Contribution of testosterone and estradiol in sexual dimorphism of early-onset Parkinson's disease.

Early-onset Parkinson's disease (EOPD) occurs during the fertile life, when circulating neuroactive sex hormones might enhance the sexual dimorphism of the disease. Here, we aimed to examine how sex hormones can contribute to sex differences in EOPD patients. A cohort of 34 EOPD patients, 20 males and 14 females, underwent comprehensive clinical evaluation of motor and non-motor disturbances. Blood levels of estradiol, total testosterone, follicle-stimulating hormone, and luteinizing hormone were measured in all patients and correlated to clinical features. We found that female patients exhibited greater non-motor symptoms and a relatively higher rate of dystonia than males. In females, lower estradiol levels accounted for higher MDS-UPDRS-II and III scores and more frequent motor complications, while lower testosterone levels were associated with a major occurrence of dystonia. In male patients, no significant correlations emerged. In conclusion, this study highlighted the relevance of sex hormone levels in the sexual dimorphism and unique phenotype of EOPD.

Motor cortex transcranial direct current stimulation improves non-motor symptoms in early-onset Parkinson's disease: a pilot study.

Early-onset Parkinson's Disease (EOPD) demands tailored treatments. The younger age of patients might account for a higher sensitivity to transcranial direct current stimulation (tDCS) based non-invasive neuromodulation, which may raise as an integrative therapy in the field. Accordingly, here we assessed the safety and efficacy of the primary left motor cortex (M1) anodal tDCS in EOPD. Ten idiopathic EOPD patients received tDCS at 2.0 mA per 20 min for 10 days within a crossover, double-blind, sham-controlled pilot study. The outcome was evaluated by measuring changes in MDS-UPDRS part III, Non-Motor Symptoms Scale (NMSS), PD-cognitive rating scale, and PD Quality of Life Questionnaire-39 scores. We showed that anodal but not sham tDCS significantly reduced the NMSS total and "item 2" (sleep/fatigue) scores. Other parameters were not modified. No adverse events occurred. M1 anodal tDCS might thus evoke plasticity changes in cortical-subcortical circuits involved in non-motor functions, supporting the value as a therapeutic option in EOPD.

Impact of Non-Motor Symptoms on Quality of Life in Patients with Early-Onset Parkinson's Disease.

BACKGROUND: Early-onset Parkinson's disease (EOPD) refers to patients with Parkinson's disease (PD) whose age at disease onset is less than 50 years. Literature on the non-motor symptoms (NMS) in these patients is very limited in the Indian context. We aimed to study the NMS in patients with EOPD and its impact on the quality of life (QoL). METHODS: We included 124 patients with EOPD with a mean age at disease onset between 21 and 45 years and 60 healthy controls (HC). NMS were assessed using validated scales, and the QoL domains were evaluated using the PD QoL-39 scale (PDQ-39). RESULTS: The mean age at disease onset in EOPD patients was 37.33 ± 6.36 years. Majority of the patients were male (66.12%). The average disease duration was 6.62 ± 5.3 years. EOPD patients exhibited a significantly higher number of NMS per patient (7.97 ± 4.69) compared to HC (1.3 ± 1.39; p < 0.001). The most common NMS reported were urinary dysfunction, body pain, poor sleep quality, constipation, anxiety, depression, cognitive impairment, and REM sleep behavior disorder. The total NMS burden correlated with the QoL measures. Distinctive patterns of QoL subdomain involvement were identified, with sleep/fatigue, mood/cognition, and urinary dysfunction independently influencing QoL metrics. CONCLUSIONS: Our study provides valuable insights into the NMS profile and its impact on QoL in patients with EOPD, addressing an important knowledge gap in the Indian context. By understanding the specific NMS and their influence on QoL, healthcare professionals can develop targeted interventions to address these symptoms and improve the overall QoL.

Pregnancy, fertile life factors, and associated clinical course in PRKN early-onset Parkinson's disease.

