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Background Molecular pathways associated with α-synuclein proteostasis have been detected in genetic studies and in cell models and include autophagy, ubiquitin-proteasome system, mitochondrial homeostasis, and synaptic plasticity. However, we lack biomarkers that are representative for these pathways in human biofluids. Objective The objective of this study was to evaluate CSF protein profiles of pathways related to α-synuclein proteostasis. Methods We assessed CSF protein profiles associated with neurotransmitter secretion, synapse plasticity, and autophagy in 2 monocentric cohorts with α-synucleinopathy (385 PD patients and 67 DLB patients). We included 80 PD patients and 17 DLB patients with variants in the glucocerebrosidase gene to serve as proxy for accelerated α-synuclein pathology with pronounced clinical trajectories. Results (1) Proteins associated with neurotransmitter secretion, synaptic plasticity, and endolysosomal autophagy were lower in PD and DLB patients compared with healthy controls. (2) These patterns were more pronounced in DLB than in PD patients, accentuated by GBA variant status in both entities. (3) CSF levels of these proteins were positively associated with CSF levels of total α-synuclein, with lower levels of proteostasis proteins related to lower levels of total α-synuclein. (4) These findings could be confirmed longitudinally. PD patients with low CSF profiles of proteostasis proteins showed lower CSF levels of α-synuclein longitudinally compared with PD patients with a normal proteostasis profile. Conclusion CSF proteins associated with neurotransmitter secretion, synaptic plasticity, and endolysosomal autophagy might serve as biomarkers related to α-synuclein proteostasis in PD and DLB. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Background With pathway-specific trials in PD associated with variants in the glucocerebrosidase gene (PDGBA ) 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 PDGBA patients compared to PDGBA_wildtype patients. Results Cross-sectionally in both cohorts and longitudinally in PPMI: (1) glucocerebrosidase activity was significantly lower in PDGBA compared to PDGBA_wildtype . (2) CSF levels of upstream substrates (glucosylceramides species) were higher in PDGBA compared to PDGBA_wildtype . (3) CSF levels of total α-synuclein were lower in PDGBA compared to PDGBA_wildtype . All of these findings were most pronounced in PDGBA with severe mutations (PDGBA_severe ). Cross-sectionally in TUEPAC-MIGAP and longitudinally in PPMI, CSF levels of downstream-products (ceramides) were higher in PDGBA_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 PDGBA_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 PDGBA with severe variants. © 2021 International Parkinson and Movement Disorder Society.

Background Sleep disturbances are common in Parkinson’s Disease (PD), with nocturnal akinesia being one of the most burdensome. Levodopa is frequently used in clinical routine to improve nocturnal akinesia, although evidence is not well proven. Methods We assessed associations of Levodopa intake with quality of sleep and perception of nocturnal akinesia in three PD cohorts, using the Parkinson’s Disease Sleep Scale (PDSS-2) in two cohorts and a question on nocturnal immobility in one cohort. In one cohort also objective assessment of mobility during sleep was performed, using mobile health technology. Results In an independent analysis of all three cohorts (in total n = 1124 PD patients), patients taking Levodopa CR reported a significantly higher burden by nocturnal akinesia than patients without Levodopa. Higher Levodopa intake and MDS-UPDRS part IV scores (indicating motor fluctuations) predicted worse PDSS-2 and higher subjective nocturnal immobility scores, while disease duration and severity were not predictive. Levodopa intake was not associated with objectively changed mobility during sleep. Conclusion Our results showed an association of higher Levodopa intake with perception of worse quality of sleep and nocturnal immobility in PD, indicating that Levodopa alone might not be suitable to improve subjective feeling of nocturnal akinesia in PD. In contrast, Levodopa intake was not relevantly associated with objectively measured mobility during sleep. PD patients with motor fluctuations may be particularly affected by subjective perception of nocturnal mobility. This study should motivate further pathophysiological and clinical investigations on the cause of perception of immobility during sleep in PD.

