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Background and purpose Parkinson disease (PD) is a complex and heterogeneous neurodegenerative disorder with a broad spectrum of clinical manifestations, determined by a complex interplay of environmental and genetic factors. This study aimed to investigate genetic variants associated with PD and assess their impact on the disease phenotype through genotype–phenotype correlations. Methods We employed a targeted resequencing panel to analyze 27 genes linked to PD in a cohort of 1185 PD patients from southern Spain. Variants were categorized based on the American College of Medical Genetics and Genomics pathogenicity criteria. Demographic and clinical data were also collected. Results Among the patients analyzed, 13.5% carried potential disease‐causing pathogenic or likely pathogenic variants in 12 different genes, indicating significant genetic heterogeneity. The most frequently affected genes were LRRK2, PRKN, and GBA1 (accounting for 72.1% of positive cases). Sex‐specific differences were observed, with a higher proportion of female patients carrying LRRK2 variants. Differences in age at onset and clinical features were also observed among the different mutated genes. Notably, variants in genes associated with atypical parkinsonism presented distinct clinical presentations, highlighting the importance of genetic factors in the differential diagnosis. Conclusions Our study provides valuable information on the genetic landscape of PD and its clinical manifestations. The observed genotype–phenotype correlations, along with sex‐specific differences, emphasize the complexity of PD pathogenesis, underlining the importance of personalized approaches to PD diagnosis and treatment. Further investigations into genetic interactions and population‐specific effects are warranted to enhance our understanding of PD etiology and improve patient care.

Peripheral inflammatory immune responses are thought to play a major role in the pathogenesis of Parkinson’s disease (PD). The neutrophil-to-lymphocyte ratio (NLR), a biomarker of systemic inflammation, has been reported to be higher in patients with PD than in healthy controls (HCs). The present study was aimed at determining if the peripheral inflammatory immune response could be influenced by the genetic background of patients with PD. We included a discovery cohort with 222 patients with PD (132 sporadic PD, 44 LRRK2 -associated PD (with p.G2019S and p.R1441G variants), and 46 GBA -associated PD), as well as 299 HCs. Demographic and clinical data were recorded. Leukocytes and their subpopulations, and the NLR were measured in peripheral blood. Multivariate lineal regression and post-hoc tests were applied to determine the differences among the groups. Subsequently, a replication study using the Parkinson’s Progression Markers Initiative cohort was performed which included 401 patients with PD (281 sPD patients, 66 LRRK2 -PD patients, 54 GBA -PD patients) and a group of 174 HCs. Patients with sporadic PD and GBA -associated PD showed a significantly lower lymphocyte count, a non-significantly higher neutrophil count and a significantly higher NLR than HCs. The peripheral inflammatory immune response of patients with LRRK2 -associated PD did not differ from HCs. Our study supports the involvement of a peripheral inflammatory immune response in the pathophysiology of sPD and GBA -associated PD. However, this inflammatory response was not found in LRRK2 -associated PD, probably reflecting different pathogenic inflammatory mechanisms.

Growing evidence supports the importance of immune processes in Parkinson’s disease (PD). However, there is a need to improve the quality of observational clinical studies investigating the role of immunity in PD. In this context, an expert panel from the COST Action IMMUPARKNET (CA21117) aimed to develop guidance recommendations for conducting optimal immune profiling in PD. Firstly, criteria for inclusion and exclusion of participants, clinical data collection and participant stratification have been considered. Secondly, brain imaging of neuroinflammation has been reviewed. Finally, this review discusses sample collection, handling and storage of biological samples. In conclusion, this document aims to guide the scientific community in the optimal design of immune profiling studies in PD, so that we can generate robust and reliable data to advance our knowledge in this field.

Brain cholesterol metabolism has been described as altered in Parkinson’s disease (PD) patients. Serum lipid levels have been widely studied in PD with controversial results among different populations and age groups. The present study is aimed at determining if the serum lipid profile could be influenced by the genetic background of PD patients. We included 403 PD patients (342 sporadic PD patients, 30 GBA-associated PD patients, and 31 LRRK2-associated PD patients) and 654 healthy controls (HCs). Total cholesterol, HDL, LDL, and triglycerides were measured in peripheral blood. Analysis of covariance adjusting for sex and age (ANCOVA) and post hoc tests were applied to determine the differences within lipid profiles among the groups. Multivariate ANCOVA revealed significant differences among the groups within cholesterol and LDL levels. GBA-associated PD patients had significantly lower levels of total cholesterol and LDL compared to LRRK2-associated PD patients and HCs. The different serum cholesterol levels in GBA-associated PD might be related to diverse pathogenic mechanisms. Our results support the hypothesis of lipid metabolism disruption as one of the main PD pathogenic mechanisms in patients with GBA-associated PD. Further studies would be necessary to explore their clinical implications.

