Cerebrospinal fluid α-synuclein species in cognitive and movements disorders

Total CSF α-synuclein (t-α-syn), phosphorylated α-syn (pS129-α-syn) and α-syn oligomers (o-α-syn) have been studied as candidate biomarkers for synucleinopathies, with suboptimal specificity and sensitivity in the differentiation from healthy controls. Studies of α-syn species in patients with other underlying pathologies are lacking. The aim of this study was to investigate possible alterations in CSF α-syn species in a cohort of patients with diverse underlying pathologies. A total of 135 patients were included, comprising Parkinson’s disease (PD; n = 13), multiple system atrophy (MSA; n = 9), progressive supranuclear palsy (PSP; n = 13), corticobasal degeneration (CBD; n = 9), Alzheimer’s disease (AD; n = 51), frontotemporal degeneration (FTD; n = 26) and vascular dementia patients (VD; n = 14). PD patients exhibited higher pS129-α-syn/α-syn ratios compared to FTD (p = 0.045), after exclusion of samples with CSF blood contamination. When comparing movement disorders (i.e., MSA vs. PD vs. PSP vs. CBD), MSA patients had lower α-syn levels compared to CBD (p = 0.024). Patients with a synucleinopathy (PD and MSA) exhibited lower t-α-syn levels (p = 0.002; cut-off value: ≤865 pg/mL; sensitivity: 95%, specificity: 69%) and higher pS129-/t-α-syn ratios (p = 0.020; cut-off value: ≥0.122; sensitivity: 71%, specificity: 77%) compared to patients with tauopathies (PSP and CBD). There are no significant α-syn species alterations in non-synucleinopathies.This study was supported by Strat-up Funding to OE from Qatar Biomedical Research Institute (SF 2007–007) and Qatar National Research Fund (NPRPNo.: 8–517–3-112)

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy vs. multiple sclerosis. Either one or sometimes both?

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL), is the most common cause of inherited cerebral small vessel disease, inherited stroke and inherited vascular dementia. It is not infrequent for CADASIL to be mistaken and mistreated for multiple sclerosis (MS). A much less frequent but existing scenario is the co-occurrence of CADASIL and MS (or MS-like inflammatory condition). Such patients may present with spinal cord lesions, brain or spinal cord enhancing lesions, positive oligoclonal bands and high IgG index in the cerebrospinal fluid and good response to corticosteroids or immunomodulating treatments. CADASIL through various mechanisms may trigger or modulate autoimmune reactions, and either be complicated by an inflammatory component or cause an MS-like disorder

Planimetric and Volumetric Brainstem MRI Markers in Progressive Supranuclear Palsy, Multiple System Atrophy, and Corticobasal Syndrome. A Systematic Review and Meta-Analysis

Background: Various MRI markers—including midbrain and pons areas (Marea, Parea) and volumes (Mvol, Pvol), ratios (M/Parea, M/Pvol), and composite markers (magnetic resonance imaging Parkinsonism Indices 1,2; MRPI 1,2)—have been proposed as imaging markers of Richardson’s syndrome (RS) and multiple system atrophy–Parkinsonism (MSA-P). A systematic review/meta-analysis of relevant studies aiming to compare the diagnostic accuracy of these imaging markers is lacking. Methods: Pubmed and Scopus were searched for studies with >10 patients (RS, MSA-P or CBS) and >10 controls with data on Marea, Parea, Mvol, Pvol, M/Parea, M/Pvol, MRPI 1, and MRPI 2. Cohen’s d, as a measure of effect size, was calculated for all markers in RS, MSA-P, and CBS. Results: Twenty-five studies on RS, five studies on MSA-P, and four studies on CBS were included. Midbrain area provided the greatest effect size for differentiating RS from controls (Cohen’s d = −3.10; p area and MRPI 1. MSA-P had decreased midbrain and pontine areas. Included studies exhibited high heterogeneity, whereas publication bias was low. Conclusions: Midbrain area is the optimal MRI marker for RS, and pons area is optimal for MSA-P. M/Parea and MRPIs produce smaller effect sizes for differentiating RS from controls

Mixed Small Vessel Disease in a Patient with Dementia with Lewy Bodies

Background: Cerebral amyloid angiopathy (CAA) is characterized by deposition of amyloid in small/medium size brain vessels, and may coexist with Alzheimer’s disease or dementia with Lewy bodies (DLB). We describe a patient with a clinical diagnosis of DLB and imaging/biochemical characteristics suggestive of mixed small vessel disease (both CAA and non-amyloid microangiopathy). Methods: Clinical evaluation according to recent diagnostic criteria, magnetic resonance imaging, dopamine-transporter scan (DAT-scan) and cerebrospinal fluid (CSF) analysis for dementia biomarkers were all performed. Results: The patient is a 71-year-old male, fulfilling criteria for probable DLB, with a positive DAT-scan, but with multiple microbleeds in a cortical-subcortical location suggestive of CAA, some microbleeds in deep brain nuclei suggestive of non-amyloid microangiopathy and abnormal levels of only amyloid-beta (Aβ42) in CSF. Conclusion: Coexistent mixed vascular and neurodegenerative disorders are frequent in older subjects with dementia and each one of the underlying pathologies may contribute to, or modify the clinical presentation