Background and objectives With disease-modifying treatment strategies on the horizon, stratification of individual patients at the earliest stages of Parkinson's disease (PD) is key-ideally already at clinical disease onset. Blood levels of neurofilament light chain (NfL) provide an easily accessible fluid biomarker that might allow capturing the conversion from prodromal to manifest PD. Methods We assessed longitudinal serum NfL levels in subjects converting from prodromal to manifest sporadic PD (converters), at-risk subjects, and matched controls (72 participants with ≈4 visits), using single-molecule array (Simoa) technique. Results While NfL levels were not increased at the prodromal stage, subjects converting to the manifest motor stage showed a significant intraindividual acceleration of the age-dependent increase of NfL levels. Conclusions The temporal dynamics of intraindividual NfL blood levels might mark the conversion to clinically manifest PD, providing a potential stratification biomarker for individual disease onset in the advent of precision medicine for PD. © 2020 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

BackgroundCurrently available treatments for Parkinson’s disease (PD) do not slow clinical progression nor target alpha-synuclein, the main pathology associated with the disease.ObjectiveThe study objective was to evaluate the efficacy and safety of prasinezumab, a humanized monoclonal antibody that binds aggregated alpha-synuclein, in individuals with early PD. The study rationale, design, and baseline characteristics of enrolled subjects are presented here.MethodsThe PASADENA study is a multicenter, randomized, double-blind, placebo-controlled treatment study. Individuals with early PD, recruited across the US and Europe, received monthly intravenous doses of prasinezumab (1500 mg or 4500 mg) or placebo for a 52-week period (Part 1), followed by a 52-week extension (Part 2) in which all participants received active treatment. Key inclusion criteria were: aged 40–80 years; Hoehn & Yahr (H&Y) Stage I or II; time from diagnosis ≤2 years; having bradykinesia plus one other cardinal sign of PD (e.g. resting tremor, rigidity); DAT-SPECT imaging consistent with PD; and either treatment naïve or on a stable monoamine oxidase B (MAO-B) inhibitor dose. Study design assumptions for sample size and study duration were built using a patient cohort from the Parkinson’s Progression Marker Initiative (PPMI). In this report, baseline characteristics are compared between the treatment-naïve and MAO-B inhibitor-treated PASADENA cohorts and between the PASADENA and PPMI populations.ResultsOf the 443 patients screened, 316 were enrolled into the PASADENA study between June 2017 and November 2018, with an average age of 59.9 years and 67.4% being male. The mean time from diagnosis at baseline was 10.11 months, with 75.3% in H&Y Stage II. Baseline motor and non-motor symptoms (assessed using Movement Disorder Society – Unified Parkinson’s Disease Rating Scale [MDS-UPDRS]) were similar in severity between the MAO-B inhibitor-treated and treatment-naïve PASADENA cohorts (MDS-UPDRS Total score [standard deviation (SD)]; 30.21 [11.96], 32.10 [13.20], respectively). The overall PASADENA population (63.6% treatment naïve and 36.4% on MAO-B inhibitor) also showed a similar severity in MDS-UPDRS scores (e.g. MDS-UPDRS Total score [SD]; 31.41 [12.78], 32.63 [13.04], respectively) to the PPMI cohort (all treatment naïve).ConclusionsThe PASADENA study population is suitable to investigate the potential of prasinezumab to slow disease progression in individuals with early PD.Trial RegistrationNCT03100149

ObjectiveTo examine whether hippocampal volume loss is primarily associated with cognitive status or pathologic β-amyloid 1–42 (Aβ42) levels, this study compared hippocampal subfield volumes between patients with Parkinson disease (PD) with mild cognitive impairment (PD-MCI) and without cognitive impairment (PD-CN) and between patients with low and high Aβ42 levels, in addition exploring the relationship among hippocampal subfield volumes, CSF biomarkers (Aβ42, phosphorylated and total tau), neuropsychological tests, and activities of daily living.MethodsForty-five patients with PD without dementia underwent CSF analyses and MRI as well as comprehensive motor and neuropsychological examinations. Hippocampal segmentation was conducted using FreeSurfer image analysis suite 6.0. Regression models were used to compare hippocampal subfield volumes between groups, and partial correlations defined the association between variables while controlling for intracranial volume (ICV).ResultsLinear regressions revealed cognitive group as a statistically significant predictor of both the hippocampal–amygdaloid transition area (HATA; β = −0.23, 95% CI −0.44 to −0.02) and the cornu ammonis 1 region (CA1; β = −0.28, 95% confidence interval [CI] −0.56 to −0.02), independent of disease duration and ICV, with patients with PD-MCI showing significantly smaller volumes than PD-CN. In contrast, no subfields were predicted by Aβ42 levels. Smaller hippocampal volumes were associated with worse performance on memory, language, spatial working memory, and executive functioning tests. The subiculum was negatively correlated with total tau levels (r = −0.37, 95% CI −0.60 to −0.09).ConclusionCognitive status, but not CSF Aβ42, predicted hippocampal volumes, specifically the CA1 and HATA. Hippocampal subfields were associated with various cognitive domains, as well as with tau pathology.

