Biomarker For Dementia Research Articles

The Open-Access European Prevention of Alzheimer’s Dementia (EPAD) MRI dataset and processing workflow

The European Prevention of Alzheimer Dementia (EPAD) is a multi-center study that aims to characterize the preclinical and prodromal stages of Alzheimer’s Disease. The EPAD imaging dataset includes core (3D T1w, 3D FLAIR) and advanced (ASL, diffusion MRI, and resting-state fMRI) MRI sequences.Here, we give an overview of the semi-automatic multimodal and multisite pipeline that we developed to curate, preprocess, quality control (QC), and compute image-derived phenotypes (IDPs) from the EPAD MRI dataset. This pipeline harmonizes DICOM data structure across sites and performs standardized MRI preprocessing steps. A semi-automated MRI QC procedure was implemented to visualize and flag MRI images next to site-specific distributions of QC features — i.e. metrics that represent image quality. The value of each of these QC features was evaluated through comparison with visual assessment and step-wise parameter selection based on logistic regression. IDPs were computed from 5 different MRI modalities and their sanity and potential clinical relevance were ascertained by assessing their relationship with biological markers of aging and dementia.The EPAD v1500.0 data release encompassed core structural scans from 1356 participants 842 fMRI, 831 dMRI, and 858 ASL scans. From 1356 3D T1w images, we identified 17 images with poor quality and 61 with moderate quality. Five QC features — Signal to Noise Ratio (SNR), Contrast to Noise Ratio (CNR), Coefficient of Joint Variation (CJV), Foreground-Background energy Ratio (FBER), and Image Quality Rate (IQR) — were selected as the most informative on image quality by comparison with visual assessment. The multimodal IDPs showed greater impairment in associations with age and dementia biomarkers, demonstrating the potential of the dataset for future clinical analyses.

Grip Strength, Gait Speed and Plasma Markers of Neurodegeneration in Asymptomatic Middle-aged and Older Adults.

Pragmatic biomarkers of preclinical dementia would allow for easy and large-scale screening of risk in populations. Physical function measures like grip strength and gait speed are potential predictive biomarkers but their relationship with plasma markers of Alzheimer's Disease and neurodegeneration have not been elucidated. To examine association between physical function measures and plasma markers of Alzheimer's Disease (AD) and neurodegeneration. Cross-sectional and longitudinal analyses. Community-based cohort in the city of Framingham, Massachusetts. 2336 participants of the Framingham Heart Study Offspring cohort with an average age of 61. Plasma Aβ40 and Aβ42 were measured in 1998-2001 (Exam-7) and plasma total tau measured 5 years later (Exam-8). Grip strength, fast walk speed and chair stand speed were measured at both exams. Quantification of Aβ isoforms in plasma was performed using INNO-BIA assays and plasma total-tau was measured using Quanterix Simoa HD-1 assay. Confounder-adjusted linear regression models examined associations between physical function and plasma markers, Results: Grip strength at Exam-7 was associated with plasma Aβ40 (β -0.006, p-value 0.032) at Exam-7 and plasma total-tau (β -0.010, p-value 0.001) at Exam-8. Grip strength and fast walk speed at Exam-8 were associated with plasma total-tau at Exam-8 (GS: β -0.009, p 0.0005; FWS: β -0.226, p-value <0.0001). Chair stand speed was not associated with plasma markers; Aβ42 was not associated with function. Grip strength and fast walk speed are associated with plasma markers of neurodegeneration in dementia-free middle aged and older individuals. Both these measures could be used as potential screening tools for identifying individuals at a higher risk for AD and related dementias alongside other validated markers.

MicroRNA biomarkers in frontotemporal dementia and to distinguish from Alzheimer's disease and amyotrophic lateral sclerosis.

Frontotemporal lobar degeneration describes a group of progressive brain disorders that primarily are associated with atrophy of the prefrontal and anterior temporal lobes. Frontotemporal lobar degeneration is considered to be equivalent to frontotemporal dementia. Frontotemporal dementia is characterized by progressive impairments in behavior, executive function, and language. There are two main clinical subtypes: behavioral-variant frontotemporal dementia and primary progressive aphasia. The early diagnosis of frontotemporal dementia is critical for developing management strategies and interventions for these patients. Without validated biomarkers, the clinical diagnosis depends on recognizing all the core or necessary neuropsychiatric features, but misdiagnosis often occurs due to overlap with a range of neurologic and psychiatric disorders. In the studies reviewed a very large number of microRNAs were found to be dysregulated but with limited overlap between individual studies. Measurement of specific miRNAs singly or in combination, or as miRNA pairs (as a ratio) in blood plasma, serum, or cerebrospinal fluid enabled frontotemporal dementia to be discriminated from healthy controls, Alzheimer's disease, and amyotrophic lateral sclerosis. Furthermore, upregulation of miR-223-3p and downregulation of miR-15a-5p, which occurred both in blood serum and cerebrospinal fluid, distinguished behavioral-variant frontotemporal dementia from healthy controls. Downregulation of miR-132-3p in frontal and temporal cortical tissue distinguished frontotemporal lobar degeneration and frontotemporal dementia, respectively, from healthy controls. Possible strong miRNA biofluid biomarker contenders for behavioral-variant frontotemporal dementia are miR-223-3p, miR-15a-5p, miR-22-3p in blood serum and cerebrospinal fluid, and miR-124 in cerebrospinal fluid. No miRNAs were identified able to distinguish between behavioral-variant frontotemporal dementia and primary progressive aphasia subtypes. Further studies are warranted on investigating miRNA expression in biofluids and frontal/temporal cortical tissue to validate and extend these findings.