Cerebrospinal fluid biomarkers and apolipoprotein E genotype in cerebral amyloid angiopathy. A narrative review

Sporadic cerebral amyloid angiopathy (CAA) is a cerebral small vessel disease, characterized by the deposition of β-amyloid within the cortical and leptomeningeal blood vessel walls. It has attracted interest concerning new therapeutic perspectives. However, there are scarce data regarding the cerebrospinal fluid biomarkers (CSF) and genetic factors in sporadic CAA.In this narrative review, we investigated the literature regarding the cerebrospinal fluid core biomarkers profile of patients with probable or possible CAA and its subtype, the CAA- related inflammation (CAA-ri), taking into account the clinical and radiological characteristics of the patients. We also analyzed the Apolipoprotein E (APOE) genotype differentiations among the different subtypes of cerebral amyloid angiopathy.Our results demonstrate specific CSF patterns of β-amyloid (Aβ42 and Aβ40) and tau-proteins (t-tau and p-tau) which may serve as molecular biomarkers for CAA/ CAA-ri and could prove helpful for novel therapeutic procedures. Specifically, decreased levels of Aβ40 and Aβ42 in both CAA and CAA-ri, mildly increased concentrations of tau protein in patients with CAA-ri and a strong association between APOE ε4/ε4 genotype and CAA-ri are the main findings

Cerebrospinal Fluid Biomarker Profile in TDP-43-Related Genetic Frontotemporal Dementia

Cerebrospinal fluid (CSF) biomarkers, namely total tau, phospho-tau and amyloid beta peptides, have received much attention specifically regarding Alzheimer’s disease (AD), since they can detect the biochemical fingerprint of AD and serve as a diagnostic tool for accurate and early diagnosis during life. In the same way, biomarkers for other neurodegenerative disease pathologies are also needed. We present a case series of six patients with genetic frontotemporal dementia (FTD), with TDP-43 underlying proteinopathy, in an attempt to assess TDP-43 as a novel biomarker alone and in combination with established AD biomarkers for this specific patient group, based on the principles of personalized and precision medicine. Our results indicate that genetic TDP-43-FTD is characterized by increased CSF TPD-43 and increased TDP-43 × τΤ/τP-181 combination. Hence, TDP-43 combined with tau proteins could be a useful tool for the diagnosis of genetic FTD with TDP-43 underling histopathology, supplementing clinical, neuropsychological and imaging data

Callosal Angle Sub-Score of the Radscale in Patients with Idiopathic Normal Pressure Hydrocephalus Is Associated with Positive Tap Test Response

The aim of the present study was the implementation of the composite imaging “Radscale” in patients with idiopathic normal pressure hydrocephalus (iNPH) and the evaluation of its score, as well as absolute stroke volume and peak flow velocity of cerebrospinal fluid (CSF) in aqueduct as indicators of a positive response following a tap test. Forty-five patients with iNPH were included. Clinical evaluation involved the 10 m timed walk test before and every 24 h for 3 consecutive days after evacuative lumbar puncture (LP). Neuropsychological evaluation comprised a mini mental state examination (MMSE), frontal assessment battery (FAB), 5-word test (5WT) and CLOX drawing test 1 and 2, which were carried out before and 48 h after LP. The tap test’s response was defined as a ≥20% improvement in gait and/or a ≥10% improvement in neuropsychological tests. All scores of neuropsychological and clinical variables, except for immediate 5WT and CLOX-1, differed significantly before and 48 h after LP. Improvement in time and steps of a 10 m timed walk test differed significantly between female and male patients. Out of 45 total patients, 19 were tap test responders and 26 non-responders. The total score of Radscale and CSF flow parameters did not differ between responders and non-responders. However, “Callosal angle” sub-score differed significantly between these two groups. A greater “callosal angle” sub-score, meaning more acute callosal angle, was associated with a positive tap test response, rendering it a useful measurement in the stratification of iNPH patients that will potentially respond to CSF shunting