The core criterion for Parkinson's disease dementia (PDD) is the impairment in activities of daily living (ADL) function primarily caused by cognitive, not motor symptoms. There is evidence to assume that mild ADL impairments in mild cognitive impairment (PD-MCI) characterize those patients at high risk for dementia. Data of 216 Parkinson's disease (PD) patients assessed with comprehensive motor and neuropsychological assessments were analysed. Based on linear regression models, subscores of the Functional Activities Questionnaire (FAQ) primarily reflecting patients' global cognitive status (FAQ(C)) or PD-related motor severity (FAQ(M)) were developed. A quotient (FAQ(Q)) of both scores was calculated, with values >1 indicating more cognitive- compared to motor-driven ADL impairment. Both FAQ(C) and FAQ(M) scores were higher in PD-MCI than cognitively normal (PD-CN) patients, indicating more severe cognitive- and motor-driven ADL impairments in this group. One third (31.6%) of the PD-MCI group had a FAQ(Q) score >1, which was significantly different from patients with PD-CN (p = .02). PD-MCI patients with an FAQ(Q) score >1 were more impaired on tests assessing attention (p = .019) and language (p = .033) compared to PD-MCI patients with lower FAQ(Q) values. The differentiation between cognitive- and motor-driven ADL is important, as the loss of functional capacity is the defining factor for a diagnosis of PDD. We were able to differentiate the cognitive-driven from the motor-driven ADL impairments for the FAQ. PD-MCI patients with more cognitive- compared to motor-driven ADL impairments may pose a risk group for conversion to PDD and can be targeted for early treatments.

Due to the aging population, dementias represent a growing challenge for the health systems and for the society. This overview summarizes the current state of already practice-relevant therapies and management of dementias. Non-pharmacological approaches have a greater impact than pharmacological treatment. Increasing evidence underlines that consistent management of cardiovascular risk factors has beneficial effects on the progression of at least some, possibly almost all types of dementias. The main pharmacological agents for symptomatic treatment of cognitive deficits in Alzheimer’s and Parkinson’s disease-associated dementias are cholinesterase inhibitors and memantine. In most other dementias, no specific pharmacological treatment is currently available. There is an urgent need for further research on the effective management of dementias.

Background: The research criteria for prodromal PD of the MDS propose a new approach for the assessment of the individual probability of prodromal PD. These criteria require a testing of their reliability in different prospective cohorts. Objectives: The objective was to evaluate the MDS prodromal PD criteria in 2 independent prospective studies. Methods: Prodromal PD probabilities of the Tubingen Evaluation of Risk Factors for Early Detection of Neurodegeneration cohort (TREND study, n = 650, recruited by the presence of probable rapid eye movement sleep behavior disorder, depression, and/or hyposmia or none of these at baseline and 2-, 4-, and 6-year follow-up) and the population-based Prospective Evaluation of Risk Factors for Idiopathic Parkinson's Syndrome cohort (PRIPS Tubingen subsample; n = 715, baseline and 3- and 5-year follow-up) were calculated. Baseline posttest probabilities, time to PD diagnosis, marker constellations, and longitudinal changes of prodromal PD probabilities were analyzed. Results: Incident PD cases (TREND, n = 10; PRIPS = 7) showed significantly higher likelihood ratios of risk and prodromal markers at baseline when compared with nonconverters. Only 2 of 17 incident PD cases met the criteria for probable prodromal PD (ie, posttest probability > 80%) and 5 had possible prodromal PD (ie, > 50%) 1.4 to 3.8 years before diagnosis. The criteria showed high specificity and negative predictive values (>98%), but low sensitivity (TREND, 30%; PRIPS, 14%) and positive predictive values (TREND, 19%, PRIPS, 50%). The individual risk for prodromal PD in incident PD cases showed an inverse correlation with the time to conversion (Spearman rho = .80, P = .006) and unlike in nonconverters, increased during follow-up. Conclusion: The MDS prodromal criteria provide a practical framework for the calculation of prodromal PD risk. Although specificity of the criteria is high, most patients will not meet the criteria before diagnosis unless testing is thoroughly performed with numerous and highly specific markers objectively assessed. © 2017 International Parkinson and Movement Disorder Society

