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Genetic workup is becoming increasingly common in the clinical assessment of neurological disorders. We evaluated its yield among middle-aged and elderly neurological patients, in a real-world context. This retrospective study included 368 consecutive Israeli patients aged 50 years and older (202 [54.9%] males), who were referred to a single neurogenetics clinic between 2017 and mid-2023. All had neurological disorders, without a previous molecular diagnosis. Demographic, clinical and genetic data were collected from medical records. The mean age at first genetic counseling at the clinic was 62.3 ± 7.8 years (range 50-85 years), and the main indications for referral were neuromuscular, movement and cerebrovascular disorders, as well as cognitive impairment and dementia. Out of the 368 patients, 245 (66.6%) underwent genetic testing that included exome sequencing (ES), analysis of nucleotide repeat expansions, detection of specific mutations, targeted gene panel sequencing or chromosomal microarray analysis. Overall, 80 patients (21.7%) received a molecular diagnosis due to 36 conditions, accounting for 32.7% of the patients who performed genetic testing. The diagnostic rates were highest for neuromuscular (58/186 patients [31.2%] in this group, 39.2% of 148 tested individuals) and movement disorders (14/79 [17.7%] patients, 29.2% of 48 tested), but lower for other disorders. Testing of nucleotide repeat expansions and ES provided a diagnosis to 28/73 (38.4%) and 19/132 (14.4%) individuals, respectively. Based on our findings, genetic workup and testing are useful in the diagnostic process of neurological patients aged ≥50 years, in particular for those with neuromuscular and movement disorders.
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GBA1-associated Parkinson's disease (GBA1-PD) is increasingly recognized as a distinct entity within the spectrum of parkinsonian disorders. This review explores the unique pathophysiological features, clinical progression, and genetic underpinnings that differentiate GBA1-PD from idiopathic Parkinson's disease (iPD). GBA1-PD typically presents with earlier onset and more rapid progression, with a poor response to standard PD medications. It is marked by pronounced cognitive impairment and a higher burden of non-motor symptoms compared to iPD. Additionally, patients with GBA1-PD often exhibit a broader distribution of Lewy bodies within the brain, accentuating neurodegenerative processes. The pathogenesis of GBA1-PD is closely associated with mutations in the GBA1 gene, which encodes the lysosomal enzyme beta-glucocerebrosidase (GCase). In this review, we discuss two mechanisms by which GBA1 mutations contribute to disease development: 'haploinsufficiency,' where a single functional gene copy fails to produce a sufficient amount of GCase, and 'gain of function,' where the mutated GCase acquires harmful properties that directly impact cellular mechanisms for alpha-synuclein degradation, leading to alpha-synuclein aggregation and neuronal cell damage. Continued research is advancing our understanding of how these mechanisms contribute to the development and progression of GBA1-PD, with the 'gain of function' mechanism appearing to be the most plausible. This review also explores the implications of GBA1 mutations for therapeutic strategies, highlighting the need for early diagnosis and targeted interventions. Currently, small molecular chaperones have shown the most promising clinical results compared to other agents. This synthesis of clinical, pathological, and molecular aspects underscores the assertion that GBA1-PD is a distinct clinical and pathobiological PD phenotype, necessitating specific management and research approaches to better understand and treat this debilitating condition.
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Glucosilceramidase , Mutação , Doença de Parkinson , Humanos , Glucosilceramidase/genética , Glucosilceramidase/metabolismo , Doença de Parkinson/genética , Doença de Parkinson/metabolismo , Doença de Parkinson/patologia , alfa-Sinucleína/metabolismo , alfa-Sinucleína/genéticaRESUMO
People with Parkinson's disease often show deficits in dexterity, which, in turn, can lead to limitations in performing activities of daily life. Previous studies have suggested that training in playing the piano may improve or prevent a decline in dexterity in this population. In this pilot study, we tested three participants on a six-week, custom, piano-based training protocol, and quantified dexterity before and after the intervention using a sensor-enabled version of the nine-hole peg test, the box and block test, a test of finger synergies using unidimensional force sensors, and the Quantitative Digitography test using a digital piano, as well as selected relevant items from the motor parts of the MDS-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) and the Parkinson's Disease Questionnaire (PDQ-39) quality of life questionnaire. The participants showed improved dexterity following the training program in several of the measures used. This pilot study proposes measures that can track changes in dexterity as a result of practice in people with Parkinson's disease and describes a potential protocol that needs to be tested in a larger cohort.