INTRODUCTION: As the most common cause of autosomal recessive early onset Parkinson's disease (EOPD), parkin type Parkinson's disease (PRKN-PD) may affect female patients in childbearing age. Accordingly, issues related to fertility must be adequately addressed. Here, we landscaped fertile life factors and pregnancy course of a PRKN-PD cohort, including both novel cases directly observed at our center and published ones. METHODS: Six patients with confirmed PRKN-PD were examined by a structured interview on reproductive factors and associated modifications of PD disturbances, including one case followed up throughout pregnancy which was described in greater detail. Six studies reporting fertile life factors of nine PRKN-PD patients were reviewed collecting homogeneous data on fertile life and pregnancy course. RESULTS: PRKN-PD female patients experienced motor fluctuations with the menstrual cycle, pregnancy, and puerperium, which suggests a role for sex hormones in PD clinical burden. In some cases, abortion and miscarriages occurred during the organogenesis phase in patients receiving oral antiparkinsonian therapy; however, levodopa/benserazide monotherapy resulted to be the safest choice in pregnancy. CONCLUSION: Collectively these data disclose the importance of pre-conception counseling in childbearing age PRKN-PD patients and EOPD in general.

Co-occurrence of PRKN and SYNJ1 variants in Early-Onset Parkinson's disease.

Parkinson's disease (PD) is the second most prevalent neurodegenerative disease globally, with a fast-growing prevalence. The etiology of PD exhibits a multifactorial complex nature and remains challenging. Herein, we described clinical, molecular, and integrative bioinformatics findings from a Brazilian female affected by Early-Onset PD (EOPD) harboring a recurrent homozygous pathogenic deletion in the parkin RBR E3 ubiquitin protein ligase gene (PRKN; NM_004562.3:c.155delA; p.Asn52Metfs*29; rs754809877), along with a novel heterozygous variant in the synaptojanin 1 gene (SYNJ1; NM_003895.3:c.62G > T; p.Cys21Phe; rs1486511197) found by Whole Exome Sequencing. Uncommon or unreported PRKN-related clinical features in the patient include cognitive decline, auditory and visual hallucinations, REM sleep disorder, and depression, previously observed in SYNJ1-related conditions. Moreover, PRKN interacts with endophilin A1, which is a major binding partner of SYNJ1. This protein plays a pivotal role in regulating the dynamics of synaptic vesicles, particularly in the context of endocytosis and recycling processes. Altogether, our comprehensive analyses underscore a potential synergistic effect between the PRKN and SYNJ1 variants over the pathogenesis of EOPD.

Early-onset Parkinson's disease with mutations in both the PRKN gene and the APOB gene: A case report. / PRKNåŸºå› åˆå¹¶APOBåŸºå› çªå˜çš„æ—©å‘åž‹å¸•é‡‘æ£®ç— 1例.

The incidence rate of Parkinson's disease ranks the second among degenerative diseases of the nervous system, only lower than Alzheimer's disease. Early-onset Parkinson's disease (EPOD) refers to Parkinson's disease with initial symptoms appearing before the age of 50. EOPD is associated with certain genetic mutations and has distinct clinical features. This study reports a case of EOPD with mutations in both the PRKN and the APOB genes. The patient presented with the initial symptom of unstable walking at the age of 28, followed by bradykinesia, limb tremors, masked face, shuffling gait, and cogwheel rigidity in both upper limbs. The blood lipid test showed total cholesterol of 6.48 mmol/L and low-density lipoprotein cholesterol of 4.13 mmol/L. Genetic testing showed a deletion in exon 5 and a point mutation [c.850G>C(p.Gly284Arg)] in exon 7 of the PRKN gene, as well as a point mutation [c.10579C>T(p.Arg3527Trp)] in exon 26 of the APOB gene. Based on these clinical manifestations and examination results, the patient was diagnosed with EOPD. The compound heterozygous mutations in the PRKN gene, as well as the combined mutations in the PRKN and APOB genes, are both reported for the first time, expanding the spectrum of genetic mutations associated with EOPD.

Anionic lipid vesicles have differential effects on the aggregation of early onset-associated α-synuclein missense mutants.

