Shubir Dutt

Objective: Age of symptom onset is highly variable in familial frontotemporal lobar degeneration (f‐FTLD). Accurate prediction of onset would inform clinical management and trial enrollment. Prior studies indicate that individualized maps of brain atrophy can predict conversion to dementia in f‐FTLD. We used a Bayesian linear mixed‐effect (BLME) prediction method for identifying accelerated brain volume loss to predict conversion to dementia. Methods: Participants included 234 asymptomatic or prodromal carriers of C9orf72 , GRN , or MAPT mutations (including 21 dementia converters) with ≥3 longitudinal magnetic resonance imaging (MRI) T1‐weighted scans. The BLME models established individual voxel‐wise gray matter trajectories using the first 2 scans. Person‐specific clusters of accelerated volume loss were estimated in subsequent scans and tested as predictors of dementia conversion compared with other approaches in time‐varying Cox proportional hazard models covarying for age. Receiver‐operating characteristic (ROC) curves estimated utility of cluster volume in discriminating which participants converted to dementia within 24 months. Results: The BLME cluster volume predicted conversion to dementia in f‐FTLD mutation carriers overall and separately in C9orf72 , GRN , and MAPT , with comparable hazard ratios observed for atrophy W‐maps and regional volumes. Within a 24‐month timeframe, BLME cluster volume discriminated dementia converters from non‐converters with larger areas under the curve (AUCs) than other approaches. Interpretation: Bayesian‐modeled individualized atrophy scores predict dementia progression among asymptomatic f‐FTLD mutation carriers and may have increased utility compared with other structural imaging methods when studying individuals over shorter timeframes that align with clinical trial design. ANN NEUROL 20269999:n/a–n/a

Cerebrovascular reactivity (CVR) represents the ability of cerebral blood vessels to regulate blood flow in response to vasoactive stimuli and is related to cognition in cerebrovascular and neurodegenerative conditions. However, few studies have examined CVR in the medial temporal lobe, known to be affected early in Alzheimer disease and to influence memory function. We aimed to examine whether medial temporal CVR is associated with memory function in older adults with and without mild cognitive impairment (MCI). In this observational study, independently living older adults free of dementia or stroke were recruited from the community and underwent brain MRI, neuropsychological assessment, and blood draw in an academic research setting. pCASL MRI quantified medial temporal lobe cerebral perfusion during CVR response to hypercapnia. Hypercapnia was induced by visually guided breathing exercises (15 seconds breath holds) during capnographic monitoring. MCI diagnosis and memory performance were assessed through comprehensive neuropsychological assessment. Aβ42/40 and pTau181 levels were quantified in blood plasma. Logistic and hierarchical linear regression examined medial temporal CVR in relation to MCI diagnosis and memory function. In a sample of 144 older adults (mean age = 69.6 years; SD = 7.4%; 34.7% male; mean education = 16.6 years, SD = 2.3), CVR to hypercapnia in the medial temporal lobe was attenuated in individuals with MCI after adjusting for age, sex, education, apolipoprotein ε4 carrier status, Aβ42/40 and pTau181 levels, and vascular risk factors (OR = 0.87, 95% CI [0.77-0.97], p = 0.013). Cerebrovascular reactivity to hypercapnia was associated with verbal memory performance for stories (B = 0.33, 95% CI [0.09-0.57], p = 0.009), a word list (B = 0.10, 95% CI [0.001-0.20], p = 0.048), and visual memory (B = 0.33, 95% CI [0.09-0.57], p = 0.008). Deficits in medial temporal CVR are observed in older adults with MCI and are related to worse memory function. Findings suggest that medial temporal cerebrovascular dysfunction is related to cognition and memory before the onset of dementia, independent of changes in Alzheimer pathophysiologic markers. Limitations of the study include the cross-sectional design. Future longitudinal studies are warranted to examine whether early cerebrovascular changes can predict progressive memory decline.

