Non-motor Symptoms In Parkinson's Disease Research Articles

The relationship between objective and subjective executive function in Parkinson’s disease

ABSTRACT Introduction Difficulties in executive functioning (EF) are common in PD; however, the relationship between subjective and objective EF is unclear. Understanding this relationship could help guide clinical EF assessment. This study examined the relationship between subjective self-reported EF (SEF) and objective EF (OEF) and predictors of SEF-OEF discrepancies in PD. Method One-hundred and sixteen non-demented PD participants completed measures of OEF (i.e. problem-solving, cognitive flexibility, inhibition, and working memory) and SEF (Frontal Systems Behavior Scale-Self Executive Dysfunction Subscale). Pearson bivariate correlations and linear regressions were performed to examine the relationship between SEF and OEF and the non-motor symptoms (e.g. mood, fatigue), demographic, and PD characteristic (e.g. MCI status) predictors of discrepancies between OEF and SEF (|OEF minus SEF scores|). Correlates of under-, over-, and accurate-reporting were also explored. Results Greater SEF complaints and worse OEF were significantly associated (β =.200, p = .009) and 64% of participants accurately identified their level of OEF abilities. Fewer years of education and greater symptoms of depression, anxiety, and fatigue significantly correlated with greater discrepancies between OEF and SEF. Fatigue was the best predictor of EF discrepancy in the overall sample (β = .281, p = .022). Exploratory analyses revealed apathy and fatigue associated with greater under-reporting, while anxiety associated with greater over-reporting. Conclusions SEF and OEF are significantly related in PD. Approximately 64% of non-demented persons with PD accurately reported their EF skill level, while 28% under-reported and 8% over-reported. SEF-OEF discrepancies were predicted by fatigue in the overall sample. Preliminary evidence suggests reduced apathy and fatigue symptoms relate to more under-reporting, while anxiety relates to greater over-reporting. Given the prevalence of these non-motor symptoms in PD, it is important to carefully consider them when assessing EF in PD.

THE IMPACT OF FORCED-RATE EXERCISE AND/OR PHOTOBIOMODULATION COMPARED TO USUAL CARE ON METABOLIC SYNDROME SEVERITY IN PEOPLE WITH PARKINSON’S DISEASE

INTRODUCTION/AIMS Metabolic syndrome (MetS) has been postulated to play a role in the progression of Parkinson’s disease (PD). Several lines of evidence also suggest that forced-rate exercise (FRE) is a potent therapy to alleviate motor and non-motor symptoms of PD, and perhaps MetS severity (MSS). However, long-term exercise adherence in people with PD (PWP) is poor. Alternative/adjunct therapies are therefore warranted. Photobiomodulation (PBM) is an emerging non-pharmaceutical/non-exercise therapy that may improve PD symptoms. Thus, this study aimed to determine the impact of FRE and/or PBM relative to usual care on MSS in PWP. METHODS Twenty participants diagnosed with PD (aged 40-80yrs) were randomised into one of four groups assigned to a different sequence of the study interventions or SHAM treatment across four 8-week study periods, each separated by a 4-week wash-out period: (1) Group A-B-C-D (n=5); (2) Group B-D- A-C (n=5); (3) Group C-A-B-D (n=5); (4) Group D-C-B-A (n=5). A-B-C-D represents PBM, FRE, FRE+PBM, and SHAM, respectively. Z-scores were derived from levels of MetS risk factors to determine the MSS (MetS z-score). Responders to a clinically significant change in MetS z-score was classified as those demonstrating a reduction of at least 0.48. RESULTS Our preliminary analysis included 17 participants with 30 complete pre- and post-MetS z-score data sets (FRE, n=5; FRE+PBM, n=7; PBM, n=9; SHAM, n=9). There was no statistically significant difference between groups in MSS change from pre-to-post intervention (p=0.82). However, the FRE group showed the greatest proportion of MSS responders: 60% (3/5) compared to FRE+PBM (43%, 3/7), PBM (44%, 4/9), and SHAM (33%, 3/9). CONCLUSION FRE may be the most efficacious method of clinically improving MSS. However, our study also suggests that a combined FRE+PBM or PBM alone could be used as an initial or supplementary treatment in ameliorating MSS and thus potentially PD progression.

