Cerebrospinal Fluid Amyloid-β Research Articles

CSF β-amyloid predicts prognosis in patients with multiple sclerosis

Background: The importance of predicting disease progression in multiple sclerosis (MS) has increasingly been recognized, and hence reliable biomarkers are needed. Objectives: To investigate the prognostic role of cerebrospinal fluid (CSF) amyloid beta1–42 (Aβ) levels by the determination of a cut-off value to classify patients in slow and fast progressors. To evaluate possible association with white matter (WM) and grey matter (GM) damage at early disease stages. Methods: Sixty patients were recruited and followed up for 3–5 years. Patients underwent clinical assessment, brain magnetic resonance imaging (MRI; at baseline and after 1 year), and CSF analysis to determine Aβ levels. T1-weighted volumes were calculated. T2-weighted scans were used to quantify WM lesion loads. Results: Lower CSF Aβ levels were observed in patients with a worse follow-up Expanded Disability Status Scale (EDSS; r = −0.65, p < 0.001). The multiple regression analysis confirmed CSF Aβ concentration as a predictor of patients’ EDSS increase (r = −0.59, p < 0.0001). Generating a receiver operating characteristic curve, a cut-off value of 813 pg/mL was determined as the threshold able to identify patients with worse prognosis (95% confidence interval (CI): 0.690–0.933, p = 0.0001). No differences in CSF tau and neurofilament light chain (NfL) levels were observed (p > 0.05). Conclusion: Low CSF Aβ levels may represent a predictive biomarker of disease progression in MS.

Dissociation of cerebrospinal fluid amyloid-β and tau levels in patients with prolonged posttraumatic disorders of consciousness

ABSTRACTBackground: Traumatic brain injury (TBI) is a major risk factor for Alzheimer’s disease (AD). Although the mechanisms that lead to AD after a TBI are unclear, we hypothesize that changes in amyloid-β (Aβ) metabolism and abnormal tau phosphorylation are reasonable candidates.Objective: To investigate Aβ and tau dynamics in the chronic phase of TBI.Methods: We evaluated Aβ1-42, total tau (t-tau), and phosphorylated tau (p-tau) levels in the cerebrospinal fluid (CSF) of 15 patients who developed a prolonged disorder of consciousness after a severe TBI (mean time from TBI 271.6 ± 176.5 days).Results: Reduced Aβ1-42 levels (median 258 pg/ml, range 90–833.6) were observed in 14/15 patients (93.3%) with severe post-TBI disorders of consciousness. These CSF analysis data did not correlate with time since TBI or with the patients’ level of consciousness as determined by the Coma Recovery Scale Revised. Normal t-tau levels (median 95.2 pg/ml, range 52–256.9) were found in all patients. Normal p-tau levels (median 22.2 pg/ml, range 14–72) were observed in 14/15 patients, with just a single patient having a slightly increased p-tau level.Conclusion: The present findings show that Aβ and tau are differently affected in the chronic phase of severe TBI.

The Progressive Acalculia Presentation of Parietal Variant Alzheimer's Disease.

Many patients with early-onset Alzheimer's disease (EOAD; age of onset <65 years) have non-amnestic presentations involving language (logopenic primary progressive aphasia, lvPPA), visuospatial abilities (posterior cortical atrophy, PCA), and even asymmetric symptoms consistent with corticobasal syndrome (CBS). An inferior parietal lobule variant of EOAD commonly presents with progressive difficulty with calculations. We reviewed 276 EOAD patients for presentations with predominant acalculia. These patients were diagnosed with clinically probable Alzheimer's disease (AD) verified by positron emission tomography (PET) or cerebrospinal fluid amyloid-β or tau biomarkers. We identified 18 (9M/9F) (6.5%) EOAD patients with progressive acalculia that did not meet most criteria for lvPPA, visual PCA, or CBS. Their ages of onset and presentation were 56.6 (5.0) and 59.4 (6.5), respectively. Their acalculia was consistent with a primary acalculia ("anarithmetia") not explained by language or visuospatial impairments. Many also had anomia (14/18), ideomotor apraxia (13/18), and the complete Gerstmann's syndrome (7/18). Visual analysis of their diverse magnetic resonance imaging disclosed biparietal atrophy, disproportionately worse on the left. Primary acalculia may be the most common manifestation of an inferior parietal presentation of EOAD affecting the left intraparietal sulcus. This parietal variant also commonly involves progressive anomia, ideomotor apraxia, and other elements of Gerstmann's syndrome. The early recognition of patients with this variant, which is distinguishable from lvPPA, visual PCA, or CBS, would be facilitated by its recognition as a unique subtype of EOAD.