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Doença de Parkinson , Humanos , Doença de Parkinson/fisiopatologia , Projetos Piloto , Masculino , Idoso , Feminino , Qualidade de Vida , Pessoa de Meia-Idade , Destreza Motora/fisiologia , Música , Inquéritos e Questionários , Atividades Cotidianas , Dedos/fisiologia , Dedos/fisiopatologiaRESUMO
Previous studies have suggested that rare biallelic SYNJ1 mutations may cause autosomal recessive parkinsonism and Parkinson's disease (PD). Our study explored the impact of rare SYNJ1 variants in non-familial settings, including 8,165 PD cases, 818 early-onset PD (EOPD, <50 years) and 70,363 controls. Burden meta-analysis using optimized sequence Kernel association test (SKAT-O) revealed an association between rare nonsynonymous variants in the Sac1 SYNJ1 domain and PD (Pfdr=0.040). Additionally, a meta-analysis focusing on patients with EOPD demonstrated an association between all rare SYNJ1 variants and PD (Pfdr=0.029). Rare SYNJ1 variants may be associated with sporadic PD, and more specifically with EOPD.
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BACKGROUND: Conventional oral levodopa therapy for the treatment of Parkinson's disease can be associated with variations in plasma concentrations. Levodopa infusion strategies might provide more consistent drug delivery and fewer motor fluctuations. We aimed to assess the safety and efficacy of a continuous 24 h/day subcutaneous infusion of ND0612 (a levodopa-carbidopa solution) compared with oral immediate-release levodopa-carbidopa for the treatment of motor fluctuations in people with Parkinson's disease. METHODS: We conducted a phase 3, randomised, double-blind, double-dummy, active-controlled, multicentre trial at 117 academic and community neurology sites in 16 countries, including in Europe, Israel, and the USA. Eligible participants were men and women aged 30 years or older with a diagnosis of Parkinson's disease (Hoehn and Yahr stage ≤3 in the on state) who experienced at least 2·5 h/day of off time. Participants underwent an open-label run-in phase (<12 weeks), during which time optimal regimens were established for both oral immediate-release levodopa-carbidopa and for 24 h/day subcutaneous ND0612 infusion (levodopa-carbidopa 60·0/7·5 mg/mL), with supplemental oral levodopa-carbidopa if needed. Participants were then randomly assigned (1:1) to 12 weeks of double-blind treatment with their optimised regimen of either subcutaneous ND0612 or oral levodopa-carbidopa, with matching oral or subcutaneous placebo given as required to maintain blinding. Randomisation was done via an interactive web response system, stratified by region, using a permuted block schedule. Participants, study partners, treating investigators, study site personnel, and the sponsor were masked to treatment group allocation. The primary efficacy endpoint was the change from baseline (ie, time of randomisation, when all patients were receiving an optimised open-label ND0612 regimen) to end of the double-blind phase in total daily on time without troublesome dyskinesia, analysed by intention to treat. This trial is registered with ClinicalTrials.gov, NCT04006210, and is complete. FINDINGS: Between Sept 30, 2019, and April 8, 2022, 381 participants were enrolled, of whom 259 (68%) were randomly assigned, 128 (49%) to subcutaneous ND0612 and 131 (51%) to oral levodopa-carbidopa. 243 (94%) participants completed the study. Treatment with subcutaneous ND0612 provided an additional 1·72 h (95% CI 1·08 to 2·36) of on time without troublesome dyskinesia compared with oral levodopa-carbidopa (change from baseline of -0·48 h [-0·94 to -0·02] with subcutaneous ND0612 vs -2·20 h [-2·65 to -1·74] with oral levodopa-carbidopa; p<0·0001). Significant treatment differences favouring subcutaneous ND0612 were also found in the first four of nine prespecified hierarchical outcomes of daily off time (-1·40 h [95% CI -1·99 to -0·80]), Movement Disorders Society-Unified Parkinson's Disease Rating Scale part II scores (-3·05 [-4·28 to -1·81]), Patients Global Impression of Change (odds ratio [OR] 5·31 [2·67 to 10·58]), and Clinical Global Impression of Improvement (OR 7·23 [3·57 to 14·64]). Hierarchical testing ended after the fourth secondary endpoint. Adverse events were reported by 287 (89%) of 322 participants during open-label ND0612 optimisation, and by 103 (80%) of 128 in the ND0612 group and 97 (74%) of 131 in the oral levodopa-carbidopa group during the double-blind phase. The most common adverse events were infusion-site reactions (266 [83%] participants during open-label ND0612, and 73 [57%] in the ND0612 group vs 56 [43%] in the oral levodopa-carbidopa group during the double-blind phase), most of which were mild. Serious adverse events in four participants in the ND0612 group were related to study treatment (infusion-site cellulitis [n=2], infusion-site abscess and infusion-site ulcer [n=1]; and paraesthesia and peripheral sensorimotor neuropathy [n=1]). One participant in the ND0612 group died during the double-blind phase, but the death was not related to study treatment (fall leading to traumatic brain injury). INTERPRETATION: Results of this phase 3 study showed that subcutaneous ND0612 used in combination with oral immediate-release levodopa-carbidopa increased on time without troublesome dyskinesia and reduced off time, with a favourable benefit-risk profile. ND0612 might offer a safe and efficacious subcutaneous levodopa infusion approach to managing motor fluctuations in people with Parkinson's disease. The ongoing open-label extension phase will provide further information on the long-term efficacy and safety of treatment. FUNDING: NeuroDerm.
