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Altered glutamatergic neurotransmission is thought to play a crucial role in the progression of Alzheimer’s disease (AD). Accordingly, the identification of peculiar biochemical patterns reflecting AD-related synaptopathy in blood and cerebrospinal fluid (CSF) could have relevant diagnostic and prognostic implications. In this study, we measured by High-Performance Liquid Chromatography the amount of glutamate, glutamine and glycine in post-mortem brain samples of AD patients, as well as in CSF and blood serum of drug-free subjects encompassing the whole AD clinical spectrum (pre-clinical AD, n = 18, mild cognitive impairment-AD, n = 29, dementia AD, n = 30). Interestingly, we found that glutamate and glycine levels, as well as total tau protein content, were significantly reduced in the superior frontal gyrus of patients with AD, compared with non-demented controls. No significant change was also found in glutamate, glutamine and glycine CSF concentrations between AD patients and neurological controls. Remarkably, serum glutamate levels were significantly higher in patients affected by early AD phases compared to controls, and were negatively correlated with CSF total tau levels. Conversely, serum glutamine concentration was significantly increased in AD patients, with a negative correlation with MMSE performances. Finally, we reported a significant correlation between seruml-glutamate concentrations and CDR score in female but not in male cohort of AD subjects. Overall, our results suggest that serum glutamate and glutamine levels in AD patients could vary across disease stages, potentially reflecting the progressive alteration of glutamatergic signaling during neurodegenerative processes.

BACKGROUND: Plasma P-tau217 and P-tau181 are associated with Alzheimer’s disease (AD) tau pathology. P-tau217 is a more novel blood-based biomarker that may be diagnostically superior to P-tau181. We compared the diagnostic value of both biomarkers in a cohort of cognitively normal participants and patients with a clinical diagnosis of Mild Cognitive Impairment, AD or frontotemporal lobar degeneration (FTLD). METHODS: In this multi-cohort diagnostic performance study, we gathered plasma samples from the University of California San Francisco Memory and Aging Center and the Advancing Research and Treatment for Frontotemporal Lobar Degeneration consortium. Plasma Ptau-181 and Ptau-217 were measured using electrochemiluminescence-based assays which only differed in the biotinylated antibody epitope specificity. Receiver operating characteristic analyses were used to determine diagnostic accuracy of both plasma markers using clinical diagnosis, neuropathological findings, and amyloid- and tau-PET measures as gold standards. Difference between two area under the curve (AUC) analyses was tested with the Delong test. FINDINGS: Data were collected from 593 participants (mean age 64 years [SD 13], 294 [49.6%] females) between July and November 2020. Plasma P-tau217 and P-181 were correlated (r=0.90, p

Multiple sclerosis (MS) has been clinically considered a chronic inflammatory disease of the white matter; however, in the last decade growing evidence supported an important role of gray matter pathology as a major contributor of MS-related disability and the involvement of synaptic structures assumed a key role in the pathophysiology of the disease. Synaptic contacts are considered central units in the information flow, involved in synaptic transmission and plasticity, critical processes for the shaping and functioning of brain networks. During the course of MS, the immune system and its diffusible mediators interact with synaptic structures leading to changes in their structure and function, influencing brain network dynamics. The purpose of this review is to provide an overview of the existing literature on synaptic involvement during experimental and human MS, in order to understand the mechanisms by which synaptic failure eventually leads to brain networks alterations and contributes to disabling MS symptoms and disease progression.

Brain vascular damage accumulate in aging and often manifest as white matter hyperintensities (WMHs) on MRI. Despite increased interest in automated methods to segment WMHs, a gold standard has not been achieved and their longitudinal reproducibility has been poorly investigated. The aim of present work is to evaluate accuracy and reproducibility of two freely available segmentation algorithms. A harmonized MRI protocol was implemented in 3T-scanners across 13 European sites, each scanning five volunteers twice (test-retest) using 2D-FLAIR. Automated segmentation was performed using Lesion segmentation tool algorithms (LST): the Lesion growth algorithm (LGA) in SPM8 and 12 and the Lesion prediction algorithm (LPA). To assess reproducibility, we applied the LST longitudinal pipeline to the LGA and LPA outputs for both the test and retest scans. We evaluated volumetric and spatial accuracy comparing LGA and LPA with manual tracing, and for reproducibility the test versus retest. Median volume difference between automated WMH and manual segmentations (mL) was −0.22[IQR = 0.50] for LGA-SPM8, −0.12[0.57] for LGA-SPM12, −0.09[0.53] for LPA, while the spatial accuracy (Dice Coefficient) was 0.29[0.31], 0.33[0.26] and 0.41[0.23], respectively. The reproducibility analysis showed a median reproducibility error of 20%[IQR = 41] for LGA-SPM8, 14% [31] for LGA-SPM12 and 10% [27] with the LPA cross-sectional pipeline. Applying the LST longitudinal pipeline, the reproducibility errors were considerably reduced (LGA: 0%[IQR = 0], p < 0.001; LPA: 0% [3], p < 0.001) compared to those derived using the cross-sectional algorithms. The DC using the longitudinal pipeline was excellent (median = 1) for LGA [IQR = 0] and LPA [0.02]. LST algorithms showed moderate accuracy and good reproducibility. Therefore, it can be used as a reliable cross-sectional and longitudinal tool in multi-site studies.