Serum immunoglobulins and biomarkers of dementia: A population‐based study

AbstractBackgroundDementia is a complex syndrome with multiple interacting pathways leading to brain damage and ultimately the clinical manifestation. In recent years, studies have identified the immune response as a novel contributing process to the aetiology of dementia, but it remains unclear how this links to established biomarkers of dementia, for instance those measured in plasma or on neuroimaging. We studied the association of serum immunoglobulins, markers of the adaptive immune response, with biomarkers of dementia.MethodBetween 1997 and 2009, serum immunoglobulins (IgA, IgG and IgM) were measured in 8,768 participants of the population‐based Rotterdam Study (median age 62.2 years, 57.0% women). Plasma biomarkers of dementia (total tau, neurofilament light chain (NfL), amyloid‐β40 (Aβ‐40), amyloid‐β42 (Aβ‐42)) were measured in a random sample of 3,455 participants. Neuroimaging was performed for 3,139 participants to quantify brain volume, white matter structural integrity and markers of cerebral small vessel disease. We used linear regression models to determine cross‐sectional associations of IgA, IgG, IgM and biomarkers of dementia in plasma and on neuroimaging, while adjusting for age, sex, cohort, education, cardiovascular risk factors and stratifying for APOE‐ε4 carriership. Plasma biomarkers were log2 transformed and neuroimaging markers were standardized to facilitate comparison.ResultHigher levels of IgA corresponded to higher log2 plasma levels of NfL (β=0.019, p=0.031), and a lower or higher tau and Aβ burden, depending on carriership of the APOE‐ε4 allele. Higher IgM was consistent with lower levels of all plasma biomarkers, particularly among no carriers of the APOE‐ε4 allele. No significant associations were found between IgG levels and plasma biomarkers, although associations were moderately driven by APOE‐ε4 allele carriership. Subsequently, higher serum immunoglobulin levels and in particular IgA, generally amounted to more brain atrophy (total brain volume (β=‐0.013, p=0.032), gray matter volume (β=‐0.026, p=0.009), decreased white matter integrity and increase of cerebral small vessel disease markers (white matter hyperintensities (β=0.041, p=0.008)).ConclusionThe associations between serum immunoglobulins and biomarkers of dementia in plasma partly depend on APOE‐ε4 carriership. Higher serum immunoglobulins generally correspond to more brain atrophy, diminished white matter integrity and more cerebral small vessel disease.

MRI and CSF markers of mild behavioural impairment: Findings from the MEMENTO cohort study

AbstractBackgroundMild behavioural impairment (MBI) is characterized by late‐life emergent and persistent neuropsychiatric symptoms (NPS). It is as an at‐risk state for incident cognitive decline and dementia. For some, MBI may be the first observable manifestation of a neurodegenerative process such as Alzheimer’s disease (AD).MethodsWe examined associations between MBI and established dementia imaging and CSF markers, in 789 participants with mild cognitive impairment (MCI). Study data were obtained from the French MEMENTO cohort study.Neuropsychiatric Inventory (NPI) scores were used to determine MBI scores using a published algorithm. NPI data at baseline and 6‐month visits were used to categorize patients into MBI+ (persistent NPS i.e., NPS at both time points) and MBI‐ (no NPS or NPS at either but not both time points). MRI and CSF measurements were completed at baseline. Linear regressions were fitted to assess if MBI status at 6 months was associated with reduced thickness or volume in each of the a priori selected regions associated with Braak stages 1‐5: entorhinal cortex, hippocampus, fusiform gyrus, inferior temporal cortex and frontal pole. To assess if MBI status was associated with CSF biomarkers (Aβ42, Aβ40, t‐tau, p‐tau, Aβ42/Aβ40, p‐tau/Aβ42 and t‐tau/Aβ42), seven linear regressions were conducted. All models controlled for age, sex, education, and mini‐mental state examination scores. Volume and thickness analysis further controlled for total intracranial volume.ResultsMBI+ (persistent NPS) status was associated with decreased entorhinal thickness and smaller hippocampal volume compared to MBI‐ (Table 1). There were no differences between MBI+ and MBI‐ groups in thickness of the Braak stage 3‐5 regions (Table 1). In the subset of MCI participants with CSF data (n=155), compared to MBI‐, MBI+ had lower CSF Aβ42 levels, higher CSF p‐tau/Aβ42 and t‐tau/Aβ42 ratios (Table 2).ConclusionIn a memory clinic sample of older adults with MCI, MBI was associated with AD markers and served as a proxy marker to capture AD changes in a non‐demented sample. These findings extend the literature linking MBI with known dementia biomarkers and emphasize the importance of appropriately ascertained NPS, in this case with respect to symptom persistence, in dementia detection and prognostication.

