Citations

Abstract Cerebral blood flow is stabilized through dynamic adjustments across both macro‐ and microvascular compartments. While dynamic cerebral autoregulation (dCA) quantifies upstream pressure–flow coupling, downstream microvascular responses are less well characterized and may represent a distinct but functionally linked process. This study tested whether a two‐component cascade model, treating dCA and an empirically derived index of microvascular function (MF) as sequential stages can represent the integrated regulation of cortical oxygenation. Data from 41 healthy adults (20–45 years) were analysed. Beat‐to‐beat mean arterial pressure (MAP), middle cerebral artery flow velocity (CBFV) and cortical oxyhaemoglobin (O 2 Hb) were recorded during supine spontaneous oscillations and forced oscillations at 0.05 Hz using repeated sit–stand manoeuvres. Transfer function analysis quantified frequency‐domain gain, phase and coherence for MAP→CBFV (dCA), CBFV→O 2 Hb (MF) and MAP→O 2 Hb (total pathway). The cascade model was computed as the product of dCA and MF transfer functions. The cascade model derived indices showed strong correlations with total pathway gain, phase and coherence measures during both spontaneous and forced oscillations, with improved linear coupling under forced oscillations. These results support the applicability of a two‐component cascade model for integrated cerebrovascular regulation and suggest that serial interactions between macrovascular and microvascular regulatory mechanisms jointly shape the frequency‐dependent propagation of arterial pressure to brain‐tissue oxygenation dynamics. image Key points Cerebral blood flow is stabilized by coordinated regulation across large arteries and microvessels, but their dynamic interaction has not been experimentally modelled. We examined whether a two‐component cascade model linking upstream dynamic cerebral autoregulation and downstream microvascular function can explain how blood pressure oscillations influence cortical oxygenation. In 41 healthy adults, we recorded beat‐to‐beat blood pressure, middle cerebral artery blood flow velocity and near‐infrared spectroscopy‐derived oxygenation during rest and sit–stand manoeuvres, and analysed them using transfer function analysis. Gains, phases and coherences derived from the cascade model closely matched those from the direct blood pressure–O 2 Hb relationship, particularly under forced oscillations during sit–stand, demonstrating the model's physiological relevance. The cascade model provides a mechanistic framework to separate and quantify large‐ and small‐vessel contributions to cerebral blood flow regulation, with potential application in future studies of ageing and cerebrovascular disease.

Objective To establish a framework for validating candidate biomarkers of cerebral small vessel diseases (SVD) associated with cognitive impairment and characterize individuals enrolled by the MarkVCID2 consortium under this framework. Methods Participants age 60 to 90 years were enrolled across 17 MarkVCID2 sites. Recruitment was targeted to enrich in cognitive symptoms (mild dementia, mild cognitive impairment, subjective cognitive decline), defined risk factors (diabetes mellitus, advanced hypertension), and Black/African American, White, and Hispanic/Latino subgroups. Enrolled participants underwent baseline visits that included cognitive testing, multimodal magnetic resonance imaging (MRI), and biofluid collection. Provisional risk for SVD‐related cognitive decline was estimated primarily by baseline cognitive symptoms plus SVD risk factors. Adjudicated risk status was estimated by cognitive symptoms plus presence of moderate‐to‐severe white matter hyperintensities, microbleeds, or lacunes on baseline MRI. Results MarkVCID2 enrolled 1883 individuals age 73.4 ± 7.5 years, 65.0% female, 24.2% Hispanic, and 27.1% non‐Hispanic Black. Among enrollees, 44.8% were provisionally designated high‐risk. After baseline MRI, 48.5% were categorized as adjudicated high‐risk status, with substantial recategorization both from low‐ to high‐risk (primarily because of MRI lesions without SVD risk factors) and high‐ to low‐risk (primarily suspected cognitive impairment at screening not confirmed by baseline testing). Interpretation MarkVCID2 baseline data indicate successful enrollment of diverse individuals enriched in factors associated with SVD‐related cognitive decline. Changes over 3 years of longitudinal follow‐up will be analyzed to validate the candidate biomarkers for 2 projected contexts of use: subject selection (identifying likelihood of future SVD progression) and study outcome (efficiently measuring SVD progression). ANN NEUROL 2026;99:449–458

Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson’s disease (PD) and Alzheimer’s disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1 *04 subtypes best accounted for the association, strongest with HLA-DRB1 *04:04 and HLA-DRB1 *04:07, and intermediary with HLA-DRB1 *04:01 and HLA-DRB1 *04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased Aβ42. Protective HLA-DRB1 *04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1 *04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues.

Is tau load associated with long-term outcomes of TBI? By using PET to assess tau deposits in patients with chronic TBI, Takahata et al. reveal elevated tau load compared to age-matched controls, and show that the abundance of tau in white matter is associated with late-onset neuropsychiatric symptoms.