Subthalamic nucleus but not entopeduncular nucleus deep brain stimulation enhances neurogenesis in the SVZ-olfactory bulb system of Parkinsonian rats.

Deep brain stimulation (DBS) is a highly effective treatment option in Parkinson's disease. However, the underlying mechanisms of action, particularly effects on neuronal plasticity, remain enigmatic. Adult neurogenesis in the subventricular zone-olfactory bulb (SVZ-OB) axis and in the dentate gyrus (DG) has been linked to various non-motor symptoms in PD, e.g., memory deficits and olfactory dysfunction. Since DBS affects several of these non-motor symptoms, we analyzed the effects of DBS in the subthalamic nucleus (STN) and the entopeduncular nucleus (EPN) on neurogenesis in 6-hydroxydopamine (6-OHDA)-lesioned hemiparkinsonian rats. In our study, we applied five weeks of continuous bilateral STN-DBS or EPN-DBS in 6-OHDA-lesioned rats with stable dopaminergic deficits compared to 6-OHDA-lesioned rats with corresponding sham stimulation. We injected two thymidine analogs to quantify newborn neurons early after DBS onset and three weeks later. Immunohistochemistry identified newborn cells co-labeled with NeuN, TH and GABA within the OB and DG. As a putative mechanism, we simulated the electric field distribution depending on the stimulation site to analyze direct electric effects on neural stem cell proliferation. STN-DBS persistently increased the number of newborn dopaminergic and GABAergic neurons in the OB but not in the DG, while EPN-DBS does not impact neurogenesis. These effects do not seem to be mediated via direct electric stimulation of neural stem/progenitor cells within the neurogenic niches. Our data support target-specific effects of STN-DBS on adult neurogenesis, a putative modulator of non-motor symptoms in Parkinson's disease.

Non-motor symptoms associated with progressive loss of dopaminergic neurons in a mouse model of Parkinson's disease.

Parkinson's disease (PD) is characterized by three main motor symptoms: bradykinesia, rigidity and tremor. PD is also associated with diverse non-motor symptoms that may develop in parallel or precede motor dysfunctions, ranging from autonomic system dysfunctions and impaired sensory perception to cognitive deficits and depression. Here, we examine the role of the progressive loss of dopaminergic transmission in behaviors related to the non-motor symptoms of PD in a mouse model of the disease (the TIF-IADATCreERT2 strain). We found that in the period from 5 to 12 weeks after the induction of a gradual loss of dopaminergic neurons, mild motor symptoms became detectable, including changes in the distance between paws while standing as well as the swing speed and step sequence. Male mutant mice showed no apparent changes in olfactory acuity, no anhedonia-like behaviors, and normal learning in an instrumental task; however, a pronounced increase in the number of operant responses performed was noted. Similarly, female mice with progressive dopaminergic neuron degeneration showed normal learning in the probabilistic reversal learning task and no loss of sweet-taste preference, but again, a robustly higher number of choices were performed in the task. In both males and females, the higher number of instrumental responses did not affect the accuracy or the fraction of rewarded responses. Taken together, these data reveal discrete, dopamine-dependent non-motor symptoms that emerge in the early stages of dopaminergic neuron degeneration.

Amantadine use in the French prospective NS-Park cohort.

To assess amantadine use and associated factors in the patients with Parkinson's disease (PD). Immediate-release amantadine is approved for the treatment of PD and is largely used in clinical practice to treat "levodopa-induced dyskinesia (LIDs). Its use varies according to countries and PD stages. The prospective NS-Park cohort collects features of PD patients followed by 26 French PD Expert Centres. Variables used for the analyses included demographics, motor and non-motor PD symptoms and motor complications [motor fluctuations (MFs), LIDs)], antiparkinsonian pharmacological classes and levodopa equivalent daily dose (LEDD). We evaluated: (i) prevalence of amantadine use and compared clinical features of amantadine users vs. non-users (cross-sectional analysis); (ii) factors associated with amantadine initiation (longitudinal analysis); (iii) amantadine effect on LIDs, MFs, apathy, impulse control disorders and freezing of gait (Fog) (longitudinal analysis). Amantadine use prevalence was 12.6% (1,585/12,542, median dose = 200mg). Amantadine users were significantly younger, with longer and more severe PD symptoms, greater LEDD and more frequent use of device-aided/surgical treatment. Factors independently associated with amantadine initiation were younger age, longer PD duration, more frequent LIDs, MFs and FoG, higher LEDD and better cognitive function. 9 of the 658 patients on amantadine had stopped it at the following visit, after 12-18months (1.3%). New users of amantadine presented a higher improvement in LIDs and MF compared to amantadine never users. About 12% of PD patients within the French NS-Park cohort used amantadine, mostly those with younger age and more severe PD. Amantadine initiation was associated with a subsequent reduction in LIDs and MFs.

