Longitudinal brain structural changes in preclinical Alzheimer's disease

Introduction

Brain structural changes in preclinical Alzheimer's disease (AD) are poorly understood.

Longitudinal change in CSF Tau and Aβ biomarkers for up to 48 months in ADNI

The dynamics of cerebrospinal fluid (CSF) tau and Aβ biomarkers over time in Alzheimer’s disease (AD) patients from prodromal pre-symptomatic to severe stages of dementia have not been clearly defined and recent studies, most of which are cross-sectional, present conflicting findings. To clarify this issue, we analyzed the longitudinal CSF tau and Aβ biomarker data from 142 of the AD Neuroimaging Initiative (ADNI) study subjects [18 AD, 74 mild cognitive impairment (MCI), and 50 cognitively normal subjects (CN)]. Yearly follow-up CSF collections and studies were conducted for up to 48 months (median = 36 months) for CSF Aβ_1–42, phosphorylated tau (p-tau₁₈₁), and total tau (t-tau). An unsupervised analysis of longitudinal measurements revealed that for Aβ_1–42 and p-tau₁₈₁ biomarkers there was a group of subjects with stable longitudinal CSF biomarkers measures and a group of subjects who showed a decrease (Aβ_1–42, mean = ?9.2 pg/ml/year) or increase (p-tau₁₈₁, mean = 5.1 pg/ml/year) of these biomarker values. Low baseline Aβ_1–42 values were associated with longitudinal increases in p-tau₁₈₁. Conversely, high baseline p-tau₁₈₁ values were not associated with changes in Aβ_1–42 levels. When the subjects with normal baseline biomarkers and stable concentrations during follow-up were excluded, the expected time to reach abnormal CSF levels and the mean AD values was significantly shortened. Thus, our data demonstrate for the first time that there are distinct populations of ADNI subjects with abnormal longitudinal changes in CSF p-tau₁₈₁ and Aβ_1–42 levels, and our longitudinal results favor the hypothesis that Aβ_1–42 changes precede p-tau₁₈₁ changes.     

CSF α-synuclein improves diagnostic and prognostic performance of CSF tau and Aβ in Alzheimer’s disease

Alzheimer’s disease (AD) and Lewy body diseases (LBD), e.g., Parkinson’s disease (PD) dementia and dementia with Lewy bodies (DLB), are common causes of geriatric cognitive impairments. In addition, AD and LBD are often found in the same patients at autopsy; therefore, biomarkers that can detect the presence of both pathologies in living subjects are needed. In this investigation, we report the assessment of α-synuclein (α-syn) in cerebrospinal fluid (CSF) and its association with CSF total tau (t-tau), phosphorylated tau₁₈₁ (p-tau₁₈₁), and amyloid beta_1-42 (Aβ_1-42) in subjects of the Alzheimer’s Disease Neuroimaging Initiative (ADNI; n = 389), with longitudinal clinical assessments. A strong correlation was noted between α-syn and t-tau in controls, as well as in patients with AD and mild cognitive impairment (MCI). However, the correlation is not specific to subjects in the ADNI cohort, as it was also seen in PD patients and controls enrolled in the Parkinson’s Progression Markers Initiative (PPMI; n = 102). A bimodal distribution of CSF α-syn levels was observed in the ADNI cohort, with high levels of α-syn in the subjects with abnormally increased t-tau values. Although a correlation was also noted between α-syn and p-tau₁₈₁, there was a mismatch (α-syn–p-tau₁₈₁-Mis), i.e., higher p-tau₁₈₁ levels accompanied by lower α-syn levels in a subset of ADNI patients. We hypothesize that this α-syn–p-tau₁₈₁-Mis is a CSF signature of concomitant LBD pathology in AD patients. Hence, we suggest that inclusion of measures of CSF α-syn and calculation of α-syn–p-tau₁₈₁-Mis improves the diagnostic sensitivity/specificity of classic CSF AD biomarkers and better predicts longitudinal cognitive changes.     