Background Deep brain stimulation (DBS) has emerged as an important therapeutic intervention for neurological and neuropsychiatric disorders. After initial programming, clinicians are tasked with fine-tuning DBS parameters through repeated in-person clinic visits. We aimed to evaluate whether DBS patients achieve clinical benefit more rapidly by incorporating remote internet-based adjustment (RIBA) of stimulation parameters into the continuum of care. Methods We conducted a randomized controlled multicenter study (ClinicalTrails.gov NCT05269862) involving patients scheduled for de novo implantation with a DBS System to treat Parkinson’s Disease. Eligibility criteria included the ability to incorporate RIBA as part of routine follow-up care. Ninety-six patients were randomly assigned in a 1:1 ratio using automated allocation, blocked into groups of 4, allocation concealed, and no stratification. After surgery and initial configuration of stimulation parameters, optimization of DBS settings occurred in the clinic alone (IC) or with additional access to RIBA. The primary outcome assessed differences in the average time to achieve a one-point improvement on the Patient Global Impression of Change score between groups. Patients, caregivers, and outcome assessors were not blinded to group assignment. Most of the data collection took place in the patient’s home environment. Results Access to RIBA reduces the time to symptom improvement, with patients reporting 15.1 days faster clinical benefit (after 39.1 (SD 3.3) days in the RIBA group ( n  = 48) and after 54.2 (SD 3.7) days in the IC group ( n  = 48)). None of the reported adverse events are related to RIBA. Conclusions This study demonstrates safety and efficacy of internet-based adjustment of DBS therapy, while providing clinical benefit earlier than in-clinic optimization of stimulation parameters by increasing patient access to therapy adjustment. Plain language summary Deep brain stimulation (DBS) uses electrical impulses to treat disorders of the nervous system such as Parkinson’s Disease. Patients undergoing DBS need to travel to a clinic to have their treatment optimized. This study investigated whether optimizing DBS settings remotely via a mobile application leads to faster symptom improvements. The control group consisted of patients whose DBS settings were adjusted only in the clinic. Patients who had the option to adjust their therapy remotely report symptom and quality of life improvement earlier without additional side effects. These results suggest that remotely adjusting DBS settings could benefit patients and improve treatment outcomes. Gharabaghi et al assess the clinical benefit of incorporating remote internet-based adjustment (RIBA) of deep brain stimulation parameters into the continuum of care. Clinical benefits were reported more than two weeks earlier with access to RIBA, compared to in-clinic therapy optimization alone, with a similar safety profile.

Background Deep brain stimulation (DBS) is an essential treatment option for disabling segmental or generalized dystonia. An underlying monogenic etiology is increasingly recognized as an important predictor of DBS outcomes. Moreover, the genetic background of dystonia is continuously expanding, posing new challenges in the tailored counseling of patients regarding advanced therapies. Methods To improve the quality of available evidence on the efficacy of DBS for treating monogenic dystonia, we conducted a systematic review in accordance with PRISMA guidelines. We applied a rigorous methodology and maximized the amount of information provided by including all patients, regardless of age or applied rating scale. Results Our findings confirm the high probability of a good DBS outcome in patients harboring TOR1A, SGCE, PANK2, and TAF1 variants. An intermediate response was associated with KMT2B and THAP1 variants. A particularly favorable outcome with > 80% improvement in dystonia symptoms was associated with a subset of DYT‐TOR1A patients and few cases with SGCE‐, KMT2B‐, THAP1‐, GNAO1‐, and TAF1‐related disease. Poor study quality, non‐systematic assessment of DBS response, and pooling of patients with different genetic etiologies were among the encountered limitations. Conclusions Based on the collected evidence, we formulated recommendations for applying DBS in monogenic dystonia. Our findings, together with the cumulative literature, advocate the introduction of genetic testing in the pre‐DBS work‐up. They furthermore highlight the need to implement and report on systematic assessments of DBS outcomes, including mandatory patient‐reported outcomes. These steps will ensure optimal counseling and continuous improvement in the care of patients with monogenic dystonia. To improve the quality of available evidence on the efficacy of DBS for treating monogenic dystonia, we conducted a systematic review in accordance with PRISMA guidelines. Based on the collected evidence, we formulated recommendations for applying DBS in monogenic dystonia. Our findings, together with the cumulative literature, advocate the introduction of genetic testing in the pre‐DBS work‐up.

Background and purpose Peripheral inflammation is probably involved in the pathogenesis of progressive supranuclear palsy (PSP) and it may be a common feature with Parkinson's disease (PD). The peripheral immune profile in PSP remains unclear, as well as whether the inflammatory pathways differ from those in PD. The neutrophil‐to‐lymphocyte ratio (NLR) has been proven to be a well‐established biomarker of systemic inflammation. This study aimed to evaluate the peripheral immune profile in PSP compared with PD. Methods A cross‐sectional study was conducted including patients with PSP and PD and healthy controls (HCs). Leukocyte subpopulations and the NLR were measured in peripheral blood. Multivariate linear regression and post hoc tests were applied. Electronic databases were searched in November 2023 to perform meta‐analyses to clarify the peripheral immune profile in PSP. Results Our cohort included 121 patients with PSP, 127 patients with PD and 266 HCs. The NLR was higher in PSP and PD compared with HCs. PSP had a higher neutrophil count compared with HCs. Whilst a lower lymphocyte count was found in PD compared with HCs, the lymphocyte count did not differ between PSP and HCs. The meta‐analyses supported this immune profile. Conclusions PSP and PD show an increased peripheral inflammation and a higher NLR compared with HCs. Different pathogenic inflammatory mechanisms are probably involved in PSP and PD, since in PSP this altered peripheral immune profile is mainly driven by neutrophils. Understanding the neutrophils' role in PSP may allow for the development of targeted therapies.

