Abstract Introduction Biomarkers monitoring synaptic degeneration/loss would be valuable for Alzheimer's disease (AD) diagnosis. Postsynaptic protein neurogranin may be a promising cerebrospinal ...fluid (CSF) biomarker but has not yet been evaluated as a plasma biomarker. Methods Using an in-house designed prototype enzyme-linked immunosorbent assay (ELISA) targeting neurogranin C-terminally, we studied neurogranin in paired CSF/plasma samples of controls (n = 29) versus patients experiencing MCI, or dementia, due to AD (in total n = 59). Results CSF neurogranin was increased in AD and positively correlated with CSF tau, whereas there was a negative relationship between CSF neurogranin (and tau) and CSF Aβ1–42 /Aβ1–40 . No differences were detected in plasma neurogranin between controls and AD. Also, there was no correlation between CSF and plasma neurogranin, excluding confounding effects of the latter. Discussion This study strengthens the potential of neurogranin as an AD CSF biomarker, which now needs validation in larger studies. As tools, straightforward immunoassays can be used, as demonstrated by the described ELISA.
Although typical forms of Alzheimer disease (AD) and Creutzfeldt-Jakob disease (CJD) are clinically distinguishable, atypical AD phenotypes may pose a diagnostic challenge. The major biological ...diagnostic biomarker for identifying CJD, 14-3-3 protein in cerebrospinal fluid (CSF), unfortunately lacks specificity when confronting a rapid dementia presentation.
To assess the relevance of total CSF prion protein (t-PrP) levels in the differential biological diagnosis between atypical AD phenotypes and CJD.
A retrospective study in an autopsy-confirmed cohort of 82 patients was performed to evaluate the relevance of CSF t-PrP to distinguish 30 definite cases of AD from 52 definite cases of CJD. Next, CSF t-PrP concentration was measured in a cohort of 104 patients including 55 patients with probable AD, 26 with probable sporadic CJD, and 23 control patients for whom 14-3-3 protein, total tau, phosphorylated tau 181 (P-tau181), and Aβ1-42 were available. We investigated 46 patients diagnosed as having probable AD who presented atypical phenotypes. A diagnosis strategy was proposed to classify atypical AD phenotypes with suspicion of CJD based on a decision tree combining CSF biomarkers.
We determined CSF t-PrP levels for all patients. We calculated the ratio of total tau and P-tau181 and determined the diagnostic accuracy of each biomarker alone or in combination. We calculated the misclassification rate for each biomarker that corresponded to the percentage of patients within the group of atypical AD phenotypes wrongly classified as CJD.
In patients with CJD, CSF t-PrP concentrations were decreased compared with control participants and patients with AD. When considering the differential diagnosis of CJD compared with atypical AD phenotypes, CSF t-PrP determination reached 82.1% sensitivity and 91.3% specificity. The misclassification rate of atypical AD phenotypes decreased from 43.5%, obtained when using the CSF 14-3-3 protein determination alone, to only 4.3% when calculating the ratio total tau/(P-tau181 × t-PrP). The proposed classification tree permitted correct classification of 98.4% of the patients.
For unusual phenotypes of AD, especially cases presenting with a biological ambiguity suggesting CJD, determination of CSF t-PrP levels increased diagnostic accuracy. The use of CSF t-PrP levels may be beneficial in clinical practice in addition to the current classic biomarkers.
The purpose of this explorative study was to investigate whether diffusion tensor imaging (DTI) and diffusion kurtosis imaging (DKI) parameter changes are reliable measures of white matter integrity ...changes in Alzheimer's disease (AD) patients using a whole brain voxel-based analysis (VBA). Therefore, age- and gender-matched patients with mild cognitive impairment (MCI) due to AD (n = 18), dementia due to AD (n = 19), and age-matched cognitively healthy controls (n = 14) were prospectively included. The magnetic resonance imaging protocol included routine structural brain imaging and DKI. Datasets were transformed to a population-specific atlas space. Groups were compared using VBA. Differences in diffusion and mean kurtosis measures between MCI and AD patients and controls were shown, and were mainly found in the splenium of the corpus callosum and the corona radiata. Hence, DTI and DKI parameter changes are suggestive of white matter changes in AD.
