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INTRODUCTION Amyloid positron emission tomography (PET) acquisition timing impacts quantification. METHODS In florbetaben (FBB) PET scans of 245 adults with and without cognitive impairment, we investigated the impact of post‐injection acquisition time on Centiloids (CLs) across five reference regions. CL equations for FBB were derived using standard methods, using FBB data collected between 90 and 110 min with paired Pittsburgh compound B data. Linear mixed models and t‐tests evaluated the impact of acquisition time on CL increases. RESULTS CL values increased significantly over the scan using the whole cerebellum, cerebellar gray matter, and brainstem as reference regions, particularly in amyloid‐positive individuals. In contrast, CLs based on white matter–containing reference regions decreased across the scan. DISCUSSION The quantification of CLs in FBB PET imaging is influenced by both the overall scan acquisition time and the choice of reference region. Standardized acquisition protocols or the application of acquisition time–specific CL equations should be implemented in clinical protocols. Highlights Acquisition timing affects florbetaben positron emission tomography (PET) scan quantification, especially in amyloid‐positive participants. The impact of acquisition timing on quantification varies across common reference regions. Consistent acquisitions and/or appropriate post‐injection adjustments are needed to ensure comparability of PET data.

Age-related episodic memory decline is characterized by striking heterogeneity across individuals. Hippocampal pattern completion is a fundamental process supporting episodic memory. Yet, the degree to which this mechanism is impaired with age, and contributes to variability in episodic memory, remains unclear. We combine univariate and multivariate analyses of fMRI data from a large cohort of cognitively normal older adults (N=100) to measure hippocampal activity and cortical reinstatement during retrieval of trial-unique associations. Trial-wise analyses revealed that (a) hippocampal activity scaled with reinstatement strength, (b) cortical reinstatement partially mediated the relationship between hippocampal activity and associative retrieval, (c) older age weakened cortical reinstatement and its relationship to memory behaviour. Moreover, individual differences in the strength of hippocampal activity and cortical reinstatement explained unique variance in performance across multiple assays of episodic memory. These results indicate that fMRI indices of hippocampal pattern completion explain within- and across-individual memory variability in older adults.

Purpose of ReviewLewy body dementia (LBD) encompasses dementia with Lewy bodies (DLB) and Parkinson’s disease dementia (PDD). This article will emphasize potential disease-modifying therapies as well as investigative symptomatic treatments for non-motor symptoms including cognitive impairment and psychosis that can present a tremendous burden to patients with LBD and their caregivers.Recent FindingsWe review 11 prospective disease-modifying therapies (DMT) including four with phase 2 data (neflamapimod, nilotinib, bosutinib, and E2027); four with some limited data in symptomatic populations including phase 1, open-label, registry, or cohort data (vodabatinib, ambroxol, clenbuterol, and terazosin); and three with phase 1 data in healthy populations (Anle138b, fosgonimeton, and CT1812). We also appraise four symptomatic therapies for cognitive impairment, but due to safety and efficacy concerns, only NYX-458 remains under active investigation. Of symptomatic therapies for psychosis recently investigated, pimavanserin shows promise in LBD, but studies of nelotanserin have been suspended.SummaryAlthough the discovery of novel symptomatic and disease-modifying therapeutics remains a significant challenge, recently published and upcoming trials signify promising strides toward that aim.

