Publications by authors named "Jasmeer P Chhatwal"

Introduction: Alzheimer disease (AD)-modifying therapies are approved for treatment of early-symptomatic AD. Autosomal dominant AD (ADAD) provides a unique opportunity to test therapies in presymptomatic individuals.

Methods: Using data from the Dominantly Inherited Alzheimer Network (DIAN), sample sizes for clinical trials were estimated for various cognitive, imaging, and CSF outcomes.

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Introduction: Though recognized as a potential cause of autosomal dominant Alzheimer's disease, the pathogenicity of many PSEN2 variants remains uncertain. We compared amyloid beta (Aβ) production across all missense PSEN2 variants in the AlzForum database and, when possible, to corresponding PSEN1 variants.

Methods: We expressed 74 PSEN2 variants, 21 of which had known, homologous PSEN1 pathogenic variants with the same amino acid substitution, in HEK293 cells lacking presenilin 1/2.

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Disease-modifying therapies for Alzheimer's disease (AD) are likely to be most beneficial when initiated in the presymptomatic phase. To track the benefit of such interventions, fluid biomarkers are of great importance, with neurofilament light chain protein (NfL) showing promise for monitoring neurodegeneration and predicting cognitive outcomes. Here, we update and complement previous findings from the Dominantly Inherited Alzheimer Network Observational Study by using matched cross-sectional and longitudinal cerebrospinal fluid (CSF) and plasma samples from 567 individuals, allowing timely comparative analyses of CSF and blood trajectories across the entire disease spectrum.

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Article Synopsis
  • The study investigates how the monoclonal antibody lecanemab, used for treating Alzheimer's by targeting amyloid beta, interacts with plasma proteins, particularly focusing on its relatively short half-life due to these interactions.
  • * Researchers employed techniques like ELISA and western blotting to analyze the binding of a lecanemab biosimilar to plasma proteins, identifying fibrinogen as a potential binding partner.
  • * The findings suggest that fibrinogen levels could affect the availability of lecanemab in the bloodstream, highlighting the importance of considering plasma protein binding in the clinical use of therapeutic antibodies for neurodegenerative diseases.
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Introduction: While the influence of cross-sectional β-amyloid (Aβ) on longitudinal changes in cognition is well established, longitudinal change-on-change between Aβ and cognition is less explored.

Methods: A series of bivariate latent change score models (LCSM) examined the relationship between changes in C-Pittsburgh Compound-B (PiB) positron emission tomography (PET) and the Preclinical Alzheimer's Cognitive Composite-5 (PACC-5) while adjusting for covariates, including cross-sectional medial temporal lobe (MTL) tau-PET burden. We selected 352 clinically normal older participants with up to 9 years of PiB-PET and PACC-5 data from the Harvard Aging Brain Study (HABS).

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Introduction: Associations between amyloid-tau-neurodegeneration (ATN) plasma biomarkers and cognition have not been characterized in adults with type 1 diabetes (T1D).

Methods: Using data from participants in the Glycemic Variability and Fluctuations in Cognitive Status in Adults with T1D (GluCog) study ( = 114), we evaluated associations between phosphorylated tau (pTau)181, pTau217, β-amyloid 42/40 ratio, glial fibrillary acidic protein (GFAP), and neurofilament light (NfL) and self-administered digital cognitive tests, adjusting for age, sex, education, comorbidities (e.g.