•icobrain dm is an automated brain MRI segmentation faster than Freesurfer.•Significantly higher accuracy was obtained for several brain structures, including hippocampus.•icobrain dm volumes had a ...test-retest error below normal annual atrophy rates.•icobrain dm temporal lobe volume had highest sensitivity in discriminating Alzheimer's.
Brain volumes computed from magnetic resonance images have potential for assisting with the diagnosis of individual dementia patients, provided that they have low measurement error and high reliability. In this paper we describe and validate icobrain dm, an automatic tool that segments brain structures that are relevant for differential diagnosis of dementia, such as the hippocampi and cerebral lobes. Experiments were conducted in comparison to the widely used FreeSurfer software. The hippocampus segmentations were compared against manual segmentations, with significantly higher Dice coefficients obtained with icobrain dm (25–75th quantiles: 0.86–0.88) than with FreeSurfer (25–75th quantiles: 0.80–0.83). Other brain structures were also compared against manual delineations, with icobrain dm showing lower volumetric errors overall. Test-retest experiments show that the precision of all measurements is higher for icobrain dm than for FreeSurfer except for the parietal cortex volume. Finally, when comparing volumes obtained from Alzheimer's disease patients against age-matched healthy controls, all measures achieved high diagnostic performance levels when discriminating patients from cognitively healthy controls, with the temporal cortex volume measured by icobrain dm reaching the highest diagnostic performance level (area under the receiver operating characteristic curve = 0.99) in this dataset.
Objectives This study aimed to evaluate the potential clinical value of a new brain age prediction model as a single interpretable variable representing the condition of our brain. Among many ...clinical use cases, brain age could be a novel outcome measure to assess the preventive effect of life-style interventions. Methods The REMEMBER study population (N = 742) consisted of cognitively healthy (HC,N = 91), subjective cognitive decline (SCD,N = 65), mild cognitive impairment (MCI,N = 319) and AD dementia (ADD,N = 267) subjects. Automated brain volumetry of global, cortical, and subcortical brain structures computed by the CE-labeled and FDA-cleared software icobrain dm (dementia) was retrospectively extracted from T1-weighted MRI sequences that were acquired during clinical routine at participating memory clinics from the Belgian Dementia Council. The volumetric features, along with sex, were combined into a weighted sum using a linear model, and were used to predict 'brain age' and 'brain predicted age difference' (BPAD = brain age-chronological age) for every subject. Results MCI and ADD patients showed an increased brain age compared to their chronological age. Overall, brain age outperformed BPAD and chronological age in terms of classification accuracy across the AD spectrum. There was a weak-to-moderate correlation between total MMSE score and both brain age (r = -0.38,p < .001) and BPAD (r = -0.26,p < .001). Noticeable trends, but no significant correlations, were found between BPAD and incidence of conversion from MCI to ADD, nor between BPAD and conversion time from MCI to ADD. BPAD was increased in heavy alcohol drinkers compared to non-/sporadic (p = .014) and moderate (p = .040) drinkers. Conclusions Brain age and associated BPAD have the potential to serve as indicators for, and to evaluate the impact of lifestyle modifications or interventions on, brain health. Keywords: Alzheimer's disease, Magnetic resonance imaging, Biomarker, Brain predicted age difference, Brain age, Automated volumetry
18FTHK5351 is a tau positron emission tomography tracer that has shown promise in quantifying tau distribution in tauopathies such as Alzheimer's disease (AD) and progressive supranuclear palsy ...(PSP). However, the interpretation of 18FTHK5351 uptake has been shown to be confounded by high monoamine oxidase B (MAO-B) availability across the brain in AD.
To test the hypothesis that the MAO-B inhibitor, rasagiline reduces 18FTHK5351 uptake in PSP.
Six individuals (4: PSP; 2: cognitively unimpaired, CU) underwent 18FTHK5351 and 18FAZD4694 to quantify baseline tau and amyloid deposition, respectively. Following a 10-day course of 1 mg rasagiline, all participants received a post-challenge 18FTHK5351 scan. The baseline and post-rasagiline challenge standardized uptake value (SUV) were generated normalized for patient weight and injected radioactivity.
The post-rasagiline regional SUV was reduced on average by 69–89% in PSP, and 53–81% in CU. The distributions of post-rasagiline 18FTHK5351 SUV among PSP individuals were not consistent with the typical pattern of tau aggregates in PSP.
