Cerebral Tau Research Articles

Tau accumulation within the default mode network as a predictor of longitudinal clinical decline in atypical Alzheimer’s disease

AbstractBackgroundIdentifying individuals with symptomatic Alzheimer’s disease (AD) at greater risk of steeper cognitive decline would allow professionals and loved‐ones to make better‐informed medical, support, and life‐planning decisions. In typical AD, the magnitude of cerebral tau accumulation in vivo predicts clinical deterioration. Despite its promise, the utility of tau PET in predicting cognitive decline in individuals with atypical clinical presentations of AD remains unclear. We examined the relationship between baseline tau PET signal and the rate of subsequent clinical decline across atypical AD syndromes.MethodFifty‐seven A/T/N‐positive patients (mean age = 64.13 ± 7.72; 24M/33F) with atypical syndromes of AD (19 Posterior Cortical Atrophy, 16 logopenic variant of Primary Progressive Aphasia, 16 dysexecutive AD, five early‐onset AD with single‐domain impairment, and one Corticobasal Syndrome) and 24 amyloid‐negative control participants were included in this study. All participants underwent 18F‐Flortaucipir (FTP) PET, amyloid PET, and structural MRI scans at baseline. The rate of clinical decline was quantified as the annualized change in Clinical Dementia Rating Sum‐of‐Boxes scores (CDR‐SB) at baseline and follow‐up visits (mean time interval = 1.24 ± 0.34 years). General linear model analyses were performed to examine the pattern of baseline cortical tau deposition in atypical AD patients and its relationship with the rate of clinical decline.ResultCompared with amyloid‐negative controls, atypical AD patients showed prominent FTP uptake in posterior cortical regions at baseline, including bilateral posterior cingulate cortex/precuneus and lateral temporo‐parietal cortices, which canonically constitute the posterior default mode network (DMN). A brain‐behavior regression analysis revealed widespread regions within the DMN where the magnitude of baseline FTP uptake predicted the rate of change in CDR‐SB, with anterior DMN regions (medial prefrontal and anterior temporal cortices) most strongly predicting clinical decline.ConclusionGreater baseline tau accumulation in the anterior DMN, possibly suggesting more extensive tau spread in this network, predicts faster clinical decline in atypical AD. This may serve as an imaging biomarker to guide prognostication for patients with atypical AD and their families and to inform the design of clinical trials, including potentially recruiting multiple clinical phenotypes of AD into a single trial.

Clinical Manifestations.

Neurodegenerative pathologies, including tau depositions, have been implicated in late-onset depression (LOD), while there is a lack of in-vivo evidence for the neuropathological basis of late-onset bipolar disorder (LOBD) despite postmortem findings of cerebral tau accumulations. The current study aimed to assess tau pathologies in LOBD and LOD patients positron emission tomography (PET) with 18F-florzolotau, a radioligand for Alzheimer's disease (AD) and non-AD tau fibrils. We studied LOBD and LOD patients who developed the first episode of mania or depression after age 45. Twenty-one patients with LOBD (68.8 ± 9.6 years old; 11 females), 15 patients with LOD (73.0 ± 5.8 years old; 11 females), and 39 age-matched healthy controls (HCs) (67.1 ± 9.1 years old; 19 females) underwent tau and amyloid PET scans with 18F-florzolotau and 11C-PiB, respectively. Amyloid positivity was determined by a visual read of 11C-PiB-PET images, and tau depositions were assessed by calculating standardized uptake value ratios (SUVRs) in 52 regions covering the cerebral grey matter and basal ganglia to the optimized reference tissue. All SUVRs were corrected for age and sex and converted to Z-score relative to HCs. The positivity and topology of tau pathologies were determined according to the presence of a region with a Z-score ≥ 2.0. 18F-florzolotau-PET positivity was observed in 13 LOBD (62%), 7 LOD (47%), and 11 HC (28%) subjects, whereas 4 LOBD, 4 LOD, and no HC individuals were 11C-PiB-PET-positive. A significant difference in the prevalence of tau pathologies was only found between LOBD and HCs (P = 0.043, corrected for multiple comparisons). Tau topologies in the cases with 11C-PiB-PET-positive AD pathologies consisted of predominant frontal (1 LOBD and 3 LODs), lateral temporal (3 LOBDs and 1 LOD), and posterior (1 LOBD) accumulations. Meanwhile, tau pathologies in 11C-PiB-negative cases showed predominant frontal (2 LOBDs and 1 LOD), temporal (1 LOBD and 1 LOD), posterior (4 LOBDs and 1 LOD), and basal ganglia (2 LOBDs) localizations. Our findings suggest that a significant subset of LOBD patients harbor tau lesions linked to various AD subtypes and non-AD tauopathies indicative of distinct early-stage frontotemporal lobar degeneration subcategories.