α-synuclein (αS) is the key component of synucleinopathies such as Parkinson's disease (PD), dementia with Lewy bodies, and multiple system atrophy. αS was first linked to PD through the identification of point mutations in the SNCA gene, causing single amino acid substitutions within αS and familial autosomal dominant forms of PD that profoundly accelerated disease onset by up to several decades. At least eight single-point mutations linked to familial PD (A30G/P, E46K, H50Q, G51D, and A53T/E/V) are located in proximity of the region preceding the non-ß amyloid component (preNAC) region, strongly implicating its pathogenic role in αS-mediated cytotoxicity. Furthermore, lipids are known to be important for native αS function, where they play a key role in the regulation of synaptic vesicle docking to presynaptic membranes and dopamine transmission. However, the role of lipids in the function of mutant αS is unclear. Here, we studied αS aggregation properties of WT αS and five of the most predominant single-point missense mutants associated with early onset PD in the presence of anionic 1,2-dimyristoyl-sn-glycero-3-phospho-l-serine lipid vesicles. Our results highlight significant differences between aggregation rates, the number of aggregates produced, and overall fibril morphologies of WT αS and the A30P, E46K, H50Q, G51D, and A53T missense mutants in the presence of lipid vesicles. These findings have important implications regarding the interplay between the lipids required for αS function and the individual point mutations known to accelerate PD and related diseases.

Heterozygous PRKN mutations are common but do not increase the risk of Parkinson's disease.

PRKN mutations are the most common recessive cause of Parkinson's disease and are a promising target for gene and cell replacement therapies. Identification of biallelic PRKN patients at the population scale, however, remains a challenge, as roughly half are copy number variants and many single nucleotide polymorphisms are of unclear significance. Additionally, the true prevalence and disease risk associated with heterozygous PRKN mutations is unclear, as a comprehensive assessment of PRKN mutations has not been performed at a population scale. To address these challenges, we evaluated PRKN mutations in two cohorts with near complete genotyping of both single nucleotide polymorphisms and copy number variants: the NIH-PD + AMP-PD cohort, the largest Parkinson's disease case-control cohort with whole genome sequencing data from 4094 participants, and the UK Biobank, the largest cohort study with whole exome sequencing and genotyping array data from 200 606 participants. Using the NIH-PD participants, who were genotyped using whole genome sequencing, genotyping array, and multi-plex ligation-dependent probe amplification, we validated genotyping array for the detection of copy number variants. Additionally, in the NIH-PD cohort, functional assays of patient fibroblasts resolved variants of unclear significance in biallelic carriers and suggested that cryptic loss of function variants in monoallelic carriers are not a substantial confounder for association studies. In the UK Biobank, we identified 2692 PRKN copy number variants from genotyping array data from nearly half a million participants (the largest collection to date). Deletions or duplications involving exon 2 accounted for roughly half of all copy number variants and the vast majority (88%) involved exons 2, 3, or 4. In the UK Biobank, we found a pathogenic PRKN mutation in 1.8% of participants and two mutations in ∼1/7800 participants. Those with one PRKN pathogenic variant were as likely as non-carriers to have Parkinson's disease [odds ratio = 0.91 (0.58-1.38), P-value 0.76] or a parent with Parkinson's disease [odds ratio = 1.12 (0.94-1.31), P-value = 0.19]. Similarly, those in the NIH-PD + AMP + PD cohort with one PRKN pathogenic variant were as likely as non-carriers to have Parkinson's disease [odds ratio = 1.29 (0.74-2.38), P-value = 0.43]. Together our results demonstrate that heterozygous pathogenic PRKN mutations are common in the population but do not increase the risk of Parkinson's disease.

Shaping the course of early-onset Parkinson's disease: insights from a longitudinal cohort.

