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Introduction: Falls are a common and debilitating complication in Parkinson's disease (PD). Previous studies have primarily focused on cohorts with prevalent falls or advanced disease stages. This study assessed risk factors for falls in early-stage falls-naïve cohort stratified by sex., Methods: A total of 172 PD patients (<5 years disease duration) were selected from a registry-based study that reported no falls at baseline. All patients were assessed with a standardized data extraction form and falls were defined according to UPDRS Item 13. Hazard Ratios were calculated with univariable and stepwise multivariable Cox Proportional Hazard regression models., Results: Among the study sample, 61 (35.4 %) patients were female. At baseline, female and male PD groups were comparable in terms of age, disease duration, and UPDRS scores, although female PD patients had higher scores for UPDRS IV. Over a mean follow-up period of 3.9 (3.0) years, falls were reported in 13 female (21.3 %) and 18 male (16.2 %) PD patients. In female PD, motor fluctuations (HR [95 %] = 1.8 [1.3 - 2.6], p < 0.001) and postural stability (HR [95 %] = 4.2 [1.6 - 10.6], p = 0.003) emerged as significant predictors for falls, whereas in male PD, stepwise Cox regression selected freezing of gait (HR [95 %] = 2.0 [1.0 - 4.2], p = 0.053) and postural instability (HR [95 %] = 2.2 [0.89 - 5.4], p = 0.089) as the primary predictors for falls, although they were non-significant., Conclusion: Our findings suggest that the risk factors for falls differ between female and male early-stage PD patients, which may have important implications for clinical management., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Parkinson's disease (PD) is characterized by motor and non-motor symptoms. Nutritional alterations are one of the non-motor symptoms that most influence the quality of life (QoL) in PD., Objective: Therefore, this review aims to evaluate whether nutritional alterations are related either to the severity of motor and non-motor symptoms through the gut-brain axis or to the different treatments for PD and whether all of this, in turn, impacts the QoL of patients., Methods: A systematic review was carried out in MEDLINE and EMBASE databases, and Mendeley from 2000 to June 2024, searching for articles related to nutritional alterations in PD that alter patients' QoL. A total of 14 articles (2,187 participants) of 924 records were included., Results: Among the 14 studies examined, two investigated the relationship between nutritional status and QoL in patients with PD. Poor nutritional status was associated with lower QoL scores. Four studies explored the connection between nutritional status and its impact on both motor and non-motor symptoms (psychiatric disturbances, cognitive impairment, and fatigue), revealing a link between nutritional status, activities of daily living, and the severity of motor symptoms. Three studies identified changes in body weight associated with the severity of symptoms related to mobility issues in PD patients. Three studies investigated the relationship between different PD treatments and their interaction with changes in weight and energy metabolism, highlighting that weight loss in the early stages of PD needs adequate monitoring of different treatments, as well as the interaction between the central and peripheral nervous systems in regulating these processes. Finally, two studies investigated how gastrointestinal alterations and changes in the microbiota were related to cognitive status, thus identifying them as risk factors and early signs of PD., Discussion: The systematic review highlighted the significant relationship between nutritional status and QoL in patients with PD, as well as how the PD treatments influenced their weight. An association was also observed in the gut-brain axis, where adequate nutritional status influenced the balance of intestinal microbiota, slowing cognitive decline, improving activities of daily living, and the QoL of PD patients. It is confirmed that the nutritional status of patients influenced both motor and non-motor symptoms of the disease, and therefore their QoL., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Mentxakatorre, Tijero, Acera, Fernández-Valle, Ruiz-Lopez, Gómez-Esteban and Del Pino.)