Traumatic brain injury and the pathways to cerebral tau accumulation.

Tau is a protein that has received national mainstream recognition for its potential negative impact to the brain. This review succinctly provides information on the structure of tau and its normal physiological functions, including in hibernation and changes throughout the estrus cycle. There are many pathways involved in phosphorylating tau including diabetes, stroke, Alzheimer's disease (AD), brain injury, aging, and drug use. The common mechanisms for these processes are put into context with changes observed in mild and repetitive mild traumatic brain injury (TBI). The phosphorylation of tau is a part of the progression to pathology, but the ability for tau to aggregate and propagate is also addressed. Summarizing both the functional and dysfunctional roles of tau can help advance our understanding of this complex protein, improve our care for individuals with a history of TBI, and lead to development of therapeutic interventions to prevent or reverse tau-mediated neurodegeneration.

Distinct Molecular Signatures of Amyloid-Beta and Tau in Alzheimer's Disease Associated with Down Syndrome.

Limited comparative data exist on the molecular spectrum of amyloid-beta (Aβ) and tau deposition in individuals with Down syndrome (DS) and sporadic Alzheimer's disease (sAD). We assessed Aβ and tau deposition severity in the temporal lobe and cerebellum of ten DS and ten sAD cases. Immunohistochemistry was performed using antibodies against eight different Aβ epitopes (6F/3D, Aβ38, Aβ39, Aβ40, Aβ42, Aβ43, pyroglutamate Aβ at third glutamic acid (AβNp3E), phosphorylated- (p-)Aβ at 8th serine (AβpSer8)), and six different pathological tau epitopes (p-Ser202/Thr205, p-Thr231, p-Ser396, Alz50, MC1, GT38). Findings were evaluated semi-quantitatively and quantitatively using digital pathology. DS cases had significantly higher neocortical parenchymal deposition (Aβ38, Aβ42, and AβpSer8), and cerebellar parenchymal deposition (Aβ40, Aβ42, AβNp3E, and AβpSer8) than sAD cases. Furthermore, DS cases had a significantly larger mean plaque size (6F/3D, Aβ42, AβNp3E) in the temporal lobe, and significantly greater deposition of cerebral and cerebellar Aβ42 than sAD cases in the quantitative analysis. Western blotting corroborated these findings. Regarding tau pathology, DS cases had significantly more severe cerebral tau deposition than sAD cases, especially in the white matter (p-Ser202/Thr205, p-Thr231, Alz50, and MC1). Greater total tau deposition in the white matter (p-Ser202/Thr205, p-Thr231, and Alz50) of DS cases was confirmed by quantitative analysis. Our data suggest that the Aβ and tau molecular signatures in DS are distinct from those in sAD.

Regional cerebral tau predicts decline in everyday functioning across the Alzheimer’s disease spectrum

BackgroundEmerging difficulty performing cognitively complex everyday tasks, or ‘instrumental activities of daily living’ (IADL) may be an early clinical sign of Alzheimer’s disease (AD). We aimed to investigate how changes over time in everyday functioning relate to cerebral tau burden across the AD clinical spectrum.MethodsWe included 581 participants (73.9 ± 7.6 years old; 52% female) from the Alzheimer’s Disease Neuroimaging Initiative who underwent tau positron emission tomography (PET) and completed at least two assessments of the Functional Activities Questionnaire (FAQ). Participants were classified as cognitively normal (n = 334) or symptomatic (n = 247). We analyzed the association between longitudinal FAQ scores and baseline tau in six temporal, parietal, and frontal brain regions in mixed-effects models. Models were run in the entire sample, as well as stratified by diagnostic group (cognitively normal or symptomatic). We additionally investigated tau-PET adjusted for, as well as interacting with, amyloid-β.ResultsGreater tau burden in several frontal, temporal, and parietal regions was associated with steeper decline over time in everyday functioning. These findings remained when adjusting for baseline global cortical amyloid-β; amyloid-β itself was only associated with change over time in FAQ scores when tau was not included in the model. When stratifying by diagnostic group, most associations between tau and everyday functioning, adjusted for amyloid-β, were present only in the symptomatic group.ConclusionsThe rate of change in everyday functioning is related to baseline tau burden in various brain regions, more strongly so than global cortical amyloid-β, specifically in cognitively symptomatic individuals. Longitudinal studies in incident dementia populations are needed to better understand functional changes in response to AD pathology across the disease.