Similar to AD, the interpretation of 18FTHK5351 uptake in PSP is likely confounded by off-target binding to MAO-B binding sites. 18FTHK5351 is not sufficient in quantifying tau aggregates in PSP using the proposed rasagiline dosing regimen.
The Alzheimer's disease (AD) cerebrospinal fluid (CSF) biomarkers Aβ
, t-tau, and p-tau
overlap with other diseases. New tau modifications or epitopes, such as the non-phosphorylated tau fraction ...(p-tau
), may improve differential dementia diagnosis. The goal of this study is to investigate if p-tau
can improve the diagnostic performance of the AD CSF biomarker panel for differential dementia diagnosis.
The study population consisted of 45 AD, 45 frontotemporal lobar degeneration (FTLD), 45 dementia with Lewy bodies (DLB), and 21 Creutzfeldt-Jakob disease (CJD) patients, and 20 cognitively healthy controls. A substantial subset of the patients was pathology-confirmed. CSF levels of Aβ
, t-tau, p-tau
, and p-tau
were determined with commercially available single-analyte enzyme-linked immunosorbent assay (ELISA) kits. Diagnostic performance was evaluated by receiver operating characteristic (ROC) curve analyses, and area under the curve (AUC) values were compared using DeLong tests.
The diagnostic performance of single markers as well as biomarker ratios was determined for each pairwise comparison of different dementia groups and controls. The addition of p-tau
to the AD biomarker panel decreased its diagnostic performance when discriminating non-AD, FTLD, and DLB from AD. As a single marker, p-tau
increased the diagnostic performance for CJD. No significant difference was found in AUC values with the addition of p-tau
when differentiating between AD or non-AD dementias and controls.
The addition of p-tau
to the AD CSF biomarker panel failed to improve differentiation between AD and non-AD dementias.
Disease-modifying treatment trials are increasingly advanced to the prodromal or preclinical phase of Alzheimer's disease (AD), and inclusion criteria are based on biomarkers rather than clinical ...symptoms. Therefore, it is of great interest to determine which biomarkers should be combined to accurately predict conversion from mild cognitive impairment (MCI) to AD dementia. However, up to date, only few studies performed a complete A/T/N subject characterization using each of the CSF and imaging markers, or they only investigated long-term (≥ 2 years) prognosis. This study aimed to investigate the association between cerebrospinal fluid (CSF), magnetic resonance imaging (MRI), amyloid- and
18
F-FDG positron emission tomography (PET) measures at baseline, in relation to cognitive changes and conversion to AD dementia over a short-term (12-month) period. We included 13 healthy controls, 49 MCI and 16 AD dementia patients with a clinical-based diagnosis and a complete A/T/N characterization at baseline. Global cortical amyloid-β (Aβ) burden was quantified using the
18
F-AV45 standardized uptake value ratio (SUVR) with two different reference regions (cerebellar grey and subcortical white matter), whereas metabolism was assessed based on
18
F-FDG SUVR. CSF measures included Aβ
1–42
, Aβ
1–40
, T-tau, P-tau
181
, and their ratios, and MRI markers included hippocampal volumes (HV), white matter hyperintensities, and cortical grey matter volumes. Cognitive functioning was measured by MMSE and RBANS index scores. All statistical analyses were corrected for age, sex, education, and
APOE
ε4 genotype. As a result, faster cognitive decline was most strongly associated with hypometabolism (posterior cingulate) and smaller hippocampal volume (e.g., Δstory recall: β = +0.43
p
< 0.001 and + 0.37
p
= 0.005, resp.) at baseline. In addition, faster cognitive decline was significantly associated with higher baseline Aβ burden only if SUVR was referenced to the subcortical white matter (e.g., Δstory recall: β = −0.28
p
= 0.020). Patients with MCI converted to AD dementia at an annual rate of 31%, which could be best predicted by combining neuropsychological testing (visuospatial construction skills) with either MRI-based HV or
18
F-FDG-PET. Combining all three markers resulted in 96% specificity and 92% sensitivity. Neither amyloid-PET nor CSF biomarkers could discriminate short-term converters from non-converters.
•
FDG-PET and MRI HV are the strongest predictors of cognitive decline and conversion to AD.
•
Combination of visuospatial construction testing with FDG-PET or MRI HV present high predicting power of conversion.
•
CSF and amyloid-PET seem less suitable markers of disease progression.
•
Increased AV45-PET predicts short-term cognitive decline if SUVR is referenced to WM instead of CB.
