Age-related differences in finger interdependence during complex hand movements.

The well-known decrease in finger dexterity during healthy aging leads to a significant reduction in quality of life. Still, the exact patterns of altered finger kinematics of older adults in daily life are fairly unexplored. Finger interdependence is the unintentional co-movement of fingers that are not intended to move, and it is known to vary across the lifespan. Nevertheless, the magnitude and direction of age-related differences in finger interdependence are ambiguous across studies and tasks and have not been explored in the context of daily life finger movements. We investigated five different free and daily-life-inspired finger movements of the right, dominant hand as well as a sequential finger tapping task of the thumb against the other fingers, in 17 younger (22 to 37 years) and 17 older (62 to 80 years) adults using an exoskeleton data glove for data recording. Using inferential statistics, we found that the unintentional co-movement of fingers generally decreases with age in all performed daily-life-inspired movements. Finger tapping, however, showed a trend towards higher finger interdependence for older compared to younger adults. Using machine learning, we predicted the age group of a person from finger interdependence features of single movement trials significantly better than chance level for the daily-life-inspired movements, but not for finger tapping. Taken together, we show that for specific tasks, decreased finger interdependence (i.e., less co-movement) could potentially act as a marker of human aging that specifically characterizes older adults' complex finger movements in daily life.

Risk factors for intracerebral hemorrhage in small-vessel disease and non-small-vessel disease etiologies-an observational proof-of-concept study.

Background: Sporadic cerebral small-vessel disease (CSVD), i.e., hypertensive arteriopathy (HA) and cerebral amyloid angiopathy (CAA), is the main cause of spontaneous intracerebral hemorrhage (ICH). Nevertheless, a substantial portion of ICH cases arises from non-CSVD etiologies, such as trauma, vascular malformations, and brain tumors. While studies compared HA- and CAA-related ICH, non-CSVD etiologies were excluded from these comparisons and are consequently underexamined with regard to additional factors contributing to increased bleeding risk beyond their main pathology. Methods: As a proof of concept, we conducted a retrospective observational study in 922 patients to compare HA, CAA, and non-CSVD-related ICH with regard to factors that are known to contribute to spontaneous ICH onset. Medical records (available for n = 861) were screened for demographics, antithrombotic medication, and vascular risk profile, and CSVD pathology was rated on magnetic resonance imaging (MRI) in a subgroup of 185 patients. The severity of CSVD was assessed with a sum score ranging from 0 to 6, where a score of ≥2 was defined as advanced pathology. Results: In 922 patients with ICH (median age of 71 years), HA and CAA caused the majority of cases (n = 670, 73%); non-CSVD etiologies made up the remaining quarter (n = 252, 27%). Individuals with HA- and CAA-related ICH exhibited a higher prevalence of predisposing factors than those with non-CSVD etiologies. This includes advanced age (median age: 71 vs. 75 vs. 63 years, p < 0.001), antithrombotic medication usage (33 vs. 37 vs. 19%, p < 0.001), prevalence of vascular risk factors (70 vs. 67 vs. 50%, p < 0.001), and advanced CSVD pathology on MRI (80 vs. 89 vs. 51%, p > 0.001). However, in particular, half of non-CSVD ICH patients were either aged over 60 years, presented with vascular risk factors, or had advanced CSVD on MRI. Conclusion: Risk factors for spontaneous ICH are less common in non-CSVD ICH etiologies than in HA- and CAA-related ICH, but are still frequent. Future studies should incorporate these factors, in addition to the main pathology, to stratify an individual's risk of bleeding.

A systematic review of progranulin concentrations in biofluids in over 7,000 people-assessing the pathogenicity of GRN mutations and other influencing factors.

BACKGROUND: Pathogenic heterozygous mutations in the progranulin gene (GRN) are a key cause of frontotemporal dementia (FTD), leading to significantly reduced biofluid concentrations of the progranulin protein (PGRN). This has led to a number of ongoing therapeutic trials aiming to treat this form of FTD by increasing PGRN levels in mutation carriers. However, we currently lack a complete understanding of factors that affect PGRN levels and potential variation in measurement methods. Here, we aimed to address this gap in knowledge by systematically reviewing published literature on biofluid PGRN concentrations. METHODS: Published data including biofluid PGRN concentration, age, sex, diagnosis and GRN mutation were collected for 7071 individuals from 75 publications. The majority of analyses (72%) had focused on plasma PGRN concentrations, with many of these (56%) measured with a single assay type (Adipogen) and so the influence of mutation type, age at onset, sex, and diagnosis were investigated in this subset of the data. RESULTS: We established a plasma PGRN concentration cut-off between pathogenic mutation carriers and non-carriers of 74.8 ng/mL using the Adipogen assay based on 3301 individuals, with a CSF concentration cut-off of 3.43 ng/mL. Plasma PGRN concentration varied by GRN mutation type as well as by clinical diagnosis in those without a GRN mutation. Plasma PGRN concentration was significantly higher in women than men in GRN mutation carriers (p = 0.007) with a trend in non-carriers (p = 0.062), and there was a significant but weak positive correlation with age in both GRN mutation carriers and non-carriers. No significant association was seen with weight or with TMEM106B rs1990622 genotype. However, higher plasma PGRN levels were seen in those with the GRN rs5848 CC genotype in both GRN mutation carriers and non-carriers. CONCLUSIONS: These results further support the usefulness of PGRN concentration for the identification of the large majority of pathogenic mutations in the GRN gene. Furthermore, these results highlight the importance of considering additional factors, such as mutation type, sex and age when interpreting PGRN concentrations. This will be particularly important as we enter the era of trials for progranulin-associated FTD.