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Discinesias , Doença de Parkinson , Masculino , Humanos , Feminino , Doença de Parkinson/tratamento farmacológico , Levodopa/uso terapêutico , Carbidopa/efeitos adversos , Antiparkinsonianos/uso terapêutico , Infusões Subcutâneas , Discinesias/tratamento farmacológico , Método Duplo-Cego , Resultado do TratamentoRESUMO
BACKGROUND: Deep brain stimulation (DBS) is a well-established treatment option for individuals with advanced Parkinson's disease (PD). The potential influence of the LRRK2 p.G2019S or GBA1 variants on its lasting efficacy and adverse effects should be better characterized. METHODS: We conducted a retrospective single-center case-control study involving PD patients who were carriers of a GBA1 variant (GBA1-PD), the LRRK2 p.G2019S variant (LRRK2-PD), and non-carriers (Nc-PD). All participants underwent DBS and were followed up for at least a year. Assessments before surgery and at 1, 2, 3, 5, and 10 years post-DBS included the following: the Movement Disorder Society's Unified PD Rating Scale (MDS-UPDRS) Part III, Hoehn and Yahr scale, Levodopa Equivalent Daily Dose (LEDD) and non-motor symptoms (psychotic episodes, depressive symptoms, and cognitive decline). RESULTS: The sample was composed of 103 patients (72 males, mean age at DBS surgery 61.5 ± 8.7 years, mean postoperative follow-up 7.0 ± 4.1 years). Of these, 19 were LRRK2-PD, 20 GBA1-PD, and 64 were Nc-PD. No significant differences in motor outcomes were observed between the groups. Compared to the Nc-PD patients, the GBA1-PD patients were at increased risk of both psychotic episodes [hazard ratio (HR) 2.76 (95 % CI: 1.12-6.80), p = 0.027], and cognitive decline [HR 2.28 (95 % CI: 1.04-5.00), p = 0.04]. CONCLUSION: LRRK2 and GBA1 variant status did not affect the motor outcomes of DBS in PD patients. However, GBA1-PD patients were at increased risk for psychosis and cognitive decline. Further studies are required to determine the role of genetic stratification in referral to DBS.
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Estimulação Encefálica Profunda , Glucosilceramidase , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina , Doença de Parkinson , Humanos , Doença de Parkinson/terapia , Doença de Parkinson/genética , Estimulação Encefálica Profunda/efeitos adversos , Masculino , Feminino , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/genética , Glucosilceramidase/genética , Pessoa de Meia-Idade , Idoso , Estudos Retrospectivos , Estudos de Casos e Controles , Resultado do Tratamento , SeguimentosRESUMO
PURPOSE: Cerebrotendinous xanthomatosis (CTX) is a rare, autosomal recessive bile acid synthesis disorder. Biallelic pathogenic variants in CYP27A1, encoding for sterol 27-hydroxylase, impair cholic acid (CA) and chenodeoxycholic acid (CDCA) synthesis and lead to accumulation of cholestanol and C27 bile alcohols. Treatment with CDCA decreases the accumulation of these harmful metabolites and slows disease progression. Currently, CDCA is contraindicated for use during pregnancy based on animal studies that showed that high-dose CDCA may cause fetal harm when administered to pregnant animals. Data regarding the safety of CDCA treatment in humans are lacking. METHODS: We present a case series of 19 pregnancies in 9 women with CTX who either received CDCA treatment throughout pregnancy or did not. RESULTS: In 11 pregnancies where mothers continued CDCA treatment, no complications were reported, and newborns were born at or near full term, with normal birth weight and Apgar scores. In 8 pregnancies where mothers did not receive CDCA, 2 newborns experienced elevated bilirubin soon after birth. One woman who stopped treatment during her pregnancy deteriorated neurologically while off treatment. CONCLUSION: The data we present support the benefit of continued CDCA treatment in pregnant women with CTX for both the affected women and their offspring.