Predicting Depression in Parkinson's Disease Using Commonly Available PD Questionnaires.

Background: Depression is common in patients with Parkinson's disease (PD) and significantly impacts both the patients and their caregivers. The associations between depression and the responses from commonly used questionnaires for PD patients were assessed. New patients presenting to the Movement Disorder Center completed a number of questionnaires, including assessments of the motor and non-motor symptoms of PD, including depression. Methods: The PD patients were grouped according to severity of depression: none, mild, and moderate-severe, based on the Geriatric Depression Scale (GDS) scores. The mean scores of the Unified PD Rating Scale (UPDRS), Montreal Cognitive Assessment (MoCA), Epworth Sleepiness Scale (ESS), Non-motor Symptoms Scale (NMSS), PD Quality of life (PDQ-39), Hoehn and Yahr score (H&Y), levodopa equivalent daily dose (LEDD), and number of antidepressants used were collected. There were 1214 PD patients included. Results: Increasing depression scores were associated with worsening motor symptoms (according to the UPDRS and H&Y), non-motor symptoms (according to the NMSS), cognition (according to the MoCA), sleepiness (according to the ESS), and quality of life (according to the PDQ-39) (all p-values of p < 0.001). Only half of the patients with mild or moderate-severe depression were taking antidepressants, and the LEDD increased with depression severity. The risk of depression increased by 16% and 5% for every 1-point increase in the NMSS and PDQ-39 scores, respectively. Conclusions: Depression is often unrecognized and undertreated and should be assessed regularly in PD patients, especially in those who demonstrate changes in motor or non-motor symptoms.

Hearing dysfunction heralds an increase in non-motor burden and a worse quality of life in Parkinson's disease: new insights from non-motor spectrum.

Sensorial non-motor symptoms (NMSs) in Parkinson's disease (PD) still lack appropriate investigation in clinical practice. This study aimed to assess if and to what extent auditory dysfunction is associated with other NMSs in PD and its impact on patient's quality of life (QoL). We selected patients with idiopathic PD, without other concomitant neurological diseases, dementia, or diagnosis of any audiological/vestibular disease. Demographic and clinical data were collected. Patients underwent otoscopic examination, audiological testing with pure tone audiometry (PTA) and distortion product otoacoustic emissions (DPOAEs) and completed Non-Motor Symptoms Scale (NMSS) and Parkinson's Disease Questionnaires-39 (PDQ-39). ANCOVA and partial correlation analysis have been used for statistical analysis. 60 patients were enrolled and completed PTA and DPOAEs. 32 patients with hearing impairment (HI), assessed by PTA, (hearing threshold ≥ 25dB) showed similar disease duration, motor impairment, and staging, compared to patients without HI, but higher scores both in NMSS and in PDQ-39, except for cardiovascular (CV), gastrointestinal (GI), urogenital (U) and sexual function (SF) of NMSS. In addition, DPOAEs showed a significant correlation with higher scores both in NMSS and PDQ-39, except for CV, SF, GI, U and perceptual problem subdomains of NMSS. This study demonstrated that PD patients with HI have a greater burden of NMS and lower related QoL and functioning. Our results highlight the importance to reconsider HI as a NMS, in parallel with the others. HI evaluation, even in asymptomatic patients, may reveal a wider pathology with a worse QoL.

Association between fatigue and MDS-UPDRS in individuals with Parkinson's disease: cross-sectional study.