Associations of the Harvard Automated Phone Task and Alzheimer's Disease Pathology in Cognitively Normal Older Adults: Preliminary Findings.

Detecting clinically meaningful changes in instrumental activities of daily living (IADL) at the earliest stages of Alzheimer's disease (AD) is critical. The objective of this exploratory study was to examine the cross-sectional relationship between a performance-based IADL test, the Harvard Automated Phone Task (APT), and cerebral tau and amyloid burden in cognitively normal (CN) older adults. Seventy-seven CN participants underwent flortaucipir tau and Pittsburgh Compound B amyloid PET. IADL were assessed using the three Harvard APT tasks: prescription refill (APT-Script), health insurance company call (APT-PCP), and bank transaction (APT-Bank). Linear regression models were used to determine associations between each APT task and entorhinal cortex, inferior temporal, or precuneus tau with or without an interaction with amyloid. Significant associations were found between APT-Bank task rate and interaction between amyloid and entorhinal cortex tau, and APT-PCP task and interactions between amyloid and inferior temporal and precuneus tau. No significant associations were found between the APT tasks and tau or amyloid alone. Our preliminary findings suggest an association between a simulated real-life IADL test and interactions of amyloid and several regions of early tau accumulation in CN older adults. However, some analyses were underpowered due to the small number of participants with elevated amyloid, and findings should be interpreted with caution. Future studies will further explore these associations cross-sectionally and longitudinally in order to determine whether the Harvard APT can serve as a reliable IADL outcome measure for preclinical AD prevention trials and ultimately in the clinic setting.

Relationships between cerebral tau and glucose metabolism in cognitively normal older adults

AbstractBackgroundAlzheimer’s disease (AD) is characterised by the accumulation of amyloid‐β and tau in the brain and subsequent neurodegeneration. The relationship between tau accumulation and glucose metabolism has been elucidated in AD, however the relationship between the two in the early stages of the AD trajectory remains elusive. Here, we examine this relationship using fluorodeoxyglucose (FDG) and flortaucipir (FTP) positron emission tomography (PET) in a cohort of cognitively normal older adults.Method72 cognitively normal participants (mean±SD age 78.7±6.3 years old) were recruited through the Harvard Ageing Brain Study and had available FDG‐PET, FTP‐PET, and structural MRI scans. Region of interest analysis was utilised to determine the regional uptake of each PET tracer. 40 participants were split into high‐tau and low‐tau groups based on the highest 20 and lowest 20 FTP uptake values from the medial temporal lobe excluding the hippocampus (MTL (no hippocampus)). FDG uptake was compared between high‐tau and low‐tau groups, while correlations between FDG and FTP uptake were examined.ResultGlucose metabolism was significantly higher in the low‐tau group than the high‐tau group in the whole brain (p = 0.023), frontal lobe (p = 0.028), temporal lobe (p = 0.014), parietal lobe (p = 0.027), MTL (p = 0.01), MTL (no hippocampus) (p = 0.002), anterior cingulate cortex (p = 0.045), and posterior cingulate cortex (p = 0.023). Significant negative correlations were found between FTP uptake in the MTL (no hippocampus) and FDG uptake in the whole brain (r = ‐0.317,p = 0.046), temporal lobe (r = ‐0.383,p = 0.015), parietal lobe (r = ‐0.316,p = 0.047), MTL (r = ‐0.437, p = 0.005), MTL (no hippocampus) (r = ‐0.444,p = 0.004), anterior cingulate (r = ‐0.320,p = 0.044), and posterior cingulate (r = ‐0.361,p = 0.022). FTP uptake in the temporal lobe negatively correlated with FDG in the temporal lobe (r = ‐0.326, p = 0.04) and MTL (no hippocampus) (r = ‐0.337,p = 0.034).ConclusionHigh tau levels in the MTL was associated with hypometabolism in cognitively normal older adults, suggesting that tau accumulation may cause decreased glucose metabolism without inducing cognitive deficits. Furthermore, negative correlations between FDG and FTP uptake highlight the link between tau accumulation and neurodegeneration before the onset of cognitive decline. The association between tau accumulation and reduced glucose metabolism in cognitively normal participants supports the need for research and intervention to be aimed at the preclinical stages of AD.

