Vascular Contributions To Cognitive Impairment And Dementia Research Articles

Investigating the Role of TDP-43 Microvasculopathy on Neurovascular unit Function in the Setting of COVID-19 and Alzheimer’s Disease and Related Dementias

Dysfunction of the blood-brain-barrier and the neurovascular unit, comprised of brain endothelial cells, pericytes, neurons, and glia, has been strongly implicated in the neurological manifestations of SARS-CoV-2 and vascular contributions to cognitive impairment and dementia (VCID) in Alzheimer’s disease (AD). A challenging unanswered question is whether the cognitive and neuropsychiatric disturbances of post-acute neurological sequelae of SARS-CoV-2 (Neuro-PASC) or long COVID are potentially linked to the development of AD. The RNA/DNA-binding protein TDP-43 (transactive response DNA-binding protein of 43 kDa) has been implicated in the pathogenesis of several viral infections and is cleaved by the main SARS-CoV-2 protease Nsp5, leading to neurotoxic TDP-43 fragments in mammalian cells. Aggregates composed of phosphorylated, ubiquitinated TDP-43 are also frequently present in AD. While TDP-43 microvasculopathy has been described in a subset of ADRD cases, its impact on blood-brain barrier integrity and neurovascular unit function is unknown. In this study, we investigated whether TDP-43 microvasculopathy is observed in AD and COVID-19 patient brains. We hypothesized that perivascular TDP-43 induces neurovascular unit dysfunction through cell autonomous and non-autonomous effects of pathologic TDP-43 deposition in astrocytic endfeet processes. To test this, hippocampus and dorsolateral prefrontal cortex (dlPFC) from human AD brains (Braak IV-VI; CERAD definite) and cognitively normal age- and sex-matched controls, with and without comorbid COVID-19, were selected from autopsy cases conducted at Yale between 2014-2018 (non-COVID), and COVID-positive cases conducted between April 2020-present; (n=10-12 per group). Our data from COVID-19 and ADRD human brain samples show a distinctive profile of phosphorylated TDP-43 (pTDP-43) and Tau expression compared to COVID-19 negative AD and control brains. Immunofluorescence analysis of hippocampus and cerebral cortex showed perivascular deposits of pTDP-43 found as threads or aggregates in close proximity to capillaries and vascular basal lamina, labeled with type IV collagen. We also observe a subset of pTDP-43 that colocalizes with neuronal tau, suggesting involvement of multiple neurovascular unit cells. Our data also revealed CD31 (platelet endothelial cell adhesion molecule-1, PECAM-1) positive cells in the microvessels colocalize with pTDP-43. Interestingly, colocalization of PECAM-1 and pTDP-43 positive cells in the perivascular zone suggests transendothelial migration. Atypical pTDP-43 accumulation was also noted in astrocytic endfeet, and astrocytic hypertrophy was identified. Furthermore the blood-brain barrier may be breached, detected by a downregulation or change in the expression and distribution of Claudin-5 in the blood vessels where pTDP-43 is present. Breakdown of these tight junction proteins has been strongly implicated in the neurological manifestations of SARS-CoV-2 and vascular contributions to cognitive impairment and dementia (VCID) in AD. These findings raise the possibility that perivascular pTDP-43 aggregates impair endothelial, neuronal, and/or astrocytic functions in the neurovascular unit, disrupt blood-brain-barrier, and potentially suggest a novel role for TDP-43 induced microvasculopathy in ADRD and COVID-19. This research and the Center for Human Brain Discovery is supported through philanthropic funds and NIH/NINDS R01NS122907 (to PPG). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Soluble Biomarkers of Cerebrovascular Pathologies.

Vascular contributions to cognitive impairment and dementia (VCID) is an all-encompassing term that describes cognitive impairment due to cerebrovascular origins. With the advancement of imaging and pathological studies, we now understand that VCID is often comorbid with Alzheimer disease. While researchers in the Alzheimer disease field have been working for years to establish and test blood-based biomarkers for Alzheimer disease diagnosis, prognosis, clinical therapy discovery, and early detection, blood-based biomarkers for VCID are in their infancy and also face challenges. VCID is heterogeneous, comprising many different pathological entities (ischemic, or hemorrhagic), and spatial and temporal differences (acute or chronic). This review highlights pathways that are aiding the search for sensitive and specific blood-based cerebrovascular dysfunction markers, describes promising candidates, and explains ongoing initiatives to discover blood-based VCID biomarkers.

SPAK inhibitor ZT-1a attenuates reactive astrogliosis and oligodendrocyte degeneration in a mouse model of vascular dementia.