A biomarker study in long-lasting amnestic mild cognitive impairment

BackgroundMild cognitive impairment (MCI) is a heterogeneous syndrome resulting from Alzheimer’s disease (AD) as well as to non-AD and non-neurodegenerative conditions. A subset of patients with amnestic MCI (aMCI) present with an unusually long-lasting course, a slow rate of clinical neuropsychological progression, and evidence of focal involvement of medial temporal lobe structures. In the present study, we explored positron emission tomography (PET) and cerebrospinal fluid (CSF) biomarkers in a sample of subjects with aMCI with such clinical features in order to provide in vivo evidence to improve disease characterisation in this subgroup.MethodsThirty consecutive subjects with aMCI who had long-lasting memory impairment (more than 4 years from symptom onset) and a very slow rate of cognitive progression were included. All subjects underwent fluorodeoxyglucose-positron emission tomography (FDG-PET) metabolic imaging. A measure of cerebral amyloid load, by PET and/or CSF, was obtained in 26 of 30 subjects. The mean clinical follow-up was 58.3 ± 10.1 months.ResultsNo patient progressed to dementia during the follow-up. The typical AD FDG-PET pattern of temporoparietal hypometabolism was not present in any of the subjects. In contrast, a selective medial temporal lobe hypometabolism was present in all subjects, with an extension to frontolimbic regions in some subjects. PET imaging showed absent or low amyloid load in the majority of samples. The values were well below those reported in prodromal AD, and they were slightly elevated in only two subjects, consistent with the CSF β-amyloid (1–42) protein values. Notably, no amyloid load was present in the hippocampal structures.ConclusionsFDG-PET and amyloid-PET together with CSF findings questioned AD pathology as a unique neuropathological substrate in this aMCI subgroup with long-lasting disease course. The possibility of alternative pathological conditions, such as argyrophilic grain disease, primary age-related tauopathy or age-related TDP-43 proteinopathy, known to spread throughout the medial temporal lobe and limbic system structures should be considered in these patients with MCI.

Update on Vascular Cognitive Impairment Associated with Subcortical Small-Vessel Disease.

Subcortical small-vessel disease (SSVD) is a disorder well characterized from the clinical, imaging, and neuropathological viewpoints. SSVD is considered the most prevalent ischemic brain disorder, increasing in frequency with age. Vascular risk factors include hypertension, diabetes, hyperlipidemia, elevated homocysteine, and obstructive sleep apnea. Ischemic white matter lesions are the hallmark of SSVD; other pathological lesions include arteriolosclerosis, dilatation of perivascular spaces, venous collagenosis, cerebral amyloid angiopathy, microbleeds, microinfarcts, lacunes, and large infarcts. The pathogenesis of SSVD is incompletely understood but includes endothelial changes and blood-brain barrier alterations involving metalloproteinases, vascular endothelial growth factors, angiotensin II, mindin/spondin, and the mammalian target of rapamycin pathway. Metabolic and genetic conditions may also play a role but hitherto there are few conclusive studies. Clinical diagnosis of SSVD includes early executive dysfunction manifested by impaired capacity to use complex information, to formulate strategies, and to exercise self-control. In comparison with Alzheimer’s disease (AD), patients with SSVD show less pronounced episodic memory deficits. Brain imaging has advanced substantially the diagnostic tools for SSVD. With the exception of cortical microinfarcts, all other lesions are well visualized with MRI. Diagnostic biomarkers that separate AD from SSVD include reduction of cerebrospinal fluid amyloid-β (Aβ)42 and of the ratio Aβ42/Aβ40 often with increased total tau levels. However, better markers of small-vessel function of intracerebral blood vessels are needed. The treatment of SSVD remains unsatisfactory other than control of vascular risk factors. There is an urgent need of finding targets to slow down and potentially halt the progression of this prevalent, but often unrecognized, disorder.

Unbiased Approach to Counteract Upward Drift in Cerebrospinal Fluid Amyloid-β 1-42 Analysis Results.

