation carriers but did not increase with proximity to HD diagnosis and were not associated with length of the HD mutation. Increased depressive symptoms were significantly associated with female gender, self-report of past history of depression, and a slight decrease in functioning, but not with time since genetic testing. The factor analysis identified symptom domains similar to prior studies in other populations. These results show that individuals with the HD mutation are at increased risk to develop depressive symptoms at any time during the HD prodrome. The clinical presentation appears to be similar to other populations. Severity and progression are not related to the HD mutation.

Risk Factors for Suicidal Ideation in People at Risk for Huntington’s Disease

BACKGROUND Suicidal ideation (SI) and attempts are increased in Huntingtons disease (HD), making risk factor assessment a priority. OBJECTIVE To determine whether, hopelessness, irritability, aggression, anxiety, CAG expansion status, depression, and motor signs/symptoms were associated with Suicidal Ideation (SI) in those at risk for HD. METHODS Behavioral and neurological data were collected from subjects in an observational study. Subject characteristics were calculated by CAG status and SI. Logistic regression models were adjusted for demographics. Separate logistic regressions were used to compare SI and non-SI subjects. A combined logistic regression model, including 4 pre-specified predictors, (hopelessness, irritability, aggression, anxiety) was used to assess the relationship of SI to these predictors. RESULTS 801 subjects were assessed, 40 were classified as having SI, 6.3% of CAG mutation expansion carriers had SI, compared with 4.3% of non- CAG mutation expansion carriers (p = 0.2275). SI subjects had significantly increased depression (p < 0.0001), hopelessness (p < 0.0001), irritability (p < 0.0001), aggression (p = 0.0089), and anxiety (p < 0.0001), and an elevated motor score (p = 0.0098). Impulsivity, assessed in a subgroup of subjects, was also associated with SI (p = 0.0267). Hopelessness and anxiety remained significant in combined model (p < 0.001; p < 0.0198, respectively) even when motor score was included. CONCLUSIONS Behavioral symptoms were significantly higher in those reporting SI. Hopelessness and anxiety showed a particularly strong association with SI. Risk identification could assist in assessment of suicidality in this group.

Psychiatric and Cognitive Effects of Deep Brain Stimulation for Parkinson’s Disease

Deep brain stimulation (DBS) is effective for Parkinson’s disease (PD), dystonia, and essential tremor (ET). While motor benefits are well documented, cognitive and psychiatric side effects from the subthalamic nucleus (STN) and globus pallidus interna (GPi) DBS for PD are increasingly recognized. Underlying disease, medications, microlesions, and post-surgical stimulation likely all contribute to non-motor symptoms (NMS).

Naltrexone for impulse control disorders in Parkinson disease: A placebo-controlled studyAuthor Response

Editors’ Note: Commenting on “Naltrexone for impulse control disorders in Parkinson disease: A placebocontrolled study,” Galduróz and colleagues argue that the negative findings of the study may be related to a confusion of concepts such as impulsivity, compulsivity, and craving. Furthermore, Liang and colleagues suggest that some impulse control disorders may be more responsive to naltrexone than others. Authors Weintraub et al. respond. Sethi and Strowd discuss the challenges of modern electronic medicine. —Chafic Karam, MD, and Robert C. Griggs, MD

J13 Prescription usage for treatment of irritability, perseverative behaviors, and chorea in huntington's disease

Background Despite large gaps in evidence-based knowledge, clinical experience supports the use of pharmacologic treatments for many symptoms of Huntingtons disease (HD). Aims The project goal is to develop consensus guidelines based on expert clinical experience to improve quality of HD care. Methods The survey was developed by 9 international experts, and designed as a highly iterative and systematic method of soliciting expert opinions on the pharmacologic treatment of irritability, perseverative behaviors, and chorea in HD. Fifty-five experts from Australia, Europe and North America responded to at least one of the surveys. Results For irritability, SSRI was first choice of 58%, an antipsychotic was first choice for 22%, a mood stabilizing anticonvulsant 14%, and benzodiazepine 2%. For perseverative behaviors, SSRI was first choice of 75%, an antipsychotic choice of 4%, a mood stabilizing anticonvulsant choice of 6%, and clomipramine 2%. The remaining 13% chose to qualify the response to include 2 first choices. For chorea, an antipsychotic was first choice for 56%, tetrabenazine 15%, amantadine 6%, and benzodiazepines 4%. The remaining 13% chose to qualify the response to include 2 first choices. Drug choice for use as adjunctive therapy was widely variable. Conclusions Many areas of variability in treatment for irritability, perseverative behaviors, and chorea in HD, have been identified. Results will guide future rounds of the Delphi process to elicit rational causes for differences identified. When complete, this process will clarify useful treatment paradigms that will improve patient care and identify areas in which clinical trials would be most useful.