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Background and purpose: Orthostatic hypotension is frequent with aging with a prevalence of 20%–30% in people aged 65 or older and is considered to increase the risk for coronary events, strokes and dementia. Our objective was to characterize the association of orthostatic hypotension and cognitive function longitudinally over 6 years in a large cohort of the elderly aged over 50 years. Methods: In all, 495 participants were assessed longitudinally with the Schellong test and comprehensive cognitive testing using the extended CERAD neuropsychological test battery at baseline and after 6 years. In a subgroup of 92 participants, cerebral magnetic resonance imaging was evaluated for white matter changes using a modified version of the Fazekas score. Results: The prevalence of orthostatic hypotension increases with aging reaching up to 30% in participants aged >70 years. Participants with orthostatic hypotension presented with a higher vascular burden index (1.03 vs. 0.69, P ≤ 0.001), tended to have a higher prevalence of cerebral white matter hyperintensities (91.7% vs. 68.8%, P = 0.091) and showed a faster deterioration in executive and memory function (Trail Making Test B 95 vs. 87 s, P ≤ 0.001; word list learning sum −0.53 vs. 0.38, P = 0.002) compared to participants without orthostatic hypotension. Conclusion: Orthostatic hypotension seems to be associated with cognitive decline longitudinally. [ABSTRACT FROM AUTHOR]

Background: Multiple sclerosis (MS) shares clinical/radiological features with several monogenic diseases that can mimic MS., Objective: We aimed to determine if exome sequencing can identify monogenic diseases in patients diagnosed with MS according to the McDonald criteria thus uncovering them as being misdiagnosed., Methods: We performed whole exome sequencing in a cohort of 278 patients with MS, clinically or radiologically isolated syndrome without cerebrospinal fluid-specific oligoclonal bands (CSF-OCBs) (n = 228), a positive family history of MS (n = 44), or both (n = 6), thereby focusing on individuals potentially more likely to have underlying monogenic conditions mimicking MS. We prioritized 495 genes associated with monogenic diseases sharing features with MS., Results: A disease-causing variant in NOTCH3 was identified in one patient without CSF-OCBs, no spinal lesions, with non-response to immunotherapy, and a family history of dementia, thereby converting the diagnosis to cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Moreover, 18 patients (6.5% of total) carried variants of unclear significance., Conclusion: Monogenic diseases being misdiagnosed as MS seem rare in patients diagnosed with MS according to the McDonald criteria, even in CSF-OCB negative cases. The detected pathogenic NOTCH3 variant emphasizes CADASIL as a rare differential diagnosis and highlights the relevance of genetic testing in selected MS cases with atypical presentations., (© The Author(s), 2024.)

Introduction: Amyotrophic lateral sclerosis (ALS) is an inevitably fatal condition that leads to a progressive loss of physical functioning, which results in a high psychosocial burden and organizational challenges related to medical care. Multidimensional and multiprofessional care is advised to meet the complex needs of patients and their families. Many healthcare systems, including Germany, may not be able to meet these needs because non-medical services such as psychological support or social counselling are not regularly included in the care of patients with ALS (pwALS). Specialised neuropalliative care is not routinely implemented nor widely available. Caregivers of pwALS are also highly burdened, but there is still a lack of support services for them., Methods: This project aims to assess the perceptions and satisfaction with ALS care in Germany in pwALS and their caregivers. This will be achieved by means of a cross-sectional, multicentre survey. The examination will assess, to which extend the patients' needs in the six domains of physical, psychological, social, spiritual, practical and informational are being met by current care structures. This assessment will be linked to mental well-being, subjective quality of life, attitudes toward life-sustaining measures and physician-assisted suicide, and caregiver burden. The study aims to recruit 500 participants from nationwide ALS centres in order to draw comprehensive conclusions for Germany. A total of 29 centres, mostly acquired via the clinical and scientific German Network for Motor Neuron Diseases (MND-NET), will take part in the project, 25 of which have already started recruitment., Perspective: It is intended to provide data-based starting points on how current practice of care in Germany is perceived pwALS and their caregivers and how it can be improved according to their needs. Planning and initiation of the study has been completed., Trial Registration: The study is registered at ClinicalTrails.gov; NCT06418646., (© 2024. The Author(s).)