Astrogliosis and white matter lesions (WML) are key characteristics of vascular contributions to cognitive impairment and dementia (VCID). However, the molecular mechanisms underlying VCID remain poorly understood. Stimulation of Na-K-Cl cotransport 1 (NKCC1) and its upstream kinases WNK (with no lysine) and SPAK (the STE20/SPS1-related proline/alanine-rich kinase) play a role in astrocytic intracellular Na+ overload, hypertrophy, and swelling. Therefore, in this study, we assessed the effect of SPAK inhibitor ZT-1a on pathogenesis and cognitive function in a mouse model of VCID induced by bilateral carotid artery stenosis (BCAS). Following sham or BCAS surgery, mice were randomly assigned to receive either vehicle (DMSO) or SPAK inhibitor ZT-1a treatment regimen (days 14-35 post-surgery). Mice were then evaluated for cognitive functions by Morris water maze, WML by exvivo MRI-DTI analysis, and astrogliosis/demyelination by immunofluorescence and immunoblotting. Compared to sham control mice, BCAS-Veh mice exhibited chronic cerebral hypoperfusion and memory impairments, accompanied by significant MRI DTI-detected WML and oligodendrocyte (OL) death. Increased activation of WNK-SPAK-NKCC1-signaling proteins was detected in white matter tissues and in C3d+ GFAP+ cytotoxic astrocytes but not in S100A10+ GFAP+ homeostatic astrocytes in BCAS-Veh mice. In contrast, ZT-1a-treated BCAS mice displayed reduced expression and phosphorylation of NKCC1, decreased astrogliosis, OL death, and WML, along with improved memory functions. BCAS-induced upregulation of WNK-SPAK-NKCC1 signaling contributes to white matter-reactive astrogliosis, OL death, and memory impairment. Pharmacological inhibition of the SPAK activity has therapeutic potential for alleviating pathogenesis and memory impairment in VCID.

Age-associated dementia among older people aging with HIV in the US: a modeling study.

Almost 400 000 people with HIV (PWH) in the United States are over age 55 years and at risk for age-associated dementias (AAD), including Alzheimer's disease and vascular contributions to cognitive impairment and dementia (VCID). We projected the cumulative incidence and mortality associated with AAD among PWH at least 60 years in the United States compared with the general population. Integrating the CEPAC and AgeD-Pol models, we simulated two cohorts of male and female individuals at least 60 years old: PWH, and general US population. We estimated AAD incidence and AAD-associated mortality rates. Projected outcomes included AAD cumulative incidence, life expectancy, and quality-adjusted life-years (QALYs). We performed sensitivity and scenario analyses on AAD-specific (e.g. incidence) and HIV-specific (e.g. disengagement from HIV care) parameters, as well as premature aging among PWH. We projected that 22.1%/16.3% of 60-year-old male individuals/female individuals with HIV would develop AAD by 80 years compared with 15.9%/13.3% of male individuals/female individuals in the general population. Accounting for age-associated and dementia-associated quality of life, 60-year-old PWH would have a lower life expectancy (QALYs): 17.4 years (14.1 QALYs) and 16.8 years (13.4 QALYs) for male and female individuals, respectively, compared with the general population [men, 21.7 years (18.4 QALYs); women, 24.7 years (20.2 QALYs)]. AAD cumulative incidence was most sensitive to non-HIV-related mortality, engagement in HIV care, and AAD incidence rates. Projected estimates of AAD-associated morbidity, mortality, and quality of life can inform decision-makers and health systems planning as the population of PWH ages. Improved AAD prevention, treatment, and supportive care planning are critical for people aging with HIV.

Angiotensin II Type 2 Receptor Agonism Alleviates Progressive Post-stroke Cognitive Impairment in Aged Spontaneously Hypertensive Rats.

Hypertension and aging are leading risk factors for stroke and vascular contributions to cognitive impairment and dementia (VCID). Most animal models fail to capture the complex interplay between these pathophysiological processes. In the current study, we examined the development of cognitive impairment in 18-month-old spontaneously hypertensive rats (SHR) before and following ischemic stroke. Sixty SHRs were housed for 18months with cognitive assessments every 6months and post-surgery. MRI scans were performed at baseline and throughout the study. On day 3 post-stroke, rats were randomized to receive either angiotensin II type 2 receptor (AT2R) agonist Compound 21 (C21) or plain water for 8weeks. SHRs demonstrated a progressive cognitive decline and significant MRI abnormalities before stroke. Perioperative mortality within 72h of stroke was low. Stroke resulted in significant acute brain swelling, chronic brain atrophy, and sustained sensorimotor and behavioral deficits. There was no evidence of anhedonia at week 8. C21 enhanced sensorimotor recovery and ischemic lesion resolution at week 8. SHRs represent a clinically relevant animal model to study aging and stroke-associated VCID. This study underscores the importance of translational disease modeling and provides evidence that modulation of the AT2R signaling via C21 may be a useful therapeutic option to improve sensorimotor and cognitive outcomes even in aged animals.