Update on the biomarker core of the Alzheimer's Disease Neuroimaging Initiative subjects

Here, we review progress by the Penn Biomarker Core in the Alzheimer's Disease Neuroimaging Initiative (ADNI) toward developing a pathological cerebrospinal fluid (CSF) and plasma biomarker signature for mild Alzheimer's disease (AD) as well as a biomarker profile that predicts conversion of mild cognitive impairment (MCI) and/or normal control subjects to AD. The Penn Biomarker Core also collaborated with other ADNI Cores to integrate data across ADNI to temporally order changes in clinical measures, imaging data, and chemical biomarkers that serve as mileposts and predictors of the conversion of normal control to MCI as well as MCI to AD, and the progression of AD. Initial CSF studies by the ADNI Biomarker Core revealed a pathological CSF biomarker signature of AD defined by the combination of Aβ1-42 and total tau (T-tau) that effectively delineates mild AD in the large multisite prospective clinical investigation conducted in ADNI. This signature appears to predict conversion from MCI to AD. Data fusion efforts across ADNI Cores generated a model for the temporal ordering of AD biomarkers which suggests that Aβ amyloid biomarkers become abnormal first, followed by changes in neurodegenerative biomarkers (CSF tau, F-18 fluorodeoxyglucose-positron emission tomography, magnetic resonance imaging) with the onset of clinical symptoms. The timing of these changes varies in individual patients due to genetic and environmental factors that increase or decrease an individual's resilience in response to progressive accumulations of AD pathologies. Further studies in ADNI will refine this model and render the biomarkers studied in ADNI more applicable to routine diagnosis and to clinical trials of disease modifying therapies.     

CSF biomarkers of Alzheimer's disease concord with amyloid-β PET and predict clinical progression: A study of fully automated immunoassays in BioFINDER and ADNI cohorts

Introduction

We studied whether fully automated Elecsys cerebrospinal fluid (CSF) immunoassay results were concordant with positron emission tomography (PET) and predicted clinical progression, even with cutoffs established in an independent cohort.

CSF Aβ42 and tau in Parkinson's disease with cognitive impairment

We tested the hypothesis that the CSF biomarker signature associated with Alzheimer's disease (AD) is present in a subset of individuals with Parkinson's disease and Dementia (PD‐D) or with PD and Cognitive Impairment, Not Dementia (PD‐CIND). We quantified CSF Aβ₄₂, total tau (T‐tau), and phospho‐tau (P181‐tau) using commercially available kits. Samples were from 345 individuals in seven groups (n): Controls ≤50 years (35), Controls >50 years (115), amnestic Mild Cognitive Impairment (aMCI) (24), AD (49), PD (49), PD‐CIND (62), and PD‐D (11). We observed expected changes in AD or aMCI compared with age‐matched or younger controls. CSF Aβ₄₂ was reduced in PD‐CIND (P < 0.05) and PD‐D (P < 0.01), whereas average CSF T‐tau and P181‐tau were unchanged or decreased. One‐third of PD‐CIND and one‐half of PD‐D patients had the biomarker signature of AD. Abnormal metabolism of Aβ₄₂ may be a common feature of PD‐CIND and PD‐D. © 2010 Movement Disorder Society     

Chronic depressive symptomatology and CSF amyloid beta and tau levels in mild cognitive impairment

Objectives

To investigate the association between chronic subsyndromal symptoms of depression (SSD), cerebrospinal fluid (CSF) biomarkers, and neuropsychological performance in individuals with mild cognitive impairment (MCI).

Methods

Participants included 238 older adults diagnosed with MCI from the Alzheimer's Disease Neuroimaging Initiative repository with cognitive and CSF amyloid beta (Aβ_1–42), total tau (t‐tau), and phosphorylated tau (p‐tau) data. The Neuropsychiatric Inventory identified individuals with chronic endorsement (SSD group N = 80) or no endorsement (non‐SSD group N = 158) of depressive symptoms across timepoints. CSF biomarker and cognitive performance were evaluated with linear regression models adjusting for age, education, gender, APOE genotype, global cognitive status, and SSD group.

Results

As compared to the non‐SSD group, the SSD group displayed lower CSF Aβ_1–42 levels (β = ?24.293, S.E. = 6.345, P < 0.001). No group differences were observed for CSF t‐tau (P = 0.497) or p‐tau levels (P = 0.392). Lower CSF Aβ_1–42 levels were associated with poorer performance on learning (β = 0.041, S.E. = 0.018, P = 0.021) and memory (β = ?0.012, S.E. = 0.005, P = 0.031) measures, whereas higher CSF t‐tau levels were associated with poorer performance on measures of global cognition (β = 0.022, S.E = 0.008, P = 0.007) and language (β = ?0.010, S.E = 0.004, P = 0.019). SSD was independently associated with diminished global cognition, learning and memory, language, and executive function performance over and above the effects of CSF biomarkers (all P < 0.05).