Cognitive impairment (CI) is a disabling concomitant of multiple sclerosis (MS) with a complex and controversial pathogenesis. The cytokine interleukin-17A (IL-17A) is involved in the immune pathogenesis of MS, but its possible effects on synaptic function and cognition are still largely unexplored. In this study, we show that the IL-17A receptor (IL-17RA) is highly expressed by hippocampal neurons in the CA1 area and that exposure to IL-17A dose-dependently disrupts hippocampal long-term potentiation (LTP) through the activation of its receptor and p38 mitogen-activated protein kinase (MAPK). During experimental autoimmune encephalomyelitis (EAE), IL-17A overexpression is paralleled by hippocampal LTP dysfunction. An in vivo behavioral analysis shows that visuo-spatial learning abilities are preserved when EAE is induced in mice lacking IL-17A. Overall, this study suggests a key role for the IL-17 axis in the neuro-immune cross-talk occurring in the hippocampal CA1 area and its potential involvement in synaptic dysfunction and MS-related CI.

Increased cerebrospinal fluid neurofilament light (NfL) is a recognized biomarker for neurodegeneration that can also be assessed in blood. Here, we investigate plasma NfL as a marker of neurodegeneration in 13 neurodegenerative disorders, Down syndrome, depression and cognitively unimpaired controls from two multicenter cohorts: King’s College London (n = 805) and the Swedish BioFINDER study (n = 1,464). Plasma NfL was significantly increased in all cortical neurodegenerative disorders, amyotrophic lateral sclerosis and atypical parkinsonian disorders. We demonstrate that plasma NfL is clinically useful in identifying atypical parkinsonian disorders in patients with parkinsonism, dementia in individuals with Down syndrome, dementia among psychiatric disorders, and frontotemporal dementia in patients with cognitive impairment. Data-driven cut-offs highlighted the fundamental importance of age-related clinical cut-offs for disorders with a younger age of onset. Finally, plasma NfL performs best when applied to indicate no underlying neurodegeneration, with low false positives, in all age-related cut-offs., Cerebrospinal fluid neurofilament light (NfL) is a biomarker for neurodegeneration that can also be assessed in blood. Here the authors show in a validation study the potential for plasma NfL as a biomarker for several neurodegenerative diseases.

The basal ganglia network is represented by an interconnected group of subcortical nuclei traditionally thought to play a crucial role in motor learning and movement execution. During the last decades, knowledge about basal ganglia physiology significantly evolved and this network is now considered as a key regulator of important cognitive and emotional processes. Accordingly, the disruption of basal ganglia network dynamics represents a crucial pathogenic factor in many neurological and psychiatric disorders. The striatum is the input station of the circuit. Thanks to the synaptic properties of striatal medium spiny neurons (MSNs) and their ability to express synaptic plasticity, the striatum exerts a fundamental integrative and filtering role in the basal ganglia network, influencing the functional output of the whole circuit. Although it is currently established that the immune system is able to regulate neuronal transmission and plasticity in specific cortical areas, the role played by immune molecules and immune/glial cells in the modulation of intra-striatal connections and basal ganglia activity still needs to be clarified. In this manuscript, we review the available evidence of immune-based regulation of synaptic activity in the striatum, also discussing how an abnormal immune activation in this region could be involved in the pathogenesis of inflammatory and degenerative central nervous system (CNS) diseases.

Diagnosis of Parkinson’s disease (PD) relies on clinical history and physical examination, but misdiagnosis is common in early stages. Identification of biomarkers for PD may allow for early and more precise diagnosis and provide information about prognosis. Developments in analytical chemistry allow for the detection of a large number of molecules in cerebrospinal fluid (CSF), which are known to be associated with the pathogenesis of PD. Given the pathophysiology of PD, CSF α-synuclein species have the strongest rationale for use, also providing encouraging preliminary results in terms of early diagnosis. In the field of classical Alzheimer’s disease (AD) biomarkers, low CSF Aβ42 levels have shown a robust prognostic value in terms of development of cognitive impairment. Other CSF biomarkers including lysosomal enzymes, neurofilament light chain, markers of neuroinflammation and oxidative stress, although promising, have not proved to be reliable for diagnostic and prognostic purposes yet. Overall, the implementation of CSF biomarkers may give a substantial contribution to the optimal use of disease-modifying drugs.

Background: The amygdala and the hippocampus are two limbic structures that play a critical role in cognition and behavior, however their manual segmentation and that of their smaller nuclei/subfields in multicenter datasets is time consuming and difficult due to the low contrast of standard MRI. Here, we assessed the reliability of the automated segmentation of amygdalar nuclei and hippocampal subfields across sites and vendors using FreeSurfer in two independent cohorts of older and younger healthy adults.Methods: Sixty-five healthy older (cohort 1) and 68 younger subjects (cohort 2), from the PharmaCog and CoRR consortia, underwent repeated 3D-T1 MRI (interval 1-90 days). Segmentation was performed using FreeSurfer v6.0. Reliability was assessed using volume reproducibility error (epsilon) and spatial overlapping coefficient (DICE) between test and retest session.Results: Significant MRI site and vendor effects (p 0.43, p 0.80).Conclusion: Our results support the use of volumetric measures of larger amygdalar nuclei and hippocampal subfields in multisite MRI studies. These measures could be useful for disease tracking and assessment of efficacy in drug trials.

