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Background: Therapeutic education programs are effective in several chronic conditions. However, evidence is lacking in multiple system atrophy (MSA). We aimed to assess efficacy and safety of a comprehensive therapeutic education program in people with MSA (PwMSA) and their caregivers., Methods: In this prospective longitudinal study we included 16 PwMSA and their main caregivers in 4 groups of 4 dyads each. The program consisted of eight 60-min interdisciplinary sessions: introduction, orthostatic hypotension, speech therapy, gait and respiratory physiotherapy, psychological support, urinary dysfunction, occupational therapy/social work. UMSARS, NMSS, PDQ39, EQ5 and Zarit scales were administered at baseline and 6 months later. After each session participants filled-out a modified EduPark satisfaction questionnaire and a Likert scale. Educational material was generated for each session after suggestions by participants., Results: At baseline PwMSA and caregivers were comparable in age and sex, with significant correlation between UMSARS-IV (disability) and PDQ39 (quality of life). Adherence to sessions was of 94,92 %. Total modified EduPark scores and Likert scales did not differ in PwMSA vs. caregivers, mild-moderate vs. severe-advanced cases or between genders. The significant difference in satisfaction across sessions (p = 0.03) was driven by higher scores in speech, respiratory and occupational therapy sessions. Longitudinally there was no significant worsening in any scale, nor a significant increase post-vs. pre-program in the number of consultations., Conclusions: The healthcare education program in MSA was feasible, satisfactory, and safe for patients and caregivers. The educational material of the program is being forwarded to incident MSA cases attending our clinic., Competing Interests: Declaration of competing interest Ana Cámara and Yaroslau Compta state on behalf of the authors that there are no conflicts of interest related to the topic of the study., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

The hypothesis that neurodegenerative diseases are proteinopathies due to toxic effect of different underlying proteins, such as amyloid-beta and 3+4R-tau in Alzheimer's disease (AD) and alpha-synuclein in Parkinson's disease (PD), while still controversial is supported by several studies in the literature. This has led to conduct clinical trials attempting to reduce the load of these allegedly toxic proteins by immunotherapy, mostly but not solely based on antibodies against these proteins. Already completed clinical trials have ranged from initially negative results to recently partial positive outcomes, specifically for anti-amyloid antibodies in AD but also albeit to lesser degree for anti-synuclein antibodies in PD. Currently, there are several ongoing clinical trials in degenerative parkinsonisms with anti-synuclein approaches in PD and multiple system atrophy (MSA), as well as with anti-tau antibodies in 4R-tauopathies such as progressive supranuclear palsy (PSP). While it can be argued that expectations that part of these clinical trials will be positive can be hope or hype, it is reasonable to consider the future possibility of "cocktail" combination of different antibodies after the available experimental evidence of cross-talk between these proteins and neuropathological evidence of coexistence of these proteinopathies more frequently than expected by chance. Moreover, such "cocktail" approaches are widespread and accepted common practice in other fields such as oncology, and the complexity of neurodegenerative parkinsonisms makes reasonable the option for testing and eventually applying such combined approaches, should these prove useful separately, in the setting of patients with evidence of underlying concomitant proteinopathies, for example through biomarkers., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: YC, KDG and MC participate as sub-investigators, AC, IZ and VR participate as study nurses; BP39529/PASADENA (F.Hoffman La Roche Ltd). KDG and MC participate as sub-investigators, IZ participates as study-nurse; BN42358/PADOVA (F.Hoffman La Roche Ltd.). YC and MC participated as sub-investigators, IZ participated as study-nurse; 228PD201/SPARK (Biogen MA Inc.). YC, KDG and MC participate as sub-investigators, IZ participates as study-nurse; 254PD101/REASON (Biogen MA Inc.). KDG and MC participate as sub-investigators, IZ participates as study-nurse; 283PD201/LUMA (Biogen MA Inc.). KDG and MC participate as sub-investigators, IZ participates as study-nurse; PD0053/ORCHESTRA (UCB Biopharma SRL). YC participated as principal investigator, MC participated as sub-investigator, IZ participated as study-nurse; PSP003-PSP002 (UCB Biopharma SRL). YC participates as principal investigator, KDG and MC participate as sub-investigators, IZ participates as study-nurse; PSP002 (UCB Biopharma SRL). YC is planned to participate as principal investigator, KDG and MC are planned to participate as sub-investigators, IZ, VR, AC are planned to participate as study-nurse in the upcoming A35-009 (AMYLYX Pharmaceuticals Inc.), FNP223-CT-2301 (Ferrer Internacional, S.A.) and GV1001-PSP-CL2-012 (GemVax & Kael, Co. Ltd.) clinical trials., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Over the last two decades there have been meaningful developments on biomarkers of neurodegenerative diseases, extensively (but not solely) focusing on their proteinopathic nature. Accordingly, in Alzheimer's disease determination of levels of total and phosphorylated tau (τ and p-τ, usually p-τ181) along with amyloid-beta1-42 (Aβ1-42) by immunodetection in cerebrospinal fluid (CSF) and currently even in peripheral blood, have been widely accepted and introduced to routine diagnosis. In the case of Parkinson's disease, α-synuclein as a potential biomarker (both for diagnosis and progression tracking) has proved more elusive under the immunodetection approach. In recent years, the emergence of the so-called seed amplification assays is proving to be a game-changer, with mounting evidence under different technical approaches and using a variety of biofluids or tissues, yielding promising diagnostic accuracies. Currently the least invasive but at once more reliable source of biosamples and techniques are being sought. Here we overview these advances., Competing Interests: Declaration of competing interest No COI., (Copyright © 2023. Published by Elsevier Ltd.)