Corticobasal syndrome (CBS) corresponds to a clinical phenotype with heterogeneous neuropathology, including corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), Alzheimer's disease (AD), and synucleinopathies such as Lewy Body Disease (LBD), in rare cases. Previous reports of CBS-LBD describe patients with diffuse LBD, a younger age of onset and occasionally lacking core features like REM sleep Behavior Disorder (RBD). We present a young patient with CBS who had a rapid progression and was found to have a high burden of limbic LBD and high AD co-pathology at autopsy. A 58-year-old right-handed woman consulted for progressively worsening apraxia, writing, and visuospatial difficulties over the year prior to presentation. She had minimal short-term memory loss initially, did not have RBD nor visual hallucinations and remained independent in activities of daily living. She scored 20/30 on the Montreal Cognitive Assessment, with difficulties in visuospatial and executive tasks. The neurological exam showed predominant apraxia, asymmetric parkinsonism and sensory neglect, all left-sided. The brain MRI confirmed striking asymmetric atrophy affecting the right parieto-temporal lobes. Cerebrospinal fluid (CSF) demonstrated decreased Abeta 42/tau index and elevated total and phosphorylated tau. Her condition progressed quickly over the next year, and she passed away four years after diagnosis. Brain autopsy showed asymmetric moderate-severe cortical atrophy with abundant phospho-synuclein positive Lewy bodies extending to the temporal but not frontal/parietal cortices, consistent with limbic (transitional) LBD and high Alzheimer's disease co-pathology (A3, B3, C3). There was severe Lewy body pathology in the hippocampal CA2 subfield, prominent phospho-tau in the substantia nigra, severe neuron loss in the locus coeruleus, and severe gliosis in the motor cortex. AD and LBD commonly occur together, but the frequency of AD and LBD as a cause of CBS is unknown. Here, we add to the literature of co-pathology in CBS and consider that early age and rapid progression could suggest dual pathology and potential synergistic effects. CSF testing limited to AD biomarkers will miss this dual pathology. Thus, CSF α-synuclein seeding amplification may help identify patients with dual AD-LBD pathology and assist prognostication.

Consumer-grade mobile devices are used by billions worldwide. Their ubiquity provides opportunities to robustly capture everyday cognition. ‘Intuition’ was a remote observational study that enrolled 23,004 US adults, collecting 24 months of longitudinal multimodal data via their iPhones and Apple Watches using a custom research application that captured routine device use, self-reported health information and cognitive assessments. The study objectives were to classify mild cognitive impairment (MCI), characterize cognitive trajectories and develop tools to detect and track cognitive health at scale. The study addresses sources of bias in current cognitive health research, including limited representativeness (for example, racial/ethnic, geographic) and accuracy of cognitive measurement tools. We describe study design and provide baseline cohort characteristics. Next, we present foundational proof-of-concept MCI classification modeling results using interactive cognitive assessment data. Initial findings support the reliability and validity of remote MCI detection and the usefulness of such data in describing at-risk cognitive health trajectories in demographically diverse aging populations. ClinicalTrials.gov identifier: NCT05058950 . A study using iPhones and Apple Watches to track and analyze cognitive health over 18 months in more than 23,000 US adults demonstrates the feasibility of remote cognitive health monitoring and uncovers potential methods for early detection of cognitive decline.

Introduction Group comparisons demonstrate greater visuospatial and memory deficits and temporoparietal-predominant degeneration on neuroimaging in patients with corticobasal syndrome (CBS) found to have Alzheimer’s disease (AD) pathology versus those with underlying frontotemporal lobar degeneration (FTLD). The value of these features in predicting underlying AD pathology in individual patients is unknown. The goal of this study is to evaluate the utility of modified clinical criteria and visual interpretations of magnetic resonance imaging (MRI) and fluorodeoxyglucose positron emission tomography (FDG-PET) for predicting amyloid deposition (as a surrogate of Alzheimer’s disease neuropathology) in patients presenting with CBS. Methods In total, 25 patients meeting CBS core criteria underwent amyloid (Pittsburgh compound B; PIB) PET scans. Clinical records, MRI, and FDG scans were reviewed blinded to PIB results. Modified clinical criteria were used to classify CBS patients as temporoparietal variant CBS (tpvCBS) or frontal variant CBS (fvCBS). MRI and FDG-PET were classified based on the predominant atrophy/hypometabolism pattern (frontal or temporoparietal). Results A total of 9 out of 13 patients classified as tpvCBS were PIB+, compared to 2out of 12 patients classified as fvCBS ( P  < 0.01, sensitivity 82%, specificity 71% for PIB+ status). Visual MRI reads had 73% sensitivity and 46% specificity for PIB+ status with moderate intra-rater reliability (Cohen’s kappa = 0.42). Visual FDG reads had higher sensitivity (91%) for PIB+ status with perfect intra-rater reliability (kappa = 1.00), though specificity was low (50%). PIB results were confirmed in all 8 patients with available histopathology (3 PIB+ with confirmed AD, 5 PIB- with FTLD). Conclusions Splitting CBS patients into frontal or temporoparietal clinical variants can help predict the likelihood of underlying AD, but criteria require further refinement. Temporoparietal-predominant neuroimaging patterns are sensitive but not specific for AD.