Fatigue is significant in the context of Parkinson's disease (PD), considering that one-third of patients classify it as the most restricting symptom in their daily life activities (DLAs). The objective was to verify the relationship (association) between fatigue and non-motor and motor symptoms of PD. A cross-sectional study which included 100 individuals with PD. Initially, demographic and clinical data (modified Hoehn and Yahr scale-HY, anxiety, and depression) were collected. To assess the non-motor and motor symptoms of PD, the Movement Disorders Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) was applied. Fatigue was evaluated using the Parkinson Fatigue Scale. A higher HY score, greater severity of non-motor aspects of DLAs and motor aspects of DLAs, more motor complications, and higher levels of anxiety as well as depression were observed in the "fatigue" group. Fatigue was associated with a lower daily equivalent levodopa dose (LEDD), a higher body mass index (BMI), anxiety, depression, and the presence of non-motor symptoms. Non-motor symptoms are more determining factors for fatigue than the motor condition itself, with an association between fatigue and higher BMI scores, increased anxiety and depression, lower LEDD, and greater severity of non-motor aspects of DLAs. Individuals in the "fatigue" group had higher HY scores, anxiety, and depression, worse non-motor and motor symptoms related to experiences of daily life, as well as motor complications.

Long-term safety and efficacy of open-label nabilone on sleep and pain in Parkinson´s Disease

The synthetic tetrahydrocannabinol-analog nabilone improved non-motor symptoms (NMS) in Parkinson’s disease (PD) patients in a placebo-controlled, double-blind, parallel-group, randomized withdrawal trial with enriched enrollment (NMS-Nab-study). This was a single-center open-label extension study to assess the long-term safety and efficacy of nabilone for NMS in PD. To be eligible for this study, patients had to be treatment responders during the previous NMS-Nab-trial and complete its double-blind phase without experiencing a drug-related serious/severe/moderate adverse event (AE). Patients were re-introduced to nabilone during an up-titration phase until their overall NMS burden improved. Nabilone was continued for six months with clinic visits every 3 months. Evaluation of AEs was based on self-report and clinical assessment. Twenty-two patients participated in the NMS-Nab2-study (age-median 68.33 y, 52% females, disease duration-median 7.42 y). Nabilone was well tolerated with concentration difficulties as the most common treatment-related AE (possibly/not related n = 1 each). One in two drop-outs discontinued because of an AE for which a prohibited concomitant medication needed to be introduced (night-time sleep problems). Efficacy evaluation showed a significant and lasting improvement in NMS burden according to the CGI-I (79% at V3). Nabilone improved overall sleep (NMSS Domain-2: –8.26 points; 95%CI –13.82 to –2.71; p = 0.004; ES = –0.72), night-time sleep problems (MDS-UPDRS-1.7: –1.42 points; 95 CI –2.16 to –0.68; p = 0.002; ES = –0.92), and overall pain (KPPS Total Score: –8.00 points; 95%CI –15.05 to –0.95; p = 0.046; ES –0.55 and MDS-UPDRS-1.9: –0.74 points; 95%CI –1.21 to –0.26; p = 0.008; ES = –0.74). This study demonstrates continuous long-term safety and efficacy in PD patients responding early to nabilone without intolerable side effects.

An Examination of Cognitive Heterogeneity in Parkinson Disease: The Dual-Syndrome Hypothesis.

Cognitive impairment is one of the most debilitating nonmotor symptoms in Parkinson disease (PD), and its presentation is heterogeneous. One proposed model to explain cognitive variability in PD is the dual-syndrome hypothesis. This hypothesis delineates two cognitive profiles, a "fronto-striatal" profile and a "posterior cortical" profile according to symptom presentation, associated motor phenotype, and risk for dementia. The current study examined the dual-syndrome hypothesis in individuals with idiopathic PD to evaluate the existence of these profiles, determine the association with the motor phenotype (tremor dominant vs. postural instability/gait disorder), and assess the relative risk for dementia. A retrospective examination was conducted using data from the Parkinson's Progression Markers Initiative database at baseline (within 2 years of diagnosis) and 5 years after baseline. Descriptive categorizations, cluster analyses, generalized linear mixed models, and logistic regressions were used to address the research questions. There was emerging evidence of cognitive profiles; however, these were not fully supported by cluster analyses. Baseline cognitive profile was associated with later motor phenotype, and as predicted, dementia risk was greatest in persons with baseline posterior cortical impairments. The current results provide mixed support for the dual-syndrome hypothesis, with some evidence that the posterior cortical cognitive profile is associated with postural instability and gait disorder as well as greater dementia risk.

Sleep disorders cause Parkinson's disease or the reverse is true: Good GABA good night.