Conclusions

MCI participants with SSD displayed diminished CSF Aβ_1–42 levels but did not differ from non‐SSD controls in CSF tau levels. Additionally, CSF biomarkers and SSD independently accounted for variance in cognitive performance, suggesting that these factors may uniquely confer cognitive risk in MCI.     

CSF Apo-E levels associate with cognitive decline and MRI changes

Apolipoprotein E (APOE) ε4 allele is the most important genetic risk factor for Alzheimer’s disease (AD) and it is thought to do so by modulating levels of its product, apolipoprotein E (Apo-E), and regulating amyloid-β (Aβ) clearance. However, information on clinical and biomarker correlates of Apo-E proteins is scarce. We examined the relationship of cerebrospinal fluid (CSF) and plasma Apo-E protein levels, and APOE genotype to cognition and AD biomarker changes in 311 AD neuroimaging initiative subjects with CSF Apo-E measurements and 565 subjects with plasma Apo-E measurements. At baseline, higher CSF Apo-E levels were associated with higher total and phosphorylated CSF tau levels. CSF Apo-E levels were associated with longitudinal cognitive decline, MCI conversion to dementia, and gray matter atrophy rate in total tau/Aβ_1–42 ratio and APOE genotype-adjusted analyses. In analyses stratified by APOE genotype, our results were only significant in the group without the ε4 allele. Baseline CSF Apo-E levels did not predict longitudinal CSF Aβ or tau changes. Plasma Apo-E levels show a mild correlation with CSF Apo-E levels, but were not associated with longitudinal cognitive and MRI changes. Based on our analyses, we speculate that increased CSF Apo-E2 or -E3 levels might represent a protective response to injury in AD and may have neuroprotective effects by decreasing neuronal damage independent of tau and amyloid deposition in addition to its effects on amyloid clearance.     

Relations between personality changes and cerebrospinal fluid biomarkers of Alzheimer's disease pathology

Specific changes in personality profiles may represent early non-cognitive symptoms of Alzheimer's disease (AD). Evaluating the subject's personality changes may add significant clinical information, as well as help to better understand the interaction between personality change, cognitive decline, and cerebral pathology. With this study we aimed to describe the relationship between personality changes and cerebrospinal fluid (CSF) markers of AD pathology at early clinical stages of the disease. One hundred and ten subjects, of whom 66 cognitively impaired patients (57 with mild cognitive impairment (MCI), and 9 with mild dementia) and 44 healthy controls, had neuropsychological examination as well as lumbar puncture to determine concentrations of CSF biomarkers of AD pathology (amyloid beta_1-42 (Aβ_1-42), phosphorylated tau (ptau-181), and total-tau (tau)). The Revised NEO Personality Inventory (NEO-PI-R) was administered twice, once to evaluate subjects' current personality and once to assess personality traits retrospectively 5 years before evaluation. Subjects with an AD CSF biomarker profile showed significant increase in neuroticism and decrease in conscientiousness over time as compared to non-AD CSF biomarker group. In regression analysis controlling for global cognition as measured by the MMSE score, increasing neuroticism and decreasing extraversion, openness to experience and conscientiousness were associated with lower Aβ_1-42 concentrations but not with tau and ptau-181 concentrations. Our findings suggest that early and specific changes in personality are associated with cerebral AD pathology. Concentrations of CSF biomarkers, additionally to severity of the cognitive impairment, significantly contribute in predicting specific personality changes.     