Introduction: Differential diagnosis between Parkinson's disease (PD) and atypical parkinsonisms (APs: multiple system atrophy[MSA], progressive supranuclear palsy[PSP], corticobasal degeneration[CBD]) remains challenging. Lately, cerebrospinal fluid (CSF) studies of neurofilament light-chain (NFL) and RT-QuIC of alpha-synuclein (α-SYN) have shown promise, but data on their combination with MRI measures is lacking., Objective: (1) to assess the combined diagnostic ability of CSF RT-QuIC α-SYN, CSF NFL and midbrain/pons MRI planimetry in degenerative parkinsonisms; (2) to evaluate if biomarker-signatures relate to clinical diagnoses and whether or not unexpected findings can guide diagnostic revision., Methods: We collected demographic and clinical data and set up α-SYN RT-QuIC at our lab in a cross-sectional cohort of 112 participants: 19 control subjects (CSs), 20PD, 37MSA, 23PSP, and 13CBD cases. We also determined CSF NFL by ELISA and, in 74 participants (10CSs, 9PD, 26MSA, 19PSP, 10CBD), automatized planimetric midbrain/pons areas from 3T-MRI., Results: Sensitivity of α-SYN RT-QuIC for PD was 75% increasing to 81% after revisiting clinical diagnoses with aid of biomarkers. Sensitivity for MSA was 12% but decreased to 9% with diagnostic revision. Specificities were 100% against CSs, and 89% against tauopathies raising to 91% with diagnostic revision. CSF NFL was significantly higher in APs. The combination of biomarkers yielded high diagnostic accuracy (PD vs. non-PD AUC = 0.983; MSA vs. non-MSA AUC = 0.933; tauopathies vs. non-tauopathies AUC = 0.924). Biomarkers-signatures fitted in most cases with clinical classification., Conclusions: The combination of CSF NFL, CSF RT-QuIC α-SYN and midbrain/pons MRI measures showed high discriminant ability across all groups. Results opposite to expected can assist diagnostic reclassification., (Copyright © 2022. Published by Elsevier Ltd.)

Objective: Non-motor symptoms (NMS) have been identified in some focal adult-onset dystonia. In the present study we aimed to evaluate the presence of NMS in patients with spasmodic dysphonia (SD), a focal action-induced dystonia that affects intrinsic laryngeal muscle control., Methods: Seventeen SD patients and 17 control subjects not significantly different in age and sex were evaluated for the presence of NMS. Additionally, voice handicap index (VHI-10), reflux symptom index, neuropsychiatric symptoms and QoL were assessed by validated scales and questionnaires., Results: Patients' group significantly differed from control group in mild depressive symptoms (4.35 ± 3.9 vs. 1.47 ± 2; p=0.01), insomnia (35.3% vs. 14.7%; p=0.016), smell and taste loss (11.8% vs. 0%; p=0.033), swallowing difficulties (17.6% vs. 0%; p=0.007) and throat pain (17.6% vs. 0%; p=0.007). In the group of SD, there was no correlation between voice perception evaluated by VHI-10, number of NMS or QoL., Conclusion: Patients with SD have a greater burden of depressive, smell, taste, and sleep NMS than control subjects., Competing Interests: Declaration of Competing Interest The authors declare to have no disclosures or conflicts of interest., (Copyright © 2021. Published by Elsevier B.V.)