Increased spatial extent of cerebral tau PET elevations in former NFL and college football players from the DIAGNOSE CTE Research Project

AbstractBackgroundWe previously found greater spatial extent of flortaucipir (tau) PET elevations in Arizona‐Boston (DETECT) Study of 26 former National Football League (NFL) players than in 31 normal controls—using a voxel‐based Majority Count Statistics (MCS) algorithm which enabled us to detect tau PET abnormalities in the player group free from the inflated Type 1 error associated with voxel‐wise multiple comparisons (Stern et al, NEJM 2019). We now confirm this finding in a larger group of former NFL players, former college football players and asymptomatic controls without exposure to repetitive head impacts from the DIAGNOSE CTE Research Project.MethodFlortaucipir PET images were acquired in 106 former NFL players, 51 former college players, and 53 unexposed controls, 57.71+8.37 years of age. An automated algorithm (SPM12) and co‐registered MRIs were used to spatially normalize PET images into Montreal Neurological Institute template, and compute statistical brain maps of group differences in regional cerebral‐to‐cerebellar crus1 standard uptake value ratio (SUVR), controlling for the participants’ age and race with P≤0.005, uncorrected for multiple comparisons. Our MCS was then applied with 1,000 iterations to test the hypothesis that there would be a greater number of cerebral voxels with SUVR elevations in each and combined player group versus control group, as well as between the NFL versus college player groups.ResultAs predicted, the NFL, college player and aggregate player groups each had significantly more cerebral voxels with flortaucipir SUVR elevations than in the control group (postulated vs opposite directions: 53,879 vs 79, 79,552 vs 89 and 100,837 vs 86 voxels), respectively, MCS P<0.001, but not between former NFL and former college players (482 versus 306, p = 0.305).ConclusionUsing a voxel based MCS analysis, former NFL and college football players have a greater spatial extent of elevations in tau PET measurements than asymptomatic controls. Additional work is needed to clarify the biological nature of these small but spatially extensive elevations, the extent to which they are related to symptom severity, cognitive performance, repetitive head impact exposure, and other risk or resilience factors, and the extent to which they are associated with subsequent clinical decline.

Correlation between cognitive assessment scores and circulating cerebral biomarkers in women with pre-eclampsia and eclampsia.

The cerebral injury biomarkers neurofilament light chain (NfL) and tau and the glial activation biomarker glial fibrillary acidic protein (GFAP) may reflect neurological injury in pre-eclampsia. We assessed if there was a correlation between cognitive function assessment scores and plasma concentrations of these biomarkers in pre-eclampsia. Women with eclampsia, pre-eclampsia and normotensive pregnancies from the South African PROVE biobank were included. Blood samples were taken at inclusion. The Montreal Cognitive Assessment was performed after delivery at the time of discharge. The correlation between cognitive assessment scores and plasma concentrations of cerebral biomarkers was analysed using Spearman correlation adjusted for time from eclamptic seizure. We included 49 women with eclampsia, 16 women with pre-eclampsia complicated by pulmonary oedema, 22 women with pre-eclampsia without pulmonary oedema, HELLP or neurological complications and 18 women with normotensive pregnancies. There was a correlation between impaired cognitive function and increased plasma concentrations of NfL in women with eclampsia and women with pre-eclampsia and pulmonary oedema (r=-0.37, p=0.009 and r=-0.56, p=0.025 respectively). No correlation between impaired cognitive function and NfL in pre-eclampsia cases without pulmonary oedema, HELLP or neurological complications or normotensive pregnancies was found. No correlation with cognitive impairment was found in any groups for tau or GFAP. We found a correlation between impaired cognitive function assessment and plasma NfL concentrations in women with eclampsia and pre-eclampsia complicated by pulmonary oedema. These findings suggest that acute neuroaxonal injury may cause or contribute to cognitive impairment in these women.

Correlation of blood-brain barrier leakage with cerebral small vessel disease including cerebral microbleeds in Alzheimer's disease.

Blood-brain barrier (BBB) damage is considered an important part of Alzheimer's disease (AD) progression, and cerebral small-vessel disease (CSVD) is commonly associated with AD. However, the relationship between BBB damage, small cerebrovascular lesions, especially cerebral microbleeds (CMBs), and amyloid and tau biomarkers remains controversial. Therefore, our study aimed to further investigate their association in our cohort of patients with AD. A total of 139 individuals were divided into probable AD (18F-florbetapir PET positive, n = 101) and control group (cognitively normal, n = 38). The levels of cerebrospinal fluid (CSF) and plasma t-tau, p-tau181, Aβ40, Aβ42, and albumin were measured using corresponding commercial assay kits, and the CSF/plasma albumin ratio (Qalb), an indicator of BBB dysfunction, was calculated. CSVD burden and the number of CMBs were defined using magnetic resonance imaging. Patients with AD had higher Qalb (p = 0.0024), higher numbers of CMBs (p = 0.03), and greater CSVD burden (p < 0.0001). In the AD group, CMBs and CSVD correlated with a higher Qalb (p = 0.03), and the numbers of CMBs negatively correlated with CSF Aβ42 (p = 0.02). Blood-brain barrier damage was accompanied by a more severe burden of CSVD, including CMB, in patients with AD.