Background: Cerebrovascular contributions to cognitive aging and Alzheimer’s disease (AD) risk represent a growing field in aging research. Studies in the young‐old have demonstrated the critical role of vascular dysregulation (i.e., altered cerebral blood flow) in relation to cognitive decline prior to the appearance of amyloid/tau biomarkers. However, cerebral perfusion has not been well‐studied in the oldest‐old (ages 90 and over), a rapidly growing population that may provide unique insight into resilience and protective factors against dementia in later life. We characterized amyloid and cerebral perfusion profiles of cognitively normal (CN) and cognitively impaired without dementia (CIND) oldest‐old individuals.Method: Participants were 97 dementia‐free older adults (70 CN and 27 CIND) from the 90+ Study who had available neuroimaging (T1‐MRI, ASL‐MRI, Florbetapir‐PET), demographic, and clinical data. We examined differences between CN and CIND in regional perfusion in areas associated with AD risk (medial temporal lobe, posterior cingulate, precuneus, frontal cortex, inferior parietal lobe) and in amyloid burden using linear regression models controlling for age, sex, education, APOE4 status, and vascular risk factors.Result: CN and CIND groups did not differ in the characteristics compared (Table 1). CIND participants had lower CBF in the posterior cingulate/precuneus than the CN group, but groups did not differ in posterior cingulate/precuneus amyloid SUVR (Figure 1). Additionally, CIND had lower CBF than CN in the inferior parietal lobe but higher CBF in the medial temporal lobe and orbitofrontal cortex (Figure 2).Conclusion: CIND individuals had lower regional perfusion in the posterior cingulate/precuneus, but groups did not differ in amyloidosis, highlighting the relationship between cerebrovascular function and cognitive status in the oldest‐old independent of amyloidosis. Our findings complement previously reported posterior cingulate/precuneus hypoperfusion in younger‐old individuals with cognitive impairment and AD. Interestingly, we observed greater medial temporal/frontal perfusion in CIND than CN, similar to previous studies demonstrating initial hyperperfusion preceding hypoperfusion across the CN‐CIND‐Dementia spectrum. This may represent a compensatory vascular mechanism supporting cognition in individuals at greater risk of developing dementia. Future studies will further characterize this cohort with longitudinal perfusion analyses, neuropsychological correlates, and relationships between perfusion and other indices of cerebrovascular dysfunction.

Background: The locus coeruleus (LC) innervates the cerebrovasculature and plays a critical role in optimally regulating cerebral blood flow. However, few studies have examined potential relationships between these systems in humans with widely available neuroimaging methods, and none have explored how relationships may change in the presence of growing Alzheimer’s disease (AD) pathology.Method: Participants were 66 community‐dwelling older adults free of dementia (ages 55‐87) recruited at the University of Southern California. Pseudocontinuous arterial spin labeling (pCASL) MRI measured regional perfusion, and T1‐fast spin echo (T1‐FSE) MRI quantified rostral LC contrast, a well‐established measure of LC structural integrity. Subsets of participants underwent neuropsychological testing (n = 36) as well as fasting venipuncture to measure plasma AD biomarker concentrations of Aβ42/40 ratio (n = 56) and ptau181 (n = 35). Multiple linear regression models examined associations among regional perfusion, LC integrity, and cognition (episodic memory, attention, executive function). Moderation analyses included additional terms for plasma AD biomarker concentrations and plasma x LC interaction effects.Result: Higher LC‐MRI contrast was linked to higher frontal (medial and lateral orbitofrontal) perfusion but lower limbic (amygdala and entorhinal) perfusion. Greater LC‐MRI contrast was also associated with better episodic memory recall and recognition but not measures of attention or executive function. Plasma Aβ42/40 ratio and ptau181 moderated LC‐perfusion relationships such that associations significantly weakened in the presence of greater pathology.Conclusion: This is the first human study to directly investigate associations between LC integrity and perfusion in a well‐characterized sample with neuroimaging, cognitive, and AD biomarker data. LC integrity tracked episodic memory performance along with cerebral perfusion, while greater AD pathology in preclinical populations disrupted LC‐perfusion relationships, suggesting that growing amyloid and tau pathology may negatively impact the LC’s ability to optimally regulate cerebral blood flow. Taken together, our findings highlight the importance of tracking the LC over the AD disease course. Concurrent multimodal imaging of the LC and cerebrovascular function may have potential as a novel non‐invasive biomarker, and future studies should track its utility longitudinally and its relationship with disease severity and other disease markers (e.g., grey matter atrophy, amyloid/tau PET).