INTRODUCTION: Early -onset Parkinson's disease (EOPD) labels those cases with onset earlier than fifty. Although peculiarities emerged either in clinical or pathological features, EOPD is managed alike typical, late-onset PD. A customized approach would be, instead, better appropriate. Accordingly, a deeper characterization of the clinical course, with an estimation of the disease progression rate, the therapy flow, and the main motor and non-motor complications occurrence, is needed. METHODS: A longitudinal cohort of 193 EOPD patients (selected on a single-centre population of 2000 PD cases) was retrospectively analysed, providing descriptive statics on a series of clinical parameters (genetics, phenotype, comorbidities, therapies, motor and non-motor complications, marital and gender issues) and modelling the trajectories from diagnosis to 10 years later of both Hoehn and Yahr (H&Y) stage and levodopa equivalent daily dose (LEDD). RESULTS: EOPD had a prevalence of 9.7%, including few monogenic cases. It mostly appeared as a motor syndrome, with asymmetric, rigid-akinetic presentation. H&Y linearly progressed with an increment of 0.92 points/10 years; LEDD flow had a non-linear trend, increasing of 526.90 mg/day in 0-5 years, and 166.83 mg/day in 5-10 years. Motor fluctuations started 6.5 ± 3.2 years from onset, affecting up to 80% of the cohort. Neuropsychiatric troubles interested the 50%, sexual complaints the 12%. Gender-specific motor disturbances emerged. CONCLUSION: We shaped EOPD course, modelling a "brain-first" PD subtype, slowly progressive, with non-linear dopaminergic requirement. Major burden mostly resulted from motor fluctuations, neuropsychiatric complications, sexual and marital complaints, with a considerable gender-effect.

Clinical Study of 668 Indian Subjects with Juvenile, Young, and Early Onset Parkinson's Disease.

OBJECTIVE: To determine the demographic pattern of juvenile-onset parkinsonism (JP, <20 years), young-onset (YOPD, 20-40 years), and early onset (EOPD, 40-50 years) Parkinson's disease (PD) in India. MATERIALS AND METHODS: We conducted a 2-year, pan-India, multicenter collaborative study to analyze clinical patterns of JP, YOPD, and EOPD. All patients under follow-up of movement disorders specialists and meeting United Kingdom (UK) Brain Bank criteria for PD were included. RESULTS: A total of 668 subjects (M:F 455:213) were recruited with a mean age at onset of 38.7 ± 8.1 years. The mean duration of symptoms at the time of study was 8 ± 6 years. Fifteen percent had a family history of PD and 13% had consanguinity. JP had the highest consanguinity rate (53%). YOPD and JP cases had a higher prevalence of consanguinity, dystonia, and gait and balance issues compared to those with EOPD. In relation to nonmotor symptoms, panic attacks and depression were more common in YOPD and sleep-related issues more common in EOPD subjects. Overall, dyskinesias were documented in 32.8%. YOPD subjects had a higher frequency of dyskinesia than EOPD subjects (39.9% vs. 25.5%), but they were first noted later in the disease course (5.7 vs. 4.4 years). CONCLUSION: This large cohort shows differing clinical patterns in JP, YOPD, and EOPD cases. We propose that cutoffs of <20, <40, and <50 years should preferably be used to define JP, YOPD, and EOPD.

Epigallocatechin gallate for Parkinson's disease.

In the last couple of decades, we have experienced increased use of nutraceuticals worldwide with a demand for organic foods, which has been elevated to an extent probably unmatched with other periods of our civilization. One of the nutraceuticals that gained attention is epigallocatechin gallate (EGCG), a polyphenol in green tea. It has been suggested that diseases of the central nervous system can benefit from consuming some antioxidants, despite current results showing little evidence for their use in preventing and treating these diseases. ECGC may be beneficial in delaying the neurodegeneration of the substantia nigra regardless of the origin of Parkinson's disease (PD). This review covers the effect of EGCG on vitro and animal models of PD, the potential mechanisms of neuroprotection involved and summaries recent clinical trials in human PD. This review also aims to provide an investigative analysis of the current knowledge in this field and to identify putative crucial issues. Environmental factors such as dietary habits, drug use and social interaction are all factors that influence the evolution of neurodegenerative diseases. Therefore, the use of nutraceuticals requires further investigation.