Abstract TP17: SPAK Kinase Inhibitor ZT-1a Prevents Reactive Astrogliosis, Blood-Brain Barrier Breakdown, and Demyelination in a Mouse Model of VCID

Background: Blood-brain barrier (BBB) breakdown, reactive astrogliosis, and myelin losses are the key features of vascular contributions to cognitive impairment and dementia (VCID). However, the molecular and cellular mechanisms underlying VCID are not well understood. Stimulation of Na-K-Cl cotransport 1 (NKCC1) and its downstream kinase SPAK (the STE20/SPS1-related proline/alanine-rich kinase) causes intracellular Na + overload, astrocytic hypertrophy, and swelling. In this study, we investigated the effect of SPAK inhibitor ZT-1a on bilateral carotid artery stenosis (BCAS)-mediated reactive astrogliosis, BBB breakdown, demyelination, and cerebral blood flow (CBF) in mice. Methods: BCAS was induced in male mice using two metal microcoils twined around both carotid arteries. Sham or BCAS mice receiving vehicle or a selective SPAK inhibitor ZT-1a were monitored for changes in CBF by laser speckle imaging and cognitive functions by the novel object recognition test. Expression of NKCC1 and BBB proteins, reactive astrogliosis, and demyelination were examined by immunofluorescence staining. Results: BCAS mice exhibited sustained CBF reduction and cognitive function deficits along with significant demyelination in corpus callosum and external capsule 8 weeks after BCAS procedure. Compared to sham mice, the BCAS mice showed increased NKCC1 expression in GFAP + astrocytes, reduced expression of ZO-1 and Claudin-5 in GLUT1 + endothelial cells, decreased APC + mature oligodendrocyte and NG2 + oligodendrocyte progenitor cells. Interestingly, delayed administration of ZT-1a (4-8 weeks post-BCAS) prevented BCAS-induced reactive astrogliosis, BBB breakdown, demyelination, and significantly improved CBF and cognitive functions. Conclusion: Our study demonstrates that BCAS-induced stimulation of NKCC1 involves in reactive astrogliosis, BBB breakdown, OL death, and cognitive impairment. Inhibition of the SPAK-NKCC1 cascade by pharmacological inhibitor has therapeutic potential for VCID therapy. This research was supported by NIH R01 166199 Grant (M.I.H.B.).

Abstract TP40: Identification of Domain-Specific Cognitive Phenotypes of Post Stroke Vascular Contributions to Cognitive Impairment and Dementia

Introduction: Vascular contributions to cognitive impairment and dementia (VCID) are variably expressed following stroke. The purpose of this investigation is to identify the domain-specific cognitive phenotypes of VCID in the acute and sub-acute post-stroke interval measured using the Mark VCID battery. Methods: Mark VCID neurocognitive test battery was administered to 33 patients with incident ischemic stroke in the left (n=15), right (n=17), and bilateral (n=1) hemispheres including the anterior and middle cerebral artery territory, and 39 age and sex matched healthy controls (HC). Participants ranged in age from 42 to 88 years (Patient M=65.64 yrs, Control M=64.97 yrs). Patient group consisted of 17 males and 22 females, and the control group had 20 males and 13 females. Mean post stroke interval was 8 weeks (Range: 2.5 to 19 weeks). The test battery assessed: language (naming, fluency), perception (facial recognition, spatial orientation), psychomotor speed (digit symbol substitution), memory (word list, story recall), and attention (trails, number span). Normative test scores were converted to z-scores for assessment of between group differences using independent t-tests. Results: Patients with stroke performed significantly worse (p<0.05) than HCs on measures of language (semantic and phonemic fluency), perception (facial recognition and spatial orientation), and psychomotor speed (symbol digit modalities test) (Figure 1). There were no significant group differences in the scores of memory (Hopkins Verbal Learning, Craft Story) and attention tracking (Oral Trails A, Number Span). Conclusion: Cognitive abnormalities in these acute stoke patients represent impairments in diverse dominant (language) and non-dominant (perceptual/spatial) hemisphere cortical and subcortical (psychomotor speed) abilities. At the group level, the findings suggest a phenotype of VCID in patients with acute middle and anterior cerebral artery ischemic stroke.

Targeting Reactive Astrocytes in Vascular Dementia: Investigation of Neuronal-Astrocyte-Vascular Interactions.

Historically known as neuronal support cells, astrocytes are now widely studied for their close structural and functional interactions with multiple neural cell types and cerebral vessels where they maintain an ideal environment for optimized brain function. Under pathological conditions, astrocytes become reactive and lose key protective functions. In this commentary, we discuss our recent work in The Journal of Neuroscience (Sompol et al., 2023) that showed Ca2+ dysregulation in reactive astrocytes, as well as hyperactivation of the Ca2+-dependent protein phosphatase calcineurin (CN) and the Nuclear Factor of Activated T Cells (NFATs), in a diet-induced hyperhomocystienemia (HHcy) mouse model of Vascular Contributions to Cognitive Impairment and Dementia (VCID). Intravital multiphoton imaging coupled with whisker stimulation was used to explore astrocyte Ca2+ signaling and neurovascular function under active phase, fully awake conditions. Interestingly, evoked Ca2+ transients in individual astrocytes were greater, even though intercorrelated Ca2+ signaling across networks of astrocytes was impaired in HHcy mice. Blockade of astrocytic CN/NFAT reduced signs of astrocyte reactivity, normalized cerebrovascular function, and improved hippocampal synaptic strength and hippocampal dependent cognition in HHcy mice, revealing a previously unrecognized deficit regarding neuron-astrocyte-vascular interactions. These findings strongly support the use of astrocyte targeting strategies to mitigate pathophysiological changes associated with VCID and other Alzheimer's-related dementias.