Background: Association of type 2 diabetes mellitus (T2D) with subsequent Parkinson's disease (PD) has supported the link between glucose metabolism and PD. We assessed the risk of PD not only in T2D but also in prediabetes., Methods: We conducted a retrospective cohort study of the population attended in primary care centres of the Catalan Health Institute in Catalonia between 2006 and 2018. The data were obtained from the Information System for Research in Primary Care (SIDIAP). We created a cohort of T2D and prediabetes patients (HbA1c ≥ 5.7-6.4% without antidiabetic drugs or previous T2D diagnosis) and compared to a reference cohort. The outcome was PD diagnosis and we excluded PD before or during the first year of follow-up. We used multivariate Cox regression models to calculate hazard ratios (HR) and 95% confidence intervals (95%CI). We excluded subjects with atypical and secondary parkinsonisms., Results: The exposed cohorts comprised of 281.153 patients with T2D and 266.379 with prediabetes and a reference cohort of 2.556.928 subjects. T2D and prediabetes were associated with higher risk of PD (HRadjusted 1.19, 95%CI 1.13-1.25, and 1.07, 1.00-1.14; respectively). In analyses stratified by sex, prediabetes was only associated with PD risk in women (1.12, 1.03-1.22 vs. 1.01, 0.99-1.10 in men). When analysis was stratified by age, T2D and prediabetes were associated with a greater PD risk both in women (2.36, 1.96-2.84 and 2.10, 1.70-2.59 respectively) and men (1.74, 1.52-2.00 and 1.90, 1.57-2.30 respectively) below 65 years-old., Conclusions: We report for the first time that prediabetes increases the odds of subsequent PD and replicate the association with established T2D. Both associations predominate in women and young individuals., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Introduction: The MDS-PSP criteria expand the phenotypic spectrum of PSP by adding to Richardson's syndrome (PSP-RS) other presentations such as PSP-parkinsonism (PSP-P), PSP-pure-gait-freezing (PSP-PGF), PSP-speech-language (PSP-SL), PSP-frontal (PSP-F), PSP-postural-instability (PSP-PI) and PSP-corticobasal-syndrome (PSP-CBS). Evidence about the prognostic differences between PSP phenotypes is scarce and focused on PSP-RS vs. non-PSP-RS. Using a brain-bank cohort we assessed PSP survival not only in PSP-RS vs. non-PSP-RS, but also in PSP-RS + cortical vs. subcortical phenotypes. Besides, we assessed sensitivity and specificity of the MDS-PSP criteria in of PSP and other degenerative parkinsonisms., Methods: We retrospectively applied the MDS-PSP diagnostic criteria to 32 definite PSP cases and 30 cases with other degenerative parkinsonian syndromes (Parkinson's disease [PD; n = 11], multiple system atrophy [MSA; n = 11], corticobasal degeneration [CBD; n = 8]). We conducted survival statistics in neuropathologically confirmed PSP cases considering PSP-RS vs. non-PSP-RS and PSP-RS + PSP-cortical (PSP-F + PSP-SL + PSP-CBS) vs. PSP-subcortical (PSP-P + PSP-PGF) phenotypes. We also adjusted survival analyses for PSP tau scores., Results: Diagnostic sensitivity was 100% and specificity ranged from 47% to 87% when excluding cases that met the "suggestive of PSP" definition early in their disease course but with other clinical features better matching with a non-PSP pathological diagnosis. Survival was significantly shorter in PSP-RS vs. non-PSP-RS cases, but it was more markedly shorter in PSP-RS + PSP-cortical vs. PSP-subcortical, independently of PSP tau scores, which were not associated with survival., Conclusions: PSP-subcortical phenotypes appear to have longer survival than PSP-RS and cortical phenotypes. This might be of prognostic relevance when informing patients upon clinical diagnosis., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Parkinson's disease (PD) is a heterogeneous condition. Cluster analysis based on cortical thickness has been used to define distinct patterns of brain atrophy in PD. However, the potential of other neuroimaging modalities, such as white matter (WM) fractional anisotropy (FA), which has also been demonstrated to be altered in PD, has not been investigated., Objective: We aim to characterize PD subtypes using a multimodal clustering approach based on cortical and subcortical gray matter (GM) volumes and FA measures., Methods: We included T1-weighted and diffusion-weighted MRI data from 62 PD patients and 33 healthy controls. We extracted mean GM volumes from 48 cortical and 17 subcortical regions using FSL-VBM, and the mean FA from 20 WM tracts using Tract-Based Spatial Statistics (TBSS). Hierarchical cluster analysis was performed with the PD sample using Ward's linkage method. Whole-brain voxel-wise intergroup comparisons of VBM and TBSS data were also performed using FSL. Neuropsychological and demographic statistical analyses were conducted using IBM SPSS Statistics 25.0., Results: We identified three PD subtypes, with prominent differences in GM patterns and little WM involvement. One group (n = 15) with widespread cortical and subcortical GM volume and WM FA reductions and pronounced cognitive deficits; a second group (n = 21) with only cortical atrophy limited to frontal and temporal regions and more specific neuropsychological impairment, and a third group (n = 26) without detectable atrophy or cognition impairment., Conclusion: Multimodal MRI data allows classifying PD patients into groups according to GM and WM patterns, which in turn are associated with the cognitive profile., (Copyright © 2020. Published by Elsevier Ltd.)