Rhus Coriaria L. Extract: Antioxidant Effect and Modulation of Bioenergetic Capacity in Fibroblasts from Parkinson's Disease Patients and THP-1 Macrophages.

Sumac, Rhus coriaria L., is a Mediterranean plant showing several useful properties, such as antioxidant and neuroprotective effects. Currently, there is no evidence about its possible neuroprotective action in Parkinson's disease (PD). We hypothesized that sumac could modulate mitochondrial functionality in fibroblasts of familial early-onset PD patients showing PARK2 mutations. Sumac extract volatile profile, polyphenolic content and antioxidant activity have been previously characterized. We evaluated ROS and ATP levels on sumac-treated patients' and healthy control fibroblasts. In PD fibroblasts, all treatments were effective in reducing H2O2 levels, while patients' ATP content was modulated differently, probably due to the varying mutations in the PARK2 gene found in individual patients which are also involved in different mitochondrial phenotypes. We also investigated the effect of sumac extract on THP-1-differentiated macrophages, which show different embryogenic origin with respect to fibroblasts. In THP-1 macrophages, sumac treatment determined a reduction in H2O2 levels and an increase in the mitochondrial ATP content in M1, assuming that sumac could polarize the M1 to M2 phenotype, as demonstrated with other food-derived compounds rich in polyphenols. In conclusion, Rhus coriaria L. extracts could represent a potential nutraceutical approach to PD.

Genetic Study of Early Onset Parkinson's Disease in Cyprus.

Parkinson's Disease (PD) is a multifactorial neurodegenerative disease characterized by motor and non-motor symptoms. The etiology of PD remains unclear. However, several studies have demonstrated the interplay of genetic, epigenetic, and environmental factors in PD. Early-onset PD (EOPD) is a subgroup of PD diagnosed between the ages of 21 and 50. Population genetic studies have demonstrated great genetic variability amongst EOPD patients. Hence, this study aimed to obtain a genetic landscape of EOPD in the Cypriot population. Greek-Cypriot EOPD patients (n = 48) were screened for variants in the six most common EOPD-associated genes (PINK1, PRKN, FBXO7, SNCA, PLA2G6, and DJ-1). This included DNA sequencing and Multiplex ligation-dependent probe amplification (MLPA). One previously described frameshift variant in PINK1 (NM_032409.3:c.889del) was detected in five patients (10.4%)-the largest number to be detected to date. Copy number variations in the PRKN gene were identified in one homozygous and 3 compound heterozygous patients (8.3%). To date, the pathogenic variants identified in this study have explained the PD phenotype for 18.8% of the EOPD cases. The results of this study may contribute to the genetic screening of EOPD in Cyprus.

Novel deep intronic mutation in PLA2G6 causing early-onset Parkinson's disease with brain iron accumulation through pseudo-exon activation.

PLA2G6 is the causative gene for a group of autosomal recessive neurodegenerative disorders known as PLA2G6-associated neurodegeneration (PLAN). We present a case with early-onset parkinsonism, ataxia, cognitive decline, cerebellar atrophy, and brain iron accumulation. Sequencing of PLA2G6 coding regions identified only a heterozygous nonsense variant, but mRNA analysis revealed the presence of an aberrant transcript isoform due to a novel deep intronic variant (c.2035-274G > A) leading to activation of an intronic pseudo-exon. These results expand the genotypic spectrum of PLAN, showing the paramount importance of detecting possible pathogenic variants in deep intronic regions in undiagnosed patients.

Genes Implicated in Familial Parkinson's Disease Provide a Dual Picture of Nigral Dopaminergic Neurodegeneration with Mitochondria Taking Center Stage.