Parkinson's disease (PD) is a progressive neurodegenerative brain disease due to degeneration of dopaminergic neurons (DNs) presented with motor and non-motor symptoms. PD symptoms are developed in response to the disturbance of diverse neurotransmitters including γ-aminobutyric acid (GABA). GABA has a neuroprotective effect against PD neuropathology by protecting DNs in the substantia nigra pars compacta (SNpc). It has been shown that the degeneration of GABAergic neurons is linked with the degeneration of DNs and the progression of motor and non-motor PD symptoms. GABA neurotransmission is a necessary pathway for normal sleep patterns, thus deregulation of GABAergic neurotransmission in PD could be the potential cause of sleep disorders in PD. Sleep disorders affect GABA neurotransmission leading to memory and cognitive dysfunction in PD. For example, insomnia and short sleep duration are associated with a reduction of brain GABA levels. Moreover, PD-related disorders including rigidity and nocturia influence sleep patterns leading to fragmented sleep which may also affect PD neuropathology. However, the mechanistic role of GABA in PD neuropathology regarding motor and non-motor symptoms is not fully elucidated. Therefore, this narrative review aims to clarify the mechanistic role of GABA in PD neuropathology mainly in sleep disorders, and how good GABA improves PD. In addition, this review of published articles tries to elucidate how sleep disorders such as insomnia and REM sleep behavior disorder (RBD) affect PD neuropathology and severity. The present review has many limitations including the paucity of prospective studies and most findings are taken from observational and preclinical studies. GABA involvement in the pathogenesis of PD has been recently discussed by recent studies. Therefore, future prospective studies regarding the use of GABA agonists in the management of PD are suggested to observe their distinct effects on motor and non-motor symptoms. There is a bidirectional relationship between the pathogenesis of PD and sleep disorders which might be due to GABA deregulation.

Machine Learning-Assisted Speech Analysis for Early Detection of Parkinson's Disease: A Study on Speaker Diarization and Classification Techniques.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by a range of motor and non-motor symptoms. One of the notable non-motor symptoms of PD is the presence of vocal disorders, attributed to the underlying pathophysiological changes in the neural control of the laryngeal and vocal tract musculature. From this perspective, the integration of machine learning (ML) techniques in the analysis of speech signals has significantly contributed to the detection and diagnosis of PD. Particularly, MEL Frequency Cepstral Coefficients (MFCCs) and Gammatone Frequency Cepstral Coefficients (GTCCs) are both feature extraction techniques commonly used in the field of speech and audio signal processing that could exhibit great potential for vocal disorder identification. This study presents a novel approach to the early detection of PD through ML applied to speech analysis, leveraging both MFCCs and GTCCs. The recordings contained in the Mobile Device Voice Recordings at King's College London (MDVR-KCL) dataset were used. These recordings were collected from healthy individuals and PD patients while they read a passage and during a spontaneous conversation on the phone. Particularly, the speech data regarding the spontaneous dialogue task were processed through speaker diarization, a technique that partitions an audio stream into homogeneous segments according to speaker identity. The ML applied to MFCCS and GTCCs allowed us to classify PD patients with a test accuracy of 92.3%. This research further demonstrates the potential to employ mobile phones as a non-invasive, cost-effective tool for the early detection of PD, significantly improving patient prognosis and quality of life.

Brazilian dance self-perceived impacts on quality of life of people with Parkinson's.

Parkinson's disease (PD) causes several motor and non-motor symptoms, resulting in negative impacts on physical, mental, emotional, and social aspects of people with PD quality of life. Dance has been considered as a potential non-pharmacological intervention to improve people with PD motor and non-motor symptoms, thereby enhancing quality of life. To analyze the self-perceive impacts of Brazilian Dance on the quality of life (physical, mental, emotional, and social) of PwPD, both before and during the COVID-19 pandemic. Fourteen participants from the "Dança & Parkinson" project were included in this qualitative study. Data collection instruments consisted of a profile and personal data sheet; assessment of accessibility to the online dance classes; Telephone Montreal Cognitive Assessment by phone call; and semi-structured interview conducted through ZOOM video call. The participants characterization data were calculated using mean, standard deviation, and percentages with the Excel Program version 2013. Qualitative data was analyzed using the Thematic Analysis technique in the Nvivo, version 8.0, qualitative analysis of text, sound, and video program. The participants reported facing various challenges in dealing with PD, which negatively impact their quality of life. However, their resilience, acceptance, and dedication to treatment play an important role in coping with the issues related to the disease. Brazilian dance, both in-person before the COVID-19 pandemic and online during the pandemic, led the participants to perceive improvements in physical, mental, emotional, and social aspects of quality of life. The Brazilian dance appears to have a positive impact on the physical, mental, emotional, and social aspects of the participants' quality of life, both before and during the COVID-19 pandemic.