Low cerebrospinal fluid (CSF) amyloid-β 1-42 (Aβ 1-42) concentrations indicate amyloid plaque accumulation in the brain, a pathological hallmark of Alzheimer disease (AD). Innotest assay values of Aβ 1-42 have gradually increased over the past 2 decades, which might lead to misclassification of AD when a single cutpoint for abnormality is used. We propose an unbiased approach to statistically correct for drift. We determined year-specific cutpoints with Gaussian mixture modeling, based on the cross-section of bimodal distributions of Aβ 1-42 concentrations in 4397 memory clinic patients. This allowed us to realign year-specific cutpoints as an unbiased method to remove drift from the data. Sensitivity and specificity to detect AD dementia were compared between corrected and uncorrected values. Aβ 1-42 values increased 22 pg/mL annually, and this could not be explained by changes in cohort composition. Our approach removed time dependencies [β (SE) = 0.07 (0.59); P = 0.91]. Statistically correcting for drift improved the sensitivity to detect AD dementia to 0.90 (95% CI, 0.89-0.92) from at least 0.66 (95% CI, 0.64-0.69) based on uncorrected data. Specificity became lower (0.69; 95% CI, 0.67-0.70) vs at most 0.80 (95% CI, 0.79-0.82) for uncorrected data. This approach may also be useful to standardize Aβ 1-42 CSF concentrations across different centers and/or platforms, and to optimize use of CSF biomarker data collected over a long period.

Interrelationship between the Levels of C9orf72 and Amyloid-β Protein Precursor and Amyloid-β in Human Cellsand Brain Samples.

A subset of C9orf72 repeat expansion-carrying frontotemporal dementia patients display an Alzheimer-like decrease in cerebrospinal fluid amyloid-β (Aβ) biomarker levels. We report that downregulation of C9orf72 in non-neuronal human cells overexpressing amyloid-β protein precursor (AβPP) resulted in increased levels of secreted AβPP fragments and Aβ, while levels of AβPP or its C-terminal fragments (CTFs) remained unchanged. In neuronal cells, AβPP and C83 CTF levels were decreased upon C9orf72 knockdown, but those of secreted AβPP fragments or Aβ remained unchanged. C9orf72 protein levels significantly increased in human brain with advancing neurofibrillary pathology and positively correlated with brain Aβ42 levels. Our data suggest that altered C9orf72 levels may lead to cell-type specific alterations in AβPP processing, but warrant further studies to clarify the underlying mechanisms.

Plasma biomarkers for Alzheimer’s

Protein clumps called amyloids accumulate in the brains of people with Alzheimer’s disease. The current methods for detecting amyloids—positron emission tomography (PET) imaging of the brain and measurement of the clumping protein amyloid-β in cerebrospinal fluid—are expensive and invasive. Researchers want more easily accessible biomarkers that can provide the same information, but they’ve had no luck so far. An international team led by Katsuhiko Yanagisawa of the Japanese National Center for Geriatrics & Gerontology now reports a promising set of amyloid biomarkers from blood plasma (Nature 2018, DOI: 10.1038/nature25456). The researchers pull target peptides out of plasma using immunoprecipitation and analyze them by mass spectrometry. Rather than use individual peptides as biomarkers, the researchers use peptide ratios. They measure levels of three peptides derived from the amyloid precursor protein—one that is involved in amyloid formation and two that are not—and calculate the ratios. The research ...

High performance plasma amyloid-β biomarkers for Alzheimer's disease.

To facilitate clinical trials of disease-modifying therapies for Alzheimer's disease, which are expected to be most efficacious at the earliest and mildest stages of the disease, supportive biomarker information is necessary. The only validated methods for identifying amyloid-β deposition in the brain-the earliest pathological signature of Alzheimer's disease-are amyloid-β positron-emission tomography (PET) imaging or measurement of amyloid-β in cerebrospinal fluid. Therefore, a minimally invasive, cost-effective blood-based biomarker is desirable. Despite much effort, to our knowledge, no study has validated the clinical utility of blood-based amyloid-β markers. Here we demonstrate the measurement of high-performance plasma amyloid-β biomarkers by immunoprecipitation coupled with mass spectrometry. The ability of amyloid-β precursor protein (APP)669-711/amyloid-β (Aβ)1-42 and Aβ1-40/Aβ1-42 ratios, and their composites, to predict individual brain amyloid-β-positive or -negative status was determined by amyloid-β-PET imaging and tested using two independent data sets: a discovery data set (Japan, n = 121) and a validation data set (Australia, n = 252 including 111 individuals diagnosed using 11C-labelled Pittsburgh compound-B (PIB)-PET and 141 using other ligands). Both data sets included cognitively normal individuals, individuals with mild cognitive impairment and individuals with Alzheimer's disease. All test biomarkers showed high performance when predicting brain amyloid-β burden. In particular, the composite biomarker showed very high areas under the receiver operating characteristic curves (AUCs) in both data sets (discovery, 96.7%, n = 121 and validation, 94.1%, n = 111) with an accuracy approximately equal to 90% when using PIB-PET as a standard of truth. Furthermore, test biomarkers were correlated with amyloid-β-PET burden and levels of Aβ1-42 in cerebrospinal fluid. These results demonstrate the potential clinical utility of plasma biomarkers in predicting brain amyloid-β burden at an individual level. These plasma biomarkers also have cost-benefit and scalability advantages over current techniques, potentially enabling broader clinical access and efficient population screening.

