Association of 10 VEGF Family Genes with Alzheimer's Disease Endophenotypes at Single Cell Resolution.

The cell-type specific role of the vascular endothelial growth factors (VEGFs) in the pathogenesis of Alzheimer's disease (AD) is not well characterized. In this study, we utilized a single-nucleus RNA sequencing dataset from Dorsolateral Prefrontal Cortex (DLFPC) of 424 donors from the Religious Orders Study and Memory and Aging Project (ROS/MAP) to investigate the effect of 10 VEGF genes ( VEGFA, VEGFB, VEGFC, VEGFD, PGF, FLT1, FLT4, KDR, NRP1 , and NRP2 ) on AD endophenotypes. Mean age of death was 89 years, among which 68% were females, and 52% has AD dementia. Negative binomial mixed models were used for differential expression analysis and for association analysis with ß-amyloid load, PHF tau tangle density, and both cross-sectional and longitudinal global cognitive function. Intercellular VEGF-associated signaling was profiled using CellChat. We discovered prefrontal cortical FLT1 expression was upregulated in AD brains in both endothelial and microglial cells. Higher FLT1 expression was also associated with worse cross-sectional global cognitive function, longitudinal cognitive trajectories, and ß-amyloid load. Similarly, higher endothelial FLT4 expression was associated with more ß-amyloid load. In contrast to the receptors, VEGFB showed opposing effects on ß-amyloid load whereby higher levels in oligodendrocytes was associated with high amyloid burden, while higher levels in inhibitory neurons was associated with lower amyloid burden. Finally, AD cells showed significant reduction in overall VEGF signaling comparing to those from cognitive normal participants. Our results highlight key changes in VEGF receptor expression in endothelial and microglial cells during AD, and the potential protective role of VEGFB in neurons.

MRI-Derived AD Signature of Cortical Thinning and Plasma P-Tau217 for Predicting Alzheimer Dementia Among Community-Dwelling Older Adults.

Background and Objectives: Structural brain MRI and blood-based phosphorylated tau (p-tau) measures are among the least invasive and least expensive Alzheimer's disease (AD) biomarkers to date. The extent to which these biomarkers may outperform one another in predicting future Alzheimer dementia diagnosis is poorly understood, however. This study investigated 2 specific AD biomarkers, i.e., a cortical thickness signature of AD (AD-CT) and plasma p-tau217, for predicting Alzheimer dementia. Methods: Data came from community-dwelling older participants of the Religious Orders Study or the Rush Memory and Aging Project. AD-CT was obtained from 3T MRI scans using a magnetization-prepared rapid acquisition gradient echo sequence and by averaging thickness from previously identified cortical regions implicated in AD. Plasma p-tau217 was quantified using an immunoassay developed by Lilly Research Laboratories on the MSD platform. Both MRI scans and blood specimens were collected at the same visits, and subsequent diagnoses of Alzheimer dementia were determined through annual detailed clinical evaluations. Cox proportional hazards models examined the associations of the 2 biomarkers with incident Alzheimer dementia, and prediction accuracy was assessed using c-statistics. Results: A total of 198 older adults, on average 84 years of age, were included. Over a mean follow-up of 4 years, 60 (30%) individuals developed Alzheimer dementia. AD-CT (hazard ratio: 1.71, 95% CI 1.26-2.31) and separately plasma p-tau217 (hazard ratio: 2.57, 95% CI 1.83-3.61) were associated with incident Alzheimer dementia. The c-statistic for prediction accuracy was consistently higher for plasma p-tau217 (between 0.74 and 0.81) than AD-CT (between 0.70 and 0.75) across a range of time horizons. Furthermore, with both biomarkers included in the same model, there was only modest improvement in the c-statistic due to AD-CT. Discussion: Plasma p-tau217 outperforms an imaging-based cortical thickness signature of AD in predicting future Alzheimer dementia diagnosis. Furthermore, the AD cortical thickness signature adds little to the prediction accuracy above and beyond plasma p-tau217.

Association of Alzheimer's Disease and Other Neuropathologies with Functional Disability in Persons With and Without Dementia.