Alzheimer's disease cerebrospinal fluid (CSF) biomarkers 42 amino acid long amyloid-β peptide (Aβ1-42), total tau protein (T-tau), and tau protein phosphorylated at threonine 181 (P-tau181) are ...considered surrogate biomarkers of Alzheimer's disease pathology, and significantly improve diagnostic accuracy. Their ability to reflect neuropathological changes later in the disease course is not well characterized. This study aimed to assess the potential of CSF biomarkers measured in mid- to late-stage Alzheimer's disease to reflect post mortem neuropathological changes. Individuals were selected from 2 autopsy cohorts of Alzheimer's disease patients in Antwerp and Amsterdam. Neuropathological diagnosis was performed according to the updated consensus National Institute on Aging-Alzheimer's Association guidelines by Montine et al, which includes quantification of amyloid beta plaque, neurofibrillary tangle, and neuritic plaque load. CSF samples were analyzed for Aβ1-42, T-tau, and P-tau181 by ELISA. 114 cases of pure definite Alzheimer's disease were included in the study (mean age 74 years, disease duration 6 years at CSF sampling, 50% females). Median interval between CSF sampling and death was one year. We found no association between Aβ1-42 and Alzheimer's disease neuropathological change profile. In contrast, an association of P-tau181 and T-tau with Alzheimer's disease neuropathological change profile was observed. P-tau181 was associated with all three individual Montine scores, and the associations became stronger and more significant as the interval between lumbar puncture and death increased. T-tau was also associated with all three Montine scores, but in individuals with longer intervals from lumbar puncture to death only. Stratification of the cohort according to APOE ε4 carrier status revealed that the associations applied mostly to APOE ε4 non-carriers. Our data suggest that similarly to what has been reported for Aβ1-42, plateau levels of P-tau181 and T-tau are reached during the disease course, albeit at later disease stages, reducing the potential of tau biomarkers to monitor Alzheimer's disease pathology as the disease progresses. As a consequence, CSF biomarkers, which are performant for clinical diagnosis of early Alzheimer's disease, may not be well suited for staging or monitoring Alzheimer's disease pathology as it progresses through later stages.
TREM2 is an innate immune receptor expressed on the surface of microglia. Loss‐of‐function mutations of TREM2 are associated with increased risk of Alzheimer's disease (AD). TREM2 is a type‐1 protein ...with an ectodomain that is proteolytically cleaved and released into the extracellular space as a soluble variant (sTREM2), which can be measured in the cerebrospinal fluid (CSF). In this cross‐sectional multicenter study, we investigated whether CSF levels of sTREM2 are changed during the clinical course of AD, and in cognitively normal individuals with suspected non‐AD pathology (SNAP). CSF sTREM2 levels were higher in mild cognitive impairment due to AD than in all other AD groups and controls. SNAP individuals also had significantly increased CSF sTREM2 compared to controls. Moreover, increased CSF sTREM2 levels were associated with higher CSF total tau and phospho‐tau181P, which are markers of neuronal degeneration and tau pathology. Our data demonstrate that CSF sTREM2 levels are increased in the early symptomatic phase of AD, probably reflecting a corresponding change of the microglia activation status in response to neuronal degeneration.
Synopsis
TREM2 is an innate immune receptor selectively expressed by microglia in the brain. Measuring its soluble variant in the CSF (sTREM2) may be a candidate as a marker of microglial activity. This study aimed to investigate how CSF sTREM2 levels change during the course of Alzheimer's disease (AD).
CSF sTREM2 levels are increased in the mild cognitive impairment (MCI) stage of AD compared to controls (P = 0.002), and to the preclinical (trend level, P = 0.062), and dementia stage of AD (P = 0.013).
CSF sTREM2 levels are increased in individuals with suspected non‐AD pathology (SNAP) compared to controls (P = 0.0004).
CSF sTREM2 levels increase with aging.
Increased CSF sTREM2 levels are associated with higher levels of T‐tau and P‐tau181P, markers of neuronal cell injury, and neurofibrillary tangles.
TREM2 is an innate immune receptor selectively expressed by microglia in the brain. Measuring its soluble variant in the CSF (sTREM2) may be a candidate as a marker of microglial activity. This study aimed to investigate how CSF sTREM2 levels change during the course of Alzheimer's disease (AD).
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