Longitudinal Evolution of Financial Capacity and Cerebral Tau and Amyloid Burden in Older Adults with Normal Cognition or Mild Cognitive Impairment.

Declining ability to independently perform instrumental activities of daily living (IADL) is a hallmark of early-stage Alzheimer's disease (AD). Financial capacity, an aspect of IADL, includes financial skills such as balancing a checkbook and making change and is potentially sensitive to early decline in cognitive abilities, raising the question of how financial capacity is affected by buildup of cerebral tau and amyloid-hallmarks of AD pathology. This study aimed to examine the relationship between cerebral tau, amyloid, and their interaction with change in financial capacity over time. Participants were selected from the Alzheimer's Disease Neuroimaging Initiative (ADNI) to have at least one yearly follow-up Financial Capacity Instrument-Short Form (FCI-SF) exam and a flortaucipir (tau) PET scan within 6 months of baseline (and in a subset, a florbetapir (amyloid) PET scan within a year of baseline). Multi-center international cohort study. Sample size was 507-322 cognitively normal (CN) and 185 with amnestic mild cognitive impairment (MCI). Sixty-two percent (N=316) had amyloid data. Linear mixed-effects models predicted FCI-SF total score from baseline tau, age, gender, premorbid intelligence, executive function, memory, and the interaction of each with time. Regions of interest included inferior temporal, entorhinal cortex, precuneus, posterior cingulate, supramarginal, and dorsolateral prefrontal (DLPF). Additional models examined amyloid and its interaction with tau. Results were adjusted for multiple comparisons. Among the whole sample and in CN participants alone, higher baseline tau in all regions, most prominently in the inferior temporal, entorhinal cortex, and supramarginal regions, was significantly associated with worse performance on the FCI-SF over time. Among MCI participants alone, this relationship was significant in the entorhinal cortex (unstandardized b = 0.27, t = 3.71, adjusted p = 0.001), inferior temporal (b = 0.27, t = 3.96, p < 0.001), precuneus (b = 0.27, t = 3.04, p = 0.01), and supramarginal (b = 0.27, t = 2.74, p = 0.02) regions. Amyloid alone was significantly associated with worse FCI-SF performance in only the whole sample (b = 0.15, t = 2.37, p = 0.04), and a three-way interaction between tau, amyloid, and time was only present for entorhinal cortex tau in CN individuals (b = -1.61, t = -2.61, p = 0.03). Early tau accumulation is linked to worsening financial capacity over time in CN older adults and MCI. Declining financial capacity may signal pathological buildup and serve as an early warning sign for AD, and future research should continue to investigate the longitudinal relationship between tau, financial capacity, and other IADL.

Synergistic interaction of high blood pressure and cerebral beta-amyloid on tau pathology

BackgroundHypertension has been associated with Alzheimer’s disease (AD) dementia as well as vascular dementia. However, the underlying neuropathological changes that link hypertension to AD remain poorly understood. In our study, we examined the relationships of a history of hypertension and high current blood pressure (BP) with in vivo AD pathologies including β-amyloid (Aβ) and tau and also investigated whether a history of hypertension and current BP respectively affect the association between Aβ and tau deposition.MethodsThis cross-sectional study was conducted as part of the Korean Brain Aging Study for Early Diagnosis and Prediction of Alzheimer’s Disease, a prospective cohort study. Cognitively normal older adults who underwent both Aβ and tau positron emission tomography (PET) (i.e., [11C]-Pittsburgh compound B and [18F] AV-1451 PET) were selected. History of hypertension and current BP were evaluated and cerebral Aβ and tau deposition measured by PET were used as main outcomes. Generalized linear regression models were used to estimate associations.ResultsA total of 68 cognitively normal older adults (mean [SD] age, 71.5 [7.4] years; 40 women [59%]) were included in the study. Neither a history of hypertension nor the current BP exhibited a direct association with Aβ or tau deposition. However, the synergistic interaction effects of high current systolic (β, 0.359; SE, 0.141; p = 0.014) and diastolic (β, 0.696; SE, 0.158; p < 0.001) BP state with Aβ deposition on tau deposition were significant, whereas there was no such effect for a history of hypertension (β, 0.186; SE, 0.152; p = 0.224).ConclusionsThe findings suggest that high current BP, but not a history of hypertension, synergistically modulate the relationship between cerebral Aβ and tau deposition in late-life. In terms of AD prevention, the results support the importance of strict BP control in cognitively normal older adults with hypertension.