Increased cerebrospinal fluid neurofilament light (NfL) is a recognized biomarker for neurodegeneration that can also be assessed in blood. Here, we investigate plasma NfL as a marker of neurodegeneration in fifteen neurodegenerative diseases from two multicenter cohorts: King’s College London (n = 847) and the Swedish BioFINDER study (n = 1464). Plasma NfL was significantly increased in all cortical neurodegenerative disorders, amyotrophic lateral sclerosis and atypical parkinsonian disorders. We further demonstrate that plasma NfL is clinically useful in identifying, i) atypical parkinsonian disorders in patients with parkinsonism, ii) dementia in individuals with Down Syndrome, iii) detect cases of frontotemporal dementia among psychiatric disorders such as moderate and severe depression, iv) identify frontotemporal dementia in patients with cognitive impairment. Data-driven cut-offs highlighted the fundamental importance of age-related plasma NfL cut-offs for disorders with a younger age of onset. Finally, our findings suggest that plasma NfL performs best when a concentration cut-off is applied to indicate no underlying neurodegeneration, with low false positives, in all age-related cut-offs.

Impaired olfactory function is one of the main features of Parkinson’s disease. However, how peripheral olfactory structures are involved remains unclear. Using diffusion tensor imaging fiber tracking, we investigated for MRI microstructural changes in the parkinsonian peripheral olfactory system and particularly the olfactory tract, in order to seek a better understanding of the structural alternations underlying hyposmia in Parkinson’s disease. All patients were assessed utilizing by the Italian Olfactory Identification Test for olfactory function and the Unified Parkinson’s Disease Rating Scale-III part as well as Hoehn and Yahr rating scale for motor disability. Imaging was performed on a 3 T Clinical MR scanner. MRI data pre-processing was carried out by DTIPrep, diffusion tensor imaging reconstruction, and fiber tracking using Diffusion Toolkit and tractography analysis by TrackVis. The following parameters were used for groupwise comparison: fractional anisotropy, mean diffusivity, radial diffusivity, axial diffusivity, and tract volume. Overall 23 patients with Parkinson’s disease (mean age 63.6 ± 9.3 years, UPDRS-III 24.5 ± 12.3, H&Y 1.9 ± 0.5) and 18 controls (mean age 56.3 ± 13.7 years) were recruited. All patients had been diagnosed hyposmic. Diffusion tensor imaging analysis of the olfactory tract showed significant fractional anisotropy, and tract volume decreases for the Parkinson’s disease group compared with controls (P < 0.05). Fractional anisotropy and age, in the control group, were significant for multiple correlations (r = − 0.36, P < 0.05, Spearman’s rank correlation). Fiber tracking diffusion tensor imaging analysis of olfactory tract was feasible, and it could be helpful for characterizing hyposmia in Parkinson’s disease.

In this study, we sought for a cerebrospinal fluid (CSF) metabolomic fingerprint in Alzheimer's disease (AD) patients characterized, according to the clinical picture and CSF AD core biomarkers (Aβ

Cerebrospinal fluid (CSF) contains different types of extracellular vesicles (EVs) with undisclosed biomarker potential for neurodegenerative diseases. The aims of the present study were: i) to compare the proteome EVs isolated using different ultracentrifugation speed ii) to preliminary explore the EVs proteome in a common neurodegenerative disorder, Alzheimer’s disease (AD) compared to neurological controls. CSF samples from control subjects and AD patients were pooled separately (15 mL) and subjected to ultracentrifugation (UC) at different speeds (20,000g and 100,000g) to isolate separate EV fractions (P20 and P100). The proteome was analysed using high-resolution mass spectrometry (LC-MS/MS) and comparisons were made using bioinformatic analysis. EVs isolated at 100,000g (P100) had a proteome consistent with vesicles secreted via an ESCRT-dependent mechanism, being highly enriched in alix (PDCD6IP), syntenin-1 (SDCBP) and TSG101. EVs isolated at 20,000g were substantially different, showing enrichment in cytoskeletal and cell adhesion molecules. The pools from patients diagnosed with AD showed a distinct protein profile of CSF EVs, with increased levels of ADAM10, SPON1, CH3IL1 and MDK in the P100 fraction. CSF EV offer a new potential biosource of protein markers for AD detection and a complementary framework to the analysis of whole biological fluids for biomarker discovery.