Structural Connectivity Alterations Along the Alzheimer's Disease Continuum: Reproducibility Across Two Independent Samples and Correlation with Cerebrospinal Fluid Amyloid-β and Tau.

Background:Gray matter changes associated with the progression of Alzheimer’s disease (AD) have been thoroughly studied. However, alterations in white matter tracts have received less attention, particularly during early or preclinical stages of the disease.Objective:To identify the structural connectivity changes across the AD continuum.Methods:We performed probabilistic tractography in a total of 183 subjects on two independent samples that include control (n = 68) and preclinical AD individuals (n = 28), patients diagnosed with mild cognitive impairment (MCI) due to AD (n = 44), and AD patients (n = 43). We compared the connectivity between groups, and with CSF Aβ42 and tau biomarkers.Results:We observed disconnections in preclinical individuals, mainly located in the temporal lobe. This pattern of disconnection spread to the parietal and frontal lobes at the MCI stage and involved almost all the brain in AD. These findings were not driven by gray matter atrophy.Discussion:Using tractography, we were able to identify white matter changes between subsequent disease stages and, notably, also in preclinical AD. Therefore, this method may be useful for detecting early and specific brain structural changes during preclinical AD stage.

Predicting progression from normal cognition to mild cognitive impairment for individuals at 5 years.

Recent evidence indicates that measures from cerebrospinal fluid, MRI scans and cognitive testing obtained from cognitively normal individuals can be used to predict likelihood of progression to mild cognitive impairment several years later, for groups of individuals. However, it remains unclear whether these measures are useful for predicting likelihood of progression for an individual. The increasing focus on early intervention in clinical trials for Alzheimer's disease emphasizes the importance of improving the ability to identify which cognitively normal individuals are more likely to progress over time, thus allowing researchers to efficiently screen participants, as well as determine the efficacy of any treatment intervention. The goal of this study was to determine which measures, obtained when individuals were cognitively normal, predict on an individual basis, the onset of clinical symptoms associated with a diagnosis of mild cognitive impairment due to Alzheimer's disease. Cognitively normal participants (n = 224, mean baseline age = 57 years) were evaluated with a range of measures, including: cerebrospinal fluid amyloid-β and phosphorylated-tau, hippocampal and entorhinal cortex volume, cognitive tests scores and APOE genotype. They were then followed to determine which individuals developed mild cognitive impairment over time (mean follow-up = 11 years). The primary outcome was progression from normal cognition to the onset of clinical symptoms of mild cognitive impairment due to Alzheimer's disease at 5 years post-baseline. Time-dependent receiver operating characteristic analyses examined the sensitivity and specificity of individual measures, and combinations of measures, as predictors of the outcome. Six measures, in combination, were the most parsimonious predictors of transition to mild cognitive impairment 5 years after baseline (area under the curve = 0.85; sensitivity = 0.80, specificity = 0.75). The addition of variables from each domain significantly improved the accuracy of prediction. The incremental accuracy of prediction achieved by adding individual measures or sets of measures successively to one another was also examined, as might be done when enrolling individuals in a clinical trial. The results indicate that biomarkers obtained when individuals are cognitively normal can be used to predict which individuals are likely to develop clinical symptoms at 5 years post-baseline. As a number of the measures included in the study could also be used as subject selection criteria in a clinical trial, the findings also provide information about measures that would be useful for screening in a clinical trial aimed at individuals with preclinical Alzheimer's disease.

Cerebrospinal Fluid Amyloid-β Levels are Increased in Patients with Insomnia.