Background and Purpose: Levodopa-entacapone-carbidopa intestinal gel (LECIG) infusion is a recently developed device-aided therapy for advanced Parkinson disease (PD) patients. The aim of this study was to report real-world evidence about the effectiveness, tolerability, and safety of LECIG in PD patients., Methods: A multicenter observational retrospective study of the first patients who initiated LECIG in Spain was performed. All neurologists with an experience of at least two patients treated until 30 March 2024 were invited to participate. Data about effectiveness and safety from the medical records (V0, pre-LECIG; V1, initiation of LECIG; V2, post-LECIG follow-up) with a total of 246 variables were collected., Results: Seventy-three PD patients (61.6% males, 70.1 ± 9.1 years old) from 21 Spanish centers with a mean disease duration of 14.4 ± 6.3 years (range = 5-31) were included. Twenty-six patients (35.6%) were switched directly from levodopa-carbidopa intestinal gel. The mean exposure to LECIG was 177.3 ± 110.5 days (range = 7-476). The mean daily OFF time decreased from 5.2 ± 3 (pre-LECIG) to 1.9 ± 1.8 (post-LECIG; n = 66, p < 0.0001). Global improvement was observed in >85% of the patients. No significant change was detected in the levodopa equivalent daily dose from V0 to V2. Only 7% received 24-h infusion, and 24.7% required more than one cartridge per day at V2. Thirty-four patients (46.6%) had at least one adverse event related to LECIG and/or the device system. Five patients (6.8%) discontinued LECIG., Conclusions: LECIG was safe and effective in advanced PD patients., (© 2024 The Author(s). European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex disorder characterized by heterogeneous symptoms, which lack specific biomarkers for its diagnosis. This study aimed to investigate plasma neurofilament light chain (NfL) levels as a potential biomarker for ME/CFS and explore associations with cognitive, autonomic, and neuropathic symptoms. Here, 67 ME/CFS patients and 43 healthy controls (HCs) underwent comprehensive assessments, including neuropsychological evaluation, autonomic nervous system (ANS) testing, and plasma NfL level analysis. ME/CFS patients exhibited significantly higher plasma NfL levels compared to HC (F = 4.30, p < 0.05). Correlations were observed between NfL levels and cognitive impairment, particularly in visuospatial perception (r = -0.42; p ≤ 0.001), verbal memory (r = -0.35, p ≤ 0.005), and visual memory (r = -0.26; p < 0.05) in ME/CFS. Additionally, higher NfL levels were associated with worsened autonomic dysfunction in these patients, specifically in parasympathetic function (F = 9.48, p ≤ 0.003). In ME/CFS patients, NfL levels explained up to 17.2% of the results in cognitive tests. Unlike ME/CFS, in HC, NfL levels did not predict cognitive performance. Elevated plasma NfL levels in ME/CFS patients reflect neuroaxonal damage, contributing to cognitive dysfunction and autonomic impairment. These findings support the potential role of NfL as a biomarker for neurological dysfunction in ME/CFS. Further research is warranted to elucidate underlying mechanisms and clinical implications.

Introduction: Olfactory dysfunction (OD) is frequent after SARS-CoV-2 infection. The aim of this study was to examine if long-term OD is common in post-COVID condition, and the relationship between olfaction, cognition, neuropsychiatric symptoms, and disease duration in these patients., Methods: This study included 121 participants with post-COVID condition and 51 healthy controls (HC). A comprehensive neuropsychological and neuropsychiatric assessment was conducted, encompassing various domains, including general cognition, processing speed, verbal fluency, attention, verbal memory, visual memory, visuoconstructive ability, visuospatial ability, abstraction, executive functions, anxious-depressive symptoms, general health perception, fatigue level, sleep quality, and olfaction. Statistical analyses were carried out to understand the relationship of OD with cognition, and its role as moderator variable., Results: In total, 25% of the post-covid patients had a reduced smell capacity, while only 9.3% of HC presented OD. Post-COVID patients had statistically significantly worse cognitive performance and clinical status than HC. Verbal fluency (AUC = 0.85, p  < 0.001), and attention (AUC = 0.82, p  < 0.001) were the variables that best discriminate between groups. OD seemed to be a moderator between fatigue and cognition, and between disease duration and attention (β = -0.04; p  = 0.014)., Discussion: The study highlights marked cognitive and neuropsychiatric sequelae in individuals post-COVID relative to HC. Olfactory impairment exhibits correlations with both cognitive performance and general health. Olfaction emerges as a potential prognostic marker owing to its moderating influence on disease severity indicators., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Azcue, Del Pino, Saenz de Argandoña, Ortiz de Echevarría, Acera, Fernández-Valle, Ayo-Mentxakatorre, Lafuente, Ruiz-Lopez, López de Munain, Gabilondo, Gómez-Esteban and Tijero-Merino.)