The mechanism of nigral dopaminergic neuronal degeneration in Parkinson's disease (PD) is unknown. One of the pathological characteristics of the disease is the deposition of α-synuclein (α-syn) that occurs in the brain from both familial and sporadic PD patients. This paper constitutes a narrative review that takes advantage of information related to genes (SNCA, LRRK2, GBA, UCHL1, VPS35, PRKN, PINK1, ATP13A2, PLA2G6, DNAJC6, SYNJ1, DJ-1/PARK7 and FBXO7) involved in familial cases of Parkinson's disease (PD) to explore their usefulness in deciphering the origin of dopaminergic denervation in many types of PD. Direct or functional interactions between genes or gene products are evaluated using the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) database. The rationale is to propose a map of the interactions between SNCA, the gene encoding for α-syn that aggregates in PD, and other genes, the mutations of which lead to early-onset PD. The map contrasts with the findings obtained using animal models that are the knockout of one of those genes or that express the mutated human gene. From combining in silico data from STRING-based assays with in vitro and in vivo data in transgenic animals, two likely mechanisms appeared: (i) the processing of native α-syn is altered due to the mutation of genes involved in vesicular trafficking and protein processing, or (ii) α-syn mutants alter the mechanisms necessary for the correct vesicular trafficking and protein processing. Mitochondria are a common denominator since both mechanisms require extra energy production, and the energy for the survival of neurons is obtained mainly from the complete oxidation of glucose. Dopamine itself can result in an additional burden to the mitochondria of dopaminergic neurons because its handling produces free radicals. Drugs acting on G protein-coupled receptors (GPCRs) in the mitochondria of neurons may hopefully end up targeting those receptors to reduce oxidative burden and increase mitochondrial performance. In summary, the analysis of the data of genes related to familial PD provides relevant information on the etiology of sporadic cases and might suggest new therapeutic approaches.

Mutation Analysis of DNAJC Family for Early-Onset Parkinson's Disease in a Chinese Cohort.

BACKGROUND: Recently, members of the DnaJ homolog C (DNAJC) family have been identified to be associated with Parkinson's disease (PD) and other neurodegenerative disorders. However, most studies are based on European-ancestry population and no comprehensive analysis is further conducted. OBJECTIVES: In this study, we aim to systematically explore the associations of DNAJCs by genetic analysis in a large Chinese early-onset PD (EOPD) cohort. METHODS: Rare variants were identified using whole exome sequencing in a cohort of 664 unrelated patients with EOPD. Allelic association analysis was performed with Fisher's exact test to clarify the associations at allele level. Gene-based burden analysis was conducted for both rare variants and damaging variants to illuminate the involvement of DNAJCs in EOPD at the gene level. RESULTS: In total, 61 rare variants were identified in the current study. At the allele level, 2 variants, p.T1109R and p.L174H, in DNAJC26 were significant after Bonferroni correction; 2 variants, p.V1271A and p.A476V, in DNAJC26; 2 variants, p.M477T and p.D1670G, in DNAJC13; 1 variant, p.L19I, in DNAJC10; and 1 variant, p.N526S, in DNAJC6 reached nominal significance. Moreover, a novel compound heterozygous mutation in DNAJC6 was identified. At the gene level, gene-based burden analysis showed a clear enrichment of rare variants in DNAJC26 in patients with EOPD, but not other DNAJCs. CONCLUSIONS: Our work identifies novel rare variants of DNAJC26 to be associated with EOPD and enhances our understanding of the role of DNAJC family members in EOPD. © 2020 International Parkinson and Movement Disorder Society.

Evaluating the Role of SNCA, LRRK2, and GBA in Chinese Patients With Early-Onset Parkinson's Disease.