National and International Collaborations to advance research into Vascular Contributions to Cognitive Decline

Cerebrovascular disease is the second most common cause of cognitive disorders, usually referred to as vascular contributions to cognitive impairment and dementia (VCID) and makes some contribution to about 70% of all dementias. Despite its importance, research into VCID has lagged as compared to cognitive impairment due to Alzheimer's disease. There is an increasing appreciation that closing this gap requires large national and international collaborations. This paper highlights 24 notable large-scale national and international efforts to advance research into VCID (MarkVCID, DiverseVCID, DISCOVERY, COMPASS-ND, HBC, RHU SHIVA, UK DRI Vascular Theme, STROKOG, Meta VCI Map, ISGC, ENIGMA-Stroke Recovery, CHARGE, SVDs@target, BRIDGET, CADASIL Consortium, CADREA, AusCADASIL, DPUK, DPAU, STRIVE, HARNESS, FINESSE, VICCCS, VCD-CRE Delphi). These collaborations aim to investigate the effects on cognition from cerebrovascular disease or impaired cerebral blood flow, the mechanisms of action, means of prevention and avenues for treatment. Consensus groups have been developed to harmonise global approaches to VCID, standardise terminology and inform management and treatment, and data sharing is becoming the norm. VCID research is increasingly a global collaborative enterprise which bodes well for rapid advances in this field.

TNFα‐mediated inflammation in mouse models of VCID

AbstractBackgroundTumor necrosis factor alpha (TNFα) is a prominent pleiotropic cytokine with dichotomous effects. Primarily produced in the brain by glial cells, TNFα interacts with two subtypes of TNF receptors (TNFRs) that dictate the cellular response, be that pro‐ or anti‐inflammator. The diverse cellular responses include cell survival, cell death, proliferation, and angiogenesis. Due to the critical role inflammation plays in the pathogenesis of Alzheimer’s disease (AD) and vascular contributions to cognitive impairment and dementia (VCID), understanding the specific roles of pleiotropic cytokines like TNFa in dementia‐causing diseases will provide mechanistic and therapeutic insights. Both inhibition of soluble TNFα (sTNFα) and deletion of pro‐inflammatory TNF receptor 1 (TNFR1) have been shown to decrease severity of amyloid deposition in AD models. However, similar studies have not been conducted regarding VCID outcomes.MethodThis study sought to examine gene and protein expression of TNFα and the two receptors, TNFR1 and TNFR2, within two mouse models of VCID; the hyperhomocysteinemia (HHcy)‐induced VCID co‐morbid with amyloid deposition and aged Tg2576 with severe cerebral amyloid angiopathy (CAA)‐associated VCID. Measures were taken via qPCR for mRNA assessment and Meso Scale Discovery assays (MSD) for protein quantification.ResultIn HHcy‐induced VCID, TNFα mRNA levels were significantly increased regardless of the presence of amyloid deposition. Similarly, protein levels of TNFα trended higher in HHcy groups compared to their controls regardless of amyloid presence. Levels of TNFR1 mRNA trended lower in the HHcy model but was significantly increased in HHcy‐amyloid co‐morbid mice. When investigated in aged Tg2576 mice with CAA, TNFR1 protein expression increased at older timepoints compared to younger, and against wild type controls. Anti‐inflammatory and innate immune‐associated TNFR2 was increased at 20 months in CAA mice when compared to age‐matched controls.ConclusionThese findings display differences in gene and protein expression of TNFa and its receptors in two models of VCID. The unique expression in these models merits further research into the differences in TNF‐mediated inflammation in VCID. Further research is also necessary to determine potential therapeutic advantages of drugs such as TNFα inhibitors in cases of VCID with and without amyloid deposition.

Glial changes are associated with cerebrovascular integrity in hyperhomocysteinemia‐induced VCID in mouse and human brain