Previous studies demonstrate that patients with sleep disorders are at risk of developing Alzheimer's disease (AD), with the mechanism unknown. It is suggested that acute sleep deprivation induces an increase of amyloid-β (Aβ), the major pathological agent in AD, in the cerebrospinal fluid (CSF). In the present study, we recruited 23 patients with chronic insomnia aged between 46 to 67 years and 23 healthy controls aged between 43 to 67 years. We investigated the CSF levels of Aβ and tau, another pathological hallmark in the AD pathogenesis. We found that CSF Aβ42 levels were significantly increased in insomnia patients. However, no significant difference was found in Aβ40, total tau (t-Tau), and phosphorylated tau (p-Tau) between the two groups. Furthermore, we found that CSF Aβ40 and Aβ42 levels are significantly correlated with the sleep quality, as reflected by the Pittsburgh Sleep Quality Index (PSQI) scores. But no significant correlation was found in CSF t-Tau and p-Tau levels with PSQI. Our results indicate that chronic sleep disorders may induce the disruption of Aβ metabolism in the brain, thus increase the risk for developing AD.

Association of Cerebrospinal Fluid (CSF) Insulin with Cognitive Performance and CSF Biomarkers of Alzheimer's Disease.

Background:Abnormal insulin signaling in the brain has been linked to Alzheimer’s disease (AD).Objective:To evaluate whether cerebrospinal fluid (CSF) insulin levels are associated with cognitive performance and CSF amyloid-β and Tau. Additionally, we explore whether any such association differs by sex or APOE ɛ4 genotype.Methods:From 258 individuals participating in the Parelsnoer Institute Neurodegenerative Diseases, a nationwide multicenter memory clinic population, we selected 138 individuals (mean age 66±9 years, 65.2% male) diagnosed with subjective cognitive impairment (n = 45), amnestic mild cognitive impairment (n = 44), or AD (n = 49), who completed a neuropsychological assessment, including tests of global cognition and memory performance, and who underwent lumbar puncture. We measured CSF levels of insulin, amyloid-β1-42, total (t-)Tau, and phosphorylated (p-)Tau.Results:CSF insulin levels did not differ between the diagnostic groups (p = 0.136). Across the whole study population, CSF insulin was unrelated to cognitive performance and CSF biomarkers of AD, after adjustment for age, sex, body mass index, diabetes status, and clinic site (all p≥0.131). Importantly, however, we observed effect modification by sex and APOE ɛ4 genotype. Specifically, among women, higher insulin levels in the CSF were associated with worse global cognition (standardized regression coefficient –0.483; p = 0.008) and higher p-Tau levels (0.353; p = 0.040). Among non-carriers of the APOE ɛ4 allele, higher CSF insulin was associated with higher t-Tau (0.287; p = 0.008) and p-Tau (0.246; p = 0.029).Conclusion:Our findings provide further evidence for a relationship between brain insulin signaling and AD pathology. It also highlights the need to consider sex and APOE ɛ4 genotype when assessing the role of insulin.

Obstructive Sleep Apnea Severity Affects Amyloid Burden in Cognitively Normal Elderly. A Longitudinal Study.

Recent evidence suggests that obstructive sleep apnea (OSA) may be a risk factor for developing mild cognitive impairment and Alzheimer's disease. However, how sleep apnea affects longitudinal risk for Alzheimer's disease is less well understood. To test the hypothesis that there is an association between severity of OSA and longitudinal increase in amyloid burden in cognitively normal elderly. Data were derived from a 2-year prospective longitudinal study that sampled community-dwelling healthy cognitively normal elderly. Subjects were healthy volunteers between the ages of 55 and 90, were nondepressed, and had a consensus clinical diagnosis of cognitively normal. Cerebrospinal fluid amyloid β was measured using ELISA. Subjects received Pittsburgh compound B positron emission tomography scans following standardized procedures. Monitoring of OSA was completed using a home sleep recording device. We found that severity of OSA indices (AHIall [F1,88 = 4.26; P < 0.05] and AHI4% [F1,87 = 4.36; P < 0.05]) were associated with annual rate of change of cerebrospinal fluid amyloid β42 using linear regression after adjusting for age, sex, body mass index, and apolipoprotein E4 status. AHIall and AHI4% were not associated with increases in ADPiB-mask (Alzheimer's disease vulnerable regions of interest Pittsburg compound B positron emission tomography mask) most likely because of the small sample size, although there was a trend for AHIall (F1,28 = 2.96, P = 0.09; and F1,28 = 2.32, not significant, respectively). In a sample of cognitively normal elderly, OSA was associated with markers of increased amyloid burden over the 2-year follow-up. Sleep fragmentation and/or intermittent hypoxia from OSA are likely candidate mechanisms. If confirmed, clinical interventions for OSA may be useful in preventing amyloid build-up in cognitively normal elderly.