Objective To characterize peripheral nerve morphology in cerebrotendinous xanthomatosis (CTX) patients using high-resolution ultrasound (HRUS) in vivo. We hypothesized that nerve enlargements might be present in CTX as a result of accumulation of abnormal lipids with deposition also in peripheral nerves. Methods Four CTX patients were examined using HRUS to assess morphological abnormalities of peripheral nerves as well as cervical nerve roots 5 and 6. Results HRUS revealed mild to moderate, hypoechogenic thickening of sensorimotor nerves (ulnar nerve in 1/4, tibial nerve in 3/4, median nerve 4/4 patients) as well as mild enlargement of pure sensory nerves (sural nerve in 2/3, superficial FN in 2/4 patients). The vagal nerve was moderately enlarged in one patient, cervical roots showed moderate enlargements of C5 in two patients, one of which also showing thickening of C6 as well as in another patient. UPSS score was slightly to moderately abnormal in all patients. The Homogeneity score was not increased suggesting regional to inhomogeneous nerve enlargement. Conclusions HRUS shows multifocal, hypoechogenic nerve thickening of peripheral nerves and nerve roots in CTX. Significance HRUS might serve as a valuable, additive and non-invasive bedside tool to assess peripheral nerve morphology in future clinical studies on CTX patients.

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.

BACKGROUND Mutations in the gene glucocerebrosidase (GBA1) are specifically associated with alpha-synucleinopathies, namely, Parkinson's disease (PD) and dementia with Lewy bodies. As disease-modifying treatment options such as alpha-synuclein lowering compounds are under way, patient stratification according to alpha-synuclein-specific enrichment strategies, possibly reflected by cerebrospinal fluid (CSF) profiles, is a much needed prerequisite. OBJECTIVE Are GBA1 mutations associated with a CSF alpha-synuclein profile in PD? METHODS Screening of the GBA1 gene and analysis of CSF levels of total alpha-synuclein were performed in 80 PDGBA , 80 PDGBA _wildtype and 39 healthy controls cross-sectionally. Subgroup analyses based on mutation severity was done for PDGBA . RESULTS Patients carrying severe GBA1 mutations showed (1) an earlier age at onset, (2) more pronounced cognitive decline and higher prevalence of rapid eye movement sleep behavior disorder, and (3) reduced CSF levels of total alpha-synuclein. CONCLUSION The effects of GBA1 mutations on CSF alpha-synuclein profiles and phenotypical characteristics seem dependent on GBA1 mutation severity. © 2019 International Parkinson and Movement Disorder Society.

The primary role of magnetic resonance imaging (MRI) in routine diagnostic work-up of motor neuron disease patients is currently still largely limited to exclusion of relevant non-degenerative pathologies. We here present an illustrative case of a 63-year-old woman with early stage Frontotemporal-Dementia-Amyotrophic-Lateral-Sclerosis (FTD-ALS) spectrum disorder showing a striking hypointense signal of the cortical band along the precentral gyrus, termed “motor band sign” (MBS). Based on this finding, we analysed the frequency of the MBS in clinical routine MRIs in a large consecutive series of ALS patients (MRIs available from 157 patients). MBS was present in 5% patients of the total series, but in 78% of patients where susceptibility-weighted images (SWI) were available. These findings suggest that the MBS is a recurrent finding in ALS, which can be identified even on clinical routine 3 T-MRI, and as part of more complex motor neuron syndromes, such as FTD-ALS. Moreover, they indicate that SWI sequences should be considered as part of the clinical routine MRI protocol in the diagnostic work-up of ALS patients.