Enlarged perivascular spaces are associated with decreased brain tau deposition.

The aim of this study was to investigate the associations of enlarged perivascular spaces (EPVS) in the basal ganglia (BG) and centrum semiovale (CSO) with beta-amyloid (Aβ) and tau deposition in older adults with a diverse cognitive spectrum. A total of 163 (68 cognitively normal and 95 cognitively impaired) older participants underwent [11 C] Pittsburgh compound B and [18 F] AV-1451 PET, and MRI. EPVS in the BG and CSO and other small vessel disease markers, such as white matter hyperintensities, lacunes, and deep and lobar microbleeds, were assessed. Increased EPVS in the BG showed a significant association with lower cerebral tau deposition, even after controlling for other small vessel disease markers. Further exploratory analyses showed that this association was significant in cognitively impaired, Aβ-positive, or APOE4-positive individuals, but not significant in the cognitively normal, Aβ-negative, or APOE4-negative participants. In contrast to EPVS in the BG, EPVS in the CSO did not have any relationship with cerebral tau deposition. In addition, none of the two types of EPVS were associated with cerebral Aβ deposition. Brain tau deposition appears to be reduced with increased EPVS in the BG, especially in individuals with cognitive impairment, pathological amyloid burden, or genetic Alzheimer's disease risk.

Bilingualism Appears to be Protective Against Cognitive Decline Related to Cerebral Tau in Mexican Americans: An HABS‐HD Study

AbstractBackgroundBilingualism is thought to provide protective effects from neurodegeneration and age‐related diseases such as Alzheimer’s Disease (AD). The protective effect is considered to be due to differences in grey and white matter between monolingual and bilinguals; however, no work to date has looked at differences in additional AD brain pathology. The aim of this study was to examine among Mexican Americans the impact of cerebral tau levels on cognitive functioning stratified by language status.MethodData were analyzed on a combined sample of n=44 Mexican American (n=15 Monolingual [n=9 Cognitively Normal; n=6 Cognitively Impaired {Mild Cognitive Impairment/Dementia}]; n=29 Bilingual [n=19 Cognitively Normal; n=10 Cognitively Impaired]) participants. One outlier case (Cognitively Impaired, Monolingual participant) was removed from subsequent analyses. All participants underwent cognitive testing and PET tau imaging using Siemens Biograph Vision 450 PET/CT scanner with PI‐2620. PET scans were co‐registered with 3T MRI scans (Siemens Vida). PET tau scans were processed using FreeSurfer‐defined regions of interest (ROIs) focused on the medial temporal lobe (average across entorhinal, hippocampus and amygdala), posterior cingulate cortex (isthmus cingulate and posterior cingulate) and lateral parietal cortex (inferior parietal, superior parietal and supramarginal). Linear regression models were generated for each language status group (monolingual, bilingual) examining the impact of each ROI on cognitive outcomes covarying for age, sex, and education.ResultAmong monolingual Mexican Americans, higher Medial Temporal SUVR was significantly related to poorer performance across measures of global cognition (MMSE p&lt;0.001), processing speed (DSST p=0.038), episodic learning and memory (WMS‐III LM I p&lt;0.001; WMS‐III LM II p&lt;0.001) as well as rote verbal learning (SEVLT Immediate Recall p=0.004). Posterior Cingulate and Lateral Parietal SUVRs were not found to be significantly related to cognitive functioning among monolinguals. Additionally, among bilinguals, cerebral tau (derived from select ROIs) was not found to be significantly related to cognition.ConclusionHigher cerebral tau, specifically in the Medial Temporal ROI, was found to be related to poorer cognitive functioning across multiple domains but only among those who were monolingual. Results provide further support for the protective effect of bilingualism.

Neuroinflammation is associated with the rising of early Alzheimer’s disease pathology in amyloid‐negative elderly