White matter hyperintensities and mild behavioural impairment: Findings from the MEMENTO Study

AbstractBackgroundMild behavioural impairment (MBI) is a neurobehavioural syndrome characterized by the onset and persistence of neuropsychiatric symptoms (NPS) in later life. While the ATN framework provides a robust overview of Alzheimer’s pathology, it does not fully capture the impact of small‐vessel cerebrovascular disease in the pathogenesis of dementia. White matter hyperintensities (WMH) may independently contribute to the development of Alzheimer’s dementia and predict risk of incident dementia in mild cognitive impairment (MCI). Few studies have established the link between NPS and WMH in MCI populations.MethodWe included 760 participants from the French MEMENTO study with MCI and WMH data. WMH volumetry on T2‐weighted fluid attenuated inversion recovery images was identified using WHASA software, visually verified with the Fazekas and Schmidt scale, and expressed in cm3. Mean age was 72.7 (SD 8.0) and 57.9% of participants were female. Neuropsychiatric Inventory items were transformed to MBI domains using a published algorithm. MBI status was based on symptom persistence: NPS at both baseline and 6‐months was considered MBI+ (n = 227), whereas non‐persistent NPS (i.e., NPS at either time point but not both) or no NPS at either baseline or 6‐months was considered MBI‐ (n=549). We investigated the association between MBI status and the outcome variable, WMH, using a linear regression model adjusted for age, sex, education, Mini‐Mental Status Exam (MMSE) score, and total intracranial volume.ResultMBI was present in 29.9% of participants (n = 227). MBI+ (i.e., persistent NPS) was significantly associated with lower MMSE score (p &lt; 0.001) and male sex (p = 0.025). Compared to MBI‐, MBI+ was associated with 9.9% higher WMH volume [p = 0.006 (95% CI 2.8% to 18%), Table 1].ConclusionIn a memory clinic sample of older adults with MCI, MBI+, operationalized as persistent NPS, is associated with higher WMH. These findings extend the evidence base linking MBI with known dementia biomarkers and raise the possibility that some forms of MBI can be caused by vascular brain injury.

Plasma TDP‐43 in neurodegenerative diseases assayed with immunomagnetic reduction

AbstractBackgroundTDP‐43 is a promising biomarker for frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). However, studies on TDP‐43 in human biofluid are rare. In this work, the authors utilized an ultrasensitive technology, called immunomagnetic reduction (IMR), to develop the reagent for assaying TDP‐43.MethodThe preclinical performance characteristics of the TDP‐43 reagent, such as the standard curve, detection limits, assay linearity, dilution recovery range, assay reproducibility, spike recovery, reagent stability, and interference tests, were explored according to the CLSI guidelines. Plasma samples from normal controls (NC, n = 27) and from patients with frontotemporal dementia (FTD, n = 9), Alzheimer’s disease (AD, n = 34) and Parkinson’s disease (PD, n = 10) were collected for TDP‐43 assays using the IMR TDP‐43 reagent.ResultThe low‐detection limit of assaying TDP‐43 was 0.68 fg/ml, and the upper‐detection limit was 100 pg/ml. There was no significant interference effect when assaying TDP‐43 mixed with hemoglobin, bilirubin, intralipid, albumin, etc. The FTD patients had significantly higher levels of plasma TDP‐43 (0.419±0.193 fg/ml) compared to the NC subjects (0.163±0.097 fg/ml), AD patients (0.165±0.082 fg/ml) and PD patients (0.069±0.068 fg/ml). Through analysis of the ROC curve, the cut‐off value of plasma TDP‐43 for discriminating FTD from the other patient groups was 0.237 fg/ml, which resulted a clinical sensitivity of 0.889 and a specificity of 0.831.ConclusionThese results demonstrate the feasibility of assaying plasma TDP‐43 to specifically identify FTD.

Plasma p‐tau231 in the Alzheimer’s disease continuum: A multi‐cohort evaluation of diagnostic performance, detection of Aβ pathology and preclinical application