Vascular dysfunction, blood-brain barrier (BBB) dysregulation, and neuroinflammation are thought to participate in Alzheimer`s disease (AD) pathogenesis, though the mechanism is poorly understood. Among pathways of interest, AD pathology appears to affect vascular endothelial growth factor-A (VEGFA) signaling in a bidirectional manner. Higher VEGF levels are thought to have a protective role and slow cognitive decline. Neuronal intracellular adhesion molecules (ICAMs) may also be a marker of BBB permeability. ICAMs participate in the immune-nervous system interactions, synaptic plasticity, and cognition. We used the SomaLogic platform for cerebrospinal fluid (CSF) proteome profiling to investigate the levels of ICAM 1, 2, 3, 5 and VEGFA as markers of vascular dysfunction and neuroinflammation in 83 participants from the Stanford Alzheimer Disease Research Center cohort (54 cognitively unimpaired healthy controls (HC) and 29 with mild cognitive impairment or dementia due to AD). All samples were blinded for analysis. Montreal Cognitive Assessment (MoCA) was used as a measure of global cognition. ANOVA compared the levels of biomarkers in diagnostic groups. Linear regression and interaction terms of group (AD vs HC) by biomarker levels were used to investigate the effect on global cognition. ICAM5 and VEGFA were significantly associated with cognition in our cohort. Both ICAM5 and VEGFA levels were lower in AD compared to HC (Figure 1). Interaction terms of diagnosis by ICAM5 were significant on MoCA (b = -59.29, p-value < .0001), and of diagnosis by VEGFA were also significant on MoCA (b = -134.8, p:0.00027), indicating a divergent role for these biomarkers in AD vs. HC (Figure 2). Other ICAMs were not significantly associated with cognition in our cohort. VEGFA and ICAM5 may play an important and dynamic role in AD. More research is needed to understand the interplay between ICAM5 and VEGF and their relationship with AD. References: Tao QQ et al. Aging Dis. 2022; Tubi MA et al. Neurobiol Aging. 2021; Petrelis AM et al. Aging (Albany NY). 2022; Yuan L et al. Aging Dis. 2017; Hino H et al. Brain Res. 1997; Yang H. Comp Funct Genomics. 2012; Birkner K et al. Front Neurol. 2019.

PurposeIn vivo measurement of the spatial distribution of neurofibrillary tangle pathology is critical for early diagnosis and disease monitoring of Alzheimer’s disease (AD).MethodsForty-nine participants were scanned with 18F-PI-2620 PET to examine the distribution of this novel PET ligand throughout the course of AD: 36 older healthy controls (HC) (age range 61 to 86), 11 beta-amyloid+ (Aβ+) participants with cognitive impairment (CI; clinical diagnosis of either mild cognitive impairment or AD dementia, age range 57 to 86), and 2 participants with semantic variant primary progressive aphasia (svPPA, age 66 and 78). Group differences in brain regions relevant in AD (medial temporal lobe, posterior cingulate cortex, and lateral parietal cortex) were examined using standardized uptake value ratios (SUVRs) normalized to the inferior gray matter of the cerebellum.ResultsSUVRs in target regions were relatively stable 60 to 90 min post-injection, with the exception of very high binders who continued to show increases over time. Robust elevations in 18F-PI-2620 were observed between HC and Aβ+ CI across all AD regions. Within the HC group, older age was associated with subtle elevations in target regions. Mildly elevated focal uptake was observed in the anterior temporal pole in one svPPA patient.ConclusionPreliminary results suggest strong differences in the medial temporal lobe and cortical regions known to be impacted in AD using 18F-PI-2620 in patients along the AD trajectory. This work confirms that 18F-PI-2620 holds promise as a tool to visualize tau aggregations in AD.

