Publications

Co-pathology is frequent in Lewy body disease, which includes clinical diagnoses of both Parkinson’s disease and dementia with Lewy bodies. Measuring concomitant pathology in vivo can improve clinical and research diagnoses and prediction of cognitive trajectories. Tau PET imaging may serve a dual role in Lewy body disease by measuring cortical tau aggregation as well as assessing dopaminergic loss attributed to binding to neuromelanin within substantia nigra. We sought to characterize ¹⁸F-PI-2620, a next generation PET tracer, in individuals with Lewy body disease. We recruited 141 participants for ¹⁸F-PI-2620 PET scans from the Stanford Alzheimer’s Disease Research Center and the Stanford Aging and Memory Study, most of whom also had β-amyloid status available (139/141) from PET or cerebrospinal fluid. We compared ¹⁸F-PI-2620 uptake within entorhinal cortex, inferior temporal cortex, precuneus and lingual gyrus, as well as substantia nigra, across participants with Lewy body disease [Parkinson’s disease (n = 29), dementia with Lewy bodies (n = 14)] and Alzheimer’s disease (n = 28), in addition to cognitively unimpaired healthy older adults (n = 70). Mean bilateral signal was extracted from cortical regions of interest in ¹⁸F-PI-2620 standard uptake value ratio (inferior cerebellar grey reference) images normalized to template space. A subset of participants received cognitive testing and/or the Movement Disorders Society Unified Parkinson’s Disease Rating Scale Part III motor exam (off medication). ¹⁸F-PI-2620 uptake was low overall in Lewy body disease and correlated with β-amyloid PET in temporal lobe regions and precuneus. Moreover, inferior temporal ¹⁸F-PI-2620 uptake was significantly elevated in β-amyloid positive relative to β-amyloid negative participants with Lewy body disease. Temporal lobe ¹⁸F-PI-2620 signal was not associated with memory in Lewy body disease, but uptake within precuneus and lingual gyrus was associated with worse executive function and attention/working memory performance. Finally, substantia nigra ¹⁸F-PI-2620 signal was significantly reduced in participants with Parkinson’s disease, and lower substantia nigra signal was associated with greater motor impairment. These findings suggest that although levels are lower than in Alzheimer’s disease, small elevations in cortical tau are associated with cognitive function in Lewy body disease relevant domains, and that reduced ¹⁸F-PI-2620 binding in substantia nigra may represent loss of dopaminergic neurons. Cortical tau and neuromelanin binding within substantia nigra represent two unique signals in the same PET image that may be informative in the context of cognitive and motor deficits, respectively, in Lewy body disease.

Rates of cognitive decline in Alzheimer’s disease (AD) are extremely heterogeneous. Although biomarkers for amyloid-beta (Aβ) and tau proteins, the hallmark AD pathologies, have improved pathology-based diagnosis, they explain only 20-40% of the variance in AD-related cognitive impairment (CI). To discover novel biomarkers of CI in AD, we performed cerebrospinal fluid (CSF) proteomics on 3,397 individuals from six major prospective AD case-control cohorts. Synapse proteins emerged as the strongest correlates of CI, independent of Aβ and tau. Using machine learning, we derived the CSF YWHAG:NPTX2 synapse protein ratio, which explained 27% of the variance in CI beyond CSF pTau₁₈₁:Aβ₄₂, 11% beyond tau positron emission tomography, and 28% beyond CSF neurofilament, growth-associated protein 43 and neurogranin in Aβ⁺ and phosphorylated tau⁺ (A+T₁+) individuals. CSF YWHAG:NPTX2 also increased with normal aging and 20 years before estimated symptom onset in carriers of autosomal dominant AD mutations. Regarding cognitive prognosis, CSF YWHAG:NPTX2 predicted conversion from A+T₁+ cognitively normal to mild cognitive impairment (standard deviation increase hazard ratio = 3.0, P = 7.0 × 10^-4) and A+T₁+ mild cognitive impairment to dementia (standard deviation increase hazard ratio = 2.2, P = 8.2 × 10^-16) over a 15-year follow-up, adjusting for CSF pTau₁₈₁:Aβ₄₂, CSF neurofilament, CSF neurogranin, CSF growth-associated protein 43, age, APOE4 and sex. We also developed a plasma proteomic signature of CI, which we evaluated in 13,401 samples, which partly recapitulated CSF YWHAG:NPTX2. Overall, our findings underscore CSF YWHAG:NPTX2 as a robust prognostic biomarker for cognitive resilience versus AD onset and progression, highlight the potential of plasma proteomics in replacing CSF measurement and further implicate synapse dysfunction as a core driver of AD dementia.