AbstractBackgroundBlood phosphorylated tau (p‐tau) has proven to be the primary candidate as an accessible and scalable biomarker for Alzheimer’s disease (AD). Both p‐tau181 and p‐tau217 are highly accurate to detect AD within dementia cases. Our recent work in cerebrospinal fluid, however, indicates p‐tau231 to be associated to incipient AD pathology. In light of this, we developed a Single molecule array (Simoa) to detect plasma p‐tau231 and assessed its performance in multiple domains, specifically, its ability to detect preclinical AD.MethodIn all cohorts, plasma p‐tau231 was quantified using an in‐house Simoa method developed at the Clinical Neurochemistry Laboratory, Gothenburg University, Sweden. Data presented in this study are samples acquired from Translational Biomarkers of Aging and Dementia (TRIAD, n=503), King’s College London (n=55), Mayo Clinic Study of Aging (n=145), KARVIAH (n=140), Baltimore Longitudinal Study of Aging (n=430), University College London (n=70), Paris University (n=213), PREVENT‐AD (n=257), University of California (n=309) and ALFA+ (n=385).ResultIn the TRIAD cohort, plasma p‐tau231 demonstrated high accuracy in determining AD from young individuals (AUC=0.95), Aβ‐ elderly (AUC=0.92), Aβ‐ MCI (AUC=0.88) and other neurodegenerative disorders (AUC=0.92). In an autopsy study, plasma p‐tau231 could detect neuropathologically confirmed AD amongst dementia cases (AUC=0.99). In comparing healthy elderly Aβ‐ and Aβ+ individuals, p‐tau231 predicted preclinical Aβ pathology (AUC=0.83). Furthermore, inflection points of the weighted regression curves demonstrate that increases in plasma p‐tau231 occur before plasma p‐tau181 as a function of Aβ deposition load. Plasma p‐tau231 data from additional cohorts will focus on cross‐sectional and longitudinal preclinical datasets. In addition, further data will show the performance of p‐tau231 in symptomatic and presymptomatic PSEN1/APP mutation carriers, memory clinic cohorts, longitudinal neuropathology confirmed and acute neurological injury.ConclusionPlasma p‐tau231 is a new biomarker specific for AD pathology and at higher concentrations relative to p‐tau181 and p‐tau217. Our initial results indicate that plasma p‐tau231 is equivalent to p‐tau181 in diagnostic utility but has greater potential as a biomarker to monitor emerging Aβ pathology. This presentation will give an overview of novel cross‐sectional and longitudinal plasma p‐tau231 data, in more than 3000 individuals, that encompasses the AD continuum, familial AD and other neurological conditions.

Tau‐load in the lingual gyrus impacts anxiety levels during the COVID‐19 pandemic in participants of longitudinal observational studies in aging

BackgroundBy obtaining a better grasp on the impact of the COVID‐19 pandemic on individuals with cognitive impairment, this knowledge could be used to improve the delivery of information to this particular group. We aimed to assess the relationship between tau deposition and the change in anxiety levels, before and during the pandemic. We hypothesized that since the pandemic, higher tau loads would lower the change in anxiety. Furthermore, we expected these anxiety levels not to be associated with COVID‐19 related stress in participants with cognitive decline.Methods63 participants of the Translational Biomarker of Aging and Dementia (TRIAD) cohort (cognitively healthy, N=38; cognitively impaired, N=25, of which 7 had dementia due to Alzheimer’s disease), were assessed to evaluate their individual change in anxiety levels (GAD‐7). This was done at three different timepoints, of which the latest fell during the COVID‐19 lockdown period. Two rates of change, one before and one during the pandemic, were determined using the following definition: (next timepoint – current timepoint)/time difference. In addition, at the latest timepoint, subjective stress due to COVID‐19 was measured using the Montreal Assessment of Stress related to COVID‐19 (MASC). To assess the levels of tau, standard uptake value ratios (SUVR) from previously obtained [18F]MK‐6240 PET‐scans were used.Results[18F]MK‐6240 tracer binding in the lingual gyrus was negatively associated with the rate of change in GAD‐7 scores after correcting for age, sex, years of education and the presence of APOE ε4, but only in cognitively impaired individuals during the pandemic (fig 1A). In addition, the GAD‐7 score at the latest timepoint was associated with stress related to COVID‐19, but only in cognitively healthy individuals (fig 1B and 1C).ConclusionsThe presence of tau in the lingual gyrus negatively affected the rate of change in GAD‐7 scores during the COVID‐19 pandemic in individuals with cognitive impairment. This could indicate that information pertaining to the pandemic does not reach these individuals in an efficient manner. The missing association between COVID‐19 induced stress and the latest GAD‐7 scores in these individuals is a further indication of this.

A data‐driven disease progression model of fluid biomarkers in genetic FTD

AbstractBackgroundSeveral fluid biomarkers for genetic frontotemporal dementia (FTD) have been proposed, including those reflecting neuroaxonal loss (neurofilament light chain (NfL) and phosphorylated neurofilament heavy chain (pNfH)), synapse dysfunction (neuronal pentraxin 2 (NPTX2)), gliosis (glial fibrillary acidic protein (GFAP)) and complement activation (C3b, C1q). Determining the sequence in which biomarkers become abnormal over the course of disease could facilitate disease staging in FTD and enable us to identify mutation carriers with prodromal or early‐stage FTD, which is especially important as pharmaceutical interventions emerge. We aimed to model the sequence of biomarker abnormalities in presymptomatic and symptomatic genetic FTD using cross‐sectional data from the Genetic Frontotemporal dementia Initiative (GENFI).Method276 presymptomatic and 142 symptomatic carriers of mutations in GRN, C9orf72 or MAPT, as well as 247 non‐carriers, were selected from the GENFI cohort based on availability of one or more of the aforementioned biomarkers. Nine presymptomatic carriers developed symptoms within 18 months of data collection (‘converters’). Sequences of biomarker abnormalities were modelled for the entire group using discriminative event‐based modelling (DEBM) and for each genetic subgroup using co‐initialized DEBM. These models estimate probabilistic biomarker abnormalities in a data‐driven way and do not rely on prior diagnostic information or biomarker cut‐off points. We estimated individual disease severity scores based on the position of subjects along the disease progression timeline through cross‐validation.ResultCerebrospinal fluid (CSF) NPTX2 was the first detectable abnormal biomarker, followed by blood and CSF NfL, blood GFAP, blood pNfH and finally CSF C1q and C3b (Fig. 1). Biomarker orderings did not differ significantly between genetic subgroups. Estimated disease severity scores (Fig. 2) could distinguish symptomatic from presymptomatic carriers and non‐carriers with areas under the curve (AUC) of 0.84 and 0.90 respectively. The AUC to distinguish converters from non‐converting presymptomatic carriers was 0.85.ConclusionIn our data‐driven disease progression models of genetic FTD, NPTX2 and NfL were the first biomarkers to become abnormal. Further research should focus on their utility as candidate selection tools for pharmaceutical trials. Estimating disease stages using DEBM could enable us to identify presymptomatic carriers approaching symptom onset and track the efficacy of therapeutic interventions.