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  • * In Alzheimer's disease, these networks become more chaotic, as indicated by a drop in the small-world coefficient, a change linked to cognitive decline throughout the disease's progression.
  • * Our study examined the relationship between 10 cerebrospinal fluid protein biomarkers and small-world coefficients in Alzheimer's mutation carriers and non-carriers, finding that certain protein abnormalities indicate early changes in grey matter networks, while markers for inflammation and axonal injury correlate with declining small-world values.
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  • The study examines the link between protective lifestyle factors and the age at symptom onset of autosomal dominant Alzheimer disease (ADAD), which is largely influenced by genetics, focusing on how resilience-related experiences may impact this relationship.
  • The researchers analyzed data from the Dominantly Inherited Alzheimer Network, assessing both clinical and lifestyle factors in two groups: one looking at general resilience among people showing cognitive stability despite high pathology and another focusing on specific genetic timelines for ADAD.
  • Findings from 320 participants indicate variations in age at onset among carriers based on lifestyle and resilience factors, revealing potential avenues for understanding how these influences might delay the onset of symptoms in genetically predisposed individuals.
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  • Anti-β-amyloid immunotherapy with lecanemab shows promise for Alzheimer’s patients, particularly those with Down syndrome, who develop Alzheimer-like brain changes by their 40s.
  • A study analyzed postmortem brain tissue from 15 individuals with Down syndrome to assess how well lecanemab binds to amyloid plaques and blood vessels in the brain.
  • Results indicated that while lecanemab effectively binds to amyloid plaques, it also binds significantly to blood vessels, raising safety concerns and highlighting the need for careful clinical trials in this population.
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This manuscript describes and summarizes the Dominantly Inherited Alzheimer Network Observational Study (DIAN Obs), highlighting the wealth of longitudinal data, samples, and results from this human cohort study of brain aging and a rare monogenic form of Alzheimer's disease (AD). DIAN Obs is an international collaborative longitudinal study initiated in 2008 with support from the National Institute on Aging (NIA), designed to obtain comprehensive and uniform data on brain biology and function in individuals at risk for autosomal dominant AD (ADAD). ADAD gene mutations in the amyloid protein precursor (), presenilin 1 (), or presenilin 2 () genes are deterministic causes of ADAD, with virtually full penetrance, and a predictable age at symptomatic onset.

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Introduction: Sleep is crucial for memory consolidation and the clearance of toxic proteins associated with Alzheimer's disease (AD). We examined the association between sleep characteristics and imaging biomarkers of early amyloid beta (Aβ) and tau pathology as well as neurodegeneration in brain regions known to be affected in the incipient stages of AD.

Methods: Thirty-nine cognitively unimpaired (CU) participants of the Harvard Aging Brain Study underwent at-home polysomnography as well as tau positron emission tomography (flortaucipir-PET), amyloid PET (Pittsburgh compound B [PiB]-PET), and magnetic resonance imaging-derived assessment of cortical thickness (CT).

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Background: Genetic variants that cause autosomal dominant Alzheimer's disease are highly penetrant but vary substantially regarding age at symptom onset (AAO), rates of cognitive decline, and biomarker changes. Most pathogenic variants that cause autosomal dominant Alzheimer's disease are in presenilin 1 (PSEN1), which encodes the catalytic core of γ-secretase, an enzyme complex that is crucial in production of amyloid β. We aimed to investigate whether the heterogeneity in AAO and biomarker trajectories in carriers of PSEN1 pathogenic variants could be predicted on the basis of the effects of individual PSEN1 variants on γ-secretase activity and amyloid β production.

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Introduction: Though recognized as a potential cause of Autosomal Dominant Alzheimer's Disease, the pathogenicity of many variants remains uncertain. We compared Aβ production across all missense variants in the Alzforum database and, when possible, to corresponding variants.

Methods: We expressed 74 variants, 21 of which had homologous variants with the same amino acid substitution, in HEK293 cells lacking PSN1/2.

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  • This study investigates cognitive resilience (CR) to Alzheimer's disease (AD) in cognitively healthy older adults by analyzing imaging biomarkers and cognitive data over time using latent class mixture modeling.
  • The research involved 200 participants from the Harvard Aging Brain Study, who were categorized into three subgroups based on their cognitive trajectories: Normal, Resilient, and Declining, with the Resilient group showing higher cognitive performance and stability.
  • The findings suggest that leveraging imaging and cognitive assessments can effectively identify different levels of CR in preclinical AD stages, which could have implications for future research and interventions.
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Background: Changes in everyday functioning constitute a clinically meaningful outcome, even in the early stages of Alzheimer's disease. Performance-based assessments of everyday functioning might help uncover these early changes. We aimed to investigate how changes over time in everyday functioning relate to tau and amyloid in cognitively unimpaired older adults.