Background Hyperhomocysteinemia is considered an independent risk factor for cognitive impairment. Objective To study the correlation between homocysteine levels and cognitive impairment in patients with PD. Methods We conducted a case–control study that included 246 patients with PD, of whom 32 were cognitively impaired. The levels of homocysteine, folate, and vitamin B12 were measured in peripheral blood. Multivariate logistic regression analysis was applied to determine differences in homocysteine levels between PD patients with and without cognitive impairment. A meta-analysis was performed to clarify the role of Hcy levels in PD with cognitive decline. Five polymorphisms in genes involved in Hcy metabolism, including MTHFR rs1801133 and rs1801131, COMT rs4680, MTRR rs1801394, and TCN2 rs1801198, were genotyped. Results Our case–control study showed that homocysteine levels were associated with cognitive impairment in PD after adjusting for possible confounding factors such as levodopa equivalent daily dose. The results of our meta-analysis further supported the positive association between homocysteine levels and cognition in PD. We found that the MTHFR rs1801133 TT genotype led to higher homocysteine levels in PD patients, whereas the MTHFR rs1801131 CC genotype resulted in higher folate levels. However, the polymorphisms studied were not associated with cognitive impairment in PD. Conclusions Increased homocysteine levels were a risk factor for cognitive decline in PD. However, no association was found between polymorphisms in genes involved in homocysteine metabolism and cognitive impairment in PD. Large-scale studies of ethnically diverse populations are required to definitively assess the relationship between MTHFR and cognitive impairment in PD.

Background Co‐morbid Alzheimer’s disease (AD) pathology is a major risk factor for cognitive impairment (CI) in PD, but whether and how AD co‐pathology affects the clinical phenotype of PD‐CI is incompletely understood. Recently validated plasma biomarkers for AD pathology, such as ptau217, hold great promise to revolutionize the diagnosis of neurodegenerative diseases. Here, we used plasma ptau217 to detect AD co‐pathology in a well‐characterized cohort of PD patients with CI and examine its associations with APOE4 genotype, cognitive profile, and cerebral hypometabolism on FDG‐PET. Method Eighty‐eight PD patients were stratified into PD‐CI (N=50; 24 PD‐MCI, 26 PDD) and PD with normal cognition (PD‐CN; N=38) using neuropsychological testing with the PD‐Cognitive Rating Scale. All patients had a blood draw and an FDG‐PET scan at study inclusion. Plasma ptau217 levels were measured using the ALZpath ptau217 Simoa immunoassay, and patients were classified as ptau217(+) and ptau217(‐) using an established threshold (0.4 pg/mL). APOE4 alleles were genotyped and coded as a binary variable. FDG‐PET data was processed using SPM12 and brain‐wide hypometabolism patterns (vs PD‐CN) were assessed across 52 atlas‐defined brain regions. In addition, we explicitly tested whether PD‐CI‐ptau217(+) had specifically more pronounced hypometabolism in an a‐priori region‐of‐interest (ROI) composed of temporo‐parietal areas typically affected in AD. Result Fourteen PD‐CI (28%) and 5 PD‐CN (13%) were classified as ptau217(+). PD‐CN‐ptau217(+) were excluded from further analyses. Compared to PD‐CI‐ptau217(‐), PD‐CI‐ptau217(+) had a higher prevalence of APOE4 carriers (50% vs 16%, p=0.04) and more impaired memory scores (p=0.03), although global cognition (MoCA) was not significantly different (p=0.10) (Table 1). When compared to PD‐CN, both PD‐CI‐ptau217(‐) and PD‐CI‐ptau217(+) showed significant hypometabolism in posterior‐occipital, temporal, and frontal areas (p<0.05, FDR‐corrected), but hypometabolism in PD‐CI‐ptau217(+) was considerably more extensive, particularly in temporo‐parietal areas (Fig‐1). ROI‐based analysis confirmed significantly more pronounced hypometabolism of AD‐related regions in PD‐CI‐ptau217(+) compared to PD‐CI‐ptau217(‐) (p=0.01), whereas occipital hypometabolism, typical for PD‐CI, did not differ (p=0.83). Conclusion AD co‐pathology results in a more memory‐predominant cognitive profile and AD‐like neurodegeneration phenotype in PD‐CI. Novel plasma biomarkers may significantly facilitate clinical detection of AD co‐pathology, which may have important implications for personalized diagnosis, prognosis, and treatment of PD patients.