CSF Aβ42 and Aβ42/Aβ40 Ratio in Alzheimer’s Disease and Frontotemporal Dementias

Background: Alzheimer’s disease dementia (ADD) may manifest with atypical phenotypes, resembling behavioral variant frontotemporal dementia (bvFTD) and corticobasal syndrome (CBS), phenotypes which typically have an underlying frontotemporal lobar degeneration with tau proteinopathy (FTLD-tau), such as Pick’s disease, corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), or FTLD with TDP-43 proteinopathy (FTLD-TDP). CSF biomarkers total and phosphorylated tau (τT and τP-181), and amyloid beta with 42 and 40 amino acids (Aβ42 and Aβ40) are biomarkers of AD pathology. The primary aim of this study was to compare the diagnostic accuracy of Aβ42 to Aβ42/Aβ40 ratio in: (a) differentiating ADD vs. frontotemporal dementias; (b) patients with AD pathology vs. non-AD pathologies; (c) compare biomarker ratios and composite markers to single CSF biomarkers in the differentiation of AD from FTD; Methods: In total, 263 subjects were included (ADD: n = 98; bvFTD: n = 49; PSP: n = 50; CBD: n = 45; controls: n = 21). CSF biomarkers were measured by commercially available ELISAs (EUROIMMUN). Multiple biomarker ratios (Aβ42/Aβ40; τT/τP-181; τT/Aβ42; τP-181/Aβ42) and composite markers (t-tau: τT/(Aβ42/Aβ40); p-tau: τP-181/(Aβ42/Aβ40) were calculated. ROC curve analysis was performed to compare AUCs of Aβ42 and Aβ42/Aβ40 ratio and relevant composite markers between ADD and FTD, as defined clinically. BIOMARKAPD/ABSI criteria (abnormal τT, τP-181 Aβ42, and Aβ42/Aβ40 ratio) were used to re-classify all patients into AD pathology vs. non-AD pathologies, and ROC curve analysis was repeated to compare Aβ42 and Aβ42/Aβ40; Results: Aβ42 did not differ from Aβ42/Aβ40 ratio in the differentiation of ADD from FTD (AUCs 0.752 and 0.788 respectively; p = 0.212). The τT/Aβ42 ratio provided maximal discrimination between ADD and FTD (AUC:0.893; sensitivity 88.8%, specificity 80%). BIOMARKAPD/ABSI criteria classified 60 patients as having AD pathology and 211 as non-AD. A total of 22 had discrepant results and were excluded. Aβ42/Aβ40 ratio was superior to Aβ42 in the differentiation of AD pathology from non-AD pathology (AUCs: 0.939 and 0.831, respectively; p 42/Aβ40 ratio is superior to Aβ42 in identifying AD pathology, irrespective of the clinical phenotype. CSF biomarker ratios and composite markers provide higher diagnostic accuracy compared to single CSF biomarkers

Alzheimer’s Disease CSF Biomarkers as Possible Indicators of Tap-Test Response in Idiopathic Normal Pressure Hydrocephalus

The aim of the present study is the evaluation of established Alzheimer’s disease (AD) cerebrospinal fluid (CSF) biomarkers in patients with idiopathic normal-pressure hydrocephalus (iNPH), both individually and as a total profile, and the investigation of their use as potential predictors of Tap-test responsiveness. Fifty-three patients with iNPH participated in the study. Aβ42, Aβ40, total Tau and phospho-Tau proteins were measured in duplicate with double-sandwich ELISA assays. Clinical evaluation involved a 10 m timed walk test before an evacuative lumbar puncture (LP) and every 24 h for three consecutive days afterwards. Neuropsychological assessment involved a mini-mental state examination, frontal assessment battery, 5-word test and CLOX drawing test 1 and 2, which were also performed before and 48 h after LP. Response in the Tap-test was defined as a 20% improvement in gait and/or a 10% improvement in neuropsychological tests. The Aβ42/Aβ40 ratio was found to be significantly higher in Tap-test responders than non-responders. Total Tau and phospho-Tau CSF levels also differed significantly between these two groups, with Tap-test responders presenting with lower levels compared to non-responders. Regarding the AD CSF biomarker profile (decreased amyloid and increased Tau proteins levels), patients with a non-AD profile were more likely to have a positive response in the Tap-test than patients with an AD profile

Biomarker-based diagnosis of cognitive disorders in a case series

The classical cerebrospinal fluid biomarkers of Alzheimer’s Disease (namely total tau, phospho-tau and amyloid beta peptide) have received much attention, since they can detect the biochemical fingerprint of Alzheimer’s disease and serve as a diagnostic aid for correct diagnosis of cognitive disorders during life. In this case series, we present 6 examples of patients with cognitive impairment of various types and severities and how biomarker data were helpful in every day diagnostic approach, combined with clinical, neuropsychological and imaging data and based on the most recent guidelines and recommendations