The worldwide prevalence of Parkinson's disease (PD) has been constantly increasing in the last decades. With rising life expectancy, a longer disease duration in PD patients is observed, further increasing the need and socioeconomic importance of adequate PD treatment. Today, PD is exclusively treated symptomatically, mainly by dopaminergic stimulation, while efforts to modify disease progression could not yet be translated to the clinics. New formulations of approved drugs and treatment options of motor fluctuations in advanced stages accompanied by telehealth monitoring have improved PD patients care. In addition, continuous improvement in the understanding of PD disease mechanisms resulted in the identification of new pharmacological targets. Applying novel trial designs, targeting of pre-symptomatic disease stages, and the acknowledgment of PD heterogeneity raise hopes to overcome past failures in the development of drugs for disease modification. In this review, we address these recent developments and venture a glimpse into the future of PD therapy in the years to come., (© 2023. The Author(s).)

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by loss of upper and lower motor neurons, resulting in progressive weakness of all voluntary muscles and eventual respiratory failure. Non-motor symptoms, such as cognitive and behavioral changes, frequently occur over the course of the disease. Considering its poor prognosis with a median survival time of 2 to 4 years and limited causal treatment options, an early diagnosis of ALS plays an essential role. In the past, diagnosis has primarily been determined by clinical findings supported by electrophysiological and laboratory measurements. To increase diagnostic accuracy, reduce diagnostic delay, optimize stratification in clinical trials and provide quantitative monitoring of disease progression and treatment responsivity, research on disease-specific and feasible fluid biomarkers, such as neurofilaments, has been intensely pursued. Advances in imaging techniques have additionally yielded diagnostic benefits. Growing perception and greater availability of genetic testing facilitate early identification of pathogenic ALS-related gene mutations, predictive testing and access to novel therapeutic agents in clinical trials addressing disease-modified therapies before the advent of the first clinical symptoms. Lately, personalized survival prediction models have been proposed to offer a more detailed disclosure of the prognosis for the patient. In this review, the established procedures and future directions in the diagnostics of ALS are summarized to serve as a practical guideline and to improve the diagnostic pathway of this burdensome disease.

In patients with spinal muscular atrophy (SMA) headache after intrathecal administration of nusinersen is usually attributed to post-lumbar puncture syndrome. However, lumbar puncture opening pressure (LOP) has also been reported to be increased in children with SMA, both before and after treatment with nusinersen, although symptoms associated with increased LOP were not observed. We report to our knowledge the first case of symptomatic intracranial hypertension in an adult SMA patient. This 21-year-old man suffered from headache and vomiting followed by visual disturbances after the 12th injection of nusinersen. Bilateral papilledema was recognized ophthalmologically. MRI of the head showed signs of intracranial hypertension and additionally arachnoid cysts but not hydrocephalus. Symptoms resolved after 8 weeks of treatment with repeated lumbar punctures and acetazolamide. This case raises the possibility of intracranial hypertension as a complication of nusinersen therapy although arachnoid cysts represent another risk factor for intracranial hypertension. We recommend that patients suffering from headache after nusinersen injections should not only be questioned and examined for symptoms suggestive of post-lumbar puncture syndrome, but also intracranial hypertension.