Adapting to the COVID‐19 pandemic in cohort studies: Validation of online assessments of cognition and neuropsychiatric symptoms in an aging population

AbstractBackgroundThe occurrence of the COVID‐19 pandemic has had a significant impact on cohort studies, particularly those whose subjects are at higher risk of developing complications from the virus. As such, assessment methods must be adapted to minimize COVID‐19 exposure risk. The TRIAD (Translational Biomarkers of Aging and Dementia) cohort assessed N=292 individuals during initial COVID‐19 lockdown measures by telephone interview to rate cognition, neuropsychiatric symptoms, and impact of the pandemic. To increase speed and efficiency of data collection, we aim to follow these individuals by means of online survey. Here, we present a validation of our online assessment tools by comparing data obtained through both methods (phone interview and online survey) in the same subjects.Methods10 subjects (4 elderly CN/3 MCI/3 AD) and their informants participated in this study. Subjects were varied for assessment language (English/French) and first assessment method (phone/online). 18 instruments were administered (listed in Table 1). Instrument scores were first compared by computing individual differences (phone‐online), then by pooling all scores by assessment type and calculating an effect size. Pearson correlation coefficient between phone and online scores was also computed.ResultsMean interval between assessments was 8.8±4.8 days. Mean length of online assessment (63.7±20.7mins) was comparable to mean phone interview length (72.6±32.4mins). Instrument scores from phone interviews had a total mean of 102.60, while scores from online surveys had a total mean of 103.93, with a pooled SD of 716.09. Effect size was ‐0.00186. Correlation of phone and online scores yielded a Pearson’s R of 0.85 (p&lt;0.05). Pearson’s R was also computed by applying bootstrapping using 1000 resamples without replacement with a sample size of 50. The Pearson R coefficient after bootstrapping was 0.91 (95% CI: [0.7699‐0.998]).ConclusionOur results suggest that instrument scores from phone and online assessments are comparable, and not significantly different from each other. The observed variance in scores between phone and online assessments may be due in part to the normal test‐retest variability associated with re‐administering instruments. This validation of online assessment tools in an aging population is of significant importance to human studies in the context of COVID‐19.

Tau368 in cerebrospinal fluid is associated with severity of tau pathology load in the Alzheimer’s continuum

AbstractBackgroundRecent developments in the biomarker field allow Alzheimer’s disease (AD) pathophysiology to be reflected at the preclinical stage. We recently presented an assay targeting tau fragments ending at residue 368, which exhibited a stage‐wise decrease in a ratio with total‐tau. The tau368/T‐tau ratio also correlated with tau positron emission tomography (PET) uptake, and was present in tau tangles. In this study, we aimed to validate these findings in a larger cohort including a larger subset spanning the AD continuum.MethodWe investigated 129 participants cross‐sectionally from the Translational Biomarkers of Aging and Dementia (TRIAD) cohort (22 young, 60 cognitively unimpaired (CU) elderly (14 Aβ+), 26 mild cognitive impairment (MCI; 10 Aβ+), 14 AD dementia and 7 frontotemporal dementia (FTD)). For all individuals, [18F]AZD4694 and [18F]MK‐6240 PET were used to index Aβ and tau load (Braak stages) respectively. T‐tau was quantified using ELISA (INNOTEST®) and Tau368 was quantified by an in house Single molecule array (Simoa) assay (Quanterix, Billerica, MA). Spearman rank tests assessed correlation between continuous variables. Linear models tested the effect of tau368/t‐tau ratio on PET summary measures and at the voxel level, always adjusting for age and sex.ResultCompared to young controls, we observed a stage‐wise decrease of tau368/t‐tau, with the lowest ratio found in AD dementia (P&lt;0.01), followed by CU‐ (P&lt;0.001), CU+ (P&lt;0.01) and MCI‐ (P&lt;0.001). MCI+ had a lower ratio than CU‐ (P&lt;0.01). Furthermore, there was a strong negative correlation between tau368/t‐tau ratio and PET Braak stages in the whole population (I‐II; ρ=‐0.46, P&lt;0.001, III‐IV; ρ=‐0.44, P&lt;0.001, V‐VI; ρ=‐0.37, P&lt;0.001), in MCI+ (I‐II; ρ=‐0.79, P&lt;0.01, III‐IV; ρ=‐0.84, P&lt;0.01, V‐VI; ρ=‐0.83, P&lt;0.01) and in AD dementia (V‐VI; ρ=‐0.57, P&lt;0.05). Voxel‐wise analysis demonstrated strong correlation between tau368/t‐tau and tau PET ligand uptake in the medial and lateral temporal lobes in cognitively impaired individuals, while no significant association was found in CU.ConclusionWe provide further evidence of a stage‐wise decrease in CSF tau368/t‐tau, which tracks cortical tau accumulation only in clinically manifest AD dementia and amyloid positive MCI. These results further support that CSF tau368/t‐tau captures severity of tau pathology within the AD continuum.