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Ácido Quenodesoxicólico , Xantomatose Cerebrotendinosa , Humanos , Feminino , Ácido Quenodesoxicólico/uso terapêutico , Xantomatose Cerebrotendinosa/tratamento farmacológico , Xantomatose Cerebrotendinosa/genética , Gravidez , Adulto , Colestanotriol 26-Mono-Oxigenase/genética , Complicações na Gravidez/tratamento farmacológico , Complicações na Gravidez/genética , Recém-NascidoRESUMO
Movement deterioration is the hallmark of Parkinson's disease (PD), characterized by levodopa-induced motor-fluctuations (i.e., symptoms' variability related to the medication cycle) in advanced stages. However, motor symptoms are typically too sporadically and/or subjectively assessed, ultimately preventing the effective monitoring of their progression, and thus leading to suboptimal treatment/therapeutic choices. Smartwatches (SW) enable a quantitative-oriented approach to motor-symptoms evaluation, namely home-based monitoring (HBM) using an embedded inertial measurement unit. Studies validated such approach against in-clinic evaluations. In this work, we aimed at delineating personalized motor-fluctuations' profiles, thus capturing individual differences. 21 advanced PD patients with motor fluctuations were monitored for 2 weeks using a SW and a smartphone-dedicated app (Intel Pharma Analytics Platform). The SW continuously collected passive data (tremor, dyskinesia, level of activity using dedicated algorithms) and active data, i.e., time-up-and-go, finger tapping, hand tremor and hand rotation carried out daily, once in OFF and once in ON levodopa periods. We observed overall high compliance with the protocol. Furthermore, we observed striking differences among the individual patterns of symptoms' levodopa-related variations across the HBM, allowing to divide our participants among four data-driven, motor-fluctuations' profiles. This highlights the potential of HBM using SW technology for revolutionizing clinical practices.
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Levodopa , Doença de Parkinson , Humanos , Levodopa/uso terapêutico , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/diagnóstico , Antiparkinsonianos/uso terapêutico , Smartphone , TremorRESUMO
Variants in the CTSB gene encoding the lysosomal hydrolase cathepsin B (catB) are associated with increased risk of Parkinson's disease (PD). However, neither the specific CTSB variants driving these associations nor the functional pathways that link catB to PD pathogenesis have been characterized. CatB activity contributes to lysosomal protein degradation and regulates signaling processes involved in autophagy and lysosome biogenesis. Previous in vitro studies have found that catB can cleave monomeric and fibrillar alpha-synuclein, a key protein involved in the pathogenesis of PD that accumulates in the brains of PD patients. However, truncated synuclein isoforms generated by catB cleavage have an increased propensity to aggregate. Thus, catB activity could potentially contribute to lysosomal degradation and clearance of pathogenic alpha synuclein from the cell, but also has the potential of enhancing synuclein pathology by generating aggregation-prone truncations. Therefore, the mechanisms linking catB to PD pathophysiology remain to be clarified. Here, we conducted genetic analyses of the association between common and rare CTSB variants and risk of PD. We then used genetic and pharmacological approaches to manipulate catB expression and function in cell lines and induced pluripotent stem cell-derived dopaminergic neurons and assessed lysosomal activity and the handling of aggregated synuclein fibrils. We find that catB inhibition impairs autophagy, reduces glucocerebrosidase (encoded by GBA1) activity, and leads to an accumulation of lysosomal content. In cell lines, reduction of CTSB gene expression impairs the degradation of pre-formed alpha-synuclein fibrils, whereas CTSB gene activation enhances fibril clearance. In midbrain organoids and dopaminergic neurons treated with alpha-synuclein fibrils, catB inhibition potentiates the formation of inclusions which stain positively for phosphorylated alpha-synuclein. These results indicate that the reduction of catB function negatively impacts lysosomal pathways associated with PD pathogenesis, while conversely catB activation could promote the clearance of pathogenic alpha-synuclein.