BACKGROUND: Dementia results from multiple neuropathologies causing cognitive impairment sufficiently severe to impact functional status. However, these pathologies and functional impairment are common in persons without dementia. We examined the association of AD and multiple other neuropathologies with instrumental and basic activities of daily living in persons with and without dementia. METHODS: Participants were 1,509 deceased from the Religious Orders Study or Rush Memory and Aging Project. Pathologic AD and three other AD indices were examined, in addition to four non-AD neurodegenerative pathologies: cerebral amyloid angiopathy (CAA), hippocampal sclerosis, TDP-43 and Lewy bodies, and four cerebrovascular pathologies: gross- and microinfarctions, athero- and arteriolosclerosis. Functional assessment included Lawton and Katz Index Instrumental and Basic Activities of Daily Living (IADL and BADL). Ordinal regression models adjusted for age, sex, and education were used to examine the association of neuropathologies with IADL and BADL. RESULTS: AD and the other neuropathologies were associated with impaired IADL (all Ps<0.001) and with impaired BADL (Ps<0.01), except for atherosclerosis and CAA which were not associated with BADL. The effects of most neuropathologies were largely affected by dementia. However, small effects on IADL remained for PHFtau tangles after adjusting models for dementia. Direct effects of gross infarcts on IADL and BADL, and of microinfarcts on BADL remained unchanged after adjusting the models for dementia. CONCLUSION: AD and all other neuropathologies are strongly associated with functional disability. The association of most neuropathologies with disability was eliminated or attenuated by dementia, except for gross infarcts and microinfarcts.

G-protein coupled estrogen receptor 1, amyloid-ß, and tau tangles in older adults.

Accumulation of amyloid-ß (Aß) and tau tangles are hallmarks of Alzheimer's disease. Aß is extracellular while tau tangles are typically intracellular, and it is unknown how these two proteinopathies are connected. Here, we use data of 1206 elders and test that RNA expression levels of GPER1, a transmembrane protein, modify the association of Aß with tau tangles. GPER1 RNA expression is related to more tau tangles (p = 0.001). Moreover, GPER1 expression modifies the association of immunohistochemistry-derived Aß load with tau tangles (p = 0.044). Similarly, GPER1 expression modifies the association between Aß proteoforms and tau tangles: total Aß protein (p = 0.030) and Aß38 peptide (p = 0.002). Using single nuclei RNA-seq indicates that GPER1 RNA expression in astrocytes modifies the relation of Aß load with tau tangles (p = 0.002), but not GPER1 in excitatory neurons or endothelial cells. We conclude that GPER1 may be a link between Aß and tau tangles driven mainly by astrocytic GPER1 expression.

Limbic-predominant age-related TDP-43 encephalopathy neuropathological change (LATE-NC) is associated with abnormalities in white matter structural integrity and connectivity: An ex-vivo diffusion MRI and pathology investigation.

Limbic predominant age-related TDP-43 encephalopathy neuropathological change (LATE-NC) is common in older adults and is associated with neurodegeneration, cognitive decline and dementia. In this MRI and pathology investigation we tested the hypothesis that LATE-NC is associated with abnormalities in white matter structural integrity and connectivity of a network of brain regions typically harboring TDP-43 inclusions in LATE, referred to here as the "LATE-NC network". Ex-vivo diffusion MRI and detailed neuropathological data were collected on 184 community-based older adults. Linear regression revealed an independent association of higher LATE-NC stage with lower diffusion anisotropy in a set of white matter connections forming a pattern of connectivity that is consistent with the stereotypical spread of this pathology in the brain. Graph theory analysis revealed an association of higher LATE-NC stage with weaker integration and segregation in the LATE-NC network. Abnormalities were significant in stage 3, suggesting that they are detectable in later stages of the disease. Finally, LATE-NC network abnormalities were associated with faster cognitive decline, specifically in episodic and semantic memory.

Elevated protease-activated receptor 4 (PAR4) gene expression in Alzheimer's disease predicts cognitive decline.