Effects of dietary supplements, foods, and dietary patterns in Parkinson's disease: meta-analysis and systematic review of randomized and crossover studies.

Diet significantly impacts Parkinson's disease (PD) with plausible biological hypotheses. Although the thesis has been explored in several human clinical trials, no current meta-analyses or reviews summarize the results. We examined the effect of intervention of dietary supplements, foods, and dietary patterns in treating PD. We conducted a meta-analysis and systematic review of randomized and crossover studies published between 1989 and 26 June 2022, searching from PubMed, Embase, Medline, Scopus, Cochrane Library databases, and Chinese databases. Twenty-four studies were included in this review. The meta-analysis results show that dietary supplements intervention significantly increased the quantitative insulin sensitivity check index (QUICKI) [MD = 0.02, 95% CI (0.01, 0.02), p < 0.00001]. Dietary supplement intervention does not significantly affect the total Unified Parkinson Disease Rating Scale (UPDRS) score and six-min walk test (6MWT) distance. We did not find evidence that dietary supplements or food intervention may minimize the UPDRS III score. However, systematic review results indicated that the Mediterranean, low-fat, and ketogenic diets significantly reduced the total UPDRS score; low-protein diets meaningfully mitigated motor symptoms. This meta-analysis result displays that diet and diet supplements had a very modest but statistically significant impact on QUICKI but no effect on motor and non-motor symptoms in PD. The systematic review concludes that dietary patterns intervention may positively attenuate the overall symptoms of PD, including both motor and non-motor symptoms.

Alleviating Stress in Parkinson's Disease: Symptomatic Treatment, Disease Modification, or Both?

Psychological stress, a state of mental strain caused by mentally or physically threatening situations, plays a significant role in Parkinson's disease (PD). Motor symptoms worsen during acute stress and common non-motor symptoms in PD, such as anxiety and depression, are linked to chronic stress. Although evidence in humans is lacking, animal models of PD suggest that chronic stress can accelerate dopaminergic cell death. This suggests that stress-reducing interventions have not only symptomatic, but perhaps also disease-modifying effects. Our objective was to identify the most promising strategies for stress-reduction in PD and to analyze their potential value for disease-modification. An unstructured literature search was performed, primarily focusing on papers published between 2020-2023. Several large clinical trials have tested the efficacy of aerobic exercise and mindfulness-based interventions on PD symptoms. The evidence is promising, but not definitive yet: some exercise trials found a reduction in stress-related symptoms, whereas others did not or did not report it. In the majority of trials, biological measures of stress and of disease progression are missing. Furthermore, follow-up periods were generally too short to measure disease-modifying effects. Hence, mechanisms underlying the intervention effects remain largely unclear. These effects may consist of attenuating progressive neurodegeneration (measured with MRI-markers of substantia nigra integrity or cortical thickness), or a strengthening of compensatory cerebral mechanisms (measured with functional neuroimaging), or both. Lifestyle interventions are effective for alleviating stress-related symptoms in PD. They hold potential for exerting disease-modifying effects, but new evidence in humans is necessary to fulfill that promise.

The Molecular Impact of Glucosylceramidase Beta 1 (Gba1) in Parkinson's Disease: a New Genetic State of the Art.