Background: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and post-COVID condition can present similarities such as fatigue, brain fog, autonomic and neuropathic symptoms., Methods: The study included 87 patients with post-COVID condition, 50 patients with ME/CFS, and 50 healthy controls (HC). The hemodynamic autonomic function was evaluated using the deep breathing technique, Valsalva maneuver, and Tilt test. The presence of autonomic and sensory small fiber neuropathy (SFN) was assessed with the Sudoscan and with heat and cold evoked potentials, respectively. Finally, a complete neuropsychological evaluation was performed. The objective of this study was to analyze and compare the autonomic and neuropathic symptoms in post-COVID condition with ME/CFS, and HC, as well as, analyze the relationship of these symptoms with cognition and fatigue., Results: Statistically significant differences were found between groups in heart rate using the Kruskal-Wallis test (H), with ME/CFS group presenting the highest (H = 18.3; p ≤ .001). The Postural Orthostatic Tachycardia Syndrome (POTS), and pathological values in palms on the Sudoscan were found in 31% and 34% of ME/CFS, and 13.8% and 19.5% of post-COVID patients, respectively. Concerning evoked potentials, statistically significant differences were found in response latency to heat stimuli between groups (H = 23.6; p ≤ .01). Latency was highest in ME/CFS, and lowest in HC. Regarding cognition, lower parasympathetic activation was associated with worse cognitive performance., Conclusions: Both syndromes were characterized by inappropriate tachycardia at rest, with a high percentage of patients with POTS. The prolonged latencies for heat stimuli suggested damage to unmyelinated fibers. The higher proportion of patients with pathological results for upper extremities on the Sudoscan suggested a non-length-dependent SFN., (© 2023. The Author(s).)

Background: Cognitive decline has been reported in premanifest and manifest Huntington's disease but reliable biomarkers are lacking. Inner retinal layer thickness seems to be a good biomarker of cognition in other neurodegenerative diseases., Objective: To explore the relationship between optical coherence tomography-derived metrics and global cognition in Huntington's Disease., Methods: Thirty-six patients with Huntington's disease (16 premanifest and 20 manifest) and 36 controls matched by age, sex, smoking status, and hypertension status underwent macular volumetric and peripapillary optical coherence tomography scans. Disease duration, motor status, global cognition and CAG repeats were recorded in patients. Group differences in imaging parameters and their association with clinical outcomes were analyzed using linear mixed-effect models., Results: Premanifest and manifest Huntington's disease patients presented thinner retinal external limiting membrane-Bruch's membrane complex, and manifest patients had thinner temporal peripapillary retinal nerve fiber layer compared to controls. In manifest Huntington's disease, macular thickness was significantly associated with MoCA scores, inner nuclear layer showing the largest regression coefficients. This relationship was consistent after adjusting for age, sex, and education and p-value correction with False Discovery Rate. None of the retinal variables were related to Unified Huntington's Disease Rating Scale score, disease duration, or disease burden. Premanifest patients did not show a significant association between OCT-derived parameters and clinical outcomes in corrected models., Conclusions: In line with other neurodegenerative diseases, OCT is a potential biomarker of cognitive status in manifest HD. Future prospective studies are needed to evaluate OCT as a potential surrogate marker of cognitive decline in HD., (© 2023. The Author(s).)

Introduction: Blood and cerebrospinal fluid represent emerging candidate fluids for biomarker identification in Parkinson's disease (PD)., Methods: We studied 8 individuals carrying the E46K-SNCA mutation (3 PD dementia (PDD), 1 tremor-dominant PD, 2 young rigid-akinetic PD and 2 asymptomatic) and 8 age- and sex-matched healthy controls. We quantified the levels of total alpha-synuclein (a-syn), neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), Tau and ubiquitin carboxy-terminal hydrolase L1 (UCHL1) with SiMoA (Quanterix) in cerebrospinal fluid (CSF) of mutation carriers and in serum of all participants. The correlation between the concentration of biofluid markers and clinical outcomes was evaluated., Results: Although based on a small number of cases, CSF a-syn was decreased in symptomatic E46K-SNCA carriers compared to the asymptomatic ones. Asymptomatic carriers exhibited similar serum biomarker levels as compared to matched controls, except for serum a-syn, which was higher in asymptomatic individuals. Carriers with PDD diagnosis displayed increased levels of serum NfL and GFAP compared to matched controls. These findings highly correlated with cognitive and motor status of E46K-SNCA carriers, but not with disease duration., Conclusions: Patients with familial forms of neurodegenerative disease exhibit variable penetrance of the phenotype and are exceptionally valuable for delineating biomarkers. Serum and CSF molecular biomarkers in E46K-SNCA