Bumetanide is a potent diuretic administered orally and is FDA approved for the treatment of edema and hypertension. Recently, repurposing Bumetanide as an Alzheimer`s disease (AD) medication was proposed based on data that showed Bumetanide \"flipped\" the APOE genotype-dependent transcriptomic signatures in AD mouse and cell culture models. Critically, this finding was then investigated in Electronic Health Record (EHR) cohorts and showed that in individuals over 65 years of age, bumetanide exposure was associated with a significantly lower AD prevalence in three independent dataset. However randomized double blinded trials are needed to investigate the safety, tolerability and benefit of bumetanide in AD. This is a phase II, randomized, double-blind, multi-arm placebo-controlled, parallel group study to evaluate the safety and tolerability of bumetanide in patients with Alzheimer's disease. This study aims to investigate bumetanide in patients with biologically confirmed AD. The primary objective is to evaluate the safety and tolerability of bumetanide when administered to participants with biomarker-confirmed AD. The secondary objective is to evaluate the clinical and biomarker effects of bumetanide in participants with mild cognitive impairment or mild dementia due to Alzheimer's disease. This ongoing study is funded by the Stanford Knight Initiative for Brain Resilience and IRB approved. The inclusion criteria include mild cognitive impairment or mild dementia due to AD, AD medications are planned to remain stable throughout, willingness and ability to complete all aspects of the study including assessments, neuropsychological testing, and MRI. Exclusion criteria includes clinically significant abnormalities in screening laboratory tests, chronic liver disease, renal insufficiency, poorly managed hypertension and participants taking the following concomitant medications, based on the current Prescribing Information for bumetanide: lithium, drugs with ototoxic potential, drugs with nephrotoxic potential, probenecid, and indomethacin CONCLUSION: We present the clinical trial protocol and design for a phase II trial evaluating the effect of bumetanide in AD.

INTRODUCTION The availability of amyloid beta (Aβ) targeting therapies for Alzheimer's disease (AD) is increasing the demand for scalable biomarkers that are sensitive to early cerebral Aβ accumulation. METHODS We evaluated fully‐automated Lumipulse plasma Aβ42/Aβ40 immunoassays for detecting cerebral Aβ in 457 clinically unimpaired (CU) and clinically impaired (CI) Stanford Alzheimer's Disease Research Center (Stanford ADRC) participants and 186 CU in the Stanford Aging and Memory Study (SAMS). Longitudinal change in ADRC plasma Aβ42/Aβ40 and cognition and cross‐sectional associations with SAMS memory and tau positron emission tomography (PET) were examined. RESULTS Plasma Aβ42/Aβ40 exhibited high performance in detecting amyloid positivity defined by PET (area under the curve [AUC]: 0.885, 95% confidence interval [CI]: 0.816–0.955). Once abnomal, plasma Aβ42/Aβ40 remained low and predicted cognitive decline in both CU and CI individuals. Among SAMS CU, plasma Aβ42/Aβ40 was associated with poorer hippocampal‐dependent memory and elevated tau accumulation. DISCUSSION Lumipulse plasma Aβ42/Aβ40 is a scalable assay for detection of cerebral Aβ and prediction of risk for cognitive decline across the AD continuum. Highlights Lumipulse plasma amyloid beta (Aβ)42/Aβ40 exhibited high accuracy in detecting amyloid positivity. Plasma amyloid‐positive (Aβ+) individuals exhibited stability of Aβ42/Aβ40 over time. Plasma Aβ42/Aβ40 predicted future cognitive decline across the Alzheimer's disease (AD) spectrum. Plasma Aβ42/Aβ40 was sensitive to memory and tau burden in clinically unimpaired older adults.