Platelet activation of protease-activated receptor 4 (PAR4) and thrombin are at the top of a chain of events leading to fibrin deposition, microinfarcts, blood-brain barrier disruption, and inflammation. We evaluated mRNA expression of the PAR4 gene F2RL3 in human brain and global cognitive performance in participants with and without cognitive impairment or dementia. Data were acquired from the Religious Orders Study (ROS) and the Rush Memory and Aging Project (MAP). F2RL3 mRNA was elevated in AD cases and was associated with worse retrospective longitudinal cognitive performance. Moreover, F2RL3 expression interacted with clinical AD diagnosis on longitudinal cognition whereas this relationship was attenuated in individuals without cognitive impairment. Additionally, when adjusting for the effects of AD neuropathology, F2RL3 expression remained a significant predictor of cognitive decline. F2RL3 expression correlated positively with transcript levels of proinflammatory markers including TNFα, IL-1ß, NFκB, and fibrinogen α/ß/γ. Together, these results reveal that F2RL3 mRNA expression is associated with multiple AD-relevant outcomes and its encoded product, PAR4, may play a role in disease pathogenesis.

The time course of motor and cognitive decline in older adults and their associations with brain pathologies: a multicohort study.

BACKGROUND: Many studies have reported that impaired gait precedes cognitive impairment in older people. We aimed to characterise the time course of cognitive and motor decline in older individuals and the association of these declines with the pathologies of Alzheimer's disease and related dementias. METHODS: This multicohort study used data from three community-based cohort studies (Religious Orders Study, Rush Memory and Aging Project, and Minority Aging Research Study, all in the USA). The inclusion criteria for all three cohorts were no clinical dementia at the time of enrolment and consent to annual clinical assessments. Eligible participants consented to post-mortem brain donation and had post-mortem pathological assessments and three or more repeated annual measures of cognition and motor functions. Clinical and post-mortem data were analysed using functional mixed-effects models. Global cognition was based on 19 neuropsychological tests, a hand strength score was based on grip and pinch strength, and a gait score was based on the number of steps and time to walk 8 feet and turn 360°. Brain pathologies of Alzheimer's disease and related dementias were assessed at autopsy. FINDINGS: From 1994 to 2022, there were 1570 eligible cohort participants aged 65 years or older, 1303 of whom had cognitive and motor measurements and were included in the analysis. Mean age at death was 90·3 years (SD 6·3), 905 (69%) participants were female, and 398 (31%) were male. Median follow-up time was 9 years (IQR 5-11). On average, cognition was stable from 25 to 15 years before death, when cognition began to decline. By contrast, gait function and hand strength declined during the entire study. The combinations of pathologies of Alzheimer's disease and related dementias associated with cognitive and motor decline and their onsets of associations varied; only tau tangles, Parkinson's disease pathology, and macroinfarcts were associated with decline of all three phenotypes. Tau tangles were significantly associated with cognitive decline, gait function decline, and hand function decline (p<0·0001 for each); however, the association with cognitive decline persisted for more than 11 years before death, but the association with hand strength only began 3·57 years before death and the association with gait began 3·49 years before death. By contrast, the association of macroinfarcts with declining gait function began 9·25 years before death (p<0·0001) compared with 6·65 years before death (p=0·0005) for cognitive decline and 2·66 years before death (p=0·024) for decline in hand strength. INTERPRETATION: Our findings suggest that average motor decline in older adults precedes cognitive decline. Macroinfarcts but not tau tangles are associated with declining gait function that precedes cognitive decline. This suggests the need for further studies to test if gait impairment is a clinical proxy for preclinical vascular cognitive impairment. FUNDING: National Institutes of Health.

Association of whole-person eigen-polygenic risk scores with Alzheimer's disease.