Blood phosphorylated tau 181 predicts early, preclinical brain amyloid deposition

AbstractBackgroundPlasma phospho‐tau181 is a promising new biomarker for Alzheimer’s disease (AD) with greater specificity than t‐tau and greater convenience compared to cerebrospinal fluid or neuroimaging biomarkers. However, its association with regional brain cortical amyloid and tau deposition is not well characterized. We evaluated 1) the association between plasma p‐tau181 levels and regional cortical amyloid and tau deposition and 2), determinants of circulating phospho‐tau181 levels.MethodPlasma p‐tau181 levels were measured in 52 [48% women, mean age 64.4 (SD 5.5)yr] cognitively normal Framingham Heart Study Offspring cohort participants at examination cycle nine (2011‐2014) who subsequently underwent 11C‐Pittsburgh Compound‐B (PiB)‐PET and/or 18F‐Flortaucipir (FTP)‐PET scans. We related phospho‐tau181 levels to PiB‐PET (composite of frontal, lateral temporal and parietal and retrosplenial cortices [FLR], as well as individual cortical regions) and FTP‐PET (entorhinal, inferior temporal and precuneus regions). Additionally, we compared p‐tau181 with plasma neurofilament light chain (NFL), and glial fibrillary acidic protein (GFAP) in predicting brain amyloid deposition.ResultThe mean time from plasma biomarker measurement to brain‐PET was 6.8 (SD 0.6)yr. On linear regression analysis adjusted for age, sex and time to PET, log p‐tau181 was associated with increased FLR (SE, 1.24±0.30, p&lt;0.0001), precuneus (1.35±0.30, p&lt;0.001), superofrontal (1.10±0.31, p=0.001), superotemporal (1.24±0.30, p&lt;0.001) and insular amyloid deposition (1.17±0.31, p&lt;0.001). Plasma p‐tau181 was not associated with tau‐PET deposition in the entorhinal (‐0.31±0.63, p=0.63), inferotemporal (‐0.19±0.64, p=0.77) or precuneus (‐0.05±0.64, p=0.94) regions, n=21 with available tau‐PET. Log NFL (1.30±0.49, p=0.01) and GFAP (1.46±0.39, p&lt;0.0001) showed univariate associations with FLR amyloid deposition. On multivariable analysis adjusting for age, sex, apoE4 allele, AD polygenic risk score and all three biomarkers, p‐tau181 (0.92±0.31, p=0.005) and GFAP (0.92±0.41, p=0.03), but not NFL (0.25±0.51) remained associated with FLR amyloid deposition. Total cholesterol was the only vascular risk factor associated with circulating p‐tau181 levels (‐0.004±0.001, p=0.01).ConclusionElevated plasma phospho‐tau181 is associated with preclinical cortical amyloid (but not tau) deposition in a relatively young, cognitively normal sample. Circulating levels of p‐tau181 appear to be independent of vascular risk factors, highlighting the potential of phospho‐tau181 as a robust and generalizable blood‐based biomarker for AD dementia in a community‐based setting. Additional studies replicating our findings are warranted.

Afternoon‐snack glycemic load is associated with plasma amyloid‐beta peptides in APOE4 carriers at risk of dementia

AbstractBackgroundRecent evidence suggests that a high refined‐carbohydrate diet is a risk factor for dementia, especially among APOE4 carriers. Thus, refined‐carbohydrate diet may modify biomarkers of dementia, such as amyloid‐β (Aβ) peptides according to APOE4 carrier status. Here, we focus on afternoon‐snack glycemic load (GL) because snacks are generally richer in refined carbohydrates. We investigated the relationship between plasma Aβ, afternoon‐snack GL, and APOE4 carrier status in participants with or without incident dementia.MethodWe followed 377 non‐demented participants from the Three‐City Study (Bordeaux and Montpellier center), aged over 65, with plasma Aβ peptide concentrations measured at baseline. At 2‐year (Bordeaux center) and 4‐year (Montpellier center), the participants completed a semi‐quantitative Food Frequency Questionnaire which was used to estimate GL (GL assesses both the carbohydrate quantity and quality, and reflects glycemic response). At each follow‐up (every 2‐3 years during 15 years), participants had clinical diagnosis of dementia. We used linear regressions to evaluate the associations between plasma Aβ40, Aβ42, Aβ42/Aβ40 ratio and GL, APOE4 carrier status, and the interaction GL x APOE4, among participants with or without incident dementia. Models were adjusted for center, age, sex, education level, total cholesterol, serum creatinine and adherence to the Mediterranean diet.ResultThe sample included 60.2% of women and mean age of the participants was 76.1 (± 5.2) years. During the follow‐up, 51 participants developed dementia. Among dementia‐free participants, GL tended to be associated with Aβ42/Aβ40 ratio (β = ‐0.006 [SE = 0.003], P = .055) but not with Aβ40 and Aβ42 concentrations. Among incident dementia participants, the interaction GL x APOE4 was associated with plasma Aβ40 concentration (β = 54.2 [SE = 25.6] pg/mL, P = .042). Regarding Aβ42, no interaction was found. Regarding Aβ42/Aβ40 ratio, GL x APOE4 was no longer significant after adjustment (β = ‐0.038 [SE = 0.024] P = .124).ConclusionIn APOE4 carriers with incident dementia, a higher afternoon‐snack GL was associated with worse plasma Aβ peptide concentrations. These results highlight that rich refined‐carbohydrate diet is a modifiable risk factor for plasma Aβ peptide concentrations and subsequent dementia risk. Experimental studies are required to explain potential mechanism involved.