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-beta1-42 , 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 DLBGBA_pathogenic compared to DLBGBA_mild and DLBGBA_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.

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_B-A when compared to non-RBD subjects. Longitudinal observation revealed a deterioration of TMT-B and delta-TMT_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.

ObjectiveTo demonstrate that mutations in the phosphatidylglycerol remodelling enzyme SERAC1 can cause juvenile-onset complicated hereditary spastic paraplegia (cHSP) clusters, thus adding SERAC1 to the increasing number of complex lipid cHSP genes.MethodsCombined genomic and functional validation studies (whole-exome sequencing, mRNA, cDNA and protein), biomarker investigations (3-methyl-glutaconic acid, filipin staining and phosphatidylglycerols PG34:1/PG36:1), and clinical and imaging phenotyping were performed in six affected subjects from two different branches of a large consanguineous family.Results5 of 6 affected subjects shared cHSP as a common disease phenotype. Three subjects presented with juvenile-onset oligosystemic cHSP, still able to walk several miles at age >10–20 years. This benign phenotypic cluster and disease progression is strikingly divergent to the severe infantile phenotype of all SERAC1 cases reported so far. Two family members showed a more multisystemic juvenile-onset cHSP, indicating an intermediate phenotype between the benign oligosystemic cHSP and the classic infantile SERAC1 cluster. The homozygous splice mutation led to loss of the full-length SERAC1 protein and impaired phosphatidylglycerol PG34:1/PG36:1 remodelling. These phosphatidylglycerol changes, however, were milder than in classic infantile-onset SERAC1 cases, which might partially explain the milder SERAC1 phenotype.ConclusionsOur findings add SERAC1 to the increasing list of complex lipid cHSP genes. At the same time they redefine the phenotypic spectrum of SERAC1 deficiency. It is associated not only with the severe infantile-onset ‘Methylglutaconic aciduria, Deafness, Encephalopathy, Leigh-like’ syndrome (MEGDEL syndrome), but also with oligosystemic juvenile-onset cHSP as part of the now unfolding SERAC1 deficiency spectrum.

Purpose One of the anatomical hallmarks of Alzheimer’s disease (AD) is the atrophy of the medial temporal lobe (MTL), yet cost-effective and broadly available methodological alternatives to the current imaging tools for screening of this brain area are not currently available. Materials and Methods Using structural transcranial ultrasound (TCS), we attempted to visualize and measure the MTL, and compared the results of 32 AD patients and 84 healthy controls (HC). The MTL and the surrounding space were defined in the coronal plane on TCS. A ratio of the height of the MTL/height of the choroidal fissure (M/F) was calculated in order to obtain a regional proportion. Results An insufficient temporal bone window was identified in 22 % of the AD patients and 12 % of the HCs. The results showed that the ratio of M/F was significantly smaller in the AD group on both sides (p = 0.004 right, p = 0.007 left side). Furthermore, the M/F ratio made it possible to discriminate AD patients from HCs with a sensitivity of 83 % (right)/73 % (left) and a specificity of 76 % (right)/72 % (left) which is basically comparable to results published for magnetic resonance imaging. The measurements showed substantial intra/interrater reliability (ICC:0.79/0.69). Conclusion These results suggest that utilization of structural TCS may possibly constitute a cheap and easy-to-use supplement to other techniques for the diagnosis of AD. It may be especially useful as a screening tool in the large population of individuals with cognitive decline. Further studies are needed to validate this novel method.

A 26-year-old Turkish patient presented with progressive spastic gait since age 20 years and premature alopecia. Cerebral and spinal MRI revealed diffuse supra- and infratentorial leukoencephalopathy with recurrent subclinical subcortical infarcts and multiple disk herniations with cervical myelopathy (figure). Targeted panel-sequencing revealed a novel homozygous splice site mutation (c.1005+1G>T; p.?) in HTRA1 , which is known to cause CARASIL (cerebral autosomal-recessive arteriopathy with subcortical infarcts and leukoencephalopathy),1 mostly described in Asians so far.