Background: Type-2-diabetes (T2D) has surfaced as a potential risk factor for Parkinson's disease (PD) in some epidemiological studies. Evidence of glucose metabolism alterations in PD from molecular studies remains conflicting. Amylin, the T2D amyloid protein, has been implicated in PD in pathological studies. We aimed to assess peripheral levels of amylin and insulin in PD patients and control subjects (Cs)., Methods: We conducted an observational cross-sectional study of 111 participants: 73 PD and 38 Cs, similar in age, sex and body mass index. All underwent motor (UPDRS-MDS-III), non-motor (NMSS) and cognitive (MDRS) scales as well as determination of four parameters: fasting glycaemia, glycated haemoglobin, fasting plasma insulin (FPI) and fasting plasma amylin (FPA)., Results: FPI was significantly lower in PD than Cs (p = 0.034). In participants with age above cohort-median-age, FPA was higher in PD than Cs (p = 0.046). The FPA/FPI ratio (FPAIR) was significantly higher in PD than Cs (p = 0.024). In PD, modest correlation was found between higher insulin-resistance and NMSS scores., Conclusions: PD patients had lower FPI and increased FPAIR. In older PD subgroup, FPA was increased. The more the insulin resistance, the higher the non-motor scores. These findings provide an additional link between pathophysiology of diabetes and PD. This might be related to a dissociated insulin and amylin secretion in PD, in line with recent evidence of endocrine pancreas role in PD pathogeny., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: The International Parkinson and Movement Disorder Society-endorsed Progressive Supranuclear Palsy Study Group published clinical diagnostic criteria for progressive supranuclear palsy in 2017, aiming to optimize early, sensitive and specific diagnosis., Objective: To assist physicians in the application of these criteria, we developed a video-based tutorial in which all core clinical features and clinical clues are depicted and explained., Methods: Patients provided written informed consent to the publication of their videos. High-quality videos along with essential descriptions were collected by the study group members. Most educational videos were selected in a structured consensus process., Results: We provide 68 videos of all core clinical features and clinical clues defined by the diagnostic criteria, along with instructive descriptions of the depicted patients, examination techniques and clinical findings., Conclusions: This comprehensive video-based tutorial will support physicians in the application of the diagnostic criteria of progressive supranuclear palsy., (Copyright © 2020. Published by Elsevier Ltd.)

Background: Improved knowledge of the prediagnostic phase of progressive supranuclear palsy (PSP) might provide information on when and how the disease starts, along with the opportunity to test therapies in disease stages with lesser neurodegeneration., Objective: To explore the symptoms in years preceding the PSP diagnosis., Methods: This is a single-center retrospective case-control study based on clinical charts review and a structured interview to PSP patients and their caregivers. Prediagnostic symptoms were defined as those present more than one year before the diagnosis. We explored 35 symptoms in the following domains: visual, dizziness, motor, mood/apathy, cognitive, behavioral, sleep, gastrointestinal/urinary and miscellaneous. Non-parametric statistics were applied, with significance set at <0.05 (FDR-corrected)., Results: We included 150 subjects: 50 PSP patients (38% females, age 75.8) and an age- and sex-matched control group of 50 Parkinson's disease (PD) and 50 subjects (CS) without neurodegenerative disease. The frequencies of visual, motor, cognitive, behaviour and dizziness domains were significantly higher in PSP vs. PD, and so were the motor, mood/apathy, cognitive, behaviour and dizziness ones in PSP vs. CS. Over 50% of prediagnostic falls, apathy and anxiety, depression and memory-attention-executive symptoms, and over 30% of gait disturbances started more than three and up to ten years before the diagnosis. PSP patients had more consultations to ENT and ophthalmologists than PD patients., Conclusion: PSP patients present a broad variety of motor and non-motor symptoms several years before the diagnosis. The definition of a prediagnostic PSP phase might be helpful to identify patients in early disease stages., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Introduction: Neuroinflammation is a potential player in neurodegenerative conditions, particularly the aggressive ones, such as multiple system atrophy (MSA). Previous reports on cytokine levels in MSA using serum or cerebrospinal fluid (CSF) have been inconsistent, including small samples and a limited number of cytokines, often without comparison to Parkinson's disease (PD), a main MSA differential diagnosis., Methods: Cross-sectional study of CSF levels of 38 cytokines using a multiplex assay in 73 participants: 39 MSA patients (19 with parkinsonian type [MSAp], 20 with cerebellar type [MSAc]; 31 probable, 