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Alexander disease (AxD) is a rare autosomal dominant leukodystrophy caused by heterozygous mutations in the glial fibrillary acid protein (GFAP) gene. The age of symptoms onset ranges from infancy to adulthood, with variable clinical and radiological manifestations. Adult-onset AxD manifests as a chronic and progressive condition, characterized by bulbar, motor, cerebellar, and other clinical signs and symptoms. Neuroradiological findings typically involve the brainstem and cervical spinal cord. Adult-onset AxD has been described in diverse populations but is rare in Israel. We present a series of patients diagnosed with adult-onset AxD from three families, all of Jewish Syrian descent. Five patients (4 females) were diagnosed with adult-onset AxD due to the heterozygous mutation c.219G > A, p.Met73Ile in GFAP. Age at symptoms onset ranged from 48 to 61 years. Clinical characteristics were typical and involved progressive bulbar and gait disturbance, followed by pyramidal and cerebellar impairment, dysautonomia, and cognitive decline. Imaging findings included medullary and cervical spinal atrophy and mostly infratentorial white matter hyperintensities. A newly recognized cluster of adult-onset AxD in Jews of Syrian origin is presented. This disorder should be considered in differential diagnosis in appropriate circumstances. Genetic counselling for family members is required in order to discuss options for future family planning.
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Doença de Alexander , Feminino , Humanos , Adulto , Pessoa de Meia-Idade , Doença de Alexander/diagnóstico por imagem , Doença de Alexander/genética , Judeus/genética , Síria , Proteína Glial Fibrilar Ácida/genética , Mutação , AtrofiaRESUMO
BACKGROUND: Interventions using split belt treadmills (SBTM) aim to improve gait symmetry (GA) in Parkinson's disease (PD). Comparative effects in conjugated SBTM conditions were not studied systematically despite potentially affecting intervention outcomes. We compared gait adaptation effects instigated by SBTM walking with respect to the type (increased\decreased speed) and the side (more/less affected) of the manipulated belt in PD. METHODS: Eight individuals with PD performed four trials of SBTM walking, each consisted of baseline tied belt configuration, followed by split belt setting - either WS or BS belt's speed increased or decreased by 50% from baseline, and final tied belt configuration. Based on the disease's motor symptoms, a 'worst' side (WS) and a 'best' side (BS) were defined for each participant. RESULTS: SB initial change in GA was significant regardless of condition (p ≤ 0.02). This change was however more pronounced for BS-decrease compared with its matching condition WS-increase (p = 0.016). Similarly, the same was observed for WS-decrease compared to BS-increase (p = 0.013). Upon returning to tied belt condition, both BS-decrease and WS-increased resulted in a significant change in GA (p = 0.04). Upper limb asymmetry followed a similar trend of GA reversal, although non-significant. CONCLUSIONS: Stronger effects on GA were obtained by decreasing the BS belt's speed of the best side, rather than increasing the speed of the worst side. Albeit a small sample size, which limits the generalisability of these results, we propose that future clinical studies would benefit from considering such methodological planning of SBTM intervention, for maximising of intervention outcomes. Larger samples may reveal arm swinging asymmetries alterations to match SBTM adaptation patterns. Finally, further research is warranted to study post-adaption effects in order to define optimal adaptation schemes to maximise the therapeutic effect of SBTM based interventions.