AbstractBackgroundWith the aged population estimated to double by 2050 and the rate of dementia expected to triple, it is critical to identify treatments for dementia. One of the leading causes of dementia is vascular contributions to cognitive impairment and dementia (VCID), and is frequently found co‐morbidly with Alzheimer’s disease, the other leading cause of dementia. A modifiable risk factor for VCID is hyperhomocysteinemia (HHcy), which is defined as elevated levels of plasma homocysteine (a non‐protein‐forming amino acid), and most late‐life HHcy is caused by impaired B vitamin absorption. Although HHcy is a risk factor for VCID, the mechanism through which it induces cognitive impairment remains unclear.MethodWe used human and mouse brain tissue to determine glial and vascular changes associated with HHcy. Wild‐type (C57Bl6J) mice were placed on a HHcy or control diet for 6, 10, 14, or 18 weeks. Using qPCR, we investigated pro‐ and anti‐inflammatory cytokines. We also determined changes in microglia (IBA‐1) and identified the number of microhemorrhages and cognitive changes. In humans, we identified 31 autopsied research volunteers with antemortem homocysteine levels; 13 cases had normal plasma homocysteine levels (<14µmol/L) and 18 had high plasma homocysteine levels (>14µmol/L). We determined whether the level of plasma homocysteine was associated with microglia (IBA‐1) and astrocytes (GFAP) as well as microhemorrhages and atherosclerosis severity in the frontal and occipital cortices. Both gene expression and protein inflammatory markers were measured to determine associations with plasma homocysteine.ResultIn our mouse model of HHcy, we identified a time course of glial changes that first begins with an increase in pro‐inflammatory cytokines and increases in microglial staining at 6 weeks on diet. This is followed by cognitive changes at 10 weeks on diet. Finally, at 14 weeks on diet, we see significant cognitive deficits due to HHcy. In human tissue, HHcy was associated with more microglia but fewer astrocytes, a significant decrease in inflammation and increased microhemorrhages in the frontal cortex.ConclusionTaken together, this data shows that in both mouse and human tissue, HHcy induces significant glial and vascular pathology that could be driven by inflammatory effects.

White Matter Hyperintensity Growth/Regression quantification: MarkVCID multi‐site Instrumental Validation

AbstractBackgroundWhite matter hyperintensities (WMH) are one of the main recognized biomarkers for the small vessel diseases related to the vascular contributions to cognitive impairment and dementia (VCID). WMH found to be dynamic, increasing in volume, but also stability or even decreasing in volume over time. The ability to measure and track such longitudinal change over periods of time, as short as one‐year, is critical for both mechanistic discoveries and for the informed future use of biomarkers to track disease modification in clinical trials of VCID. The NINDS‐funded MarkVCID Consortium engaged to test such a protocol for cross‐site inter‐rater and test‐retest reliability to establish instrumental validation of this candidate biomarker for VCID.MethodT1 and 3D FLAIR MRI acquisitions were collected longitudinally and analyzed across six independent sites, using a unique post‐acquisition processing protocol. The analytic platform was built within a Singularity Container to provide the necessary software tools for rigorous uniform co‐registration and intensity corrections that enabled precise measurement of WMH change in regard to growth, stability and regression over a one‐year interval. Baseline and 12‐month follow‐up scans were acquired across MarkVCID sites and pooled to generate the validation dataset used for cross‐site inter‐rater reliability (n = 30). To evaluate test‐retest reliability, two baseline scans (acquired approximately one‐week apart) were independently co‐registered to the 12‐month follow‐up scan (n = 18). Cross‐site inter‐rater and test‐retest reliability were assessed using intraclass correlational analyses (ICC).ResultICC values for test‐retest reliability of WMH growth and regression were 0.97 and 0.94 respectively. Mean ICC values for cross‐center WMH masks were 1.0 for both time points, see Fig. 1 and 2, and WMH growth and regression were 0.99 for both see Fig. 3 and 4.ConclusionThe present data demonstrate robust ICC validity of a WMH growth/regression protocol over a one‐year period as measured by cross‐site inter‐rater and test‐retest reliability. These data suggest that this approach may serve an important role in clinical trials of disease modifying agents for VCID that may preferentially affect WMH growth, stability, or regression.

Meta‐analysis of NIH Alzheimer’s Disease‐Related Dementias (ADRD) programs responsive to the National Plan to Address Alzheimer’s Disease (AD)

AbstractBackgroundAD/ADRD diseases currently impact more than 6 million people in the US. Rare forms of AD/ADRD are caused directly and unambiguously by genetic mutations. However, most AD/ADRD burden is complex in etiology and thought to result from an interplay among multiple incompletely understood genetic, biochemical, lifestyle, environmental and psychosocial risk factors. Moreover, risk factors interact with other health factors to impact AD/ADRD outcomes. For example, while the most common dementia diagnosis is AD, research over the past decade revealed most people with a diagnosis of AD have multiple brain pathologies, other comorbidities, and many people diagnosed with clinical AD do not have AD pathology at all. This new knowledge highlights the importance of better understanding dementia syndromes, and the relationships among them, to increase chances of developing effective interventions. The NINDS partners with the NIA, the NIH lead for AD/ADRD, in the NIH response to the National Plan. NINDS leads ADRD including frontotemporal dementia (FTD), Lewy body dementias (LBD), vascular contributions to cognitive impairment and dementia (VCID) and multiple etiology dementias (MED). This project aims to evaluate NIH and the ADRD field’s responsiveness to ADRD research milestones from triennial NINDS ADRD Summits by mapping NIH‐funded research activities to ADRD milestones.MethodThe approach used text‐based analysis/mining of grant titles, abstracts, and specific aims to map awards and activities to ADRD milestones. Mappings were vetted by expert concurrence. The ongoing study includes new or competitively renewed NIH ADRD awards starting from fiscal year 2017. Findings help NIH to better understand the state of the field, identify research gaps and opportunities for future efforts, and enable public communication of research activities with an accurate, accessible, compact, and updatable data visualizations.ResultResults indicate the approach is feasible, and importantly the field and NIH have largely been responsive to the ADRD milestones in the National Plan to Address AD.ConclusionThe analysis points to several cross‐cutting ADRD research areas that may benefit from increased attention going forward, including health equity, the multiple etiology hypothesis of common dementias, emerging risk factors for common dementias (e.g. COVID‐19, TBI, and TDP‐43 proteinopathy), and clinical trials.