The clinical course and treatment of neurodegenerative disease are complicated by immune-system interference and chronic inflammatory processes, which remain incompletely understood. Mapping immune signatures in larger human cohorts through single-cell gene expression profiling supports our understanding of observed peripheral changes in neurodegeneration. Here, we employ single-cell gene expression profiling of over 909k peripheral blood mononuclear cells (PBMCs) from 121 healthy individuals, 48 patients with mild cognitive impairment (MCI), 46 with Parkinson’s disease (PD), 27 with Alzheimer’s disease (AD), and 15 with both PD and MCI. The dataset is interactively accessible through a freely available website ( https://www.ccb.uni-saarland.de/adrcsc ). In this work, we identify disease-associated changes in blood cell type composition and the gene expression in a sex-specific manner, offering insights into peripheral and solid tissue signatures in AD and PD.

Changes in β-amyloid (Aβ) and hyperphosphorylated tau (T) in brain and cerebrospinal fluid (CSF) precede Alzheimer’s disease (AD) symptoms, making the CSF proteome a potential avenue to understand disease pathophysiology and facilitate reliable diagnostics and therapies. Using the AT framework and a three-stage study design (discovery, replication, and meta-analysis), we identified 2,173 analytes (2,029 unique proteins) dysregulated in AD. Of these, 865 (43%) were previously reported, and 1,164 (57%) are novel. The identified proteins cluster in four different pseudo-trajectories groups spanning the AD continuum and were enriched in pathways including neuronal death, apoptosis, and tau phosphorylation (early stages), microglia dysregulation and endolysosomal dysfunction (mid stages), brain plasticity and longevity (mid stages), and microglia-neuron crosstalk (late stages). Using machine learning, we created and validated highly accurate and replicable (area under the curve [AUC] > 0.90) models that predict AD biomarker positivity and clinical status. These models can also identify people that will convert to AD.

Recent studies demonstrate that Parkinson’s disease (PD) is associated with dysregulated metabolic flux through the kynurenine pathway (KP), in which tryptophan is converted to kynurenine (KYN), and KYN is subsequently metabolized to neuroactive compounds quinolinic acid (QA) and kynurenic acid (KA). Here, we used mass-spectrometry to compare blood and cerebral spinal fluid (CSF) KP metabolites between 158 unimpaired older adults and 177 participants with PD. We found increased neuroexcitatory QA/KA ratio in both plasma and CSF of PD participants associated with peripheral and cerebral inflammation and vitamin B₆ deficiency. Furthermore, increased QA tracked with CSF tau, CSF soluble TREM2 (sTREM2) and severity of both motor and non-motor PD clinical symptoms. Finally, PD patient subgroups with distinct KP profiles displayed distinct PD clinical features. These data validate the KP as a site of brain and periphery crosstalk, integrating B-vitamin status, inflammation and metabolism to ultimately influence PD clinical manifestation.

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.

Effective memory formation declines in human aging. Diminished neural selectivity-reduced differential responses to preferred versus nonpreferred stimuli-may contribute to memory decline, but its drivers remain unclear. We investigated the effects of top-down attention and preclinical Alzheimer’s disease (AD) pathology on neural selectivity in 166 cognitively unimpaired older participants using functional magnetic resonance imaging during a word-face/word-place associative memory task. During learning, neural selectivity in place- and, to a lesser extent, face-selective regions was greater for subsequently remembered than forgotten events; positively scaled with variability in dorsal attention network activity, within and across individuals; and negatively related to AD pathology, evidenced by elevated plasma phosphorylated Tau₁₈₁ (pTau₁₈₁). Path analysis revealed that neural selectivity mediated the effects of age, attention, and pTau₁₈₁ on memory. These data reveal multiple pathways that contribute to memory differences among older adults-AD-independent reductions in top-down attention and AD-related pathology alter the precision of cortical representations of events during experience, with consequences for remembering.