Late-Onset Alzheimer's Disease (LOAD) is a heterogeneous neurodegenerative disorder with complex etiology and high heritability. Its multifactorial risk profile and large portions of unexplained heritability suggest the involvement of yet unidentified genetic risk factors. Here we describe the "whole person" genetic risk landscape of polygenic risk scores for 2218 traits in 2044 elderly individuals and test if novel eigen-PRSs derived from clustered subnetworks of single-trait PRSs can improve the prediction of LOAD diagnosis, rates of cognitive decline, and canonical LOAD neuropathology. Network analyses revealed distinct clusters of PRSs with clinical and biological interpretability. Novel eigen-PRSs (ePRS) from these clusters significantly improved LOAD-related phenotypes prediction over current state-of-the-art LOAD PRS models. Notably, an ePRS representing clusters of traits related to cholesterol levels was able to improve variance explained in a model of the brain-wide beta-amyloid burden by 1.7% (likelihood ratio test P = 9.02 × 10-7). All associations of ePRS with LOAD phenotypes were eliminated by the removal of APOE-proximal loci. However, our association analysis identified modules characterized by PRSs of high cholesterol and LOAD. We believe this is due to the influence of the APOE region from both PRSs. We found significantly higher mean SNP effects for LOAD in the intersecting APOE region SNPs. Combining genetic risk factors for vascular traits and dementia could improve current single-trait PRS models of LOAD, enhancing the use of PRS in risk stratification. Our results are catalogued for the scientific community, to aid in generating new hypotheses based on our maps of clustered PRSs and associations with LOAD-related phenotypes.

Lower GLUT1 and unchanged MCT1 in Alzheimer's disease cerebrovasculature.

The brain is a highly demanding organ, utilizing mainly glucose but also ketone bodies as sources of energy. Glucose transporter-1 (GLUT1) and monocarboxylates transporter-1 (MCT1) respectively transport glucose and ketone bodies across the blood-brain barrier. While reduced glucose uptake by the brain is one of the earliest signs of Alzheimer's disease (AD), no change in the uptake of ketone bodies has been evidenced yet. To probe for changes in GLUT1 and MCT1, we performed Western immunoblotting in microvessel extracts from the parietal cortex of 60 participants of the Religious Orders Study. Participants clinically diagnosed with AD had lower cerebrovascular levels of GLUT1, whereas MCT1 remained unchanged. GLUT1 reduction was associated with lower cognitive scores. No such association was found for MCT1. GLUT1 was inversely correlated with neuritic plaques and cerebrovascular ß-secretase-derived fragment levels. No other significant associations were found between both transporters, markers of Aß and tau pathologies, sex, age at death or apolipoprotein-ε4 genotype. These results suggest that, while a deficit of GLUT1 may underlie the reduced transport of glucose to the brain in AD, no such impairment occurs for MCT1. This study thus supports the exploration of ketone bodies as an alternative energy source for the aging brain.

Association of Age-Related Neuropathologic Findings at Autopsy With a Claims-Based Epilepsy Diagnosis in Older Adults.

BACKGROUND AND OBJECTIVES: Epilepsy is 1 of the 3 most common neurologic diseases of older adults, but few studies have examined its underlying pathologies in older age. We examined the associations of age-related brain pathologies with epilepsy in older persons. METHODS: Clinical and pathologic data came from 2 ongoing clinical pathologic cohort studies of community-dwelling older adults. Epilepsy was ascertained using Medicare fee-for-service Parts A and B claims data that were linked to data from the cohort studies. The postmortem pathologic assessment collected indices of 9 pathologies including Alzheimer disease, hippocampal sclerosis, macroinfarcts, and cerebral amyloid angiopathy. The fixed brain hemisphere was imaged using 3T MRI scanners before the pathologic assessments in a subgroup of participants. RESULTS: The participants (n = 1,369) were on average 89.3 (6.6) years at death, and 67.0% were women. Epilepsy was identified in 58 (4.2%) participants. Cerebral amyloid angiopathy (odds ratio [OR] = 2.21, 95% CI 1.24-3.95, p = 0.007) and cortical macroinfarcts (OR = 2.74, 95% CI 1.42-5.28, p = 0.003) were associated with a higher odds of epilepsy. Of note, hippocampal sclerosis and Alzheimer disease pathology were not associated with epilepsy (both p's > 0.25), although hippocampal sclerosis was not common and thus hard to examine with the modest number of epilepsy cases here. In 673 participants with MRI data, the association of cerebral amyloid angiopathy and cortical macroinfarcts with epilepsy did not change after controlling for cortical gray matter atrophy, which was independently associated with a higher odds of epilepsy (OR = 1.06, 95% CI 1.02-1.10, p = 0.003). By contrast, hippocampal volume was not associated with epilepsy. DISCUSSION: Cerebrovascular pathologies and cortical atrophy were associated with epilepsy in older persons.