PSMD, a novel biomarker of small vessel disease, and its association with cognitive function — A comprehensive clinical validation study

AbstractBackgroundA recent instrumental validation analysis positioned peak‐width of skeletonized mean diffusivity (PSMD) as a biomarker for vascular contributions to cognitive impairment and dementia (VCID) with excellent reliability, repeatability, and reproducibility. As the next step of biomarker development, the current study aimed to (1) perform a clinical validation of PSMD and cognitive function in MarkVCID and three independent replication samples, and (2) assess whether PSMD explains cognitive function above and beyond white matter hyperintensities (WMH).MethodThe clinical validation of PSMD included n = 395 participants from the multi‐site MarkVCID consortium, n = 6172 from population‐based CHARGE cohorts, n = 287 from RUSH, and n = 435 from the UC Davis ADRC cohort spanning diverse ages and racial/ethnic backgrounds. PSMD was derived from DTI using an automated algorithm and further log‐transformed to normalize its distribution. A composite measure of general cognitive function was calculated from neuropsychological tests assessing at least three different cognitive domains. Linear regression models were run to determine the association between PSMD and cognitive function, adjusting for age, sex, and education. A secondary model was adjusted for vascular risk factors: hypertension, diabetes, and smoking. Lastly, both models included WMH volume to evaluate PSMD beyond WMH.ResultHigher PSMD values were associated with lower general cognitive function in the MarkVCID (Beta (95% CI), ‐0.82 (‐1.03, ‐0.61), p<0.001) in primary models, and remained unchanged after additional adjustment for vascular risk factors in secondary model (‐0.87 (‐1.09, ‐0.65), p<0.001). These findings were replicated across the CHARGE, RUSH, and UC Davis ADRC cohorts (Table 1). We further observed that PSMD explained an additional 0.2% of the variance in cognitive function beyond WMH in the youngest cohort (48.1 ±8.9 years), whereas the variance explained rose to 2.51% for the oldest cohort (76.4 ±5.2 years).ConclusionThis comprehensive clinical validation study suggests that PSMD is related to general cognition across diverse samples, potentially explaining more variation in cognitive function than a classic cerebrovascular marker such as WMH. Together, our instrumental and clinical validation studies support using PSMD as a robust biomarker with potential for risk stratification and disease monitoring in multi‐site clinical trials of VCID. Additional longitudinal validation studies are underway.

Vascular risk, gait, behavioral, and plasma indicators of VCID.

Cost-effective screening tools for vascular contributions to cognitive impairment and dementia (VCID) has significant implications. We evaluated non-imaging indicators of VCID using magnetic resonance imaging (MRI)-measured white matter (WM) damage and hypothesized that these indicators differ based on age. In 745 participants from the Mayo Clinic Study of Aging (≥50 years of age) with serial WM assessments from diffusion MRI and fluid-attenuated inversion recovery (FLAIR)-MRI, we examined associations between baseline non-imaging indicators (demographics, vascular risk factors [VRFs], gait, behavioral, plasma glial fibrillary acidic protein [GFAP], and plasma neurofilament light chain [NfL]) and WM damage across three age tertiles. VRFs and gait were associated with diffusion changes even in low age strata. All measures (VRFs, gait, behavioral, plasma GFAP, plasma NfL) were associated with white matter hyperintensities (WMHs) but mainly in intermediate and high age strata. Non-imaging indicators of VCID were related to WM damage and may aid in screening participants and assessing outcomes for VCID. Non-imaging indicators of VCID can aid in prediction of MRI-measured WM damage but their importance differed by age. Vascular risk and gait measures were associated with early VCID changes measured using diffusion MRI. Plasma markers explained variability in WMH across age strata. Most non-imaging measures explained variability in WMH and vascular WM scores in intermediate and older age groups. The framework developed here can be used to evaluate new non-imaging VCID indicators proposed in the future.