Parkinson's disease (PD) is a neurodegenerative disorder affecting 2-3% of those aged over 65, characterized by motor symptoms like slow movement, tremors, and muscle rigidity, along with non-motor symptoms such as anxiety and dementia. Lewy bodies, clumps of misfolded proteins, contribute to neuron loss in PD. Mutations in the GBA1 gene are considered the primary genetic risk factor of PD. GBA1 mutations result in decreased activity of the lysosomal enzyme glucocerebrosidase (GCase) resulting in α-synuclein accumulation. We know that α-synuclein aggregation, lysosomal dysfunction, and endoplasmic reticulum disturbance are recognized factors to PD susceptibility; however, the molecular mechanisms connecting GBA1 gene mutations to increased PD risk remain partly unknown. Thus, in this narrative review conducted according to a systematic review method, we aimed to present the main contributions arising from the molecular impact of the GBA1 gene to the pathogenesis of PD providing new insights into potential impacts for advances in the clinical care of people with PD, a neurological disorder that has contributed to the substantial increase in the global burden of disease accentuated by the aging population. In summary, this narrative review highlights the multifaceted impact of GBA1 mutations in PD, exploring their role in clinical manifestations, genetic predispositions, and molecular mechanisms. The review emphasizes the importance of GBA1 mutations in both motor and non-motor symptoms of PD, suggesting broader therapeutic and management strategies. It also discusses the potential of CRISPR/Cas9 technology in advancing PD treatment and the need for future research to integrate these diverse aspects for improved diagnostics and therapies.

Patient With Parkinson Disease and Care Partner Perceptions of Key Domains Affecting Health-Related Quality of Life: Systematic Review

To effectively customize Parkinson disease (PD) programs, it is important to incorporate the "individual's voice" and have a thorough understanding of the symptom priorities of people with PD (PwP) and care partners (CP). In this convergent integrated mixed-method systematic review, we aimed to analyze qualitative and quantitative evidence of PD motor and nonmotor symptoms affecting health-related quality of life (HRQOL) in PwP and CP, comparing priorities across different levels of disease severity. We searched MEDLINE, PsycINFO, Web of Science, Embase, and Scopus; ProQuest Dissertations and Theses Global; and the Michael J. Fox Foundation Data Resources for studies published up to June 29, 2022. We included qualitative, quantitative, and mixed-method studies investigating PD symptom priorities among PwP and CP. We critically appraised eligible studies for methodological quality using the Mixed-Methods Appraisal Tool. Derived terms were mapped and coded according to thematic attribution. Independent syntheses of qualitative and quantitative evidence and transformation of quantitative data into qualitative formats were performed. Of the 7,716 identified studies, we included 70 that provided qualitative (n = 13), quantitative (n = 53), and mixed (n = 4) evidence. We included 604 mapped terms representing 11 PwP-identified and CP-identified motor and nonmotor symptom categories. Across all PD stages, both PwP and CP considered 5 domains more affecting their HRQOL, namely: "motor functionality," "mood," "cognition," "gait, balance, posture, and falls," and "nighttime sleep disorders." In early disease, PwP and CP considered "mood" the domain that most affected their HRQOL. In advanced PD, PwP considered "pain" the domain that most affects their HRQOL, while CP considered "psychiatric symptoms." The domain "gait, balance, posture, and falls" was equally considered by both PwP and CP as the second domain that most affects their HRQOL in the advanced stage of PD. The ranking of the priority of symptoms is largely shared by PwP and CP, and motor symptom priorities dominate the full disease spectrum. However, the nonmotor symptom priorities shift according to the disease severity stage. Tailored care and research require that providers consider these shifting priorities and incorporate the "individual's voice" into treatment decisions.

Relationship between increased serum neurofilament light chain and glial fibrillary acidic protein levels with non-motor symptoms in patients with Parkinson's disease.

This study set out to investigate the relationship between serum neurofilament light chain (NFL), glial fibrillary acidic protein (GFAP), and various non-motor symptoms (NMSs) in patients with Parkinson's disease (PD). The study included 37 healthy controls (HCs) and 51 PD patients. Clinical assessments of PD symptoms were conducted for all PD patients. The NMSS was utilised to evaluate the NMS burden (NMSB) in individuals. Based on the severity of NMSB, we further categorised the PD group into two subgroups: mild-moderate NMSB group and severe-very severe NMSB group. The amounts of NFL and GFAP in the serum were measured using an extremely sensitive single molecule array (Simoa) method. Statistical analyses were performed on the collected data using SPSS 26.0 and R (version 3.6.3). Serum GFAP and NFL levels in the PD group with severe-very severe NMSB were significantly higher than those in the mild-moderate NMSB group (GFAP: P < 0.007; NFL: P < 0.009). Serum NFL and GFAP levels had positive correlations with NMSS total scores (GFAP: r = 0.326, P = 0.020; NFL: r = 0.318, P = 0.023) and multiple subdomains. The relationship between the attention/memory domains of NMSS and NFL levels is significantly positive (r = 0.283, P = 0.044). Similarly, the mood/apathy domains of NMSS are also significantly positively correlated with GFAP levels (r = 0.441, P = 0.001). Patients with emotional problems or cognitive impairment had higher GFAP or NFL levels, respectively. Furthermore, it has been demonstrated that NMSs play a mediating role in the quality of life of patients with PD. Moreover, the combination of NFL and GFAP has proven to be more effective than using a single component in identifying PD patients with severe-very severe NMSB. The severity of NMSs in PD patients, particularly cognitive and emotional symptoms, was found to be associated with the levels of serum NFL and GFAP. This study marks the first attempt to examine the connection between NMSs of PD and the simultaneous identification of NFL and GFAP levels.