Genetic associations with dementia-related proteinopathy: Application of item response theory.

INTRODUCTION: Although dementia-related proteinopathy has a strong negative impact on public health, and is highly heritable, understanding of the related genetic architecture is incomplete. METHODS: We applied multidimensional generalized partial credit modeling (GPCM) to test genetic associations with dementia-related proteinopathies. Data were analyzed to identify candidate single nucleotide variants for the following proteinopathies: Aß, tau, α-synuclein, and TDP-43. RESULTS: Final included data comprised 966 participants with neuropathologic and WGS data. Three continuous latent outcomes were constructed, corresponding to TDP-43-, Aß/Tau-, and α-synuclein-related neuropathology endophenotype scores. This approach helped validate known genotype/phenotype associations: for example, TMEM106B and GRN were risk alleles for TDP-43 pathology; and GBA for α-synuclein/Lewy bodies. Novel suggestive proteinopathy-linked alleles were also discovered, including several (SDHAF1, TMEM68, and ARHGEF28) with colocalization analyses and/or high degrees of biologic credibility. DISCUSSION: A novel methodology using GPCM enabled insights into gene candidates for driving misfolded proteinopathies. HIGHLIGHTS: Latent factor scores for proteinopathies were estimated using a generalized partial credit model. The three latent continuous scores corresponded well with proteinopathy severity. Novel genes associated with proteinopathies were identified. Several genes had high degrees of biologic credibility for dementia risk factors.

Cell subtype-specific effects of genetic variation in the Alzheimer's disease brain.

The relationship between genetic variation and gene expression in brain cell types and subtypes remains understudied. Here, we generated single-nucleus RNA sequencing data from the neocortex of 424 individuals of advanced age; we assessed the effect of genetic variants on RNA expression in cis (cis-expression quantitative trait loci) for seven cell types and 64 cell subtypes using 1.5 million transcriptomes. This effort identified 10,004 eGenes at the cell type level and 8,099 eGenes at the cell subtype level. Many eGenes are only detected within cell subtypes. A new variant influences APOE expression only in microglia and is associated with greater cerebral amyloid angiopathy but not Alzheimer's disease pathology, after adjusting for APOEε4, providing mechanistic insights into both pathologies. Furthermore, only a TMEM106B variant affects the proportion of cell subtypes. Integration of these results with genome-wide association studies highlighted the targeted cell type and probable causal gene within Alzheimer's disease, schizophrenia, educational attainment and Parkinson's disease loci.

Association between hippocampal microglia, AD and LATE-NC, and cognitive decline in older adults.

INTRODUCTION: This study investigates the relationship between microglia inflammation in the hippocampus, brain pathologies, and cognitive decline. METHODS: Participants underwent annual clinical evaluations and agreed to brain donation. Neuropathologic evaluations quantified microglial burden in the hippocampus, amyloid beta (Aß), tau tangles, and limbic age-related transactive response DNA-binding protein 43 (TDP-43) encephalopathy neuropathologic changes (LATE-NC), and other common brain pathologies. Mixed-effect and linear regression models examined the association of microglia with a decline in global and domain-specific cognitive measures, and separately with brain pathologies. Path analyses estimated direct and indirect effects of microglia on global cognition. RESULT: Hippocampal microglia were associated with a faster decline in global cognition, specifically in episodic memory, semantic memory, and perceptual speed. Tau tangles and LATE-NC were independently associated with microglia. Other pathologies, including Aß, were not related. Regional hippocampal burden of tau tangles and TDP-43 accounted for half of the association of microglia with cognitive decline. DISCUSSION: Microglia inflammation in the hippocampus contributes to cognitive decline. Tau tangles and LATE-NC partially mediate this association.

Delineating cognitive resilience using fractal regulation: Cross-sectional and longitudinal evidence from the Rush Memory and Aging Project.