Atorvastatin rescues hyperhomocysteinemia-induced cognitive deficits and neuroinflammatory gene changes

BackgroundEpidemiological data suggests statins could reduce the risk of dementia, and more specifically, Alzheimer’s disease (AD). Pre-clinical data suggests statins reduce the risk of dementia through their pleiotropic effects rather than their cholesterol lowering effects. While AD is a leading cause of dementia, it is frequently found co-morbidly with cerebral small vessel disease and other vascular contributions to cognitive impairment and dementia (VCID), which are another leading cause of dementia. In this study, we determined if atorvastatin ameliorated hyperhomocysteinemia (HHcy)-induced VCID.MethodsWild-type (C57Bl6/J) mice were placed on a diet to induce HHcy or a control diet each with or without atorvastatin for 14 weeks. Mice underwent novel object recognition testing before tissue collection. Plasma total cholesterol and total homocysteine as well as related metabolites were measured. Using qPCR and NanoString technology, we profiled glial cell-associated gene expression changes. Finally, microglial morphology, astrocyte end feet, and microhemorrhages were analyzed using histological methods.ResultsAtorvastatin treatment of HHcy in mice led to no changes in total cholesterol but decreases in total homocysteine in plasma. While HHcy decreased expression of many glial genes, atorvastatin rescued these gene changes, which mostly occurred in oligodendrocytes and microglia. Microglia in HHcy mice with atorvastatin were trending towards fewer processes compared to control with atorvastatin, but there were no atorvastatin effects on astrocyte end feet. While atorvastatin treatment was trending towards increasing the area of microhemorrhages in HHcy mice in the frontal cortex, it only slightly (non-significantly) reduced the number of microhemorrhages. Finally, atorvastatin treatment in HHcy mice led to improved cognition on the novel object recognition task.ConclusionsThese data suggest that atorvastatin rescued cognitive changes induced by HHcy most likely through lowering plasma total homocysteine and rescuing gene expression changes rather than impacts on vascular integrity or microglial changes.

Function and regulation of cis P-tau in the pathogenesis and treatment of conventional and nonconventional tauopathies.

Conventional tauopathies are a group of disease characterized by tau inclusions in the brains, including Alzheimer's disease (AD), Pick's disease (PiD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and certain types of frontotemporal dementia (FTD), among which AD is the most prevalent. Extensive post-translational modifications, especially hyperphosphorylation, and abnormal aggregation of tau protein underlie tauopathy. Cis-trans isomerization of protein plays an important role in protein folding, function, and degradation, which is regulated by peptidyl-proline isomerases (PPIases). Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (Pin1), the only PPIase found to isomerize Pro following phosphorylated Ser or Thr residues, alters phosphorylated tau protein conformation at pT231-P motif. The cis P-tau but not trans P-tau serves as an early driver of multiple neurodegenerative disease, encompassing AD, traumatic brain injury (TBI), chronic traumatic encephalopathy (CTE), and vascular contributions to cognitive impairment and dementia (VCID). Cis but not trans P-tau is resistant to protein dephosphorylation and degradation, and also prone to protein aggregation. Cis P-tau loses its ability to stabilize microtubule, causing and spreading tauopathy mainly in axons, a pathological process called cistauosis. The conformation-specific monoclonal antibody that targets only the cis P-tau serves as a very early diagnosis method and a potential treatment of not only conventional tauopathies but also nonconventional tauopathies such as VCID, with clinical trials ongoing. Notably, cis P-tau antibody is the only clinical-stage Alzheimer's therapeutic that has shown the efficacy in animal models of not only AD but also TBI and stroke, which are very early stages of dementia. Here we review the identification and pathological consequences of cis pt231-tau, the role of its regulator Pin1, as well as the clinical implication of cis pt231-tau conformation-specific antibody in conventional and nonconventional tauopathies.

MRI free water as a biomarker for cognitive performance: Validation in the markvcid consortium

AbstractBackgroundFree Water (FW), a Diffusion Tensor Imaging‐based biomarker kit has been demonstrated by the MarkVCID consortium to have excellent instrumental validity1. We sought to determine its clinical relevance by investigating association of FW with clinically meaningful aspects of vascular contributions to cognitive impairment and dementia (VCID) in the MarkVCID consortium cohort as well as 5 independent settings.MethodThis study included individuals from the MarkVCID UH3 phase cohort2 (N = 523) and 5 independent legacy cohorts: University of California Davis Alzheimer Disease Research Center3 (ADRC UCD, N = 173), MarkVCID UH2‐ phase data from University of California San Francisco4 (UH2 UCSF, N = 182) and RUSH Alzheimer Disease Center5 (N = 302), Framingham Heart Study6,7 (FHS, N = 2902) and Atherosclerosis Risk in Communities8 (ARIC, N = 1837). Table 1 summarizes participants’ characteristics. Our goal was to evaluate whether mean FW (mFW) computed within the white matter tissue as provided by the kit1 is cross‐sectionally associated with a composite measure of executive functions (EFC) derived from item‐response theory (IRT) generated score9,10, which incorporates scores from NACC Uniform Data Set Version 3 neuropsychological tests11. To test this hypothesis, a linear regression was used with EFC score as the dependent variable and mFW as the independent variable, adjusting for age, sex and education. In a second model, this model was additionally adjusted for presence of diabetes, smoking and hypertension to estimate the added contribution of mFW above vascular risk factors.ResultHigher mFW was associated with lower EFC scores (see Figure 1) in all the subject groups studied. In the MarkVCID cohort (ß = ‐3.54, p<0.0001), as well as in the five legacy cohorts (UH2 UCSF: ß = ‐3.54, p<0.0001, RUSH: ß = ‐1.905, p = 0.00597, ADRC: ß = ‐6.18, p<0.0001, FHS: ß = ‐4.06, p<0.0001, ARIC: ß = ‐1.24, p<0.0001). Adjusting for vascular risk factors did not significantly change these associations (p values< 0.01).ConclusionFindings from this study indicated that mean FW is a sensitive biomarker of cognitive performances, providing strong evidence of the clinical rational of FW as a sensitive biomarker of WM injury in association with cognition for future observational studies and clinical trials in the context of VCID.

