Background Disease-modifying treatments are in development for Huntington's disease; crucial to their success is to identify a timepoint in a patient's life when there is a measurable biomarker of early neurodegeneration while clinical function is still intact. We aimed to identify this timepoint in a novel cohort of young adult premanifest Huntington's disease gene carriers (preHD) far from predicted clinical symptom onset. Methods We did the Huntington's disease Young Adult Study (HD-YAS) in the UK. We recruited young adults with preHD and controls matched for age, education, and sex to ensure each group had at least 60 participants with imaging data, accounting for scan fails. Controls either had a family history of Huntington's disease but a negative genetic test, or no known family history of Huntington's disease. All participants underwent detailed neuropsychiatric and cognitive assessments, including tests from the Cambridge Neuropsychological Test Automated Battery and a battery assessing emotion, motivation, impulsivity and social cognition (EMOTICOM). Imaging (done for all participants without contraindications) included volumetric MRI, diffusion imaging, and multiparametric mapping. Biofluid markers of neuronal health were examined using blood and CSF collection. We did a cross-sectional analysis using general leastsquares linear models to assess group differences and associations with age and CAG length, relating to predicted years to clinical onset. Results were corrected for multiple comparisons using the false discovery rate (FDR), with FDR <0•05 deemed a significant result. Findings Data were obtained between Aug 2, 2017, and April 25, 2019. We recruited 64 young adults with preHD and 67 controls. Mean ages of participants were 29•0 years (SD 5•6) and 29•1 years (5•7) in the preHD and control groups, respectively. We noted no significant evidence of cognitive or psychiatric impairment in preHD participants 23•6 years (SD 5•8) from predicted onset (FDR 0•22-0•87 for cognitive measures, 0•31-0•91 for neuropsychiatric measures). The preHD cohort had slightly smaller putamen volumes (FDR=0•03), but this did not appear to be closely related to predicted years to onset (FDR=0•54). There were no group differences in other brain imaging measures (FDR >0•16). CSF neurofilament light protein (NfL), plasma NfL, and CSF YKL-40 were elevated in this far-from-onset preHD cohort compared with controls (FDR<0•0001, =0•01, and =0•03, respectively). CSF NfL elevations were more likely in individuals closer to expected clinical onset (FDR <0•0001). Interpretation We report normal brain function yet a rise in sensitive measures of neurodegeneration in a preHD cohort approximately 24 years from predicted clinical onset. CSF NfL appears to be a more sensitive measure than plasma NfL to monitor disease progression. This preHD cohort is one of the earliest yet studied, and our findings could be used to inform decisions about when to initiate a potential future intervention to delay or prevent further neurodegeneration wh...
Drug induced parkinsonism and tardive dyskinesia are iatrogenic consequences of the use of antidopaminergic drugs. Both entities share risk factors, physiopathological mechanisms and to some degree, therapeutic approaches. Here we review both entities and discuss emerging therapies including the recently approved drug deutetrabenazine and relevant aspects for clinical practice such as new diagnostic techniques. Key points:-Drug induced parkinsonism and tardive dyskinesia are iatrogenic consequences of the use of antidopaminergic drugs.-DIP is considered a direct consequence of the blockage of D2 receptors while TD has a more complex physiopathology, including enhanced sensitivity of dopamine receptors.-Both entities are more frequent in older people due to a progressive loss of dopaminergic neurons with age.-New therapies are available for TD, including deutetrabenazine. Compliance with ethical Standards:Disclosure of potential conflicts of interest: no funding was received for this study.The risks of drug-induced parkinsonism/tardive dyskinesia in the elderly and current methods to overcome it. 1.