INTRODUCTION: Degradation of fractal patterns in actigraphy independently predicts dementia risk. Such observations motivated the study to understand the role of fractal regulation in the context of neuropathologies. METHODS: We examined associations of fractal regulation with neuropathologies and longitudinal cognitive changes in 533 older participants who were followed annually with actigraphy and cognitive assessments until death with brain autopsy performed. Two measures for fractal patterns were extracted from actigraphy, namely, α1 (representing the fractal regulation at time scales of <90 min) and α2 (for time scales 2 to 10 h). RESULTS: We found that larger α1 was associated with lower burdens of Lewy body disease or cerebrovascular disease pathologies; both α1 and α2 were associated with cognitive decline. They explained an additional significant portion of the variance in the rate of cognitive decline above and beyond neuropathologies. DISCUSSION: Fractal patterns may be used as a biomarker for cognitive resilience against dementia-related neuropathologies.

Distinctive retinal peri-arteriolar versus peri-venular amyloid plaque distribution correlates with the cognitive performance.

Introduction: The vascular contribution to Alzheimer's disease (AD) is tightly connected to cognitive performance across the AD continuum. We topographically describe retinal perivascular amyloid plaque (AP) burden in subjects with normal or impaired cognition. Methods: Using scanning laser ophthalmoscopy, we quantified retinal peri-arteriolar and peri-venular curcumin-positive APs in the first, secondary and tertiary branches in twenty-eight subjects. Perivascular AP burden among cognitive states was correlated with neuroimaging and cognitive measures. Results: Peri-arteriolar exceeded peri-venular AP count (p<0.0001). Secondary branch AP count was significantly higher in cognitively impaired (p<0.01). Secondary small and tertiary peri-venular AP count strongly correlated with clinical dementia rating, hippocampal volumes, and white matter hyperintensity count. Discussion: Our topographic analysis indicates greater retinal amyloid accumulation in the retinal peri-arteriolar regions overall, and distal peri-venular regions in cognitively impaired individuals. Larger longitudinal studies are warranted to understand the temporal-spatial relationship between vascular dysfunction and perivascular amyloid deposition in AD. Highlights: Retinal peri-arteriolar region exhibits more amyloid compared with peri-venular regions.Secondary retinal vascular branches have significantly higher perivascular amyloid burden in subjects with impaired cognition, consistent across sexes.Cognitively impaired individuals have significantly greater retinal peri-venular amyloid deposits in the distal small branches, that correlate with CDR and hippocampal volumes.

Chronic traumatic encephalopathy and aging-related tau astrogliopathy in community-dwelling older persons with and without moderate-to-severe traumatic brain injury.

This study examined the frequency of chronic traumatic encephalopathy-neuropathologic change (CTE-NC) and aging-related tau astrogliopathy (ARTAG) in community-dwelling older adults and tested the hypothesis that these tau pathologies are associated with a history of moderate-to-severe traumatic brain injury (msTBI), defined as a TBI with loss of consciousness >30 minutes. We evaluated CTE-NC, ARTAG, and Alzheimer disease pathologies in 94 participants with msTBI and 94 participants without TBI matched by age, sex, education, and dementia status TBI from the Rush community-based cohorts. Six (3%) of brains showed the pathognomonic lesion of CTE-NC; only 3 of these had a history of msTBI. In contrast, ARTAG was common in older brains (gray matter ARTAG = 77%; white matter ARTAG = 54%; subpial ARTAG = 51%); there were no differences in severity, type, or distribution of ARTAG pathology with respect to history of msTBI. Furthermore, those with msTBI did not have higher levels of PHF-tau tangles density but had higher levels of amyloid-ß load (Estimate = 0.339, SE = 0.164, p = 0.040). These findings suggest that CTE-NC is infrequent while ARTAG is common in the community and that both pathologies are unrelated to msTBI. The association of msTBI with amyloid-ß, rather than with tauopathies suggests differential mechanisms of neurodegeneration in msTBI.

Identification of retinal tau oligomers, citrullinated tau, and other tau isoforms in early and advanced AD and relations to disease status.