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Doença de Parkinson , Humanos , Projetos Piloto , Marcha , Caminhada , Adaptação Fisiológica , Teste de Esforço/métodos , Fenômenos BiomecânicosRESUMO
BACKGROUND: Several lysosomal genes are associated with Parkinson's disease (PD), yet the association between PD and ARSA remains unclear. OBJECTIVES: To study rare ARSA variants in PD. METHODS: To study rare ARSA variants (minor allele frequency < 0.01) in PD, we performed burden analyses in six independent cohorts with 5801 PD patients and 20,475 controls, followed by a meta-analysis. RESULTS: We found evidence for associations between functional ARSA variants and PD in four cohorts (P ≤ 0.05 in each) and in the meta-analysis (P = 0.042). We also found an association between loss-of-function variants and PD in the United Kingdom Biobank cohort (P = 0.005) and in the meta-analysis (P = 0.049). These results should be interpreted with caution as no association survived multiple comparisons correction. Additionally, we describe two families with potential co-segregation of ARSA p.E382K and PD. CONCLUSIONS: Rare functional and loss-of-function ARSA variants may be associated with PD. Further replications in large case-control/familial cohorts are required. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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Doença de Parkinson , Humanos , Frequência do Gene , Doença de Parkinson/genética , Doença de Parkinson/complicações , Reino Unido , Cerebrosídeo SulfataseRESUMO
INTRODUCTION: Freezing of gait (FoG) is a debilitating symptom of advanced Parkinson's disease (PD) characterized by a sudden, episodic stepping arrest despite the intention to continue walking. The etiology of FoG is still unknown, but accumulating evidence unraveled physiological signatures of the autonomic nervous system (ANS) around FoG episodes. Here we aim to investigate for the first time whether detecting a predisposition for upcoming FoG events from ANS activity measured at rest is possible. METHODS: We recorded heart-rate for 1-min while standing in 28 persons with PD with FoG (PD + FoG), while OFF, and in 21 elderly controls (EC). Then, PD + FoG participants performed walking trials containing FoG-triggering events (e.g., turns). During these trials, n = 15 did experience FoG (PD + FoG+), while n = 13 did not (PD + FoG-). Most PD participants (n = 20: 10 PD + FoG+ and 10 PD + FoG-) repeated the experiment 2-3 weeks later, while ON, and none experienced FoG. We then analyzed heart-rate variability (HRV), i.e., the fluctuations in time intervals between adjacent heartbeats, mainly generated by brain-heart interactions. RESULTS: During OFF, HRV was significantly lower in PD + FoG + participants, reflecting imbalanced sympathetic/parasympathetic activity and disrupted self-regulatory capacity. PD + FoG- and EC participants showed comparable (higher) HRV. During ON, HRV did not differ among groups. HRV values did not correlate with age, PD duration, levodopa consumption, nor motor -symptoms severity scores. CONCLUSIONS: Overall, these results document for the first time a relation between HRV at rest and FoG presence/absence during gait trials, expanding previous evidence regarding the involvement of ANS in FoG.
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Transtornos Neurológicos da Marcha , Doença de Parkinson , Humanos , Idoso , Doença de Parkinson/complicações , Frequência Cardíaca , Transtornos Neurológicos da Marcha/etiologia , Marcha/fisiologia , Caminhada/fisiologia , Suscetibilidade a Doenças/complicaçõesRESUMO
BACKGROUND: Whole-plant medical cannabis (MC) products are widely used for controlling symptoms associated with Parkinson's disease (PD). Despite its widespread use, few studies have investigated the long-term impact of MC on the progression of PD or its safety profile. This study examined the effects of MC on PD in a real-life setting. METHODS: A retrospective case-control study of 152 idiopathic PD patients (mean age 69.1 ± 9.0 years), followed at the Sheba Medical Center Movement Disorders Institute (SMDI) from 2008 to 2022 was conducted. Seventy-six patients who used licensed whole-plant medical cannabis (MC) for at least a year were compared to a matched group who did not receive MC in terms of their Levodopa Equivalent Daily Dose (LEDD), Hoehn and Yahr (H&Y) stage, and cognitive, depressive, and psychotic symptoms. RESULTS: The median monthly dose of MC was 20 g (IQR: 20-30), with a median Tetrahydrocannabinol (THC) percentage of 10 (IQR: 9.5-14.15) and a median Cannabidiol (CBD) percentage of 4 (IQR: 2-10). There were no significant differences between the MC and the control groups for LEDD or H&Y stage progression (p = 0.90, 0.77, respectively). A Kaplan-Meier analysis showed no evidence of relative worsening of psychotic, depressive, or cognitive symptoms reported by patients to their treating physicians over time in the MC group (p = 0.16-0.50). CONCLUSION: Over the 1-3 years of follow-ups, the MC treatment regimens appeared to be safe. MC did not exacerbate neuropsychiatric symptoms and had no detrimental effects on disease progression.
