Nonmotor Symptoms in LRRK2 G2019S Associated Parkinson's Disease

BACKGROUND: Idiopathic Parkinson's disease (IPD) and LRRK2-associated PD (LRRK2-PD) might be expected to differ clinically since the neuropathological substrate of LRRK2-PD is heterogeneous. The range and severity of extra-nigral nonmotor features associated with LRRK2 mutations is also not well-defined. OBJECTIVE: To evaluate the prevalence and time of onset of nonmotor symptoms (NMS) in LRRK2-PD patients. METHODS: The presence of hyposmia and of neuropsychiatric, dysautonomic and sleep disturbances was assessed in 33 LRRK2-G2019S-PD patients by standardized questionnaires and validated scales. Thirty-three IPD patients, matched for age, gender, duration of parkinsonism and disease severity and 33 healthy subjects were also evaluated. RESULTS: University of Pennsylvania Smell Identification Test (UPSIT) scores in LRRK2-G2019S-PD were higher than those in IPD (23.5±6.8 vs 18.4±6.0; p = 0.002), and hyposmia was less frequent in G2019S carriers than in IPD (39.4% vs 75.8%; p = 0.01). UPSIT scores were significantly higher in females than in males in LRRK2-PD patients (26.9±4.7 vs 19.4±6.8; p<0.01). The frequency of sleep and neuropsychiatric disturbances and of dysautonomic symptoms in LRRK2-G2019S-PD was not significantly different from that in IPD. Hyposmia, depression, constipation and excessive daytime sleepiness, were reported to occur before the onset of classical motor symptoms in more than 40% of LRRK2-PD patients in whom these symptoms were present at the time of examination. CONCLUSION: Neuropsychiatric, dysautonomic and sleep disturbances occur as frequently in patients with LRRK2-G2019S-PD as in IPD but smell loss was less frequent in LRRK2-PD. Like in IPD, disturbances such as hyposmia, depression, constipation and excessive daytime sleepiness may antedate the onset of classical motor symptoms in LRRK2-G2019S-PD

Recognition and diagnosis of sleep disorders in Parkinson's disease

Contains fulltext : 109296.pdf (publisher's version ) (Open Access)Sleep disturbances are among the most frequent and incapacitating non-motor symptoms of Parkinson's disease (PD), and are increasingly recognized as an important determinant of impaired quality of life. Here we review several recent developments regarding the recognition and diagnosis of sleep disorders in PD. In addition, we provide a practical and easily applicable approach to the diagnostic process as a basis for tailored therapeutic interventions. This includes a stepwise scheme that guides the clinical interview and subsequent ancillary investigations. In this scheme, the various possible sleep disorders are arranged not in order of prevalence, but in a 'differential diagnostic' order. We also provide recommendations for the use of sleep registrations such as polysomnography. Furthermore, we point out when a sleep specialist could be consulted to provide additional diagnostic and therapeutic input. This structured approach facilitates early detection of sleep disturbances in PD, so treatment can be initiated promptly

GWAS meta-analysis of over 29,000 people with epilepsy identifies 26 risk loci and subtype-specific genetic architecture

Epilepsy is a highly heritable disorder affecting over 50 million people worldwide, of which about one-third are resistant to current treatments. Here we report a multi-ancestry genome-wide association study including 29,944 cases, stratified into three broad categories and seven subtypes of epilepsy, and 52,538 controls. We identify 26 genome-wide significant loci, 19 of which are specific to genetic generalized epilepsy (GGE). We implicate 29 likely causal genes underlying these 26 loci. SNP-based heritability analyses show that common variants explain between 39.6% and 90% of genetic risk for GGE and its subtypes. Subtype analysis revealed markedly different genetic architectures between focal and generalized epilepsies. Gene-set analyses of GGE signals implicate synaptic processes in both excitatory and inhibitory neurons in the brain. Prioritized candidate genes overlap with monogenic epilepsy genes and with targets of current antiseizure medications. Finally, we leverage our results to identify alternate drugs with predicted efficacy if repurposed for epilepsy treatment

Biomarker candidates of neurodegeneration in Parkinson’s disease for the evaluation of disease-modifying therapeutics