Background: With pathway-specific trials in PD associated with variants in the glucocerebrosidase gene (PD GBA ) under way, we need markers that confirm the impact of genetic variants in patient-derived biofluids in order to allow patient stratification merely based on genetics and that might serve as biochemical read-out for target engagement., Objective: To explore GBA-pathway-specific biomarker profiles cross-sectionally (TUEPAC-MIGAP, PPMI) and longitudinally (PPMI)., Methods: We measured enzyme activity of the lysosomal glucocerebrosidase, CSF levels of glucosylceramides (upstream substrate of glucocerebrosidase), CSF levels of ceramides (downstream product of glucocerebrosidase), lactosylceramides, sphingosines, sphingomyelin (by-products) and CSF levels of total α-synuclein in PD GBA patients compared to PD GBA_wildtype patients., Results: Cross-sectionally in both cohorts and longitudinally in PPMI: (1) glucocerebrosidase activity was significantly lower in PD GBA compared to PD GBA_wildtype . (2) CSF levels of upstream substrates (glucosylceramides species) were higher in PD GBA compared to PD GBA_wildtype . (3) CSF levels of total α-synuclein were lower in PD GBA compared to PD GBA_wildtype . All of these findings were most pronounced in PD GBA with severe mutations (PD GBA_severe ). Cross-sectionally in TUEPAC-MIGAP and longitudinally in PPMI, CSF levels of downstream-products (ceramides) were higher in PD GBA_severe . Cross-sectionally in TUEPAC-MIGAP by-products sphinganine and sphingosine-1-phosphate and longitudinally in PPMI species of by-products lactosylceramides and sphingomyelin were higher in PD GBA_severe ., Interpretation: These findings confirm that GBA mutations have a relevant functional impact on biomarker profiles in patients. Bridging the gap between genetics and biochemical profiles now allows patient stratification for clinical trials merely based on mutation status. Importantly, all findings were most prominent in PD GBA with severe variants. © 2021 International Parkinson and Movement Disorder Society., (© 2021 International Parkinson and Movement Disorder Society.)

Background: Parkinson´s disease (PD) has a large phenotypic variability, which may, at least partly, be genetically driven including alterations of gene products. Candidates might not only be proteins associated with disease risk but also pathways that play a role in aging., Objective: To evaluate phenotype-modifying effects of genetic variants in Klotho, a longevity gene., Methods: We analyzed two longitudinal cohorts: one local cohort comprising 459 PD patients who underwent genotyping for the KL-VS haplotype in Klotho including a subgroup of 125 PD patients and 50 healthy controls who underwent biochemical cerebrospinal fluid (CSF) analyses of Klotho and fibroblast growth factor 23 as well as vitamin D metabolites. The second cohort comprised 297 patients from the Parkinson's Progression Markers Initiative (PPMI) for validation of genetic-clinical findings., Results: PD patients carrying the KL-VS haplotype demonstrated a shorter interval between PD onset and onset of cognitive impairment (both cohorts) and higher Unified Parkinson´s Disease Rating Scale part III (UPDRS III) scores (PPMI). CSF protein levels of Klotho and fibroblast growth factor 23 were lower in PD patients irrespective of gender compared to controls. Moreover, low CSF levels of Klotho were associated with higher scores in the UPDRS III and Hoehn and Yahr Scale., Conclusions: Our results indicate that genetic variants in Klotho together with its corresponding CSF protein profiles are associated with aspects of disease severity in PD. These findings suggest that pathways associated with aging might be targets for future biomarker research in PD., (© 2021 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Background: Neurofilament light protein is an unspecific biofluid marker that reflects the extent of neuronal/axonal damage and thereby offers the chance monitor disease severity and progression. The objective of this study was to investigate cerebrospinal fluid (CSF) levels of neurofilament light protein in Parkinson's disease (PD) patients with clinical trajectories of motor and cognitive function longitudinally., Methods: CSF neurofilament light protein levels were assessed in 371 PD sporadic , 126 genetic PD patients (91 PD GBA , 8 PD LRRK2 , 21 PD PRKN/PINK1/DJ1&#95;heterozygous , 6 PD PRKN/PINK1/DJ1&#95;homozygous ), and 71 healthy controls. Participants were followed up longitudinally for up to 8 years., Results: At baseline, mean CSF neurofilament light protein levels were highest in PD patients with cognitive impairment (Montreal Cognitive Assessment score ≤ 25; 1207 pg/mL) but also higher in PD patients with normal cognitive function (757 pg/mL) compared with healthy controls (593 pg/mL; P ≤ 0.001). In healthy controls and in PD patients older age was associated with higher CSF levels of neurofilament light protein (P ≤ 0.001). In PD patients, male gender, older age at onset, longer disease duration, higher Hoehn and Yahr stages, higher UPDRS-III scores, and lower Montreal Cognitive Assessment scores were associated with higher CSF levels of neurofilament light protein (P < 0.01). In patients who developed cognitive impairment during study, CSF neurofilament light protein levels prior to conversion to cognitive impairment were not significantly different compared with CSF neurofilament light protein levels of patients who remained cognitively normal., Conclusions: Increased CSF levels of neurofilament light protein are associated with cognitive decline and motor impairment in PD. However, this increase seems not a very early event and does not mark the conversion to cognitive impairment beforehand. Therefore, the predictive value needs to be discussed critically. © 2020 International Parkinson and Movement Disorder Society., (© 2020 International Parkinson and Movement Disorder Society.)