The Cerebrospinal Fluid Aβ1-42/Aβ1-40 Ratio Improves Concordance with Amyloid-PET for Diagnosing Alzheimer's Disease in a Clinical Setting.

Background:Evidence suggests that the concordance between amyloid-PET and cerebrospinal fluid (CSF) amyloid-β (Aβ) increases when the CSF Aβ1–42/Aβ1–40 ratio is used as compared to CSF Aβ1–42 levels alone.Objective:In order to test this hypothesis, we set up a prospective longitudinal study comparing the concordance between different amyloid biomarkers for Alzheimer’s disease (AD) in a clinical setting.Methods:Seventy-eight subjects (AD dementia (n = 17), mild cognitive impairment (MCI, n = 48), and cognitively healthy controls (n = 13)) underwent a [18F]Florbetapir ([18F]AV45) PET scan, [18F]FDG PET scan, MRI scan, and an extensive neuropsychological examination. In a large subset (n = 67), a lumbar puncture was performed and AD biomarkers were analyzed (Aβ1–42, Aβ1–40, T-tau, P-tau181).Results:We detected an increased concordance in the visual and quantitative (standardized uptake value ratio (SUVR) and total volume of distribution (VT)) [18F]AV45 PET measures when the CSF Aβ1–42/Aβ1–40 was applied compared to Aβ1–42 alone. CSF biomarkers were stronger associated to [18F]AV45 PET for SUVR values when considering the total brain white matter as reference region instead of cerebellar grey matterConclusions:The concordance between CSF Aβ and [18F]AV45 PET increases when the CSF Aβ1–42/Aβ1–40 ratio is applied. This finding is of most importance for the biomarker-based diagnosis of AD as well as for selection of subjects for clinical trials with potential disease-modifying therapies for AD.

Cerebrospinal Fluid Amyloid-β 42, Total Tau and Phosphorylated Tau are Low in Patients with Normal Pressure Hydrocephalus: Analogies and Differences with Alzheimer's Disease.

Co-existence of Alzheimer's disease (AD) in normal pressure hydrocephalus (NPH) is a frequent finding, thus a common pathophysiological basis between AD and NPH has been postulated. We measured CSF amyloid-β 42 (Aβ42), total tau (t-tau), and phosphorylated tau (p-tau) concentrations in a sample of 294 patients with different types of dementia and 32 subjects without dementia. We then compared scores on neuropsychological tests of NPH patients with pathological and normal CSF Aβ42 values. Aβ42 levels were significantly lower in NPH than in control patients, with no significant differences between AD and NPH. On the contrary, t-tau and p-tau levels were significantly lower in NPH than in AD, with no differences between NPH and controls. NPH patients with pathological Aβ42 levels did not perform worse than NPH patients with normal Aβ42 levels in any cognitive domains. Our data seem to support the hypothesis of amyloid accumulation in brains of NPH patients. Nevertheless, amyloid does not seem to play a pathogenetic role in the development of cognitive deficits in NPH.

DERIVING A CUT-OFF FOR THE ELECSYS® β-AMYLOID (1–42) IMMUNOASSAY FOR USE IN CLINICAL TRIALS SUPPORTED BY ELI LILLY FOR PATIENTS WITH CLINICALLY DEFINED ALZHEIMER’S DISEASE (AD)

