Associations of mitochondrial genomic variation with successful neurological aging.

Mitochondrial health is an integral factor in aging, with mitochondrial dysfunction known to increase with age and contribute to the development of age-related neurodegenerative disorders. Additionally, the mitochondrial genome (mtDNA) has been shown to acquire potentially damaging somatic variation as part of the aging process, while mtDNA single nucleotide polymorphism (SNPs) have been shown to be both protective and detrimental for various neurodegenerative diseases. Yet, little is known about the involvement of mtDNA variation in longevity and successful neurological aging.

Dopamine Pathway and Parkinson's Risk Variants Are Associated with Levodopa-Induced Dyskinesia.

Background: Levodopa-induced dyskinesia (LID) is a common adverse effect of levodopa, one of the main therapeutics used to treat the motor symptoms of Parkinson's disease (PD). Previous evidence suggests a connection between LID and a disruption of the dopaminergic system as well as genes implicated in PD, including GBA1 and LRRK2.

Objectives: Our goal was to investigate the effects of genetic variants on risk and time to LID.

Deciphering Distinct Genetic Risk Factors for FTLD-TDP Pathological Subtypes via Whole-Genome Sequencing.

Frontotemporal lobar degeneration with neuronal inclusions of the TAR DNA-binding protein 43 (FTLD-TDP) is a fatal neurodegenerative disorder with only a limited number of risk loci identified. We report our comprehensive genome-wide association study as part of the International FTLD-TDP Whole-Genome Sequencing Consortium, including 985 cases and 3,153 controls, and meta-analysis with the Dementia-seq cohort, compiled from 26 institutions/brain banks in the United States, Europe and Australia. We confirm as the strongest overall FTLD-TDP risk factor and identify as a novel FTLD-TDP risk factor.

Systematic rare variant analyses identify RAB32 as a susceptibility gene for familial Parkinson's disease.

Despite substantial progress, causal variants are identified only for a minority of familial Parkinson's disease (PD) cases, leaving high-risk pathogenic variants unidentified. To identify such variants, we uniformly processed exome sequencing data of 2,184 index familial PD cases and 69,775 controls. Exome-wide analyses converged on RAB32 as a novel PD gene identifying c.

Enhancing outcomes in deep brain stimulation: a comparative study of direct targeting using 7T versus 3T MRI.

Objective: The aim of this study was to compare outcomes of direct targeting in deep brain stimulation (DBS) for essential tremor using 7T MRI versus 3T MRI. The authors hypothesized that 7T MRI direct targeting would be noninferior to 3T MRI in early tremor outcomes.

Methods: A retrospective study was conducted on patients undergoing unilateral thalamic DBS for essential tremor between 2021 and 2023.

Diagnostic utility of 7T neuromelanin imaging of the substantia nigra in Parkinson's disease.

Parkinson's disease (PD) is a prevalent neurodegenerative disorder that presents a diagnostic challenge due to symptom overlap with other disorders. Neuromelanin (NM) imaging is a promising biomarker for PD, but adoption has been limited, in part due to subpar performance at standard MRI field strengths. We aimed to evaluate the diagnostic utility of ultra-high field 7T NM-sensitive imaging in the diagnosis of PD versus controls and essential tremor (ET), as well as NM differences among PD subtypes.

Genetics of Parkinson's disease heterogeneity: A genome-wide association study of clinical subtypes.

Introduction: Substantial heterogeneity between individual patients in the clinical presentation of Parkinson's disease (PD) has led to the classification of distinct PD subtypes. However, genetic susceptibility factors for specific PD subtypes are not well understood. Therefore, the present study aimed to investigate the genetics of PD heterogeneity by performing a genome-wide association study (GWAS) of PD subtypes.

Frequency of Comorbid Pathologies and Their Clinical Impact in Multiple System Atrophy.

Background: Mixed pathology is common at autopsy for a number of age-associated neurodegenerative disorders; however, the frequency of comorbid pathologies in multiple system atrophy (MSA) and their clinical correlations are poorly understood.

Objective: We determined the frequency of comorbid pathologic processes in autopsy-confirmed MSA and assessed their clinical correlates.

Methods: This study included 160 neuropathologically established MSA from the Mayo Clinic brain bank.

Validation Study of the MDS Criteria for the Diagnosis of Multiple System Atrophy in the Mayo Clinic Brain Bank.

Background And Objective: The second consensus criteria in 2008 have been used in diagnosing multiple system atrophy (MSA). The International Parkinson and Movement Disorder Society (MDS) proposed new diagnostic criteria for MSA in 2022. This study aimed to compare the diagnostic accuracy between these 2 criteria and validate the clinical utility of the newly proposed criteria for MSA.

Dopamine pathway and Parkinson's risk variants are associated with levodopa-induced dyskinesia.

Background: Levodopa-induced dyskinesia (LID) is a common adverse effect of levodopa, one of the main therapeutics used to treat the motor symptoms of Parkinson's disease (PD). Previous evidence suggests a connection between LID and a disruption of the dopaminergic system as well as genes implicated in PD, including and .