Amyloid and tau pathological accumulation should be considered for Alzheimer's disease (AD) definition and before subjects' enrollment in disease-modifying trials. Although age, APOEε4, and sex influence cerebrospinal fluid (CSF) biomarker levels, none of these variables are considered by current normality/abnormality cutoffs. Using baseline CSF data from 2 independent cohorts (PharmaCOG/European Alzheimer's Disease Neuroimaging Initiative and Alzheimer's Disease Neuroimaging Initiative), we investigated the effect of age, APOEε4 status, and sex on CSF Aβ42/P-tau distribution and cutoff extraction by applying mixture models with covariates. The Aβ42/P-tau distribution revealed the presence of 3 subgroups (AD-like, intermediate, control-like) and 2 cutoffs. The identification of the intermediate subgroup and of the higher cutoff was APOEε4 dependent in both cohorts. APOE-specific classification (higher cutoff for APOEε4+, lower cutoff for APOEε4-) showed higher diagnostic accuracy in identifying MCI due to AD compared to single Aβ42 and Aβ42/P-tau cutoffs. APOEε4 influences amyloid and tau CSF markers and AD progression in MCI patients supporting i) the use of APOE-specific cutoffs to identify MCI due to AD and ii) the utility of considering APOE genotype for early AD diagnosis.

BACKGROUND Dopaminergic medications in Parkinson's disease (PD) are usually associated with the development of both levodopa-induced dyskinesias (LID) and impulse control and repetitive behavior disorders (ICRB). OBJECTIVE To assess the prevalence and the severity of ICRB in a cohort of moderate and advanced PD patients and to investigate the potential interplay between ICRB, LID and dopaminergic therapies. METHODS 117 PD patients were consecutively recruited. LID were assessed by using the Rush Dyskinesia Rating Scale (RDRS). ICRB were tested by means of Questionnaire for Impulsive Compulsive Disorders in Parkinson's Disease Rating Scale (QUIP-RS). RESULTS 55 patients were affected by LID. Among them, 37 were treated only by oral therapy, OT (LID/OT), while 18 were on treatment with jejunal levodopa infusion, JLI (LID/JLI). 62 patients were not affected by LID (NLID) and all of them were on therapy only with oral drugs. The overall prevalence of clinically significant ICRB was 34% (95% CI = 26% to 43%) and the mean value (±SD) of QUIP-RS total score was 5.4±8.5. Prevalence of clinically significant ICRB, as well as severity of ICRB, was higher in patients with LID compared to NLID patients (p = 0.016 and p

Neuropathological investigations report that in synucleinopathies with dementia, namely Parkinson&rsquo, s disease (PD) with dementia (PDD) and dementia with Lewy bodies (DLB), the histopathological hallmarks of Alzheimer&rsquo, s Disease (AD), in particular amyloid plaques, are frequently observed. In this study, we investigated the cerebrospinal fluid (CSF) AD biomarkers in different clinical phenotypes of synucleinopathies. CSF A&beta, 42/A&beta, 40 ratio, phosphorylated tau and total tau were measured as markers of amyloidosis (A), tauopathy (T) and neurodegeneration (N) respectively, in 98 PD (48 with mild cognitive impairment, PD-MCI, 50 cognitively unimpaired, PD-nMCI), 14 PDD and 15 DLB patients, and 48 neurological controls (CTRL). In our study, CSF AD biomarkers did not significantly differ between CTRL, PD-MCI and PD-nMCI patients. In PD-nMCI and PD-MCI groups, A-/T-/N- profile was the most represented. Prevalence of A+ was similar in PD-nMCI and PD-MCI (10% and 13%, respectively), being higher in PDD (64%) and in DLB (73%). DLB showed the lowest values of A&beta, 40 ratio. Higher total tau at baseline predicted a worse neuropsychological outcome after one year in PD-MCI. A+/T+, i.e., AD-like CSF profile, was most frequent in the DLB group (40% vs. 29% in PDD).

Neuroinflammatory and neurodegenerative diseases are characterized by the interplay of a number of molecular pathways that can be assessed through biofluids, especially cerebrospinal fluid and blood. Accordingly, the definition and classification of these disorders will move from clinical and pathological to biological criteria. The consequences of this biomarker-based diagnostic and prognostic approach are highly relevant to the field of drug development. Indeed, in view of the availability of disease-modifying drugs, fluid biomarkers offer a unique opportunity for improving the quality and applicability of results from clinical trials. Herein, we discuss the benefits of using fluid biomarkers for patient stratification, target engagement, and outcome assessment, as well as the most recent developments in neuroinflammatory and neurodegenerative diseases.