Qualification of the analytical and clinical performance of CSF biomarker analyses in ADNI

The close correlation between abnormally low pre-mortem cerebrospinal fluid (CSF) concentrations of amyloid-??1-42 (A??_1?C42) and plaque burden measured by amyloid imaging as well as between pathologically increased levels of CSF tau and the extent of neurodegeneration measured by MRI has led to growing interest in using these biomarkers to predict the presence of AD plaque and tangle pathology. A challenge for the widespread use of these CSF biomarkers is the high variability in the assays used to measure these analytes which has been ascribed to multiple pre-analytical and analytical test performance factors. To address this challenge, we conducted a seven-center inter-laboratory standardization study for CSF total tau (t-tau), phospho-tau (p-tau₁₈₁) and A??_1?C42 as part of the Alzheimer??s Disease Neuroimaging Initiative (ADNI). Aliquots prepared from five CSF pools assembled from multiple elderly controls (n?=?3) and AD patients (n?=?2) were the primary test samples analyzed in each of three analytical runs by the participating laboratories using a common batch of research use only immunoassay reagents (INNO-BIA AlzBio3, xMAP technology, from Innogenetics) on the Luminex analytical platform. To account for the combined effects on overall precision of CSF samples (fixed effect), different laboratories and analytical runs (random effects), these data were analyzed by mixed-effects modeling with the following results: within center %CV 95% CI values (mean) of 4.0?C6.0% (5.3%) for CSF A??_1?C42; 6.4?C6.8% (6.7%) for t-tau and 5.5?C18.0% (10.8%) for p-tau₁₈₁ and inter-center %CV 95% CI range of 15.9?C19.8% (17.9%) for A??_1?C42, 9.6?C15.2% (13.1%) for t-tau and 11.3?C18.2% (14.6%) for p-tau₁₈₁. Long-term experience by the ADNI biomarker core laboratory replicated this degree of within-center precision. Diagnostic threshold CSF concentrations for A??_1?C42 and for the ratio t-tau/A??_1?C42 were determined in an ADNI independent, autopsy-confirmed AD cohort from whom ante-mortem CSF was obtained, and a clinically defined group of cognitively normal controls (NCs) provides statistically significant separation of those who progressed from MCI to AD in the ADNI study. These data suggest that interrogation of ante-mortem CSF in cognitively impaired individuals to determine levels of t-tau, p-tau₁₈₁ and A??_1?C42, together with MRI and amyloid imaging biomarkers, could replace autopsy confirmation of AD plaque and tangle pathology as the ??gold standard?? for the diagnosis of definite AD in the near future.     

Cerebrospinal fluid markers for Alzheimer's disease in a cognitively healthy cohort of young and old adults

BackgroundLow amyloid β₄₂ (Aβ₄₂) and high total tau and phosphorylated tau (p-tau) concentrations in the cerebrospinal fluid (CSF) are biomarkers of Alzheimer’s disease (AD), reflecting brain deposition of amyloid plaques and tangles. Age and apolipoprotein E allele E4 are two strong risk factors for AD, but few data are still available on their effect on CSF markers in normal aging.ObjectiveTo study the effect of age on CSF Aβ₄₂, total tau, and p-tau levels in a well-characterized group of cognitively normal subjects.MethodsCSF Aβ₄₂ levels of 81 subjects (27% female, 53 ± 15.3 years, range: 21–88) were determined with sandwich enzyme-linked immunosorbent assay; of these, total tau and p-tau levels were measured in 61 (75%) and 42 (52%) cases, respectively. A linear regression analysis between age and CSF markers was carried out on the whole sample and separately in apolipoprotein E allele ɛ4 carriers and noncarriers.ResultsThe median levels of all markers were significantly different between young (<65 years) and old (≥65 years) subjects (Aβ₄₂: P = .03; tau: P = .02; p-tau: P = .002; tau/Aβ₄₂: P = .004; p-tau/Aβ₄₂: P = .03). The association of marker levels with age was confirmed in linear regression models, where a positive relationship with age was observed for total tau (B = 2.3; 95% confidence interval [CI]: 0.89 to 3.7; P = .002), p-tau (B = 0.5; 95% CI: 0.1 to 0.9; P = .02), and tau/Aβ₄₂ ratio (B = 0.006; 95% CI: 0.002 to 0.01; P = .002). No subjects showed abnormal tau, whereas 19% showed abnormal CSF Aβ₄₂ concentrations.ConclusionIn cognitively normal subjects, the concentrations of CSF biomarkers of AD are associated with age. Further longitudinal studies could clarify whether Aβ₄₂ low levels represent a preclinical AD biomarker.     