Amyloid plaque is a histopathological hallmark of AD. In recent trials (EXPEDITION/EXPEDITION2; NCT00905372/NCT00904683) 26% of patients with clinically diagnosed mild-to-moderate AD lacked evidence of amyloid pathology (Siemers, Alzheimers Dement 2016). A subsequent trial, EXPEDITION3 (NCT01900665), was enriched for patients with objective, biomarker-based evidence of amyloid pathologies assessed by (18F)-florbetapir imaging or cerebrospinal fluid (CSF) β-Amyloid (1–42) analysis using the INNO-BIA AlzBio3 immunoassay (Fujirebio) and a 249pg/mL cut-off (Dean, AAIC 2014). The present study established a cut-off for use of the Elecsys®β-Amyloid (1–42) immunoassay (Roche Diagnostics) in future clinical trials, based on exploratory analysis of EXPEDITION/EXPEDITION2 CSF samples. Frozen archived CSF samples collected from a subset of patients with mild-to-moderate AD enrolled in EXPEDITION/EXPEDITION2 (for lumbar puncture addendum analysis) and where AlzBio3 data were available, were analyzed using the Elecsys® β-Amyloid (1–42) immunoassay on a cobas e analyzer. Methods used to estimate a cut-off for Elecsys® β-Amyloid (1–42) were: (a) comparison of results from Elecsys® β-Amyloid (1–42) and AlzBio3 immunoassays (n=206); (b) mixture modeling (n=216) and; (c) concordance with (18F)-florbetapir imaging-based categorical patient classification (n=75 scans). The Elecsys® β-Amyloid (1–42) immunoassay showed good concordance with the AlzBio3 immunoassay (Table). A cut-off estimate of 1065pg/mL was derived, which provided 93.7% (95% CI 89.5–96.6) overall percentage agreement (OPA) and 97.2% (95% CI 93.5–99.1) positive percentage agreement (PPA) with AlzBio3. A comparable cut-off estimate was derived from mixture modeling: 1017pg/mL. A cut-off estimate optimized relative to (18F)-florbetapir visual interpretation was derived as 1198pg/mL and had good concordance: 96.0% (95% CI 88.8–99.2) OPA and 98.4% (95% CI 91.2–100.0) PPA (standard uptake value ratio data were comparable). The cut-off estimates presented are specific to Lilly-sponsored trials and may not be appropriate for other applications. Three methods were used to derive cut-off estimates for the Elecsys® β-Amyloid (1–42) immunoassay in patients with AD in Eli Lilly-sponsored trials; these produced close numerical values with considerable overlap in 95% CIs for all estimates. The Elecsys® β-Amyloid (1–42) immunoassay-based patient classification showed good concordance with classification based on CSF β-Amyloid (1–42) determined by the AlzBio3 immunoassay and (18F)-florbetapir imaging.

A VISUAL COGNITIVE ASSESSMENT TOOL FOR THE DIAGNOSIS OF YOUNG-ONSET DEMENTIA: A BIOMARKER-SUPPORTED STUDY

Recent work has demonstrated the Montreal Cognitive Assessment (MoCA) and Visual Cognitive Assessment Test (VCAT)1 to be superior to MMSE in detecting cognitive impairment. However, the diagnostic performance of these cognitive screening tools is not well known in patients with young onset dementia (YOD) of the Alzheimer's type. Patients under the age of 65-year-old with memory complaints were recruited from the National Neuroscience Institute in a prospective study. Demographics, cognitive data and biomarker data including cerebrospinal fluid (CSF) were collected. Cognitive tests were administered by trained psychologists and CSF Amyloidβ, total tau and phosphor-tau were performed using ELISA techniques. Sensitivity (Se), Specificity (Sp), Positive Predicting Value (PPV), Negative Predicting Value (NPV) were calculated for MMSE, MoCA and VCAT using a 2x2 table where patients were classified by their CSF results based on the Tau/Amyloidβ Duit's score2(CSF negative= ≤0.52, CSF positive= >0.52,) and whether they were cognitively impaired based on a validated cut-off on the respective screening tools. VCAT individual domain scores were also correlated with domain-specified tests like the WMS story recall, REYS copy task, ADAS cancellation task, Boston Naming and Colour Trials 2. A total of 29 Young Dementia patients with CSF Amyloidβ and tau were recruited, and 16 of them fulfilled Duit's criteria for AD. Their mean (SD) age was 57.07 (6.65), mean (SD) year of education was 11.62 (4.18). 44.8% were males and 75.9% were Chinese. MMSE attained the lowest Se of 68.75% while MoCA and VCAT were quite comparable on Se and PPV at 93.75% vs 87.50 % and 85.71% vs 84,62% respectively, VCAT performed the most favorably in Sp (84.62%) and PPV (87.50%). VCAT individual domains of memory (r=0.836, p<0.001), visuo-spatial (r=0.746, p<0.001), language (r=0.732, p<0.001) and executive function (r=0.793, p<0.001) showed significant correlation to the other domain-specific tests. Our results support that VCAT will be a useful and effective tool in the diagnosis of Young Onset dementia. The high performance of the VCAT in this cohort is likely related to the large range of cognitive domains tested, including visual perception and agnosia. 1 Kandiah N, et al. Early detection of dementia in multilingual populations: Visual Cognitive Assessment Test (VCAT). Journal of Neurology, Neurosurgery & Psychiatry. 2016 Feb 1;87(2):156–60. 2 Duits FH, et al. The cerebrospinal fluid “Alzheimer profile”: easily said, but what does it mean? Alzheimer's & Dementia. 2014 Nov 30;10(6):713–23.