Background The ε4 allele of apolipoprotein E (APOE) gene and increasing age are two of the most important known risk factors for developing Alzheimer disease (AD). The diagnosis of AD based on clinical symptoms alone is known to have poor specificity; recently developed diagnostic criteria based on biomarkers that reflect underlying AD neuropathology allow better assessment of the strength of the associations of risk factors with AD. Accordingly, we examined the global and age-specific association between APOE genotype and AD by using the A/T/N classification, relying on the cerebrospinal fluid (CSF) levels of β-amyloid peptide (A, β-amyloid deposition), phosphorylated tau (T, pathologic tau), and total tau (N, neurodegeneration) to identify patients with AD. Methods and findings This case–control study included 1,593 white AD cases (55.4% women; mean age 72.8 [range = 44–96] years) with abnormal values of CSF biomarkers from nine European memory clinics and the American Alzheimer’s Disease Neuroimaging Initiative (ADNI) study. A total of 11,723 dementia-free controls (47.1% women; mean age 65.6 [range = 44–94] years) were drawn from two longitudinal cohort studies (Whitehall II and Three-City), in which incident cases of dementia over the follow-up were excluded from the control population. Odds ratio (OR) and population attributable fraction (PAF) for AD associated with APOE genotypes were determined, overall and by 5-year age categories. In total, 63.4% of patients with AD and 22.6% of population controls carried at least one APOE ε4 allele. Compared with non-ε4 carriers, heterozygous ε4 carriers had a 4.6 (95% confidence interval 4.1–5.2; p < 0.001) and ε4/ε4 homozygotes a 25.4 (20.4–31.2; p < 0.001) higher OR of AD in unadjusted analysis. This association was modified by age (p for interaction < 0.001). The PAF associated with carrying at least one ε4 allele was greatest in the 65–70 age group (69.7%) and weaker before 55 years (14.2%) and after 85 years (22.6%). The protective effect of APOE ε2 allele for AD was unaffected by age. Main study limitations are that analyses were based on white individuals and AD cases were drawn from memory centers, which may not be representative of the general population of patients with AD. Conclusions In this study, we found that AD diagnosis based on biomarkers was associated with APOE ε4 carrier status, with a higher OR than previously reported from studies based on only clinical AD criteria. This association differs according to age, with the strongest effect at 65–70 years. These findings highlight the need for early interventions for dementia prevention to mitigate the effect of APOE ε4 at the population level., In a case-control study using cerebrospinal fluid biomarkers, Hana Saddiki and colleagues investigate how age is related to the association between Apolipoprotein E genotype and Alzheimer's disease, among individuals with and without Alzheimer's disease in Europe and the US., Author summary Why was this study done? The ε4 allele of apolipoprotein E (APOE) gene (APOE4) and increasing age are two of the most important known risk factors for developing Alzheimer disease (AD). The recent development of diagnostic criteria based on biomarkers that reflect brain β-amyloid and tau lesions (β-amyloid deposition, pathologic tau, neurodegeneration [A/T/N] classification]) increases homogeneity in diagnosed cases. The strength of association of AD with risk factors can be better determined using biomarker-based AD compared with AD diagnosis based only on clinical criteria because the latter are known to lack specificity as a result of difficulties in ruling out other causes of dementia. What did the researchers do and find? We compared the overall and age-specific association between APOE4 and AD using a case–control study that included 1,593 AD cases from memory clinics with positive cerebrospinal fluid biomarkers and 11,723 dementia-free controls drawn from two longitudinal cohort studies. The use of a large number of cases and controls allows assessment of whether the association between APOE4 and AD is dependent on age. Compared with controls, patients with AD were more likely to carry one APOE4 (odds ratio [OR] = 4.6) or two APOE4 (OR = 25.3). This association was significantly modified by age, with the strongest association seen between 65 and 70 years of age and weaker associations at the two tails of the age distribution. What do these findings mean? Incorporating biomarkers for diagnosis of AD identified an association with APOE4 that is apparently greater than has been previously reported using clinical diagnosis of the disease. The impact of APOE4 on the risk of AD was strongest between the 65 and 70 years of age, earlier than the mean age at diagnosis in this study, which was 72.8 years.

The diagnosis of Alzheimer's disease (AD) relies on the presence of amyloidosis and tauopathy, as reflected in cerebrospinal fluid (CSF), independently from the clinical stage. Recently, CSF d-serine has been proposed as a possible new AD biomarker, reflecting dysfunctional activation of neuronal glutamatergic N-methyl-d-aspartate receptor (NMDAR). In this study, we measured blood serum and CSF concentration of two NMDAR modulators, such as d-serine and d-aspartate, in a cohort of drug-free subjects encompassing the whole AD clinical spectrum. In addition, we also analyzed d-serine levels in a cohort of post-mortem AD and control cortex samples. We reported unaltered serum and CSF concentrations of d-serine and d-aspartate in AD patients both during the AD progression and compared to non-demented controls. Accordingly, no correlation was detected between serum or CSF d-serine content and mini-mental state examination or Clinical Dementia Rating. Similarly, cortical d-serine levels were also unaltered in post-mortem samples of AD patients. Overall, our results failed to confirm previous findings indicating the CSF d-serine as a novel biomarker for AD.