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Maconha Medicinal , Doença de Parkinson , Humanos , Pessoa de Meia-Idade , Idoso , Doença de Parkinson/complicações , Doença de Parkinson/tratamento farmacológico , Maconha Medicinal/efeitos adversos , Estudos Retrospectivos , Estudos de Casos e Controles , Levodopa/uso terapêuticoRESUMO
Background: Several lysosomal genes are associated with Parkinson's disease (PD), yet the association between PD and ARSA , which encodes for the enzyme arylsulfatase A, remains controversial. Objectives: To evaluate the association between rare ARSA variants and PD. Methods: To study possible association of rare variants (minor allele frequency<0.01) in ARSA with PD, we performed burden analyses in six independent cohorts with a total of 5,801 PD patients and 20,475 controls, using optimized sequence Kernel association test (SKAT-O), followed by a meta-analysis. Results: We found evidence for an association between functional ARSA variants and PD in four independent cohorts (P≤0.05 in each) and in the meta-analysis (P=0.042). We also found an association between loss-of-function variants and PD in the UKBB cohort (P=0.005) and in the meta-analysis (P=0.049). However, despite replicating in four independent cohorts, these results should be interpreted with caution as no association survived correction for multiple comparisons. Additionally, we describe two families with potential co-segregation of the ARSA variant p.E384K and PD. Conclusions: Rare functional and loss-of-function ARSA variants may be associated with PD. Further replication in large case-control cohorts and in familial studies is required to confirm these associations.
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The association between glucocerebrosidase, encoded by GBA, and Parkinson's disease (PD) highlights the role of the lysosome in PD pathogenesis. Genome-wide association studies in PD have revealed multiple associated loci, including the GALC locus on chromosome 14. GALC encodes the lysosomal enzyme galactosylceramidase, which plays a pivotal role in the glycosphingolipid metabolism pathway. It is still unclear whether GALC is the gene driving the association in the chromosome 14 locus and, if so, by which mechanism. We first aimed to examine whether variants in the GALC locus and across the genome are associated with galactosylceramidase activity. We performed a genome-wide association study in two independent cohorts from (i) Columbia University; and (ii) the Parkinson's Progression Markers Initiative study, followed by a meta-analysis with a total of 976 PD patients and 478 controls with available data on galactosylceramidase activity. We further analysed the effects of common GALC variants on expression and galactosylceramidase activity using genomic colocalization methods. Mendelian randomization was used to study whether galactosylceramidase activity may be causal in PD. To study the role of rare GALC variants, we analysed sequencing data from 5028 PD patients and 5422 controls. Additionally, we studied the functional impact of GALC knockout on alpha-synuclein accumulation and on glucocerebrosidase activity in neuronal cell models and performed in silico structural analysis of common GALC variants associated with altered galactosylceramidase activity. The top hit in PD genome-wide association study in the GALC locus, rs979812, is associated with increased galactosylceramidase activity (b = 1.2; SE = 0.06; P = 5.10 × 10-95). No other variants outside the GALC locus were associated with galactosylceramidase activity. Colocalization analysis demonstrated that rs979812 was also associated with increased galactosylceramidase expression. Mendelian randomization suggested that increased galactosylceramidase activity may be causally associated with PD (b = 0.025, SE = 0.007, P = 0.0008). We did not find an association between rare GALC variants and PD. GALC knockout using CRISPR-Cas9 did not lead to alpha-synuclein accumulation, further supporting that increased rather than reduced galactosylceramidase levels may be associated with PD. The structural analysis demonstrated that the common variant p.I562T may lead to improper maturation of galactosylceramidase affecting its activity. Our results nominate GALC as the gene associated with PD in this locus and suggest that the association of variants in the GALC locus may be driven by their effect of increasing galactosylceramidase expression and activity. Whether altering galactosylceramidase activity could be considered as a therapeutic target should be further studied.
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Doença de Parkinson , Humanos , Doença de Parkinson/metabolismo , alfa-Sinucleína/metabolismo , Galactosilceramidase/genética , Galactosilceramidase/metabolismo , Glucosilceramidase/genética , Estudo de Associação Genômica Ampla , Mutação , Hidrolases/genéticaRESUMO
Practical methods for early identification of Parkinson's disease (PD) mild cognitive impairment (PD-MCI) through changes in real-life daily functioning are scarce. The aim of the study was to examine whether the cognitive functional (CF) feature, comprising of seven self-reported Movement Disorder Society's (MDS) Unified Parkinson's Disease Rating Scale (UPDRS) items, predicts PD patients' cognitive functional status after a year. We conducted a 1-year follow-up of 34 PD patients (50-78 year; 70.6% men) suspected of MCI using the following measures: the MDS-UPDRS, UPDRS-CF feature, Beck Depression Inventory (BDI), Montreal Cognitive Assessment (MoCA), Trail Making Test (TMT), Parkinson's Disease Cognitive Functional Rating Scale (PD-CFRS), and Daily Living Questionnaire (DLQ). The first and second UPDRS-CF feature scores, and additional measures at the 1-year follow-up significantly correlated. Hierarchical regression revealed that the initial MoCA, TMT, and BDI scores predicted the second UPDRS-CF, and the first UPDRS-CF predicted 31% of the second PD-CFRS score variance. Depression moderated the relationship between the first UPDRS-CF score and the DLQ Part A. These results suggest practical, self-reported, daily functional markers for identifying gradual decline in PD patients. They consider the patients' heterogeneity, underlying cognitive pathology, and implications on daily functioning, health, and well-being.