-IntroductionTardive dyskinesia (TD) and drug-induced parkinsonism (DIP) are iatrogenic disorders caused by dopamine receptor blockers (DRB) [1]. They were recognized early after the introduction of antipsychotics[2] to the clinical practice, leading to the finding that DIP caused by reserpine, a dopamine depleter, was related to dopamine deficiency [3].Elderly patients are more susceptible to these side effects, probably due to an age-related decrease in nigral neurons and dopamine [4]. Since the introduction of newer second generation antipsychotics (SGA) the frequency and intensity of these side effects has improved [5] , [6] , [7] , [8] but there is still room for concern [9], [10].TD and DIP share risk factors, pathological mechanisms and management, and might coexist in one given subject. Latest available evidence has clarified some intriguing features of TD and DIP. Meanwhile, new medications to treat TD are now available, highlighting the importance of a thorough, updated, knowledge of this pathologies.This article offers a comprehensive review of the incidence, clinical features and mechanisms behind DIP and TD. The benefits and risks of previous available drugs and those that have been recently approved by regulatory agencies are discussed. Drug induced Parkinsonism DefinitionDIP occurs when symptoms emerge after exposure to drugs, usually those that either deplete dopamine storages [11] or block dopamine receptors [12]. By definition, symptoms should be reversible, six months after the offending agent has been withdrawn[13] but actually up to 20% of patients develop persistent deficits despite drug discontinuation [14] leading to the hypothesis that these patients might have subclinical Parkinson's Disease (PD) unmasked by neuroleptic exposure (umPD), complicating the differential diagnosis [15], especially between aged patients, who are more prone to both PD and DIP. Epidemiology and risk factorsAfter PD, DI...
Background Pathological processes in Huntington's disease (HD) begin many years prior to symptom onset. Recently we demonstrated that in a premanifest cohort approximately 24 years from predicted disease onset, despite intact function, there was evidence of subtle neurodegeneration. Here, we use novel imaging techniques to determine whether macro- and micro-structural changes can be detected across the whole-brain in the same cohort. Methods 62 premanifest HD (PreHD) and 61 controls from the HD Young Adult Study (HD-YAS) were included. Grey and white matter volume, diffusion weighted imaging (DWI) measures of white matter microstructure, multiparametric maps (MPM) estimating myelin and iron content from magnetization transfer (MT), proton density (PD), longitudinal relaxation (R1) and effective transverse relaxation (R2*), and myelin g-ratio were examined. Group differences between PreHD and controls were assessed; associations between all imaging metrics and disease burden and CSF neurofilament light (NfL) were also performed. Volumetric and MPM results were corrected at a cluster-wise value of familywise error (FWE) 0.05. Diffusion and g-ratio results were corrected via threshold-free cluster enhancement at FWE 0.05. Findings We showed significantly increased R1 and R2*, suggestive of increased iron, in the putamen, globus pallidum and external capsule of PreHD participants. There was also a significant association between lower cortical R2*, suggestive of reduced myelin or iron, and higher CSF NfL in the frontal lobe and the parieto-occipital cortices. No other results were significant at corrected levels. Interpretation Increased iron in subcortical structures and the surrounding white matter is a feature of very early PreHD. Furthermore, increases in CSF NfL were linked to microstructural changes in the posterior parietal-occipital cortex, a region previously shown to undergo some of the earliest cortical changes in HD. These findings suggest that disease related process are occurring in both subcortical and cortical regions more than 20 years from predicted disease onset.