Background Cerebrospinal fluid (CSF) amyloid-beta (Aβ) 42/40 ratio, threonine-181-phosphorylated-tau (p-tau), and total-tau (t-tau) represent core biomarkers of Alzheimer disease (AD). The recent availability of automated platforms has represented a significant achievement for reducing the pre-analytical variability of these determinations in clinical setting. With respect to classical manual ELISAs, these platforms give us also the possibility to measure any single sample and to get the result within approximately 30 min. So far, reference values have been calculated from measurements obtained in frozen samples. In this work, we wanted to check if the values obtained in fresh CSF samples differ from those obtained in frozen samples, since this issue is mandatory in routine diagnostic work. Methods Fifty-eight consecutive CSF samples have been analyzed immediately after lumbar puncture and after 1-month deep freezing (− 80 °C). As an automated platform, we used Lumipulse G600-II (Fujirebio Inc.). Both the fresh and the frozen aliquots were analyzed in their storage tubes. Results In fresh samples, a mean increase of Aβ40 (6%), Aβ42 (2%), p-tau (2%), and t-tau (4%) was observed as compared to frozen samples, whereas a slight decrease was observed for Aβ42/Aβ40 ratio (4%), due to the higher deviation of Aβ40 in fresh samples compared to Aβ42. These differences are significant for Aβ40, Aβ42/Aβ40 ratio, p-tau, and t-tau. Nevertheless, the Aβ42/Aβ40 ratio showed a lower variability (smaller standard deviation of relative differences) with respect to Aβ42. With respect to the AD profile according to the A/T/(N) criteria for AD diagnosis, no significant changes in classification were observed when comparing results obtained in fresh vs frozen samples. Conclusions Small but significant differences have been found for Aβ40, Aβ42/Aβ40 ratio, p-tau, and t-tau in fresh vs frozen samples. Importantly, these differences did not imply a modification in the A/T/(N) classification system. In order to know if different cutoffs for fresh and frozen samples are required, larger, multi-center investigations are needed.

Objective: Here we tested if cortical sources of resting state electroencephalographic (rsEEG) rhythms may differ in sub-groups of patients with prodromal and overt dementia with Lewy bodies (DLB) as a function of relevant clinical symptoms.Methods: We extracted clinical, demographic and rsEEG datasets in matched DLB patients (N = 60) and control Alzheimer's disease (AD, N = 60) and healthy elderly (Nold, N = 60) seniors from our international database. The eLORETA freeware was used to estimate cortical rsEEG sources.Results: As compared to the Nold group, the DLB and AD groups generally exhibited greater spatially distributed delta source activities (DLB > AD) and lower alpha source activities posteriorly (AD > DLB). As compared to the DLB ``controls", the DLB patients with (1) rapid eye movement (REM) sleep behavior disorders showed lower central alpha source activities (p < 0.005); (2) greater cognitive deficits exhibited higher parietal and central theta source activities as well as higher central, parietal, and occipital alpha source activities (p < 0.01); (3) visual hallucinations pointed to greater parietal delta source activities (p < 0.005).Conclusions: Relevant clinical features were associated with abnormalities in spatial and frequency features of rsEEG source activities in DLB patients.Significance: Those features may be used as neurophysiological surrogate endpoints of clinical symptoms in DLB patients in future cross-validation prospective studies. Ministry of Health, Italy; H2020 Marie S. Curie ITN-ETN project; H2020-TWINN-2015 project

Whereas the diagnostic criteria for clinical Parkinson's disease (PD) remain centered on the motor syndrome, it is well-known that PD is a multisystemic disorder characterized by a broad spectrum of motor and non-motor features encompassing neuropsychiatric, dysautonomic, and gastrointestinal disturbances. Non-motor disturbances can appear early in the disease course, often preceding the development of classical motor signs. In view of etiological treatments, early diagnosis is needed; accordingly, the concept of prodromal PD has also been introduced. Different clinical PD subtypes based on age at onset (early versus late onset) and baseline motor profile (postural instability or gait difficulty versus tremor-dominant) are probably insufficient to provide a complete prognostic characterization. By combining motor and non-motor features, cluster analysis has been used to provide a better definition of PD subtypes according to their different prognostic profiles. Regardless of PD subtype classifications, prognosis of patients is mainly determined by motor progression and cognitive impairment. Motor progression includes development of motor fluctuations and dyskinesia. Falls also have a greatly negative impact on quality of life. Older age, symmetrical involvement, cognitive impairment, and longer disease duration have been reported as the strongest predictive factors for motor progression. Established prognostic factors for cognitive impairment and dementia include advanced age and more severe parkinsonism, especially with predominant gait involvement. Reduced cerebrospinal fluid Aβ42 levels have consistently been shown to predict the development of cognitive impairment. Genetic factors also influence the risk for developing PD, phenotypic features, and disease course. α-Synuclein gene point mutations and triplications correlate with motor and cognitive impairment. Glucocerebrosidase gene mutations lead to early dementia and psychosis. A better knowledge of prognostic factors in PD will allow physicians to personalize treatment when disease-modifying drugs will be available.

Compared with Alzheimer's disease (AD), Parkinson's disease (PD) shows peculiar clinical manifestations related to vigilance (i.e., executive cognitive deficits and visual hallucinations) that may be reflected in resting-state electroencephalographic rhythms. To test this hypothesis, clinical and resting-state electroencephalographic rhythms in age-, sex-, and education-matched PD patients (N = 136) and Alzheimer's disease patients (AD, N = 85), and healthy older participants (Nold, N = 65), were available from an international archive. Electroencephalographic sources were estimated by eLORETA software. The results are as follows: (1) compared to the Nold participants, the AD and PD patients showed higher widespread delta source activities (PD > AD) and lower posterior alpha source activities (AD > PD); (2) the PD patients with the most pronounced motor deficits exhibited very low alpha source activities in widespread cortical regions; (3) the PD patients with the strongest cognitive deficits showed higher alpha source activities in widespread cortical regions; and (4) compared to the PD patients without visual hallucinations, those with visual hallucinations were characterized by higher posterior alpha sources activities. These results suggest that in PD patients resting in quiet wakefulness, abnormalities in cortical neural synchronization at alpha frequencies are differently related to cognitive, motor, and visual hallucinations. Interestingly, parallel PD neuropathological processes may have opposite effects on cortical neural synchronization mechanisms generating cortical alpha rhythms in quiet wakefulness. (C) 2020 Elsevier Inc. All rights reserved.