8 possible), 19 PD patients and 15 neurologically unimpaired controls. None of the participants was under non-steroidal anti-inflammatory drugs at the time of the lumbar puncture., Results: There were not significant differences in sex and age among participants. In global non-parametric comparisons FDR-corrected for multiple comparisons, CSF levels of 5 cytokines (FGF-2, IL-10, MCP-3, IL-12p40, MDC) differed among the three groups. In pair-wise FDR-corrected non-parametric comparisons 12 cytokines (FGF-2, eotaxin, fractalkine, IFN-α2, IL-10, MCP-3, IL-12p40, MDC, IL-17, IL-7, MIP-1β, TNF-α) were significantly higher in MSA vs. non-MSA cases (PD + controls pooled together). Of these, MCP-3 and MDC were the most significant ones, also differed in MSA vs. PD, and were significant MSA-predictors in binary logistic regression models and ROC curves adjusted for age. CSF levels of fractalkine and MIP-1α showed a strong and significant positive correlation with UMSARS-2 scores., Conclusion: Increased CSF levels of cytokines such as MCP-3, MDC, fractalkine and MIP-1α deserve consideration as potential diagnostic or severity biomarkers of MSA., (Copyright © 2019. Published by Elsevier Ltd.)

Background: Three cortical atrophy patterns were previously identified in non-demented Parkinson's disease patients using a data-driven approach based on cortical thickness data: i) parieto-temporal pattern of atrophy with worse cognitive performance (pattern 1), ii) occipital and frontal cortical atrophy with younger disease onset (pattern 2), and iii) non-detectable cortical atrophy (pattern 3). We aimed to investigate the evolution of these three patterns over time., Methods: Magnetic resonance imaging and neuropsychological assessment were obtained at baseline and follow-up (3.8 ± 0.4 year apart) in a group of 45 Parkinson's disease patients and 22 healthy controls. FreeSurfer was used for cortical thickness analysis and global atrophy measures., Results: Temporo-parietal cortical thinning occurred in pattern 2, 3 and controls groups, and patients showed decline in processing speed (as measured by the Stroop Word-Color test, the Symbol Digits Modalities test and the Trail Making Test Part B) and in semantic fluency (animals). Pattern 3 patients showed more progressive cortical thinning in the left prefrontal cortex than controls and more right occipital thinning than pattern 2 patients over time. Pattern 1 patients had greater compromise in activities of the daily living and suffered higher attrition rate., Conclusion: The Parkinson's disease phenotypes identified using cluster analysis of cortical thickness data showed different progression over time. The presence of prefrontal thinning and younger disease onset at baseline was associated to less cortical degeneration, while non-atrophic patients progressed showing a temporo-parietal cortical thinning., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Introduction: Experimental studies suggest that low-frequency (LF) (63 Hz) deep brain stimulation (DBS) of the substantia nigra pars reticulata (SNr) could be useful to regulate gait disorders refractory to medical treatment in Parkinson's disease (PD). The SNr neurons could act as high-frequency (HF) pacemakers within locomotor control systems. Currently, no specific therapies can treat gait disorders in PD with insufficient response to dopaminergic treatment., Objective: To investigate whether LF-SNr-DBS combined with standard HF stimulation of the subthalamic nucleus (STN) is clinically relevant in improving gait disorders that no longer respond to levodopa in PD patients, compared with HF-STN or LF-SNr stimulation alone., Methods: Patients received LF-SNr or HF-STN stimulation alone or combined (COMB) stimulation of both nuclei (crossover design). The nucleus to be stimulated was randomly assigned and clinical evaluations performed by a blinded examiner after three months follow-up for each. Clinical assessment included the Freezing of Gait questionnaire, Tinetti Balance and Walking Assessing tool, and Unified Parkinson's Disease Rating., Results: We included six patients (mean age 59.1 years, disease duration 16.1 years). All patients suffered motor fluctuations and dyskinesias. The best results were obtained with COMB in four patients (who preferred and remained with COMB over 3 years of follow-up) and with HF-STN in two patients. SNr stimulation alone did not produce better results than COMB or STN in any patient., Conclusion: COMB and HF-STN stimulation improved PD-associated gait disorders in this preliminary case series, sustained over time. Further multicenter investigations are required to better explore this therapeutic option., (Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: Cortical brain atrophy detectable with MRI in non-demented advanced Parkinson's disease (PD) is well characterized, but its presence in early disease stages is still under debate. We aimed to investigate cortical atrophy patterns in a large sample of early untreated PD patients using a hypothesis-free data-driven approach., Methods: Seventy-seven de novo PD