Background: Patients with dementia with Lewy bodies reveal a variable pathology including alpha-synuclein, amyloid-beta, and Tau. Mutations in GBA1 are specifically associated with synucleinopathies. PD patients with GBA1 mutations show reduced CSF levels of total alpha-synuclein., Objective: Whether GBA1 mutations are associated with a CSF alpha-synuclein profile in dementia with Lewy bodies., Methods: Screening of the GBA1 gene and single-nucleotide polymorphisms in SNCA rs356220, APOE rs429358, and MAPT rs1052587 as well as CSF levels of total alpha-synuclein, amyloid-beta 1-42 , total-Tau, phospho-Tau, and neurofilament light chain were assessed in 100 dementia with Lewy bodies and 39 controls cross-sectionally., Results: Severity of GBA1 mutations was associated with a younger age at onset and higher prevalence of rapid eye movement sleep behavior disorder. CSF levels of total alpha-synuclein were lowest in DLB GBA&#95;pathogenic compared to DLB GBA&#95;mild and DLB GBA&#95;wildtype ., Conclusion: Similar to PD, pathogenic GBA1 mutations seem to be associated with CSF alpha-synuclein profiles in dementia with Lewy bodies. That might be useful for patient stratification for specific alpha-synuclein-lowering compounds. © 2019 International Parkinson and Movement Disorder Society., (© 2019 International Parkinson and Movement Disorder Society.)