Lipids are fundamental components of brain cells as they are involved in several essential processes like remodeling of plasma membrane, synaptic function and receptor–ligand interactions. Systemic and brain alterations in lipid metabolism have been linked to the pathogenesis of neurodegenerative disorders like dementia and parkinsonisms. Intracellular transport of lipids is regulated by fatty acid-binding proteins. Recently, a member of this family, the fatty acid-binding protein 3 has been proposed as a potential biomarker across a range of neurodegenerative diseases, including Alzheimer's disease and dementia with Lewy bodies. In this special report, we describe recent progresses in characterizing the role of fatty acid-binding protein 3 in neurodegeneration and its putative role as biomarker measurable in biological fluids.

Dysfunction of NMDA receptor (NMDAR)-mediated transmission is supposed to contribute to the motor and non-motor symptoms of Parkinson's Disease (PD), and to L-DOPA-induced dyskinesia. Besides the main agonist L-glutamate, two other amino acids in the atypical D-configuration, D-serine and D-aspartate, activate NMDARs. In the present work, we investigated the effect of dopamine depletion on D-amino acids metabolism in the brain of MPTP-lesioned Macaca mulatta, and in the serum and cerebrospinal fluid of PD patients. We found that MPTP treatment increases D-aspartate and D-serine in the monkey putamen while L-DOPA rescues both D-amino acids levels. Conversely, dopaminergic denervation is associated with selective D-serine reduction in the substantia nigra. Such decrease suggests that the beneficial effect of D-serine adjuvant therapy previously reported in PD patients may derive from the normalization of endogenous D-serine levels and consequent improvement of nigrostriatal hypoglutamatergic transmission at glycine binding site. We also found reduced D-serine concentration in the cerebrospinal fluid of L-DOPA-free PD patients. These results further confirm the existence of deep interaction between dopaminergic and glutamatergic neurotransmission in PD and disclose a possible direct influence of D-amino acids variations in the changes of NMDAR transmission occurring under dopamine denervation and L-DOPA therapy. Dysfunction of NMDA receptor (NMDAR)-mediated transmission is supposed to contribute to the motor and non-motor symptoms of Parkinson’s Disease (PD), and to L-DOPA-induced dyskinesia. Besides the main agonist L-glutamate, two other amino acids in the atypical D-configuration, D-serine and D-aspartate, activate NMDARs. In the present work, we investigated the effect of dopamine depletion on D-amino acids metabolism in the brain of MPTP-lesioned Macaca mulatta, and in the serum and cerebrospinal fluid of PD patients. We found that MPTP treatment increases D-aspartate and D-serine in the monkey putamen while L-DOPA rescues both D-amino acids levels. Conversely, dopaminergic denervation is associated with selective D-serine reduction in the substantia nigra. Such decrease suggests that the beneficial effect of D-serine adjuvant therapy previously reported in PD patients may derive from the normalization of endogenous D-serine levels and consequent improvement of nigrostriatal hypoglutamatergic transmission at glycine binding site. We also found reduced D-serine concentration in the cerebrospinal fluid of L-DOPA-free PD patients. These results further confirm the existence of deep interaction between dopaminergic and glutamatergic neurotransmission in PD and disclose a possible direct influence of D-amino acids variations in the changes of NMDAR transmission occurring under dopamine denervation and L-DOPA therapy.

Background The accumulation of misfolded α-synuclein aggregates is associated with PD. However, the diagnostic value of the α-synuclein levels in CSF is still under investigation. Methods A comprehensive search of the literature was performed, yielding 34 studies eligible for meta-analysis. We included studies that reported data on CSF total, oligomeric and phosphorylated α-synuclein in patients with PD and healthy participants, neurological controls, or other parkinsonisms. Standardized mean differences were pooled using random-effects models, and heterogeneity was reported as I2. Bivariate random effects meta-analysis was also performed on diagnostic data. Methodological quality of the selected studies was assessed using the QUADAS-2 tool. Results Concentrations of α-synuclein species in PD did not show significant differences with respect to the levels found in other parkinsonisms. Total α-synuclein was significantly reduced in PD when compared with controls (standardized mean differences −0.48; P < .001, I2 = 60%). Oligomeric (standardized mean differences 0.57; P < .001, I2 = 44%) and phosphorylated α-synuclein (standardized mean differences 0.86; P < .001) were significantly increased in PD when compared with controls. Sensitivity and specificity for distinguishing PD and controls were 0.72 and 0.65, respectively, for total α-synuclein, and 0.71 and 0.64, respectively, for oligomeric α-syn. Conclusion Most of the studies were at high risk of bias and have concerns regarding applicability. Diagnostic performance of CSF α-synuclein species is still below what would be considered acceptable for their introduction in clinical practice. Future research should focus on combining α-synuclein species with other biochemical markers as well on improving the standardization of current assays. © 2017 International Parkinson and Movement Disorder Society