Menopause causes metabolic and cognitive impairments in a chronic cerebral hypoperfusion model of vascular contributions to cognitive impairment and dementia

BackgroundThe vast majority of women with dementia are post-menopausal. Despite clinical relevance, menopause is underrepresented in rodent models of dementia. Before menopause, women are less likely than men to experience strokes, obesity, and diabetes—known risk factors for vascular contributions to cognitive impairment and dementia (VCID). During menopause, ovarian estrogen production stops and the risk of developing these dementia risk factors spikes. Here, we aimed to determine if menopause worsens cognitive impairment in VCID. We hypothesized that menopause would cause metabolic dysfunction and increase cognitive impairment in a mouse model of VCID.MethodsWe performed a unilateral common carotid artery occlusion surgery to produce chronic cerebral hypoperfusion and model VCID in mice. We used 4-vinylcyclohexene diepoxide to induce accelerated ovarian failure and model menopause. We evaluated cognitive impairment using behavioral tests including novel object recognition, Barnes maze, and nest building. To assess metabolic changes, we measured weight, adiposity, and glucose tolerance. We explored multiple aspects of brain pathology including cerebral hypoperfusion and white matter changes (commonly observed in VCID) as well as changes to estrogen receptor expression (which may mediate altered sensitivity to VCID pathology post-menopause).ResultsMenopause increased weight gain, glucose intolerance, and visceral adiposity. VCID caused deficits in spatial memory regardless of menopausal status. Post-menopausal VCID specifically led to additional deficits in episodic-like memory and activities of daily living. Menopause did not alter resting cerebral blood flow on the cortical surface (assessed by laser speckle contrast imaging). In the white matter, menopause decreased myelin basic protein gene expression in the corpus callosum but did not lead to overt white matter damage (assessed by Luxol fast blue). Menopause did not significantly alter estrogen receptor expression (ERα, ERβ, or GPER1) in the cortex or hippocampus.ConclusionsOverall, we have found that the accelerated ovarian failure model of menopause caused metabolic impairment and cognitive deficits in a mouse model of VCID. Further studies are needed to identify the underlying mechanism. Importantly, the post-menopausal brain still expressed estrogen receptors at normal (pre-menopausal) levels. This is encouraging for any future studies attempting to reverse the effects of estrogen loss by activating brain estrogen receptors.

Sex differences in the effects of high fat diet on underlying neuropathology in a mouse model of VCID

BackgroundDamage to the cerebral vasculature can lead to vascular contributions to cognitive impairment and dementia (VCID). A reduction in blood flow to the brain leads to neuropathology, including neuroinflammation and white matter lesions that are a hallmark of VCID. Mid-life metabolic disease (obesity, prediabetes, or diabetes) is a risk factor for VCID which may be sex-dependent (female bias).MethodsWe compared the effects of mid-life metabolic disease between males and females in a chronic cerebral hypoperfusion mouse model of VCID. C57BL/6J mice were fed a control or high fat (HF) diet starting at ~ 8.5 months of age. Three months after diet initiation, sham or unilateral carotid artery occlusion surgery (VCID model) was performed. Three months later, mice underwent behavior testing and brains were collected to assess pathology.ResultsWe have previously shown that in this VCID model, HF diet causes greater metabolic impairment and a wider array of cognitive deficits in females compared to males. Here, we report on sex differences in the underlying neuropathology, specifically white matter changes and neuroinflammation in several areas of the brain. White matter was negatively impacted by VCID in males and HF diet in females, with greater metabolic impairment correlating with less myelin markers in females only. High fat diet led to an increase in microglia activation in males but not in females. Further, HF diet led to a decrease in proinflammatory cytokines and pro-resolving mediator mRNA expression in females but not males.ConclusionsThe current study adds to our understanding of sex differences in underlying neuropathology of VCID in the presence of a common risk factor (obesity/prediabetes). This information is crucial for the development of effective, sex-specific therapeutic interventions for VCID.