Discriminatory and predictive capabilities of enzyme-linked immunosorbent assay and multiplex platforms in a longitudinal Alzheimer’s disease study

BackgroundMultiplex assays such as xMAP have been proposed for the assessment of Alzheimer’s disease (AD) biomarkers amyloid β 42 (Aβ₄₂), tau (Tau), and phosphorylated tau (pTau) in cerebrospinal fluid (CSF). Here, we compared the traditional enzyme-linked immunosorbent assay (ELISA) and xMAP with respect to their: (1) absolute biomarker concentration, (2) ability to distinguish AD from nondemented subjects, (3) ability to monitor AD longitudinally, and (4) ability to predict progression from mild cognitive impairment (MCI) to AD.MethodsWe selected 68 AD, 62 MCI, and 24 nondemented subjects, performed clinical examinations, and obtained CSF at baseline and 2 years later. Aβ₄₂, Tau, and pTau were measured with both ELISA and xMAP.ResultsBiomarker levels differed considerably between the two assays, and the differences were concentration dependent. No differences were observed in ability to distinguish nondemented subjects from AD patients between ELISA (area under curve of 0.84 for Aβ₄₂, 0.79 for Tau, and 0.75 for pTau) and xMAP (area under curve of 0.82 for Aβ₄₂, 0.75 for Tau, and 0.73 for pTau), all P < .05. Increased Aβ₄₂ levels of AD patients at follow-up compared with baseline were detected with ELISA, whereas increased Tau levels for nondemented subjects and MCI patients were only detected with xMAP. The hazard ratios for progression from MCI to AD did not differ between the assays.ConclusionBoth ELISA and multiplex assays can be used to measure AD biomarker levels in CSF to support clinical diagnosis and predict progression from MCI to AD with similar accuracy. Importantly, the assays’ output in absolute biomarker concentrations is remarkably different, and this discrepancy cannot be reconciled with simple correction factors.     

Alzheimer CSF biomarkers in routine clinical setting

Tabaraud F, Leman JP, Milor AM, Roussie JM, Barrière G, Tartary M, Boutros‐Toni F, Rigaud M. Alzheimer CSF biomarkers in routine clinical setting.
Acta Neurol Scand: 2012: 125: 416–423.
© 2011 John Wiley & Sons A/S. Objectives – Our work was aimed to evaluate Alzheimer’s disease diagnosis improvement using cerebrospinal fluid biomarkers (CSF) in neurological daily practice. Materials and Methods – For this purpose, 150 patients clinically and neurochemically classified as having AD or cognitive impairment with or without other dementia type were included in the study. The following CSF peptides were studied, blindly to the clinical diagnosis: beta‐amyloid_1–42 peptide (Aβ_1–42), Tau (T‐tau), threonine‐181 hyperphosphorylated tau protein (P‐tau₁₈₁), and beta‐amyloid_1–40 peptide (Aβ_1–40). From these measurements, Innotest® Amyloid Tau Index (IATI) was calculated for each patient. Results – This assessment allowed to separate 83 biochemical profiles of AD and 67 non‐Alzheimer’s disease (non‐AD), both AD and non‐AD categories match with clinical data amounting to 73% and 90%, respectively. Among mild cognitive impairment (MCI) patients, CSF biomarkers led to discriminate those who are likely to be AD. We devoted a special section to Aβ_1–40 which is not a routine parameter but can help to confirm a pathological amyloid process as Aβ_1–42/Aβ_1–40 ratio underlining the real decline of the Aβ_1–42. Conclusions – The interest of biomarkers and their ability to solve awkward cases were carefully noticed all the more when a discrepancy between clinical and CSF biological data was involved. The final proposed algorithm allowed to identify pathogenic forms of AD according to the prevailing role of hyperphosphorylated tau or amyloid beta peptide.     