BACKGROUND: Defects in the α-synuclein, leucine-rich repeat kinase 2, or glucocerebrosidase genes have been regarded as essential contributors to PD. However, genetic variability of these genes with respect to early-onset PD remains poorly defined for the Chinese demographic. OBJECTIVES: We aim to systematically characterize the clinical and genetic architecture of α-synuclein, leucine-rich repeat kinase 2, and glucocerebrosidase in Chinese early-onset PD patients. METHODS: Whole-exome sequencing and Sanger sequencing were used to identify variants of α-synuclein, leucine-rich repeat kinase 2, and glucocerebrosidase in 662 Chinese early-onset PD patients. Haplotype and burden analyses were conducted to investigate the role of rare variants of these three genes in early-onset PD. RESULTS: Sixty rare variants, including 23 novel variants, were identified in 73 patients (11.0%). Frequencies of patients with rare pathogenic/likely pathogenic variants of α-synuclein, leucine-rich repeat kinase 2, and glucocerebrosidase were 0.6%, 3.0%, and 5.4%, respectively. Evidences of two founder events exclusive to Asians were identified in 2 patients with leucine-rich repeat kinase 2 p.R1441C and 3 patients with α-synuclein p.A53V. Gene-based burden analysis supported glucocerebrosidase as a strong risk factor for early-onset PD, but argued against over-representation of rare variants in α-synuclein or leucine-rich repeat kinase 2 in early-onset PD. Clinically, no differences in motor or nonmotor symptoms were found between glucocerebrosidase variants carriers, and noncarriers or between leucine-rich repeat kinase 2 carriers and noncarriers. Patients with α-synuclein variants showed both rapid progression and worse cognitive impairment. CONCLUSION: Our study provides a better understanding of the clinical and genetic correlations of α-synuclein, leucine-rich repeat kinase 2, and glucocerebrosidase in early-onset PD, which may be beneficial for drafting genetic scanning strategies and evaluating disease progression. © 2020 International Parkinson and Movement Disorder Society.

Brain mitochondrial impairment in early-onset Parkinson's disease with or without PINK1 mutation.

BACKGROUND: PINK1 mutations are likely to affect mitochondrial function. The objective of this study was to study brain mitochondrial function in patients with early-onset Parkinson's disease, with or without PINK1 mutations. METHODS: We investigated brain intracellular pH, mitochondrial activity, and energetics with functional magnetic resonance spectroscopy in patients with early-onset Parkinson's disease with PINK1 mutations (n = 10), early-onset Parkinson's disease without PINK1 mutations (n = 10), and healthy sex- and age-matched subjects (n = 20). We measured peak areas of phosphocreatine and beta adenosine triphosphate. RESULTS: The EOPD- group had normal PCr + ßATP contents at rest (P = NS) and under activation (P = NS), but reduced contents during recovery (P < 0.001). The EOPD+ group had abnormal PCr + ßATP contents at rest (P < 0.001) and during activation (P < 0.001); during recovery, the contents only partially recovered (P < 0.001). Brain intracellular pH alterations were more severe with EOPD+ than with EOPD-. CONCLUSIONS: Brain mitochondrial impairments were similar in early-onset Parkinson's disease without PINK1 mutations and late-onset Parkinson's disease. However, mitochondrial impairments were more severe in early-onset Parkinson's disease with PINK1 mutations. © 2020 International Parkinson and Movement Disorder Society.

Physical activity and cognition in young-onset Parkinson's disease.

BACKGROUND: A relationship has been observed between physical activity and cognition in older-onset Parkinson's disease, as well as improvements in cognition after a physical activity intervention. To date, this has not been investigated in young-onset Parkinson's disease (YOPD). OBJECTIVES: To examine the baseline relationship between physical activity and cognition in YOPD; and to examine whether a physical activity intervention can improve cognition in YOPD. METHODS: Two interrelated online studies were conducted. In the first study, 132 participants with YOPD completed self-reported measures of physical activity, and objective and subjective measures of cognition. A subset of 38 participants was then randomly allocated to either a six-week physical activity intervention or control condition. Following the intervention, participants repeated the objective and subjective cognitive measures. RESULTS: No relationship was found between self-reported physical activity and objective cognition; however, there was a relationship between physical activity and subjective cognition. Similarly, following the intervention subjective improvements were found for concentration, attention, and processing speed, but not for memory. Furthermore, medium effect sizes were evident for objective measures of processing speed and small-medium effect sizes for planning and cognitive flexibility, although statistical significance was not reached. CONCLUSIONS: In this first study investigating physical activity and cognition in YOPD, the results suggest that increased physical activity relates to improved processing speed and attention. Replication is recommended with a larger sample size. A longer, more intense physical activity manipulation and utilizing the study's strengths of online recruitment and intervention delivery are also recommended.