patients and 50 controls from the Parkinson's Progression Marker Initiative database with T1-weighted images in a 3-tesla Siemens scanner were included in this study. Mean cortical thickness was extracted from 360 cortical areas defined by the Human Connectome Project Multi-Modal Parcellation version 1.0, and a hierarchical cluster analysis was performed using Ward's linkage method. A general linear model with cortical thickness data was then used to compare clustering groups using FreeSurfer software., Results: We identified two patterns of cortical atrophy. Compared with controls, patients grouped in pattern 1 (n = 33) were characterized by cortical thinning in bilateral orbitofrontal, anterior cingulate, and lateral and medial anterior temporal gyri. Patients in pattern 2 (n = 44) showed cortical thinning in bilateral occipital gyrus, cuneus, superior parietal gyrus, and left postcentral gyrus, and they showed neuropsychological impairment in memory and other cognitive domains., Conclusions: Even in the early stages of PD, there is evidence of cortical brain atrophy. Neuroimaging clustering analysis is able to detect two subgroups of cortical thinning, one with mainly anterior atrophy, and the other with posterior predominance and worse cognitive performance., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Growing evidence highlights the relevance of posterior cortically-based cognitive deficits in Parkinson's disease (PD) as possible biomarkers of the evolution to dementia. Cross-sectional correlational studies have established a relationship between the degree of atrophy in posterior brain regions and visuospatial and visuoperceptual (VS/VP) impairment. The aim of this study is to address the progressive cortical thinning correlates of VS/VP performance in PD., Methods: Forty-four PD patients and 20 matched healthy subjects were included in this study and followed for 4 years. Tests used to assess VS/VP functions included were: Benton's Judgement of Line Orientation (JLOT), Facial Recognition (FRT), and Visual Form Discrimination (VFDT) Tests; Symbol Digit Modalities Test (SDMT); and the Pentagon Copying Test (PCT). Structural magnetic resonance imaging data and FreeSurfer were used to evaluate cortical thinning evolution., Results: PD patients with normal cognition (PD-NC) and PD patients with mild cognitive impairment (PD-MCI) differed significantly in the progression of cortical thinning in posterior regions. In PD-MCI patients, the change in VS/VP functions assessed by PCT, JLOT, FRT, and SMDT correlated with the symmetrized percent change of cortical thinning of occipital, parietal, and temporal regions. In PD-NC patients, we also observed a correlation between changes in FRT and thinning in parieto-occipital regions., Conclusion: In this study, we establish the neuroanatomical substrate of progressive changes in VS/VP performance in PD patients with and without MCI. In agreement with cross-sectional data, VS/VP changes over time are related to cortical thinning in posterior regions., (Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: The finding of mutations of the COQ2 gene and reduced coenzyme Q10 levels in the cerebellum in multiple system atrophy (MSA) suggest that coenzyme Q10 is relevant to MSA pathophysiology. Two recent studies have reported reduced coenzyme Q10 levels in plasma and serum (respectively) of MSA patients compared to Parkinson's disease and/or control subjects, but with largely overlapping values, limited comparison with other parkinsonisms, or dependence on cholesterol levels. We hypothesized that cerebrospinal fluid (CSF) is reliable to assess reductions in coenzyme Q10 as a candidate biomarker of MSA., Methods: In this preliminary cross-sectional study we assessed CSF coenzyme Q10 levels in 20 patients with MSA from the multicenter Catalan MSA Registry and of 15 PD patients, 10 patients with progressive supranuclear palsy (PSP), and 15 control subjects from the Movement Disorders Unit Biosample Collection of Hospital Clinic de Barcelona. A specific ELISA kit was used to determine CSF coenzyme Q10 levels. CSF coenzyme Q10 levels were compared in MSA vs. the other groups globally, pair-wise, and by binary logistic regression models adjusted for age, sex, disease severity, disease duration, and dopaminergic treatment., Results: CSF coenzyme Q10 levels were significantly lower in MSA than in other groups in global and pair-wise comparisons, as well as in multivariate regression models. Receiver operating characteristic curve analyses yielded significant areas under the curve for MSA vs. PD, PSP and controls., Conclusions: These findings support coenzyme Q10 relevance in MSA. Low CSF coenzyme Q10 levels deserve further consideration as a biomarker of MSA., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: Olfactory dysfunction is present in a large proportion of patients with Parkinson's disease (PD) upon diagnosis. However, its progression over time has been poorly investigated. The few available longitudinal studies lack control groups or MRI data., Objective: To investigate the olfactory