Cerebrospinal fluid Aβ levels correlate with structural brain changes in Parkinson's disease

ParkWest is a large Norwegian multicenter study of newly diagnosed drug‐naïve subjects with Parkinson's disease (PD). Cognitively normal PD subjects (PDCN) and PD subjects with mild cognitive impairment (PDMCI) from this cohort have significant hippocampal atrophy and ventricular enlargement, compared to normal controls. Here, we aimed to investigate whether the same structural changes are associated with cerebrospinal fluid (CSF) levels of amyloid beta (Aβ)₃₈, Aβ₄₀, Aβ₄₂, total tau (t‐tau), and phosphorylated tau (p‐tau). We performed three‐dimensional radial distance analyses of the hippocampi and lateral ventricles using the MRI data from ParkWest subjects who provided CSF at baseline. Our sample consisted of 73 PDCN and 18 PDMCI subjects. We found significant associations between levels of all three CSF Aβ analytes and t‐tau and lateral ventricular enlargement in the pooled sample. In the PDCN sample, all three amyloid analytes showed significant associations with the radial distance of the occipital and frontal horns of the lateral ventricles. CSF Aβ₃₈ and Aβ₄₂ showed negative associations, with enlargement in occipital and frontal horns of the lateral ventricles in the pooled sample, and a negative association with the occipital horns in PDMCI. CSF Aβ levels in early PD correlate with ventricular enlargement, previously associated with PD dementia. Therefore, CSF and MRI markers may help identify PD patients at high risk for developing cognitive decline and dementia in the course of their illness. Contrary to Alzheimer's disease, we found no associations between CSF t‐tau and p‐tau and hippocampal atrophy. © 2013 Movement Disorder Society     

Patients with mild cognitive impairment and a reduced CSF Aβ₁₋₄₂ protein progress rapidly to Alzheimer's disease

Introduction

Some studies have shown that CSF amyloid-beta 1-42 (Aβ_1-42), total tau (T-tau) and tau phosphorylated at threonine 181 (P-tau_181p) proteins are useful diagnostic markers for distinguishing between clinically stable mild cognitive impairment (MCI) patients and those who will develop Alzheime?s disease (AD).Our objective was to test the ability of this technique to discriminate in our cohort of MCI patients, according to the clinical outcome, one year after the lumbar puncture.

Material and methods

A total of 36 MCI patients were included from the local hospital memory clinic. Using INNO-BIA Alzbio-3 reagents from Innogenetics, we measured CSF Aβ_1-42, T-tau and P-tau_181p proteins, and calculated the T-tau/Aβ_1-42 y P-tau_181p/Aβ_1-42 ratios. This project was approved by the local ethics committee.

Results

One year after the lumbar puncture, 14 MCI patients (38%) developed AD. These patients had lower Aβ _1-42 protein levels (285.3 vs 377 ng/ml, P < .02) and higher P-tau_181p/Aβ_1-42 ratio (0,25 vs 0,16, p < .02) than the clinically stable patients.

Conclusions

Our MCI patients with lower Aβ_1-42 protein levels and an increased P-tau_181p /Aβ_1-42 ratio progressed quickly to AD. These results may help to identify those MCI patients with a poorer prognosis.     

The clinical use of cerebrospinal fluid biomarker testing for Alzheimer's disease diagnosis: A consensus paper from the Alzheimer's Biomarkers Standardization Initiative

BackgroundCerebrospinal fluid (CSF) biomarkers β-amyloid 1-42 (Aβ_1-42), also expressed as Aβ_1-42:Aβ_1-40 ratio, T-tau, and P-tau_181P, have proven diagnostic accuracy for mild cognitive impairment and Alzheimer's disease (AD). How to use, interpret, and disclose biomarker results drives the need for standardization.MethodsPrevious Alzheimer's Biomarkers Standardization Initiative meetings discussed preanalytical issues affecting Aβ_1-42 and tau in CSF. This second round of consensus meetings focused on issues related to clinical use of AD CSF biomarkers.ResultsConsensus was reached that lumbar puncture for AD CSF biomarker analysis be considered as a routine clinical test in patients with early-onset dementia, at the prodromal stage or with atypical AD. Moreover, consensus was reached on which biomarkers to use, how results should be interpreted, and potential confounding factors.ConclusionsChanges in Aβ_1-42, T-tau, and P-tau_181P allow diagnosis of AD in its prodromal stage. Conversely, having all three biomarkers in the normal range rules out AD. Intermediate conditions require further patient follow-up.     

Plasma amyloid levels within the Alzheimer's process and correlations with central biomarkers

Introduction

Diagnostic relevance of plasma amyloid β (Aβ) for Alzheimer's disease (AD) process yields conflicting results. The objective of the study was to assess plasma levels of Aβ₄₂ and Aβ₄₀ in amnestic mild cognitive impairment (MCI), nonamnestic MCI, and AD patients and to investigate relationships between peripheral and central biomarkers.