Objective: To evaluate the evolution of cognitive impairment in relation to cerebrospinal fluid (CSF) profiles of amyloid-β (Aβ), total-Tau and phosphorylated-Tau in Parkinson's disease (PD)., Methods: Prospective, longitudinal, observational study up to 10 years with follow-up every 2  years. We assessed CSF profiles in 415 patients with sporadic PD (median age 66; 63% men) and 142 healthy controls (median age 62; 43% men)., Results: Patients with PD with low CSF Aβ 1-42 levels at baseline were more often cognitively impaired than patients with intermediate and high Aβ 1-42 levels. Sixty-seven per cent of the patients with low Aβ 1-42 levels at baseline and normal cognition developed cognitive impairment during follow-up, compared with 41% and 37% of patients having intermediate and high CSF Aβ 1-42 levels. Kaplan-Meier survival curves and Cox regression revealed that patients with low CSF Aβ 1-42 levels at baseline developed cognitive impairment more frequently and earlier during follow-up., Conclusion: We conclude that in patients with sporadic PD, low levels of Aβ 1-42 are associated with a higher risk of developing cognitive impairment earlier in the disease process at least in a subgroup of patients., Competing Interests: Competing interests: DB has served on scientific advisory boards for Novartis, UCB/ SCHWARZ PHARMA, Lundbeck, Prexton Therapeutics and GE Healthcare; and has received research support from Michael J Fox Foundation, Janssen Pharmaceutica N.V. German Parkinson’s Disease Association (dPV), BMWi, BMBF, Parkinson Fonds Deutschland gGmbH, UCB Pharma GmbH, TEVA Pharma GmbH, EU, Novartis Pharma GmbH and Lundbeck. KB has received research support from the University of Tuebingen (Clinician Scientist), the German Society of Parkinson’s Disease (dpv), the Michael J Fox Foundation (MJFF) and BMBF (the Federal Ministry of Education and Research FKZ 01EK1606D), travel grants from the Movement Disorders Society and speaker honoraria from Lundbeck, Zambon, UCB and Abbvie. TG serves on the editorial boards of Parkinsonism & Related Disorders, Movement Disorders and Journal of Neurology; holds a patent re: KASPP (LRRK2) Gene, its Production and Use for the Detection and Treatment of Neurodegenerative Diseases; serves as a consultant for Cephalon, Inc. and Merck Serono; serves on speaker’s bureaus of Novartis, Merck Serono, SCHWARZ PHARMA, Boehringer Ingelheim and Valeant Pharmaceuticals International; and receives research support from Novartis, the European Union, BMBF (the Federal Ministry of Education and Research) and Helmholtz Association. OH has consultant relationships with GE Healthcare, Hoffmann-La Roche and Eli Lilly and received funding from the European Research Council, Swedish Research Council and the Michael J Fox Foundation. GM is supported by an Edmond J Safra Fellowship in Movement Disorders from the Michael J Fox Foundation. WM received and receives funding from the European Union, the Michael J Fox Foundation, Robert Bosch Foundation, Neuroalliance, Lundbeck and Janssen, and holds part of a patent for the assessment of dyskinesias (German patent office, 102015220741.2). He received speaker honoraria from GlaxoSmithKline, Abbvie, UCB, Licher MT and Rölke Pharma, and was invited to Advisory Boards of Market Access & Pricing Strategy GmbH and Abbvie. HZ is one of the founders of Brain Biomarker Solutions in Gothenburg AB, a GU Venture-based platform company at the University of Gothenburg. SL, IW, BR, MZ, FB, ES, CD and CS have nothing to disclose., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

REM sleep behavior disorder (RBD) represents a major and relatively specific prodromal marker for synucleinopathies such as Parkinson's disease (PD), dementia with Lewy bodies, and multisystem atrophy. Because PD patients primarily suffer from executive dysfunction, we hypothesized that individuals with RBD show an impairment in the nonamnestic executive domain rather than in amnestic domains. To address this question, we investigated a cohort of 1145 healthy elderly (183 with RBD) cross-sectionally and a subgroup of 544 of them longitudinally (144 with RBD) over 6 years. Assessments included the RBD screening questionnaire, the extended Consortium to Establish a Registry for Alzheimer's Disease test battery, and genetic testing for the risk variant rs356219 in the alpha-synuclein gene. In the cross-sectional analysis, the RBD subgroup showed worse performance in the Trail Making Test (TMT) part B and the delta-TMT&#95;B-A when compared to non-RBD subjects. Longitudinal observation revealed a deterioration of TMT-B and delta-TMT&#95;B-A in RBD subjects, a phenomenon that was not observed in the group of non-RBD subjects. These data argue for an early and progressive deterioration of executive dysfunction associated with RBD. Of the total cohort, 18 developed Parkinsonism including 16 with sporadic PD after a mean follow-up of 4.6 years. Of the sporadic PD cases, 4.4% were from the probable RBD group and 0.8% of the non-RBD group. The potential of this dynamic for the detection of prodromal synucleinopathies seems relevant, but has to be determined in studies including converters., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Introduction: The early diagnosis of mild cognitive impairment (PD-MCI) in Parkinson's disease (PD) is essential as it increases the future risk for PD dementia (PDD). Recently, a novel weighting algorithm for the Montreal Cognitive Assessment (MoCA) subtests has been reported, to best discriminate between those with and without cognitive impairment in PD. The aim of our study was to validate this scoring algorithm in a large sample of non-demented PD patients, hypothesizing that the weighted MoCA would have a higher diagnostic accuracy for PD-MCI than the original MoCA., Methods: In 202 non-demented PD patients, we evaluated cognitive status, clinical and demographic data, as well as the MoCA with a weighted and unweighted score. Receiver operating characteristic (ROC) curve analysis was used to evaluate discriminative ability of the MoCA. Group comparisons and ROC analysis were performed for PD-MCI classifications with a cut-off ≤ 1, 1.5, and 2 standard deviation (SD) below appropriate norms., Results: PD-MCI patients scored lower on the weighted than the original MoCA version (p < 0.001) compared to PD patients with normal cognitive function. Areas under the curve only differed significantly for the 2 SD cut-off, leading to an increased sensitivity of the weighted MoCA score (72.9% vs. 70.5%) and specificity compared to the original version (79.0% vs. 65.4%)., Conclusions: Our results indicate better discriminant power for the weighted MoCA compared to the original for more advanced stages of PD-MCI (2 SD cut-off). Future studies are needed to evaluate the predictive value of the weighted MoCA for PDD.