Objectives: To investigate the effects of genetic variants on risk and time to LID.

Cancer in pathologically confirmed multiple system atrophy.

Purpose: The aim of this study was to assess whether cancer occurs with increased frequency in multiple system atrophy (MSA). The pathological hallmark of MSA is glial cytoplasmic inclusions containing aggregated α-synuclein, and the related protein γ-synuclein correlates with invasive cancer. We investigated whether these two disorders are associated clinically.

Genetic architecture of Parkinson's disease subtypes - Review of the literature.

The heterogeneity of Parkinson's disease (PD) has been recognized since its description by James Parkinson over 200 years ago. The complexity of motor and non-motor PD manifestations has led to many attempts of PD subtyping with different prognostic outcomes; however, the pathophysiological foundations of PD heterogeneity remain elusive. Genetic contributions to PD may be informative in understanding the underpinnings of PD subtypes.

Mitochondrial genomic variation in dementia with Lewy bodies: association with disease risk and neuropathological measures.

Dementia with Lewy bodies (DLB) is clinically diagnosed when patients develop dementia less than a year after parkinsonism onset. Age is the primary risk factor for DLB and mitochondrial health influences ageing through effective oxidative phosphorylation (OXPHOS). Patterns of stable polymorphisms in the mitochondrial genome (mtDNA) alter OXPHOS efficiency and define individuals to specific mtDNA haplogroups.

Cathepsin B p.Gly284Val Variant in Parkinson's Disease Pathogenesis.

Parkinson's disease (PD) is generally considered a sporadic disorder, but a strong genetic background is often found. The aim of this study was to identify the underlying genetic cause of PD in two affected siblings and to subsequently assess the role of mutations in Cathepsin B in susceptibility to PD. A typical PD family was identified and whole-exome sequencing was performed in two affected siblings.

PLA2G6-associated neurodegeneration in four different populations-case series and literature review.

Background: PLA2G6-Associated Neurodegeneration, PLAN, is subdivided into: Infantile neuroaxonal dystrophy, atypical neuroaxonal dystrophy, and adult-onset dystonia parkinsonism [1]. It is elicited by a biallelic pathogenic variant in phospholipase A2 group VI (PLA2G6) gene. In this study we describe new cases and provide a comprehensive review of previously published cases.

Effects of sex and APOE on Parkinson's Disease-related cognitive decline.

Introduction: Cognitive impairment is common in Parkinson's Disease, but the impact of predictive factors on incidence and rate of cognitive decline is incompletely understood. We aimed to determine the effects of sex and APOE allele status on cognitive performance in patients with Parkinson's Disease (PD).

Material And Methods: We conducted a retrospective analysis of 325 clinically diagnosed PD patients who underwent one or more cognitive screenings with a Mini-Mental Status Examination (MMSE) or Mattis Dementia Rating Scale (DRS-2).

Connectivity correlates to predict essential tremor deep brain stimulation outcome: Evidence for a common treatment pathway.

Background And Purpose: Deep brain stimulation (DBS) is the most common surgical treatment for essential tremor (ET), yet there is variation in outcome and stimulation targets. This study seeks to consolidate proposed stimulation "sweet spots," as well as assess the value of structural connectivity in predicting treatment outcomes.

Materials And Methods: Ninety-seven ET individuals with unilateral thalamic DBS were retrospectively included.

Directed stimulation of the dentato-rubro-thalamic tract for deep brain stimulation in essential tremor: a blinded clinical trial.

Objective: Observational studies utilising diffusion tractography have suggested a common mechanism for tremor alleviation in deep brain stimulation for essential tremor: the decussating portion of the dentato-rubro-thalamic tract. We hypothesised that directional stimulation of the dentato-rubro-thalamic tract would result in greater tremor improvement compared to sham programming, as well as comparable improvement as more tedious standard-of-care programming.

Methods: A prospective, blinded crossover trial was performed to assess the feasibility, safety and outcomes of programming based solely on dentato-rubro-thalamic tract anatomy.

Clinical features of autopsy-confirmed multiple system atrophy in the Mayo Clinic Florida brain bank.

Background: Multiple system atrophy (MSA) presents with various combinations of autonomic dysfunction, parkinsonism, and cerebellar ataxia. Although clinical diagnostic criteria have been widely used, the sensitivity and specificity are suboptimal. This study aims to provide evidence supporting the revision of the current diagnostic criteria for MSA.

Urine levels of the polyglutamine ataxin-3 protein are elevated in patients with spinocerebellar ataxia type 3.

Introduction: Accumulation of polyglutamine (polyQ) ataxin-3 (ATXN3) contributes to the pathobiology of spinocerebellar ataxia type 3 (SCA3). Recently, we showed that polyQ ATXN3 is elevated in the plasma and cerebrospinal fluid (CSF) of SCA3 patients, and has the potential to serve as a biological marker for this disease [1]. Based on these findings, we investigated whether polyQ ATXN3 can also be detected in urine samples from SCA3 patients.