Background Reduced β-glucocerebrosidase activity was observed in postmortem brains of both GBA1 mutation carrier and noncarrier Parkinson's disease patients, suggesting that lower β-glucocerebrosidase activity is a key feature in the pathogenesis of PD. The objectives of this study were to confirm whether there is reduced β-glucocerebrosidase activity in the CSF of GBA1 mutation carrier and noncarrier PD patients and verify if other lysosomal enzymes show altered activity in the CSF. Methods CSF β-glucocerebrosidase, cathepsin D, and β-hexosaminidase activities were measured in 79 PD and 61 healthy controls from the BioFIND cohort. The whole GBA1 gene was sequenced. Results Enzyme activities were normalized according to CSF protein content (specific activity). β-glucocerebrosidase specific activity was significantly decreased in PD versus controls (-28%, P < 0.001). GBA1 mutations were found in 10 of 79 PD patients (12.7%) and 3 of 61 controls (4.9%). GBA1 mutation carrier PD patients showed significantly lower β-glucocerebrosidase specific activity versus noncarriers. β-glucocerebrosidase specific activity was also decreased in noncarrier PD patients versus controls (-25%, P < 0.001). Cathepsin D specific activity was lower in PD versus controls (-21%, P < 0.001). β-Hexosaminidase showed a similar trend. β-Glucocerebrosidase specific activity fairly discriminated PD from controls (area under the curve, 0.72; sensitivity, 0.67; specificity, 0.77). A combination of β-glucocerebrosidase, cathepsin D, and β-hexosaminidase improved diagnostic accuracy (area under the curve, 0.77; sensitivity, 0.71; specificity, 0.85). Lower β-glucocerebrosidase and β-hexosaminidase specific activities were associated with worse cognitive performance. Conclusions CSF β-glucocerebrosidase activity is reduced in PD patients independent of their GBA1 mutation carrier status. Cathepsin D and β-hexosaminidase were also decreased. The possible link between altered CSF lysosomal enzyme activities and cognitive decline deserves further investigation. © 2017 International Parkinson and Movement Disorder Society

Parkinson's disease (PD) is a complex and phenotypically heterogeneous neurodegenerative disease, for which the diagnosis is mainly based on clinical parameters (even if neuroimaging plays a role in diagnostic assessment); as a consequence, misdiagnosis is common, especially in early stages. Thus, there is an urgent need of having available biomarkers in order to achieve an early and accurate diagnosis. Since molecular changes in the brain are reliably and timely reflected in cerebrospinal fluid (CSF), CSF represents an ideal source for biomarkers of different pathophysiological processes characterizing the disease since its early phases. Areas covered: The aim of this review is to provide an update on the role, development and validation of most studied CSF biomarkers showing a role in the diagnosis and/or prognosis of PD. Oligomeric alpha-synuclein, DJ-1, lysosomal enzymes (namely, glucocerebrosidase) show consistent evidence as potential diagnostic biomarkers of PD. Neurofilament light chain may also have a significant role in differentiating PD from other parkinsonisms. Amyloid beta peptide 1-42 has consistently shown a prognostic value in terms of development of cognitive impairment and dementia in PD patients. Expert commentary: CSF biomarkers represent a very promising approach to early and differential diagnosis of PD. The biomarkers available so far need preanalytical and analytical validation in order to have these CSF biomarkers ready for clinical use.

There is growing evidence of epidemiological, genetic, molecular and clinical links between Alzheimer's disease (AD) and age-related macular degeneration (AMD). Major interest in the relationship between AD and AMD has derived from the evidence that beta-amyloid, the main component of senile plaques, the hallmark of AD, is also an important component of drusen, the hallmark of AMD. This finding has a great potential in the present era of anti-amyloid agents for the treatment of AD. The connection between AD and AMD is also supported by the evidence that the two diseases share other pathophysiological factors, such as oxidative stress and neuroinflammation. Accordingly, a few clinical trials have evaluated the efficacy of antioxidants on visual and cognitive performance in patients presenting both disorders. In this review, we summarize the pathophysiological and clinical evidence of the relationship between these two age-related disorders. Considering the increasing prevalence of both conditions along with the aging of the population, further investigations of this important issue are highly needed.

With sincere satisfaction and pride, I present to you the new journal, NeuroSci, for which I am pleased to serve as editor-in-chief. To date, the world of neurology has been rapidly advancing, NeuroSci is a cross-disciplinary, open-access journal that offers an opportunity for presentation of novel data in the field of neurology and covers a broad spectrum of areas including neuroanatomy, neurophysiology, neuropharmacology, clinical research and clinical trials, molecular and cellular neuroscience, neuropsychology, cognitive and behavioral neuroscience, and computational neuroscience. Members of our editorial board will welcome the contributions in this wide field of neurosciences. The following are welcome messages from some editorial board members.