Assuntos
Disfunção Cognitiva , Doença de Parkinson , Masculino , Humanos , Feminino , Doença de Parkinson/complicações , Doença de Parkinson/diagnóstico , Projetos Piloto , Estudos Longitudinais , Disfunção Cognitiva/diagnóstico , CogniçãoRESUMO
Parkinson's disease (PD) is taking a staggering toll on healthcare systems worldwide, with the bulk of the expenditures invested in the late stages of the disease. Considering the rising life expectancy and the increasing prevalence of PD across the globe, a clear understanding of the early signs and treatment options available for advanced PD (APD), will facilitate tailoring management programs and support services. This task is complicated by the lack of both global consensus in defining APD and standardized care guidelines. This perspective prepared by a panel of movement disorder specialists, proposes to extend and optimize currently accepted PD coding to better reflect the diverse disease manifestations, with emphasis on non-motor features. The panel seeks to promote timely diagnosis by adjustment of evaluation tools for use by community neurologists and suggests modification of eligibility criteria for advanced therapy. Moreover, it advocates multidisciplinary assessments of APD patients to drive personalized, patient-centered and holistic management. Overall, earlier and more targeted intervention is expected to markedly improve patient quality of life.
RESUMO
Recessive mutations in PRKN, PARK7, and PINK1 are established causes of early-onset Parkinson's disease (EOPD). Previous studies have interrogated the role of heterozygous variants in these genes but mainly focused on rare (minor allele frequency [MAF] <1%) damaging variants or established mutations. Here, we assessed heterozygous private PRKN, PARK7 and PINK1 variants in PD risk in four large-scale PD case-control datasets by performing gene-wise burden analyses using sequencing data totaling 5,829 PD cases and 7,221 controls, and summary allele counts from 9,501 PD cases and 48,207 controls. Results showed no significant burden in all three genes after meta-analyses. Burden in EOPD (age at onset <50 years) and late-onset PD (≥50 years) remained nonsignificant. In summary, we found no evidence to support the association of the excess burden of heterozygous private variants in PRKN, PARK7, and PINK1 with PD risk in the European population. Larger, more diverse cohorts are needed to accurately determine their role in PD.
Assuntos
Doença de Parkinson , Proteína Desglicase DJ-1 , Proteínas Quinases , Ubiquitina-Proteína Ligases , Humanos , Idade de Início , Testes Genéticos , Mutação , Doença de Parkinson/genética , Doença de Parkinson/epidemiologia , Proteína Desglicase DJ-1/genética , Proteínas Quinases/genética , Ubiquitina-Proteína Ligases/genéticaRESUMO
This study aimed to capture subjective daily functional cognitive decline among patients with Parkinson's disease. Participants (40-79 y; 78 with Parkinson's disease and 41 healthy matched controls) completed the Unified Parkinson's Disease Rating Scale (MDS-UPDRS), Parkinson's Disease Cognitive Functional Rating Scale (CFRS), Daily Living Questionnaire (DLQ), and Time Organisation and Participation Scale (TOPS) questionnaires. Patients with Parkinson's disease were divided into groups with or without suspected mild cognitive decline according to their scores on the Cognitive Functional (CF) feature, which is based on certain items of the MDS-UPDRS. Significant between-group differences were found in the DLQ and TOPS scores. Significant correlations were found among the questionnaire results, with specific DLQ and TOPS items accounting for 35% of the variance in the CF feature, which correlated with daily cognitive functional states. This study's results are relevant for detecting subtle deficits in Parkinson's disease patients suspected of mild cognitive decline, which can affect health and quality of life and relates to risk for later dementia.