Reliable biomarkers that can be used for early diagnosis and tracking disease progression are the cornerstone of the development of disease-modifying treatments for Parkinson’s disease (PD). The German Society of Experimental and Clinical Neurotherapeutics (GESENT) has convened a Working Group to review the current status of proposed biomarkers of neurodegeneration according to the following criteria and to develop a consensus statement on biomarker candidates for evaluation of disease-modifying therapeutics in PD. The criteria proposed are that the biomarker should be linked to fundamental features of PD neuropathology and mechanisms underlying neurodegeneration in PD, should be correlated to disease progression assessed by clinical rating scales, should monitor the actual disease status, should be pre-clinically validated, and confirmed by at least two independent studies conducted by qualified investigators with the results published in peer-reviewed journals. To date, available data have not yet revealed one reliable biomarker to detect early neurodegeneration in PD and to detect and monitor effects of drug candidates on the disease process, but some promising biomarker candidates, such as antibodies against neuromelanin, pathological forms of α-synuclein, DJ-1, and patterns of gene expression, metabolomic and protein profiling exist. Almost all of the biomarker candidates were not investigated in relation to effects of treatment, validated in experimental models of PD and confirmed in independent studies

REM Sleep Behavior Disorder Is Not Associated with a More Rapid Cognitive Decline in Mild Dementia

Objectives: REM sleep behavior disorder (RBD) is associated with cognitive dysfunctions and is a risk factor for development of mild cognitive impairment and dementia. However, it is unknown whether RBD is associated with faster cognitive decline in already established dementia. The main goal of this study was to determine if patients with mild dementia with and without RBD differ in progression rate and in specific neuropsychological measures over 4-year follow-up. Methods: This longitudinal, prospective study based on data from the DemVest study compares neuropsychological measures in a mild dementia cohort. A diagnosis of probable RBD (pRBD) was made based on the Mayo Sleep Questionnaire. Neuropsychological domains were assessed by Mini Mental State Examination, total score and figure copying, California Verbal Learning Test-II, Visual Object and Space Perception Cube and Silhouettes, Boston Naming Test, Stroop test, Verbal Category Fluency, Trail Making Test A and B. Results: Among the 246 subjects, 47 (19.1%) had pRBD at the baseline, and pRBD group was younger and with male predominance. During 4-year follow-up, we did not observe any significant differences in the rate of decline in neuropsychological measures. Patients with pRBD performed generally poorer in visuoconstructional, visuoperceptual, and executive/attention tests in comparison to RBD negative. Conclusion: We did not find any significant differences in progression rate of neurocognitive outcomes between dementia patients with and without RBD.publishedVersio

Renal and Extrarenal Phenotypes in Patients With HNF1B Variants and Chromosome 17q12 Microdeletions

Introduction: Hepatocyte nuclear factor 1-beta (HNF1B) gene variants or the chromosome 17q12 deletion (17q12del) represent the most common monogenic cause of developmental kidney disease. Although neurodevelopmental disorders have been associated with the 17q12del, specific genotype-phenotype associations with respect to kidney function evolution have not yet been fully defined. Here, we aimed to determine whether 17q12del or specific HNF1B variants were associated with kidney survival in a large patient population with HNF1B disease. Methods: This was a retrospective observational study involving 521 patients with HNF1B disease from 14 countries using the European Reference Network for rare kidney diseases with detailed information on the HNF1B genotype (HNF1B variants or the 17q12del). Median follow-up time was 11 years with 6 visits per patient. The primary end point was progression to chronic kidney disease (CKD) stage 3 (estimated glomerular filtration rate [eGFR] < 60 ml/min per 1.73 m2). Secondary end points were the development of hypomagnesemia or extrarenal disorders, including hyperuricemia and hyperglycemia. Results: Progression toward CKD stage 3 was significantly delayed in patients with the 17q12del compared to patients with HNF1B variants (hazard ratio [HR]: 0.29, 95% confidence interval [CI]: 0.19–0.44, P < 0.001). Progression toward CKD stage 3 was also significantly delayed when HNF1B variants involved the HNF1B Pit-1, Oct-1, and Unc-86 homeodomain (POUh) DNA-binding and transactivation domains rather than the POU-specific domain (POUs) DNA-binding domain (HR: 0.15 [95% CI: 0.06–0.37), P < 0.001 and HR: 0.25 (95% CI: 0.11–0.57), P = 0.001, respectively). Finally, the 17q12del was positively associated with hypomagnesemia and negatively associated with hyperuricemia, but not with hyperglycemia. Conclusion: Patients with the 17q12del display a significantly better kidney survival than patients with other HNF1B variants; and for the latter, variants in the POUs DNA-binding domain lead to the poorest kidney survival. These are clinically relevant HNF1B kidney genotype-phenotype correlations that inform genetic counseling