Addressing dementia challenges through international networks: Evidence from the Latin American and Caribbean Consortium on Dementia (LAC-CD).

LAC-CD has recently reported that challenges faced by LAC countries are very similar to those experienced by HIC, and that regional networks will be needed to bridge gaps. ReDLat is a US-LAC multi-partner consortium aimed at expanding dementia research in LAC. The UK-Latin America Brain Connectivity Research Network (UL-BCRN) focuses on developing new affordable EEG-based biomarkers for dementia. The Language and Brain Health Network (LBHN) integrate international multidisciplinary efforts to reveal linguistic markers of neurodegenerative diseases. ReDLat is collecting genomic, neuroimaging, clinical, cognitive, and socioeconomic data from a first-in-class cohort anchored in six LAC (Argentina, Chile, Colombia, Brazil, Mexico, and Peru) and will compare these to US data (> 4200 participants, including 2100 controls, 1050 AD patients, and 1050 FTD patients). The 5-year project will develop innovative, harmonized, and cross-nation approaches on two of the most prevalent neurodegenerative diseases, Alzheimer's disease (AD) and Frontotemporal Dementia (FTD). The UL-BCRN currently links seven EEG labs from Colombia, Argentina, Chile, Brazil and the UK. The network's vision is to forge strong relationships between labs through which new methodologies, EEG plus multidimensional datasets, and experience will be developed and shared. The LBHN will analyze speech samples from massive AD, FTD, and control cohorts across LAC, Spain, and the US. This effort aims to identify low-cost disease-specific markers in diverse Latino and English-speaking patients. ReDLat will aims to reveal unique risk factors for AD and FTD in LAC compared to US populations. Data collection strategies have been adapted to face the challenges brought by the COVID-19 pandemic. The UL-BCRN has now standardised recording protocols across LAC and UK labs and is collecting data from longitudinal cohorts of patients at risk of dementia relying on novel culture-free cognitive paradigms. Preliminary LBHN data shows that, automated speech analyses can identify Latinos with AD and FTD, with good generalization across socio-biological profiles, dialects, and languages. By broadening our understanding of dementia phenotypes, risk factors, and affordable diagnostic approaches in LAC, adding new evidence on variability across HIC and LMIC, the above networks will contribute unique knowledge that will help enhance future global dementia strategies.

Characterizing proteoforms of the granin family of neuropeptides in dementia pathophysiology

The granin family of neurotransmitter-like molecules, neuropeptides, are proteolytically processed into functional peptides, also known as proteoforms. This family contains secretogranin VII (VGF), which was highlighted by AMP-AD as the most nominated potential therapeutic target for Alzheimer's disease (AD) due to its levels being decreased in CSF samples and brain sections from patients with AD. Full-length granins and their proteoforms are involved in diverse neuronal and synaptic functions, but their physiological processing pathways, contribution to dementia pathogenesis and potential use as a biomarker of dementia remain understudied. This project investigated the proteolytic processing of granins in silico and in vitro to improve our understanding of whether specific granin proteoforms represent potential therapeutic targets and biomarkers of dementia.Proteasix and the human protein atlas were used to identify brain-expressed proteases that may produce granin proteoforms. These granin proteoforms had been previously identified by our group in the CSF of patients with AD and healthy controls using mass spectrometry. Links to dementia pathogenesis were assessed in the literature. Cleavage specificity was assessed using recombinant protein assays and overexpression of granins and proteases in immortalized cell lines. Analysis was performed using gel electrophoresis and immunoblotting with granin-specific antibodies.Using Proteasix and the human protein atlas; 29 proteases that potentially cleave granins were also identified as expressed in the brain and 22 of these had been previously linked to dementia pathogenesis. Assays using recombinant proteins and immortalized cell lines identified that five proteases involved in dementia pathophysiology, ADAMTS4, calpain-1, cathepsin S, granzyme A and MMP-3 cleaved granins into a plethora of different proteoforms. Further work using mass spectrometry is ongoing to map these proteoforms against those identified in the CSF samples.Our results show that granins are proteolytically processed by proteases involved in dementia pathophysiology. This work improves our mechanistic understanding of granin processing and further establishes their potential as biomarkers of synaptic health in dementia and potential therapeutic targets.