Objectives: In order to evaluate the influence of the genetic load of 49 genetic variants known to be associated with PD on the age at onset as well as on clinical outcome parameters., Background: PD patients show a large variability in phenotype and progression reflecting interindividual heterogeneity. This might be influenced by a diverse genetic architecture., Methods: Six hundred seventeen PD patients were included in this study and stratified by their "genetic load," which is based on the weighted odds ratios of 49 genetic variants known to be associated with PD from genome-wide association studies. Clinical parameters (H & Y, UPDRS-III, MMSE, and Beck's Depression Inventory) were evaluated cross-sectionally and in a subgroup longitudinally over 8 years., Results: PD patients with the highest genetic load were younger at disease onset, whereas severity of clinical parameters were similar compared to patients with the lowest genetic load. These findings could be confirmed regarding progression to clinical endpoints in the longitudinal analysis., Conclusion: A high genetic load is associated with a younger age at onset, which, in turn, might possibly promote more effective compensatory mechanisms resulting in a similar rate of disease progression. © 2018 International Parkinson and Movement Disorder Society., (© 2018 International Parkinson and Movement Disorder Society.)

The search for treatments for neurodegenerative diseases is a major concern in light of today's aging population and an increasing burden on individuals, families, and society. Although great advances have been made in the last decades to understand the underlying genetic and biological cause of these diseases, only some symptomatic treatments are available. Metformin has long since been used to treat Type 2 Diabetes and has been shown to be beneficial in several other conditions. Metformin is well-tested in vitro and in vivo and an approved compound that targets diverse pathways including mitochondrial energy production and insulin signaling. There is growing evidence for the benefits of metformin to counteract age-related diseases such as cancer, cardiovascular disease, and neurodegenerative diseases. We will discuss evidence showing that certain neurodegenerative diseases and diabetes are explicitly linked and that metformin along with other diabetes drugs can reduce neurological symptoms in some patients and reduce disease phenotypes in animal and cell models. An interesting therapeutic factor might be how metformin is able to balance survival and death signaling in cells through pathways that are commonly associated with neurodegenerative diseases. In healthy neurons, these overarching signals keep energy metabolism, oxidative stress, and proteostasis in check, avoiding the dysfunction and neuronal death that defines neurodegenerative disease. We will discuss the biological mechanisms involved and the relevance of neuronal vulnerability and potential difficulties for future trials and development of therapies.

This report deals with a 15-year-old girl suffering from the verrucous type of Thomson's syndrome. Initial poikilodermatous skin changes developed on both cheeks at the age of 3 months. Subsequently, rapid generalization of typical skin findings was observed. The clinical heterogenity of this syndrome is discussed with reference to the existing literature and the present case. Up to now, very few comparable cases of associated neurological symptoms have been described.