YOUNG-ONSET DEMENTIA IN A SOUTHEAST ASIAN POPULATION FROM SINGAPORE: CLINICAL AND BIOMARKER CHARACTERIZATION

Patients with Young onset dementia (YOD) are less likely to have mixed pathology, have a higher genetic predisposition and thus detailed characterization of this cohort may offer an opportunity for biomarker development and discovery of novel drug interventions. Existing Asian YOD cohorts are largely from Japan and thus little is known about the clinical and biomarker profile of YOD in Southeast Asia. We present the clinical and biomarker characteristics of Southeast Asian YOD patients from multiethnic Singapore. Patients were recruited from the National Neuroscience Institute beginning January 2012. Beginning July 2015, additional biomarker data including volumetric MRI, genetics and cerebrospinal fluid (CSF) were collected. Volumetric MRI was performed on a 3T Siemens machine. CSF Amyloidβ, total tau and phosphor-tau were performed using ELISA techniques. Diagnosis of dementia was made at consensus meetings comprising of cognitive neurologists, neuroradiologists, psychologists and dementia nurses. Alzheimer's disease (AD) was diagnosed based on the NIA-AA criteria, Vascular Dementia (VaD) based on the NINDS-ADRDA criteria and Frontotemporal Dementia (FTD) based on the Rascovsky criteria. MCI was diagnosed based on the Petersen's criteria. A total 309 patients were recruited between 2012 and Dec 2016. There were 250 patients with dementia (N, AD=145, VaD=30, FTD=48) and 59 patients with MCI. Mean (SD) age of onset for AD, VaD and FTD was 56.77 (5.06), 56.84 (5.61) and 56.60 (5.32) respectively. Family history of YOD among first degree relatives were present in 28.7% of AD, 10.0% of VAD and 22.9% of FTD. Of the 143 patients with Young Onset AD, 90.9% had amnestic AD, 2.1 % had behavioral variant AD and 1.4% had logopenic variant and 5.6% had Posterior Cortical Atrophy type of AD. 39.0% consented for CSF analyses. Further analyses with clinical, neuropsychological, volumetric MRI and CSF findings are on-going. This is the first report of YOD in Southeast Asians. AD continues to be the major subtype of YOD. Non-amnestic AD is present in about 10% and 29% of Young AD have a positive family history. Greater awareness on the clinical presentation of YOD among Southeast Asians is needed for earlier diagnosis and timely intervention.

THE LEFT PARIETAL VARIANT OF EARLY-ONSET ALZHEIMER’S DISEASE

A significant portion of patients with early-onset Alzheimer's disease (age of onset <65 years) have non-amnestic presentations, such as logopenic primary progressive aphasia (lvPPA), posterior cortical atrophy (PCA), and the behavioral/executive variant. The NIA-AA criteria for probable AD recognize language, visuospatial, and executive variants but do not specify other presentations for AD. We reviewed 220 patients with clinically diagnosed early-onset AD by NIA-AA criteria from a subspecialty university clinic. All patients had biomarker-supported clinically probably AD either by fluorodeoxyglucose positron emission tomography (FDG-PET) or cerebrospinal fluid β-amyloid or tau biomarkers. The presenting symptoms and clinical and neuroimaging characteristics were reviewed. We identified 15 (6M/9F) right-handed patients with AD who presented with predominant non-aphasic, non-visuospatial symptoms referable to the left parietal lobe. All lacked family history for an autosomal dominant disorder. Their ages of presentation and onset were 57.82 (8.9) and 55.11 (5.51), respectively. Mini-Mental State at onset was 23.1 (3.67) with retrospective Clinical Dementia Rating Scores of 1.23 (0.53). The predominant presenting symptoms were decreased writing (lexical and transitional motor) (9) decreased manual dexterity (3), and acalculia (5). On examination, the agraphia was usually lexical plus transitional motor; 12 had limb apraxia (10 ideomotor and 6 limb-kinetic); the acalculia was an anarithmetia; and 3 had the full Gerstmann syndrome. Neuroimaging, including FDG-PET was consistent with prominent dysfunction of the left parietal lobe. Patients with early-onset AD may present with variants such as lvPPA and PCA, and it is now possible to diagnose them with clinical AD using NIA-AA criteria. However, other variant presentations of early-onset AD need to be considered, including the combination of symptoms referable to disproportionate involvement of the left parietal lobe.