Changes of cerebrospinal fluid Aβ<Subscript>42</Subscript>, t-tau,and p-tau in Parkinson’s disease patients with cognitive impairment relative to those with normal cognition: a meta-analysis

The cerebrospinal fluid (CSF) signature of reduced amyloid beta 1–42 (Aβ₄₂), elevated total tau (t-tau), and phosphorylated tau181 (p-tau) is important for the early diagnosis of Alzheimer’s disease (AD). Aβ₄₂, t-tau, and p-tau have been reported in numerous studies to contribute to predicting cognitive impairment in Parkinson’s disease (PDCI). However, no consistent conclusion can be drawn so far. Literatures regarding Aβ₄₂, t-tau, and p-tau in CSF were systematically reviewed, and a meta-analysis was thus performed to evaluate the changes of these biomarkers in PDCI patients, including PD with mild cognitive impairment (PDMCI) and PD dementia (PDD) patients, relative to PD with normal cognition (PDNC) patients. Databases of “PubMed,” “EBSCO,” and “Springer” were retrieved for articles concerning Aβ₄₂, t-tau, and p-tau in PDCI patients relative to those in PDNC patients published from January 1, 2000 to February 1, 2017. The following keywords were set, namely, “dementia” or “cognitive impairment” or “mild cognitive impairment” and “cerebrospinal fluid” and “Parkinson*.” Sixteen articles comprising 590 PDCI patients and 1182 PDNC patients were included. The results showed that CSF Aβ₄₂ level in PDCI cohort was lower than that in PDNC cohort (pooled Std.MD = ?0.44, 95% CI [?0.61, ?0.26], p < 0.00001). Reduced Aβ₄₂ (pooled Std.MD = ?0.60, 95% CI [?0.75, ?0.45], p < 0.00001) as well as elevated t-tau (pooled Std.MD = 0.21, 95% CI [0.06, 0.35], p = 0.006) and p-tau (pooled Std.MD = 0.36, 95% CI [0.02, 0.69], p = 0.04) could be observed in PDD cohort compared with PDNC cohort. Therefore, amyloid pathology and tauopathy may participate in the development of PDD, which is similar to AD.     

Cerebrospinal fluid α-synuclein contributes to the differential diagnosis of Alzheimer's disease

Introduction

The ability of Alzheimer's disease (AD) cerebrospinal fluid (CSF) biomarkers (amyloid β peptide 1–42, total tau, and phosphorylated tau) to discriminate AD from related disorders is limited. Biomarkers for other concomitant pathologies (e.g., CSF α-synuclein [α-syn] for Lewy body pathology) may be needed to further improve the differential diagnosis.

Contribution of CSF biomarkers to early‐onset Alzheimer's disease and frontotemporal dementia neuroimaging signatures

Prior studies have described distinct patterns of brain gray matter and white matter alterations in Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD), as well as differences in their cerebrospinal fluid (CSF) biomarkers profiles. We aim to investigate the relationship between early‐onset AD (EOAD) and FTLD structural alterations and CSF biomarker levels. We included 138 subjects (64 EOAD, 26 FTLD, and 48 controls), all of them with a 3T MRI brain scan and CSF biomarkers available (the 42 amino acid‐long form of the amyloid‐beta protein [Aβ42], total‐tau protein [T‐tau], neurofilament light chain [NfL], neurogranin [Ng], and 14‐3‐3 levels). We used FreeSurfer and FSL to obtain cortical thickness (CTh) and fraction anisotropy (FA) maps. We studied group differences in CTh and FA and described the “AD signature” and “FTLD signature.” We tested multiple regression models to find which CSF‐biomarkers better explained each disease neuroimaging signature. CTh and FA maps corresponding to the AD and FTLD signatures were in accordance with previous literature. Multiple regression analyses showed that the biomarkers that better explained CTh values within the AD signature were Aβ and 14‐3‐3; whereas NfL and 14‐3‐3 levels explained CTh values within the FTLD signature. Similarly, NfL levels explained FA values in the FTLD signature. Ng levels were not predictive in any of the models. Biochemical markers contribute differently to structural (CTh and FA) changes typical of AD and FTLD.