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Article Synopsis
  • Lecanemab is a monoclonal antibody designed to target amyloid beta in Alzheimer's disease, with its short half-life influenced by plasma protein interactions.
  • The study investigated how lecanemab binds to plasma proteins, with a focus on its biosimilar, using techniques like ELISA and Western blotting.
  • Results showed that fibrinogen is a binding partner for lecanemab, potentially affecting the availability of free antibodies in the bloodstream and highlighting the importance of plasma protein binding in therapeutic antibody treatment for neurodegenerative diseases.
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Introduction: Amyloid beta and tau pathology are the hallmarks of sporadic Alzheimer's disease (AD) and autosomal dominant AD (ADAD). However, Lewy body pathology (LBP) is found in ≈ 50% of AD and ADAD brains.

Methods: Using an α-synuclein seed amplification assay (SAA) in cerebrospinal fluid (CSF) from asymptomatic (n = 26) and symptomatic (n = 27) ADAD mutation carriers, including 12 with known neuropathology, we investigated the timing of occurrence and prevalence of SAA positive reactivity in ADAD in vivo.

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  • The study investigates early Alzheimer's disease changes in the brains of people with Down syndrome and those with genetic variants linked to Alzheimer's, aiming to better understand disease development and improve prevention strategies.
  • Using cross-sectional data from two cohort studies, researchers analyzed tau protein spread and its relationship with amyloid accumulation in participants aged 25 and older.
  • Findings revealed significant differences in the pattern and timing of tau accumulation in the two groups, suggesting implications for early intervention and clinical trials targeting Alzheimer's pathology.
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In addition to amyloid and tau pathology, elevated systemic vascular risk, white matter injury, and reduced cerebral blood flow contribute to late-life cognitive decline. Given the strong collinearity among these parameters, we proposed a framework to extract the independent latent features underlying cognitive decline using the Harvard Aging Brain Study (N = 166 cognitively unimpaired older adults at baseline). We used the following measures from the baseline visit: cortical amyloid, inferior temporal cortex tau, relative cerebral blood flow, white matter hyperintensities, peak width of skeletonized mean diffusivity, and Framingham Heart Study cardiovascular disease risk.

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Introduction: Amyloidosis, including cerebral amyloid angiopathy, and markers of small vessel disease (SVD) vary across dominantly inherited Alzheimer's disease (DIAD) presenilin-1 (PSEN1) mutation carriers. We investigated how mutation position relative to codon 200 (pre-/postcodon 200) influences these pathologic features and dementia at different stages.

Methods: Individuals from families with known PSEN1 mutations (n = 393) underwent neuroimaging and clinical assessments.

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Cerebral amyloid angiopathy (CAA) is a type of cerebrovascular disorder characterised by the accumulation of amyloid within the leptomeninges and small/medium-sized cerebral blood vessels. Typically, cerebral haemorrhages are one of the first clinical manifestations of CAA, posing a considerable challenge to the timely diagnosis of CAA as the bleedings only occur during the later disease stages. Fluid biomarkers may change prior to imaging biomarkers, and therefore, they could be the future of CAA diagnosis.

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Vascular dysfunction is increasingly recognized as an important contributor to the pathogenesis of Alzheimer's disease. Alterations in vascular endothelial growth factor (VEGF) pathways have been implicated as potential mechanisms. However, the specific impact of VEGF proteins in preclinical Alzheimer's disease and their relationships with other Alzheimer's disease and vascular pathologies during this critical early period remain to be elucidated.

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Article Synopsis
  • "Brain-predicted age" (BAG) uses neuroimaging to estimate biological age and reveals that those with autosomal dominant Alzheimer's disease (ADAD) show advanced brain aging about 7 years before symptoms start.
  • The study analyzed BAG in 257 ADAD mutation carriers and 179 non-carriers, finding that BAG correlates with markers of neurodegeneration, cognitive function, and tau protein levels.
  • BAG provides a straightforward measure for assessing ADAD progression, complementing existing MRI indicators while requiring less complex data analysis.
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Introduction: A wide array of post-translational modifications of the tau protein occurs in Alzheimer's disease (AD) and they are critical to pathogenesis and biomarker development. Several promising tau markers, pT181, pT217, and pT231, rely on increased phosphorylation within a common molecular motif threonine-proline-proline (TPP).

Methods: We validated new and existing antibodies against pT217, pT231, pT175, and pT181, then combined immunohistochemistry (IHC) and immunoassays (ELISA) to broadly examine the phosphorylation of the tau TPP motif in AD brains.

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