AbstractBackground[11C]pyridinyl‐butadienyl‐benzothiazole 3 is a PET imaging agent designed for capturing pathological tau aggregates in diverse neurodegenerative disorders, and would be of clinical utility for neuropathological investigations of PSP.ObjectivesTo explore the usefulness of [11C]pyridinyl‐butadienyl‐benzothiazole 3/PET in assessing characteristic distributions of tau pathologies and their association with clinical symptoms in the brains of living PSP patients.MethodsWe assessed 13 PSP patients and 13 age‐matched healthy control subjects. Individuals negative for amyloid β PET with [11C]Pittsburgh compound B underwent clinical scoring, MR scans, and [11C]pyridinyl‐butadienyl‐benzothiazole 3/PET.ResultsThere were significant differences in binding potential for [11C]pyridinyl‐butadienyl‐benzothiazole 3 between PSP patients and healthy control subjects (P = 0.02). PSP patients exhibited greater radioligand retention than healthy control subjects in multiple brain regions, including frontoparietal white matter, parietal gray matter, globus pallidus, STN, red nucleus, and cerebellar dentate nucleus. [11C]pyridinyl‐butadienyl‐benzothiazole 3 deposition in frontoparietal white matter, but not gray matter, was correlated with general severity of parkinsonian and PSP symptoms, whereas both gray matter and white matter [11C]pyridinyl‐butadienyl‐benzothiazole 3 accumulations in the frontoparietal cortices were associated with nonverbal cognitive impairments. Autoradiographic and fluorescence labeling with pyridinyl‐butadienyl‐benzothiazole 3 was observed in gray matter and white matter of PSP motor cortex tissues.ConclusionsOur findings support the in vivo detectability of tau fibrils characteristic of PSP by [11C]pyridinyl‐butadienyl‐benzothiazole 3/PET, and imply distinct and synergistic contributions of gray matter and white matte tau pathologies to clinical symptoms. [11C]pyridinyl‐butadienyl‐benzothiazole 3/PET potentially provides a neuroimaging‐based index for the evolution of PSP tau pathologies promoting the deterioration of motor and cognitive functions. © 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Abstract The variable clinical success with immune checkpoint inhibitors in the treatment of solid tumors challenges us to further understand the regulatory mechanisms of immune cells infiltration – a critical step of tumor elimination – in a highly heterogenous tumor microenvironment (TME). Systemic analyses of the tumor-immune cell interface and interactions are of particular significance with direct clinical impact. We employed a multiplexed immunofluorescence (MxIF) method, a novel technology that allows in situ quantitative single cell characterization with high order protein multiplexing on whole tumor sections, to elucidate the key components in TME governing the immune cells' composition and function in metastatic melanoma lymph node metastases. Here, we show that the expression of tumor cell Human Leukocyte Antigen 1 (HLA-1) is highly heterogeneous both within the TME and between patients. The level of tumor HLA-1 expression directly correlates with the magnitude of cytotoxic T lymphocytes (CTLs) infiltration in the TME. In addition, decreased tumor HLA-1 expression is associated with accumulation of CD20+ cells at the edge of the tumor as well as an increased population of CD4+FOXP3+ cells. The association between tumor HLA-1 expression and immune cell distribution is highly consistent yet heterogenous across the entire tumor mass. Moreover, using quantitative single cell data, we developed algorithms for computational and spatial modeling of tumor-immune cell interfaces, allowing statistical comparison of cellular interactions in the context of tumor heterogeneity. Spatial analysis demonstrates that tumor HLA-1 expression favors CTL invasion, while lack of tumor HLA-1 expression results in CTL evasion. Furthermore, in a cohort of 166 Stage III melanoma patients, we confirm that CTLs infiltration is only present in regions with high tumor HLA-1 expressions, and that patients with tumors high in both tumor HLA-1 and CTLs have significantly improved progression free survival (PFS) compared with those with tumors low in HLA-1 and/or CTLs. Our study demonstrates that the heterogeneous tumor HLA-1 expression results in various immune cell distribution patterns in the TME, directly contributing to the varied antitumor immunities and ultimately influencing tumor outcomes. As part of the antigen presentation machinery, HLA-1 expression on tumors is necessary for CTLs infiltration and is indispensable for T cell mediated tumor elimination with direct clinical benefits. We also establish a novel platform for visualization and spatial representation of the cellular heterogeneity within the TME, providing data processing and modeling algorithms necessary for understanding the cellular interplay mediating tumor surveillance, which will ultimately improve therapeutic efficacy and clinical outcomes. Citation Format: Yiyi Yan, Alexey Leontovich, Thomas Flotte, Michael Gerdes, Fiona Ginty, Alberto Santamaria-Pang, Anup Sood, Keyur Desai, Chrystal Chadwick, Rong Zhang, Svetomir N. Markovic. Tumor HLA Class I expression influences immune cells infiltration in metastatic melanoma tumor microenvironment. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2016 Oct 20-23; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2017;5(3 Suppl):Abstract nr A71.