Age and gender differences in non-motor symptoms in people with Parkinson's disease.

Non-motor symptoms of Parkinson's disease (PD) are highly prevalent and heterogenic. Previous studies aimed to gain more insight on this heterogeneity by investigating age and gender differences in non-motor symptom severity, but findings were inconsistent. Furthermore, besides examining the single effects of age and gender, the interaction between them in relation to non-motor functioning has -as far as we know- not been investigated before. To investigate the association of age and gender identity -as well as the interaction between age and gender identity- with non-motor symptoms and their impact on quality of life. We combined three large and independent studies. This approach resulted in a total number of unique participants of 1,509. We used linear regression models to assess the association of age and gender identity, and their interaction, with non-motor symptoms and their impact on quality of life. Older people with PD generally had worse cognitive functioning, worse autonomic functioning and worse quality of life. Women with PD generally experienced more anxiety, worse autonomic functioning and worse quality of life compared to men with PD, whereas men with PD generally had worse cognitive functioning. In interaction analyses by age and gender identity, depressive symptoms and anxiety were disproportionally worse with increasing age in women compared to men. Our findings indicate that both age and gender -as well as their interaction- are differentially associated with non-motor symptoms of PD. Both research and clinical practice should pay more attention to demographic subgroups differences and possible different treatment approaches with respect to age and gender. We showed how combining datasets is of added value in this kind of analyses and encourage others to use similar approaches.

Reviving: restoring depression-like behaviour through glial cell-derived neurotrophic factor treatment in the medial prefrontal cortex.

Depression is a prevalent nonmotor symptom in Parkinson disease and can greatly reduce the quality of life for patients; the dopamine receptors found in glutamatergic pyramidal cells in the medial prefrontal cortex (mPFC) play a role in regulating local field activity, which in turn affects behavioural and mood disorders. Given research showing that glial cell-derived neurotrophic factor (GDNF) may have an antidepressant effect, we sought to evaluate the impact of exogenous GDNF on depression-like behaviour in mouse models of Parkinson disease. We used an established subacute model of Parkinson disease in mice involving intraperitoneal injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), followed by brain stereotaxic injection of GDNF into the mPFC region. Subsequently, we assessed depression-like behaviour using the sucrose preference test, forced swimming test and tail suspension test, while also evaluating protein expression in the mPFC. We included 60 mice, divided into 3 groups, including a control group (saline injection), an MPTP plus saline injection group and an MPTP plus GDNF injection group. We found that exogenous GDNF injection into the mPFC led to an increase in dopamine receptor D1 (DRD1) protein levels. We also observed that activating the protein kinase A pathway through DRD1 produced a prolonged antidepressant response. Under GDNF stimulation, the expression of dopamine receptor D2 (DRD2) remained constant, suggesting that the DRD2 signal was ineffective in alleviating depression-like symptoms. Moreover, our investigation involved Golgi staining and Western blot techniques, which found enhanced synaptic plasticity, including increased dendritic branches, dendritic spines and retrograde protection after GDNF treatment in Parkinson disease models. A subtle motor phenotype became evident only toward the conclusion of the behavioural testing period. The study exclusively involved male mice, and no separate control group receiving only GDNF treatment was included in the experimental design. Our findings support a positive effect of exogenous GDNF on synaptic plasticity, mediated by DRD1 signalling in the mPFC, which could facilitate depression remission in Parkinson disease.