A BS TRACT: Background: Complex parkinsonism is the commonest phenotype in late-onset PLA2G6associated neurodegeneration. Objectives: The aim of this study was to deeply characterize phenogenotypically PLA2G6-related parkinsonism in the largest cohort ever reported. Methods: We report 14 new cases of PLA2G6-related parkinsonism and perform a systematic literature review. Results: PLA2G6-related parkinsonism shows a fairly distinct phenotype based on 86 cases from 68 pedigrees. Young onset (median age, 23.0 years) with parkinsonism/ dystonia, gait/balance, and/or psychiatric/cognitive symptoms were common presenting features. Dystonia occurred in 69.4%, pyramidal signs in 77.2%, myoclonus in 65.2%, and cerebellar signs in 44.6% of cases. Early bladder overactivity was present in 71.9% of cases. Cognitive impairment affected 76.1% of cases and psychiatric features 87.1%, the latter being an isolated presenting feature in 20.1%. Parkinsonism was levodopa responsive but complicated by early, often severe dyskinesias. Five patients benefited from deep brain stimulation. Brain magnetic resonance imaging findings included cerebral (49.3%) and/or cerebellar (43.2%) atrophy, but mineralization was evident in only 28.1%. Presynaptic dopaminergic terminal imaging was abnormal in all where performed. Fifty-four PLA2G6 mutations have hitherto been associated with parkinsonism, including four new variants reported in this article. These are mainly nontruncating,
Botulinum toxin type A is one of the most useful treatments of sialorrhea in neurological disorders. Evidence for the use of incobotulinumtoxin A (inco-A) in the treatment of sialorrhea is limited. Thirty-six patients with sialorrhea were treated with infiltrations of inco-A into both parotid glands. The severity of sialorrhea was evaluated by the Drooling Severity Scale (DSS), and the Drooling Frequency Scale (DFS). Patients’ perceptions of clinical benefit were recorded via the Patient Global Impression of Improvement (PGI-I) scale. Following treatment, there was a significant difference in both the DFS and the DSS (p < 0.001). Clinical benefits on the basis of the PGI-I were present in up to 90% of patients.
A BS TRACT: X-linked parkinsonism encompasses rare heterogeneous disorders mainly inherited as a recessive trait, therefore being more prevalent in males. Recent developments have revealed a complex underlying panorama, including a spectrum of disorders in which parkinsonism is variably associated with additional neurological and non-neurological signs. In particular, a childhoodonset encephalopathy with epilepsy and/or cognitive disability is the most common feature. Their genetic basis is also heterogeneous, with many causative genes and different mutation types ranging from "classical" coding variants to intronic repeat expansions. In this review, we provide an updated overview of the phenotypic and genetic spectrum of the most relevant X-linked parkinsonian syndromes, namely X-linked dystonia-parkinsonism (XDP, Lubag disease), fragile X-associated tremor/ataxia syndrome (FXTAS), beta-propeller protein-associated neurodegeneration (BPAN, NBIA/PARK-WDR45), Fabry disease, Waisman syndrome, methyl CpG-binding protein 2 (MeCP2) spectrum disorder, phosphoglycerate kinase-1 deficiency syndrome (PGK1) and X-linked parkinsonism and spasticity (XPDS). All clinical and radiological features reported in the literature have been reviewed. Epilepsy occasionally represents the symptom of onset, predating parkinsonism even by a few years; action tremor is another common feature along with akinetic-rigid parkinsonism. A focus on the genetic background and its pathophysiological implications is provided. The pathogenesis of these disorders ranges from well-defined metabolic alterations (PGK1) to non-specific lysosomal dysfunctions (XPDS) and vesicular trafficking alterations (Waisman syndrome). However, in other cases it still remains poorly defined. Recognition of the phenotypic and genetic heterogeneity of X-linked parkinsonism has important implications for diagnosis, management, and genetic counseling.
Purpose of reviewHuntington's disease (HD) is a fatal autosomal dominant neurodegenerative disorder caused by a trinucleotide expansion in the HTT gene, and current therapies focus on symptomatic treatment. This review explores therapeutic approaches that directly target the pathogenic mutation, disrupt HTT mRNA or its translation. Recent findingsZinc-finger transcription repressors and CRISPR-Cas9 therapies target HTT DNA, thereby preventing all downstream pathogenic mechanisms. These therapies, together with RNA interference (RNAi) require intraparenchymal delivery to the brain in viral vectors, with only a single delivery potentially required, though they may carry the risk of irreversible side effects.Along with RNAi, antisense oligonucleotides (ASOs) target mRNA, but are delivered periodically and intrathecally. ASOs have safely decreased mHTT levels in the central nervous system of patients, and a phase 3 clinical trial is currently under way.Finally, orally available small molecules, acting on splicing or posttranslational modification, have recently been shown to decrease mHTT in animal models.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.