Mass spectrometry approaches for the selection of primary calibrators in the development of reference method

AbstractBackgroundNeurofilament‐light chain (NF‐L) is a known early marker for neurodegeneration. This marker which is essential for the axonal structure, is quantifiable in biological fluids after neuronal damage but is not specific to a given pathology. Currently, the methods for detecting/quantifying this biomarker are mainly based on immunoassays. While the performance of immunoassay‐based assays is good in term of sensitivity and precision, mass spectrometry (MS) approaches are required to achieve standardisation. Those aiding to improved characterisation/quantification of the calibrator and potential for developing a reference measurement procedure traceable to the International System of Units. Furthermore MS has the potential of multiplexing NF‐L with other specific biomarkers for dementia. The characterization and quantification of a number of primary calibrators and their suitability for harmonization of immunoassay based results and development of a reference measurement procedure is here assessed.MethodMicrowaver hydrolysis and isotope dilution MS was used for quantification of NF‐L from different manufactures. An Orbitrap mass spectrometer (Q‐Exactive, Thermofischer) was used to provide high resolution intact protein analysis information. A QQQ mass spectrometer (Xevo TQ‐XS, Waters) was utilized to assess the potential of developing a reference measurement procedure for NF‐L.ResultThe quantitative analysis of the three NF‐L by amino acid analysis (AAA) showed for all samples discrepancy between the nominal concentrations and the experimental results with a general overestimation for the nominal concentration due to water and salt contents. Separation, identification and quantification of impurities present in the preparations was attempted to obtain a total protein content from the AAA and the NF‐L content from the AAA results corrected for the impurities. The sequence of NF‐L was verified by high resolution intact protein MS and tryptic digestion. A QQQ method was developed to monitor the tryptic digest peptides and assess their suitability to be used for the development of a reference measurement procedure. This was based on specificity, limits of detection and limits of quantification.ConclusionThese studies allow us to characterize three NF‐L proteins from different suppliers and to perform a first selection of the most relevant ones as primary calibrators for the development of a reference method.

Differences in care between younger and older patients in the 2019 English national memory service audit.

This paper analyses how practice varied between patients aged <65 and ≥65 years in the 2019 UK national memory service audit. Data on 3959 patients were analysed. Those aged <65 (7% of the sample) were less likely than those aged ≥65 to be diagnosed with dementia (23 v. 67%) and more likely to receive a functional, psychiatric or no diagnosis. Younger patients were more likely to have magnetic resonance imaging; use of dementia biomarkers was low in both groups. Frontotemporal dementia and functional cognitive disorder were diagnosed infrequently. Use of dementia navigators/advisors and carer psychoeducation was similar between groups; younger patients were less likely to be offered but more likely to accept cognitive stimulation therapy. Memory services seeing younger people need expertise in functional cognitive disorder, alongside clinical skills and technologies to diagnose rarer forms of dementia. Further work is needed to understand why cognitive stimulation therapy is less frequently offered to younger people.

Neurotechnology and AI Approach for Early Dementia Onset Biomarker from EEG in Emotional Stimulus Evaluation Task.

We present an efficient utilization of a machine learning (ML) method concentrating on the 'AI for social good' application. We develop a digital dementia biomarker for early-onset dementia forecast. The paper demonstrates encouraging preliminary results of EEG-wearable-based signal analysis and a subsequent classification adopting a signal complexity test of a multifractal detrended fluctuation analysis (MFDFA) in emotional faces working memory training and evaluation tasks. For the digital biomarker of dementia onset detection, we examine shallow- and deep-learning machine learning models. We report the best median accuracies in a range of 90% for random forest and fully connected neural network classifier models in both emotional faces learning and evaluation experimental tasks. In addition, the classifiers are trained in a ten-fold cross-validation regime to discriminate normal versus mild cognitive impairment (MCI) cognition stages using MFDFA patterns from four-channel EEG recordings. Thirty-five volunteer elderly subjects participate in the current study concentrating on simple wearable EEG-based objective dementia biomarker progression. The reported outcomes showcase an essential social benefit of artificial intelligence (AI) employment for early dementia prediction. Furthermore, we improve ML employment for the succeeding application in an uncomplicated and applied EEG-wearable examination.

Retinal Imaging as Potential Biomarkers for Dementia

Alzheimer's disease (AD) is a leading cause of dementia, and the current diagnostic methods of AD, such as positron emission tomography imaging, have a high cost and poor accessibility. Amyloidβ accumulates in the brain long before the symptomatic onset of AD, and can also be found in the inner retina. Anatomically and developmentally, the retina is an extension of the brain, and is the only part of the central nervous system that can be imaged non-invasively. Therefore, retinal imaging has potential as a potential biomarker for dementia. Previous studies have demonstrated that inner retinal thinning (measured using optical coherence tomography [OCT]) is associated with an increased risk of dementia, including AD. In addition, retinal vascular changes assessed using fundus photographs and OCT angiography were associated with dementia. We propose that artificial intelligence algorithms could be applied to process these retinal images and contribute to the automated interpretation of retinal images and screening for dementia. In addition, amyloidβ in the retina has been identified using hyperspectral imaging, a non-invasive retinal imaging, as a surrogate marker of brain amyloidβ. Retinal imaging may provide a novel biomarker and contribute to screening individuals at risk of dementia, monitoring disease progression, and assessing therapeutic efficacy.