changes and their structural correlates in non-demented PD over a four-year follow-up., Methods: We assessed olfactory function in a sample of 25 PD patients and 24 normal controls of similar age using the University of Pennsylvania Smell Identification test (UPSIT). Structural magnetic resonance imaging data, obtained with a 3-T Siemens Trio scanner, were analyzed using FreeSurfer software., Results: Analysis of variance showed significant group (F = 53.882; P < 0.001) and time (F = 6.203; P = 0.016) effects, but the group-by-time interaction was not statistically significant. UPSIT performance declined ≥1.5 standard deviations in 5 controls and 7 patients. Change in UPSIT scores of patients correlated positively with volume change in the left putamen, right thalamus, and right caudate nucleus., Conclusion: Olfactory loss over time in PD and controls is similar, but we have observed significant correlation between this loss and basal ganglia volumes only in patients., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: Substantia nigra hyperechogenicity (SN+) has been proposed as a risk marker of Parkinson's disease (PD). Asymptomatic LRRK2 mutation carriers (aLRRK2+), at high risk for developing PD, provide an opportunity for the study of preclinical biomarkers., Objective: To assess SN echogenicity and other echographic features in LRRK2 G2019S carriers and their clinical and imaging correlates., Methods: Transcranial sonography was performed in 26 LRRK2 G2019S PD patients, 50 first-degree relatives, 31 idiopathic PD (IPD) patients and 26 controls. SN echogenicity and other echographic features were assessed in all study subjects. Dopamine transporter imaging (DAT-SPECT) was performed in 29 first-degree relatives., Results: 75% of the LRRK2-PD and 87.5% of the IPD showed SN+ (p = 0.087). aLRRK2+ had a higher frequency of SN+ than non carriers (58.3% vs. 25%, p = 0.039) and controls (58.3% vs. 12.5%; p = 0.002) and had a larger area of SN echogenicity than non carriers (p = 0.030) and controls (p < 0.001). The width of the third ventricle was significantly lower in LRRK2-PD than in IPD (1.9 mm [1.38; 2.75] vs. 3.0 mm [2.3; 5.3]; p = 0.003). Four out of 5 (80%) of the aLRRK2+ with an abnormal DAT-SPECT and four of the 5 (80%) of those with REM sleep behaviour disorder (RBD) had SN+., Conclusions: SN+ is very frequent in LRRK2-PD and aLRRK2+. Most aLRRK2 with possible surrogate markers of PD such as abnormal DAT-SPECT or RBD, also had SN+, which supports that this echofeature might be a marker of PD in these asymptomatic population., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: Cognitive impairment in Parkinson's disease (PD) is common and recent studies have focused on addressing the most suitable screening tool for its assessment. MMSE is commonly used in clinical practice and longitudinal studies found a relationship between the MMSE pentagon copying item and progression to dementia, but its neuroanatomical correlates have been poorly investigated. The aim of this study is to investigate the MRI structural correlates of the global MMSE and the pentagon item scores in PD patients in the absence of dementia., Methods: We selected a sample of 92 PD patients and 36 controls. MMSE was used as a global measure of cognitive status, and the pentagon copying test as a measure of visuospatial performance. FreeSurfer software was used to assess intergroup differences in cortical thickness (CTh) and global atrophy measures, as well as their relationship with cognitive performance., Results: Compared to controls, patients showed significant differences in measures of global atrophy, which correlated with performance on MMSE and the pentagon item. Regional differences in CTh were seen between PD patients and controls bilaterally in the temporo-parietal-occipital region. Patients with impaired performance compared with those of normal performance also showed CTh reductions in these regions., Conclusion: Our results suggest MMSE and the pentagon item reflect brain changes which at a regional level involve mainly posterior regions. Correlates of the pentagon item were seen in the same regions where PD patients exhibited significant thinning, and involved more areas and bigger cluster sizes than the correlates of MMSE global scores., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Unlabelled: Vascular parkinsonism (VP) may occur as a distinct clinicopathological entity but the comorbid presence of vascular damage in Parkinson's disease (PD) is very frequent too. This differential diagnosis has therapeutic and prognostic implications but remains challenging as the usefulness of a number of supporting tools is still controversial., Objective: To ascertain the clinical value of cardiac (123)I-meta-iodobenzylguanidine ((123)I-MIBG) SPECT, olfactory function and (123)I-FP-CIT SPECT as supporting tools in the differential diagnosis between VP and PD., Methods: Cross-sectional study of 15 consecutive patients with suspected VP, 15 PD patients and 9 healthy subjects. Cardiac (123)I-MIBG SPECT (heart-to-mediastinum ratio) and olfactory testing (University of Pennsylvania Smell Identification Test-UPSIT) were performed in all of them. (123)I-FP-CIT SPECT was performed in VP-suspected patients., Results: Heart-to-mediatinum ratio was significant lower in suspected VP (mean 1.45) and PD (mean 1.16) compared to control group (mean 1.69) (p = 0.017 and p < 0.0001). VP patients presented a higher ratio than PD patients (p = 0.001). Control group presented a significant higher UPSIT score (mean 30.71) when compared to both VP (mean 18.33) and PD (mean 15.29) (p = 0.001 for both groups). Those VP with a cardiac (123)I-MIBG non suggestive of PD were more likely to have a higher UPSIT score (p = 0.006). (123)I-FP-CIT SPECT imaging was heterogeneous (7/15 VP normal, 3/15 abnormal suggestive of PD and 5/15 abnormal but atypical for PD)., Conclusions: The use of cardiac (123)I-MIBG SPECT and to a lesser extent UPSIT could assist the differential diagnosis between VP and PD in subjects in which the diagnosis remains uncertain despite (123)I-FP-CIT SPECT imaging., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Neuropsychological (mostly posterior-cortical) deficits, quantitative magnetic resonance imaging (MRI) atrophy patterns, and low cerebrospinal fluid (CSF) levels of amyloid-β have been separately related to worsening cognition in Parkinson's disease (PD). However, these biomarkers have not been longitudinally assessed in combination as PD-dementia predictors. In this prospective longitudinal study, 27 non-demented PD patients underwent CSF, neuropsychological and 3-T brain-MRI studies at baseline and were re-assessed 18 months later in terms of progression to dementia (primary outcome) and longitudinal neuropsychological and cortical thickness changes (secondary outcomes). At follow-up 11 patients (41%) had progressed to dementia. Lower CSF amyloid-β, worse verbal learning, semantic fluency and visuoperceptual scores, and thinner superior-frontal/anterior cingulate and precentral regions were significant baseline dementia predictors in binary logistic regressions as quantitative and/or dichotomised traits. All participants without baseline biomarker abnormalities remained non-demented whereas all with abnormalities in each biomarker type progressed to dementia, with intermediate risk for those showing abnormalities in a single to two biomarker types (p = 0.006). Both the dementia-outcome and low baseline CSF amyloid-β were prospectively associated with limbic and posterior-cortical neuropsychological decline and frontal, limbic and posterior-cortical thinning from baseline to follow-up. These findings suggest that the combination of CSF amyloid-β, neuropsychological and cortical thickness biomarkers might provide a basis for dementia-risk stratification and progression monitoring in PD., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Regional brain grey matter volume (GMV) reductions and abnormal cerebrospinal fluid (CSF) levels of τ and Aβ, extensively studied as biomarkers of Alzheimer's disease (AD), have also been reported in Parkinson's disease (PD) and related dementia (PDD). However, the relationship between these CSF and MRI biomarkers in PD and PDD remains unexplored. We studied these associations in 33 PD patients (18 with no dementia [PDND]; 15 fulfilling PDD criteria) and 12 neurologically unimpaired controls, with neuropsychological assessment, CSF ELISA studies, and voxel-based morphometry (VBM) analysis of high-field brain MRI. Neuropsychological assessment showed a gradation in cognitive performance from controls to PDND (significantly worse on visuospatial performance) and then to PDD (more impaired on memory, naming, fluency and visuospatial functions). No CSF-VBM correlations were found in controls or PDND patients. In contrast, in the analysis of both the PDD subgroup and the entire PD (PDND + PDD) sample, we found significant negative CSF-GMV correlations for τ and phospho-τ and significant positive CSF-GMV correlations for Aβ in mostly frontal and temporal structures. The correlations in the entire PD sample fitted with a linear model and were thus unlikely to have been driven solely by the PDD subgroup. Additionally, an association between both the CSF markers and the CSF-associated GMV reductions with several neuropsychological functions was found. We interpret that CSF markers of AD pathology are associated with VBM-measures of brain atrophy in PD-related dementia and within the PD cognitive continuum, and deserve further attention as putative biomarkers of cognitive impairment and dementia in PD., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

There is growing evidence that a variety of symptoms can precede the classical motor features of Parkinson's disease (PD). The period when these symptoms arise can be referred to as the premotor phase of the disease. Well-documented premotor symptoms in PD include constipation, loss of smell, sleep disturbances such as REM sleep behavior disorder (RBD), and mood disturbances like depression. Diagnostic and therapeutic implications linked to improved identification of these premotor features are discussed.