AbstractBackgroundAmyloid‐β (Aβ) and tau are the two well‐recognised pathological hallmarks of Alzheimer’s disease (AD). In the recent decades, increasing evidence supports neuroinflammation as one of the earliest pathomechanistic alterations throughout the AD continuum. However, little is known about the spatial and temporal patterns of neuroinflammatory processes based on AD pathological status. Furthermore, it also remains elusive how longitudinal change of neuroinflammation affects cerebral amyloid and tau load in the trajectory of AD.MethodWe examined a total number of 122 subjects (mean age= 65.6 years, 66.4% women, 33.1% APOEɛ4 carriers) from the TRIAD cohort at McGill University Research Centre for Studies in Aging. Neuroinflammation, cerebral Aβ load and tau deposition were assessed with positron emission tomography (PET) radiotracers [11C]PBR28, [18F]AZD4694 ([18F]NAV4694) and [18F]MK6240 respectively. Amyloid‐β positivity was determined by a cortical composite [18F]NAV4694 SUVR threshold of 1.55, based on previously published method. Voxelwise analyses were performed to evaluate the relationships between cerebral amyloid load and neuroinflammation. A subgroup of 42 subjects who had underwent two‐year follow‐up PET scans were used to study how the longitudinal change of neuroinflammation affects other AD hallmarks.ResultAt early stages of amyloid pathology, we found a positive linear relationship between neuroinflammation and amyloid load. Voxelwise analyses also revealed a stronger association between amyloid and neuroinflammation among the Aβ‐negative subjects. Longitudinally, the increase of neuroinflammation was linked to the accumulation of cerebral amyloid and tau in Aβ‐negative subjects.ConclusionNeuroinflammation was associated with amyloid at early stages of amyloid pathology. In addition, elevation of neuroinflammation was associated with the increase of amyloid and tau accumulation in Aβ‐negative subjects.

The relationship between everyday functioning and cerebral tau burden in cognitively normal older adults

AbstractBackgroundAlzheimer’s disease is characterized by accumulation of amyloid and tau in the brain. While amyloid is hypothesized to accumulate earlier, tau has been shown to be more strongly related to clinical outcomes. Higher‐order cognitive functioning in daily life is a clinically meaningful outcome that has been shown to decline, even in early disease stages. We aimed to understand the cross‐sectional relationship between regional cerebral tau accumulation and everyday functioning in cognitively normal older adults.MethodWe used data from the A4 and LEARN Studies and included participants who underwent tau positron emission tomography (PET) scans using 18F‐flortaucipir (n = 447, age 71.9±4.9 years, 57.5% female). Everyday functioning was reported by both participant and study partner using the Alzheimer’s Disease Cooperative Study Activities of Daily Living‐Prevention Instrument (ADCS ADL‐PI). We dichotomized ADCS ADL‐PI total scores as ≤44 vs 45 (the maximum score). Additionally, based on previous analyses, we focused on four items and dichotomized scores as no difficulty vs. some/a lot of difficulty. We performed logistic regressions adjusting for age, sex and education.ResultParticipants (median 45, range 33–45) and study partners (median 45, range 23–45) reported high levels of everyday functioning. Neither entorhinal nor inferior temporal tau was associated with overall self‐ or study partner‐reported everyday functioning (Table; Figure1). Greater entorhinal tau was associated with study partner‐reported difficulties remembering important dates (odds ratio (OR) = 1.24, 95% confidence interval (95%CI) = [1.06, 1.45], p = 0.008). Greater inferior temporal tau was associated with self‐reported difficulties managing to find personal belongings (OR = 1.23, 95%CI = [1.04, 1.46], p = 0.018). Greater entorhinal and inferior temporal tau were associated with study partner‐reported difficulties remembering the details of TV programs and movies (OR = 1.32, 95%CI = [1.08, 1.61], p = 0.007 and OR = 1.39, 95%CI = [1.11, 1.75], p = 0.005, respectively). Tau was not associated with difficulties remembering current events (Table; Figure2).ConclusionOur results suggest a weak cross‐sectional relationship between everyday functioning and tau in cognitively normal older adults. These findings are likely driven by the restricted variability in scores on the ADCS ADL‐PI, which could improve with longitudinal data. Moreover, future work should incorporate a measurement of everyday functioning that has a wider range of performance in this population even at baseline.

Post‐mortem assessment of retinal phosphorylated tau and amyloid beta in a cohort of neurodegenerative diseases.