mutation carriers show that a-syn might be suitable to track the conversion from asymptomatic to PD, whereas NfL and GFAP might serve to foresee the progression to PD dementia. These findings should be interpreted with caution and need to be replicated in other genetic synucleinopathy cohorts., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Visual impairment is frequent and highly disabling in Parkinson's disease (PD); however, few studies have comprehensively evaluated its impact on vision-related quality of life., Objective: To evaluate the relationship between visual function tests and the visual impairment perceived by PD patients in daily living activities., Methods: We cross-sectionally evaluated 62 PD patients and 33 healthy controls (HC). Visual disability was measured with a comprehensive battery of primary visual function and visual cognition tests (visual outcomes), and vision-related quality of life was evaluated with the National Eye Institute 25-Item Visual Function Questionnaire (NEI VFQ-25). The relationship between visual outcomes and NEI VFQ-25 sub-scores was analyzed with Pearson's correlations and stepwise linear regression., Results: In PD patients, and not in HC, most NEI VFQ-25 sub-scores were significantly correlated with Cube Analysis and Dot Counting from Visual Object and Space Perception (VOSP) battery (visual perception), Clock Drawing Test (visuoconstructive capacity) and Trail Making Test part-A (visual attention and processing speed) and to a lesser extent with high- and low-contrast visual acuity. Dot Counting (VOSP) was the test primarily associated with most NEI VFQ-25 sub-scores (5 out of 12). Roth-28 color test was the one that best explained the variance of Peripheral Vision (R2: 0.21) and Role Difficulties (R2: 0.36) sub-scores of NEI VFQ-25, while photopic contrast sensitivity explained 41% of Driving sub-score variance., Conclusion: Vision-related quality of life in PD is mainly influenced by alterations in visual perception, visuoconstructive capacity and visual attention and processing speed. Future studies are warranted to confirm and further extend our findings.

Objective: This study was undertaken to analyze longitudinal changes of retinal thickness and their predictive value as biomarkers of disease progression in idiopathic Parkinson's disease (iPD)., Methods: Patients with Lewy body diseases were enrolled and prospectively evaluated at 3 years, including patients with iPD (n = 42), dementia with Lewy bodies (n = 4), E46K-SNCA mutation carriers (n = 4), and controls (n = 17). All participants underwent Spectralis retinal optical coherence tomography and Montreal Cognitive Assessment, and Unified Parkinson's Disease Rating Scale score was obtained in patients. Macular ganglion cell-inner plexiform layer complex (GCIPL) and peripapillary retinal nerve fiber layer (pRNFL) thickness reduction rates were estimated with linear mixed models. Risk ratios were calculated to evaluate the association between baseline GCIPL and pRNFL thicknesses and the risk of subsequent cognitive and motor worsening, using clinically meaningful cutoffs., Results: GCIPL thickness in the parafoveal region (1- to 3-mm ring) presented the largest reduction rate. The annualized atrophy rate was 0.63μm in iPD patients and 0.23μm in controls (p < 0.0001). iPD patients with lower parafoveal GCIPL and pRNFL thickness at baseline presented an increased risk of cognitive decline at 3 years (relative risk [RR] = 3.49, 95% confidence interval [CI] = 1.10-11.1, p = 0.03 and RR = 3.28, 95% CI = 1.03-10.45, p = 0.045, respectively). We did not identify significant associations between retinal thickness and motor deterioration., Interpretation: Our results provide evidence of the potential use of optical coherence tomography-measured parafoveal GCIPL thickness to monitor neurodegeneration and to predict the risk of cognitive worsening over time in iPD. ANN NEUROL 2021;89:165-176., (© 2020 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder. It is characterized by a slow and progressive loss of dopaminergic neurons. Its neuropathological hallmark is the accumulation of aggregated form of α-synuclein (α-syn) protein in intracellular inclusions known as Lewy bodies. This aggregated α-syn is believed to be central to the pathogenesis of PD. Emerging evidence suggests that aggregated forms of α-syn self-amplificates and propagates spreading from cell-to-cell in a "prion-like" fashion. Genetics and environmental factors are known causes for the pathogenesis of PD. In last years, inflammation in the pathophysiology of PD is gaining more importance. This neuroinflammation seems to contribute to the progressive degeneration of dopaminergic neurons. The currently available therapies for PD fail to modify the disease progression and neurodegeneration. The connection between α-syn and PD makes α-syn the major therapeutic target. We summarize the possible therapeutic strategies to target α-syn according to the steps in the molecular pathogenesis. The contribution of neuroinflammation to the progression of the disease and the "prion-like" hypothesis which enables targeting the extracellular phase of transmission of α-syn, make immunotherapy probably the most promising therapeutic approach for PD., (© 2019 Elsevier Inc. All rights reserved.)