Importance: This study identifies and quantifies diverse pathological tau isoforms in the retina of both early and advanced-stage Alzheimer's disease (AD) and determines their relationship with disease status. Objective: A case-control study was conducted to investigate the accumulation of retinal neurofibrillary tangles (NFTs), paired helical filament (PHF)-tau, oligomeric tau (oligo-tau), hyperphosphorylated tau (p-tau), and citrullinated tau (Cit-tau) in relation to the respective brain pathology and cognitive dysfunction in mild cognitively impaired (MCI) and AD dementia patients versus normal cognition (NC) controls. Design setting and participants: Eyes and brains from donors diagnosed with AD, MCI (due to AD), and NC were collected (n=75 in total), along with clinical and neuropathological data. Brain and retinal cross-sections-in predefined superior-temporal and inferior-temporal (ST/IT) subregions-were subjected to histopathology analysis or Nanostring GeoMx digital spatial profiling. Main outcomes and measure: Retinal burden of NFTs (pretangles and mature tangles), PHF-tau, p-tau, oligo-tau, and Cit-tau was assessed in MCI and AD versus NC retinas. Pairwise correlations revealed associations between retinal and brain parameters and cognitive status. Results: Increased retinal NFTs (1.8-fold, p=0.0494), PHF-tau (2.3-fold, p<0.0001), oligo-tau (9.1-fold, p<0.0001), CitR 209 -tau (4.3-fold, p<0.0001), pSer202/Thr205-tau (AT8; 4.1-fold, p<0.0001), and pSer396-tau (2.8-fold, p=0.0015) were detected in AD patients. Retinas from MCI patients showed significant increases in NFTs (2.0-fold, p=0.0444), CitR 209 -tau (3.5-fold, p=0.0201), pSer396-tau (2.6-fold, p=0.0409), and, moreover, oligo-tau (5.8-fold, p=0.0045). Nanostring GeoMx quantification demonstrated upregulated retinal p-tau levels in MCI patients at phosphorylation sites of Ser214 (2.3-fold, p=0.0060), Ser396 (1.8-fold, p=0.0052), Ser404 (2.4-fold, p=0.0018), and Thr231 (3.3-fold, p=0.0028). Strong correlations were found between retinal tau forms to paired-brain pathology and cognitive status: a) retinal oligo-tau vs. Braak stage (r=0.60, P=0.0002), b) retinal PHF-tau vs. ABC average score (r=0.64, P=0.0043), c) retinal pSer396-tau vs. brain NFTs (r=0.68, P<0.0001), and d) retinal pSer202/Thr205-tau vs. MMSE scores (r= -0.77, P=0.0089). Conclusions and Relevance: This study reveals increases in immature and mature retinal tau isoforms in MCI and AD patients, highlighting their relationship with brain pathology and cognition. The data provide strong incentive to further explore retinal tauopathy markers that may be useful for early detection and monitoring of AD staging through noninvasive retinal imaging.

Pathology-based brain arterial disease phenotypes and their radiographic correlates.

INTRODUCTION: Brain arterial diseases, including atherosclerosis, vasculitis, and dissections, are major contributors to cerebrovascular morbidity and mortality worldwide. These diseases not only increase the risk of stroke but also play a significant role in neurodegeneration and dementia. Clear and unambiguous terminology and classification of brain arterial disease phenotypes is crucial for research and clinical practice. MATERIAL AND METHODS: This review aims to summarize and harmonize the terminology used for brain large and small arterial phenotypes based on pathology studies and relate them to imaging phenotypes used in medical research and clinical practice. CONCLUSIONS AND RESULTS: Arteriosclerosis refers to hardening of the arteries but does not specify the underlying etiology. Specific terms such as atherosclerosis, calcification, or non-atherosclerotic fibroplasia are preferred. Atherosclerosis is defined pathologically by an atheroma. Other brain arterial pathologies occur and should be distinguished from atherosclerosis given therapeutic implications. On brain imaging, intracranial arterial luminal stenosis is usually attributed to atherosclerosis in the presence of atherosclerotic risk factors but advanced high-resolution arterial wall imaging has the potential to more accurately identify the underlying pathology. Regarding small vessel disease, arteriosclerosis is ambiguous and arteriolosclerosis is often used to denote the involvement of arterioles rather than arteries. Lipohyalinosis is sometimes used synonymously with arteriolosclerosis, but less accurately describes this common small vessel thickening which uncommonly shows lipid. Specific measures of small vessel wall thickness, the relationship to the lumen as well as changes in the layer composition might convey objective, measurable data regarding the status of brain small vessels.