AbstractBackgroundThe retina provides an opportunity for development of a screening tool to detect early stages of AD. Studies showing the presence of Aβ and p‐tau in AD retina are contradictory, and their characterization in a large, neuropathologically confirmed cohort with different neurodegenerative diseases is scarce. In this study we assessed the presence of different tau isoforms and Aβ (4G8) in the retinas of AD cases, control cases, as well as other neurodegenerative diseases, and correlated these directly to cortical cerebral tau and amyloid pathology loads.MethodPost mortem eyes (N = 62) with both clinical history and post‐mortem neuropathological reports available were collected through the Netherlands Brain Bank. Donors included AD, PSP, CBD, FTLD, PD(D), DLB, MSA, ALS, MS and controls, with and without cerebral cortical p‐tau. Superior‐temporal quadrants were cut in 10 µm sections. Sections were immunostained using antibodies directed against p‐tau (AT270, AT100, AT8, pS422) and Aβ (4G8). Linear mixed models were used to analyze between‐group differences and the relation between brain and retina.ResultTau appeared as a diffuse neuritic staining, and in some cases as somatodendritic‐like staining and was mainly present in the plexiform layers of the retina. AT8, AT100 and AT270 immunoreactivity showed a predilection in the far periphery. AT8 was generally found in tauopathy cases as opposed to non‐tauopathy cases. A strong correlation was found between retinal AT8 and brain cortical tau pathology. 4G8 appeared sporadically as extracellular structures, mainly present in the retinal nerve fiber layer, ganglion cell layer and near blood vessels. 4G8 did not differ between control and disease cases, and no group differences or relation with cortical amyloid load was found.ConclusionP‐tau measured with AT8 in the retina correlates with the presence of tau pathology in cortical brain areas. In contrast, Aβ (4G8) immunoreactivity is sporadically present in the retina, is not specific for AD and does not correlate with cortical amyloid load in a large cross‐disease cohort. Our study shows that p‐tau detected in the retina by AT8 is a potential biomarker candidate for tauopathies.

Association of low meal frequency with decreased in vivo Alzheimer’s pathology

Little is known about the association between meal frequency and Alzheimer's disease (AD) in humans. We tested the hypothesis that low meal frequency (LMF) is associated with reduced invivo AD pathology in human brain, and additionally investigated the mediation of serum ghrelin, a hunger-related hormone, for the association. A total of 411 non-demented older adults were systematically interviewed to identify their dietary patterns including meal frequency and underwent multi-modal neuroimaging for cerebral beta-amyloid (Aβ) and tau deposition, glucose metabolism, and cerebrovascular injury. LMF (less than three meals a day) was significantly associated with lower Aβ deposition compared to high meal frequency (HMF). In addition, both LMF and reduced Aβ deposition were significantly related to elevated serum ghrelin. Our findings suggest that LMF may be related to the lower risk of AD through reduced brain amyloid deposition. Additionally, ghrelin appears mediate the association between LMF and lower amyloid deposition.

Diagnostic, Prognostic, and Mechanistic Biomarkers of Diabetes Mellitus-Associated Cognitive Decline.

Cognitive dysfunctions such as mild cognitive impairment (MCI), Alzheimer’s disease (AD), and other forms of dementia are recognized as common comorbidities of type 2 diabetes mellitus (T2DM). Currently, there are no disease-modifying therapies or definitive clinical diagnostic and prognostic tools for dementia, and the mechanisms underpinning the link between T2DM and cognitive dysfunction remain equivocal. Some of the suggested pathophysiological mechanisms underlying cognitive decline in diabetes patients include hyperglycemia, insulin resistance and altered insulin signaling, neuroinflammation, cerebral microvascular injury, and buildup of cerebral amyloid and tau proteins. Given the skyrocketing global rates of diabetes and neurodegenerative disorders, there is an urgent need to discover novel biomarkers relevant to the co-morbidity of both conditions to guide future diagnostic approaches. This review aims to provide a comprehensive background of the potential risk factors, the identified biomarkers of diabetes-related cognitive decrements, and the underlying processes of diabetes-associated cognitive dysfunction. Aging, poor glycemic control, hypoglycemia and hyperglycemic episodes, depression, and vascular complications are associated with increased risk of dementia. Conclusive research studies that have attempted to find specific biomarkers are limited. However, the most frequent considerations in such investigations are related to C reactive protein, tau protein, brain-derived neurotrophic factor, advanced glycation end products, glycosylated hemoglobin, and adipokines.

TAU ablation in excitatory neurons and postnatal TAU knockdown reduce epilepsy, SUDEP, and autism behaviors in a Dravet syndrome model.

Intracellular accumulation of TAU aggregates is a hallmark of several neurodegenerative diseases. However, global genetic reduction of TAU is beneficial also in models of other brain disorders that lack such TAU pathology, suggesting a pathogenic role of nonaggregated TAU. Here, conditional ablation of TAU in excitatory, but not inhibitory, neurons reduced epilepsy, sudden unexpected death in epilepsy, overactivation of the phosphoinositide 3-kinase-AKT-mammalian target of rapamycin pathway, brain overgrowth (megalencephaly), and autism-like behaviors in a mouse model of Dravet syndrome, a severe epileptic encephalopathy of early childhood. Furthermore, treatment with a TAU-lowering antisense oligonucleotide, initiated on postnatal day 10, had similar therapeutic effects in this mouse model. Our findings suggest that excitatory neurons are the critical cell type in which TAU has to be reduced to counteract brain dysfunctions associated with Dravet syndrome and that overall cerebral TAU reduction could have similar benefits, even when initiated postnatally.