Background/objective Plasma levels of amyloid-beta (Aβ) 1-40 peptide have been proposed to be associated with cardiovascular mortality in patients with coronary artery disease (CAD). Therefore, we aimed to investigate the association of plasma Aβ levels with CAD, cardiovascular risk factors (CVRF), and APOE genotype in non-demented elderly individuals. Methods Plasma Aβ1 - 40 and Aβ1 - 42 levels of 526 individuals (mean age of 63.0±7.3 years) were quantified with the INNO-BIA plasma Aβ forms assay based on multiplextrademark technique. APOE genotype was determined with an established protocol. Presence of CAD and CVRFs were ascertained using a questionnaire and/or medical records. Results Plasma Aβ1 - 40 levels were significantly higher in individuals with CAD (p = 0.043) and, independently, in individuals with diabetes mellitus (DM) type 2 (p = 0.001) while accounting for age- and gender-effects. Plasma Aβ1 - 42 levels were higher in APOEɛ4 carriers (p = 0.004), but were neither relevantly associated with CAD nor with any CVRF. Plasma Aβ1 - 40 showed no association with APOE genotype. Discussion Our findings argue for an association of circulating plasma Aβ1 - 40 peptides with incident CAD and DM. Further investigations are needed to entangle the role of Aβ1 - 40 role in the pathophysiology of cardiovascular disease independent of its known role in Alzheimer's disease.

Frontotemporal dementia (FTD) is a devastating neurodegenerative disorder for which readily available biomarkers are needed to monitor disease progression and response to future therapies. Neurofilament light chain (NfL), a cytoskeletal protein, is elevated in the cerebrospinal fluid (CSF) of patients with FTD, correlating with disease severity.1 ,2 As CSF sampling is more invasive than venepuncture and requires higher subject compliance, we tested the hypothesis that NfL levels in FTD are elevated not only in CSF, but also in serum. NfL levels in FTD were also compared with those in amyotrophic lateral sclerosis (ALS).3 CSF and serum samples of a consecutive series of 41 FTD, 25 ALS and 46 healthy control subjects were collected from 2009 until 2014 (see online supplement 1: Methodological and statistical details, see online supplement 2: Subject characteristics). Only participants with normal CSF white cell counts (cell count 600 pg/mL, Innotest ELISA, Innogenetics, Belgium) were included. CSF and serum NfL concentrations were measured by a previously established electrochemiluminescence immunoassay.4 CSF levels of total tau (h-tau) were determined by a commercial ELISA (Innogenetics). ### Supplementary data [jnnp-2015-312972supp.pdf] NfL levels in CSF differed significantly between FTD, ALS and control subjects (F (2, 109)=88.36, p

Background: Enormous effort is being put into the identification and characterization of symptoms that may be used as predictive and progression markers in Parkinson's disease (PD). An impressive number of PD patients and individuals at risk for or in the prodromal stage of PD are currently followed in longitudinal studies; however, there does not exist an overview on the kind of markers evaluated and the assessments used. Methods: Information on the design, sample size, evaluated markers and assessments of 21 studies of the Joint Programme - Neurodegenerative Disease Research BioLoC-PD working group were collected by questionnaire. The studies were classified into at risk/prodromal or clinical PD cohorts. The assessments were grouped into quantitative assessments, investigator-rated assessments, investigator interviews, patient-rated questionnaires and caregiver-rated questionnaires. Results: Compilation of these data revealed an interesting consensus on evaluated markers, but there was an enormous variability of assessments. Furthermore, there is a remarkable similarity in the markers assessed and evaluation methods applied in the risk/prodromal and clinical PD cohorts. Conclusions: The inventory of the longitudinal cohorts that are part of the BioLoC-PD consortium reveals that there is a growing consensus on the markers that should be assessed in longitudinal cohort studies in PD. However, controversy still exists on the specific type of assessment. To allow comparison of data and common analyses it will be essential to harmonize scales and assessment outcomes.