Objective:The locus coeruleus (LC) innervates the cerebrovasculature and plays a crucial role in optimal regulation of cerebral blood flow. However, no human studies to date have examined links between these systems with widely available neuroimaging methods. We quantified associations between LC structural integrity and regional cortical perfusion and probed whether varying levels of plasma Alzheimer’s disease (AD) biomarkers (Aß42/40 ratio and ptau181) moderated these relationships.Participants and Methods:64 dementia-free community-dwelling older adults (ages 55-87) recruited across two studies underwent structural and functional neuroimaging on the same MRI scanner. 3D-pCASL MRI measured regional cerebral blood flow in limbic and frontal cortical regions, while T1-FSE MRI quantified rostral LC-MRI contrast, a well-established proxy measure of LC structural integrity. A subset of participants underwent fasting blood draw to measure plasma AD biomarker concentrations (Aß42/40 ratio and ptau181). Multiple linear regression models examined associations between perfusion and LC integrity, with rostral LC-MRI contrast as predictor, regional CBF as outcome, and age and study as covariates. Moderation analyses included additional terms for plasma AD biomarker concentration and plasma x LC interaction.Results:Greater rostral LC-MRI contrast was linked to lower regional perfusion in limbic regions, such as the amygdala (ß = -0.25, p = 0.049) and entorhinal cortex (ß = -0.20, p = 0.042), but was linked to higher regional perfusion in frontal cortical regions, such as the lateral (ß = 0.28, p = 0.003) and medial (ß = 0.24, p = 0.05) orbitofrontal (OFC) cortices. Plasma amyloid levels moderated the relationship between rostral LC and amygdala CBF (Aß42/40 ratio x rostral LC interaction term ß = -0.31, p = 0.021), such that as plasma Aß42/40 ratio decreased (i.e., greater pathology), the strength of the negative relationship between rostral LC integrity and amygdala perfusion decreased. Plasma ptau181levels moderated the relationship between rostral LC and entorhinal CBF (ptau181 x rostral LC interaction term ß = 0.64, p = 0.001), such that as ptau181 increased (i.e., greater pathology), the strength of the negative relationship between rostral LC integrity and entorhinal perfusion decreased. For frontal cortical regions, ptau181 levels moderated the relationship between rostral LC and lateral OFC perfusion (ptau181 x rostral LC interaction term ß = -0.54, p = .004), as well as between rostral LC and medial OFC perfusion (ptau181 x rostral LC interaction term ß = -0.53, p = .005), such that as ptau181 increased (i.e., greater pathology), the strength of the positive relationship between rostral LC integrity and frontal perfusion decreased.Conclusions:LC integrity is linked to regional cortical perfusion in non-demented older adults, and these relationships are moderated by plasma AD biomarker concentrations. Variable directionality of the associations between the LC and frontal versus limbic perfusion, as well as the differential moderating effects of plasma AD biomarkers, may signify a compensatory mechanism and a shifting pattern of hyperemia in the presence of aggregating AD pathology. Linking LC integrity and cerebrovascular regulation may represent an important understudied pathway of dementia risk and may help to bridge competing theories of dementia progression in preclinical AD studies.

Background: The primary genetic risk factor for Alzheimer’s disease is the apolipoprotein ε4 (APOE‐ε4) allele, which confers significant risk for early symptom onset and future dementia. Prior studies have examined links between memory function and medial temporal perfusion in APOE‐ε4 carriers and non‐carriers, but findings have been mixed regarding the direction of relationships. Additionally, prior work has not examined whether other cognitive domains, such as executive function, are similarly associated with functionally relevant regional perfusion (i.e., in frontal regions). The present study aimed to 1) clarify the relationship between medial temporal perfusion and memory performance and 2) examine novel links between executive function and frontal perfusion in APOE‐ε4 carriers and non‐carriers.Method: Dementia‐free older adults recruited from the community were classified as APOE‐ε4 carriers (n=18) or non‐carriers (n=30) via genotype analysis. We used pseudocontinuous arterial spin labeling MRI to quantify cerebral perfusion in regions involved in memory (medial temporal) and executive function (medial frontal). Comprehensive neuropsychological testing assessed memory (Logical Memory I & II; Visual Reproduction I & II) and executive function (Stroop color‐word interference; Trail making tests A & B, category fluency). Multiple linear regression, modeled separately within carriers and non‐carriers, examined associations between perfusion and cognition, with age, sex, and education as covariates.Result: Within APOE‐ε4 carriers, medial temporal hypoperfusion was associated with worse immediate and delayed recall memory in verbal and visual paradigms. Similarly, frontal hypoperfusion was associated with worse verbal category fluency. In non‐carriers, relationships between medial temporal perfusion and memory were absent. Relationships between frontal perfusion and executive function were in the opposite direction as those observed in APOE‐ε4 carriers, with frontal hyperperfusion predicting worse Stroop color‐word, Trails A, and Trails B performance.Conclusion: We observed positive associations between regional perfusion and corresponding cognitive domains in APOE‐ε4 carriers, while relationships were absent or negative within non‐carriers. Our findings highlight the importance of examining preclinical cerebrovascular dysfunction in relation to cognition in individuals at risk for progression to dementia. Future longitudinal studies will be needed to further examine the value of perfusion, cognition, and APOE‐ε4 carrier status in predicting future decline.