Predictors for Adherence to Recommended Anticoagulation after Stroke Unit Discharge in Patients with Atrial Fibrillation.

INTRODUCTION: Non-adherence to recommended secondary preventive anticoagulation in stroke patients with atrial fibrillation (AF) is a common phenomenon although the introduction of direct oral anticoagulants (DOACs) has simplified anticoagulation management for physicians as well as for patients. METHODS: We examined the adherence of secondary preventive anticoagulation in AF patients after re-integration in their social environment 6 to 12 weeks after stroke unit and rehabilitation clinic treatment and analyzed for predictors for adherence and non-adherence. We conducted a telephone survey in consecutive patients treated between January 2013 and December 2021 at our institutional stroke unit with an acute cerebrovascular ischemic event and we analyzed discharge letters of rehabilitation clinics of those patients not anticoagulated at follow-up. All patients had known or newly diagnosed AF and in all we had recommended secondary preventive anticoagulation. RESULTS: Follow-up information about anticoagulant intake could be obtained in 1348 of 1685 patients (80.0%) treated within the study period. Anticoagulation rate was 91.5% with 83.6% of patients receiving DOACs and 7.9% receiving vitamin K antagonists (VKAs). Adherence to recommended anticoagulation was associated with intake of the recommended anticoagulant already at discharge (adjusted OR, 18.357; CI, 9.637 to 34.969), recommendation of a specific DOAC and dose (in contrast to "DOAC" as drug category) (adjusted OR, 2.971; CI, 1.173 to 7.255), a lower modified Rankin Scale at discharge (per point; adjusted OR, 0.813; CI, 0.663 to 0.996), younger age (per year; adjusted odds ratio [OR], 0.951; confidence interval [CI], 0.926 to 0.976), and the absence of peripheral vascular disease (adjusted OR, 0.359; CI, 0.173 to 0.746). In patients already anticoagulated at discharge adherence was 98.5%, irrespective of a patient's age, functional deficit at discharge, and peripheral vascular disease. Avoidable obstacles for non-adherence in patients not on anticoagulants at stroke unit discharge were (1) non-implementation of recommended anticoagulation by rehabilitation physicians predominantly in patients with moderate-severe or severe stroke disability (2.1%), (2) delegation of anticoagulation start from rehabilitation physicians to general practitioners/resident radiologists (1.3%), and (3) rejection of recommended anticoagulation because of patients' severe stroke disability (0.5%). Non-avoidable obstacles were contraindications to anticoagulation (2.1%) and patients' refusal (0.7%). CONCLUSIONS: Commencing drug administration already during stroke unit hospitalization and providing an explanation for the selection of the recommended anticoagulant in discharge letters ensures high adherence at patients' re-integration in their social environment after acute stroke treatment. If drug administration cannot be commenced before discharge, education of rehabilitation physicians by stroke physicians and the involvement of stroke physicians into the post-stroke decision process might hinder avoidable obstacles.

Microvascular damage, neuroinflammation and extracellular matrix remodeling in Col18a1 knockout mice as a model for early cerebral small vessel disease.

Collagen type XVIII (COL18) is an abundant heparan sulfate proteoglycan in vascular basement membranes. Here, we asked (i) if the loss of COL18 would result in blood-brain barrier (BBB) breakdown, pathological alterations of small arteries and capillaries and neuroinflammation as found in cerebral small vessel disease (CSVD) and (ii) if such changes may be associated with remodeling of synapses and neural extracellular matrix (ECM). We found that 5-month-old Col18a1-/- mice had elevated BBB permeability for mouse IgG in the deep gray matter, and intravascular erythrocyte accumulations were observed brain-wide in capillaries and arterioles. BBB permeability increased with age and affected cortical regions and the hippocampus in 12-month-old Col18a1-/- mice. None of the Col18a1-/- mice displayed hallmarks of advanced CSVD, such as hemorrhages, and did not show perivascular space enlargement. Col18a1 deficiency-induced BBB leakage was accompanied by activation of microglia and astrocytes, a loss of aggrecan in the ECM of perineuronal nets associated with fast-spiking inhibitory interneurons and accumulation of the perisynaptic ECM proteoglycan brevican and the microglial complement protein C1q at excitatory synapses. As the pathway underlying these regulations, we found increased signaling through the TGF-ß1/Smad3/TIMP-3 cascade. We verified the pivotal role of COL18 for small vessel wall structure in CSVD by demonstrating the protein's involvement in vascular remodeling in autopsy brains from patients with cerebral hypertensive arteriopathy. Our study highlights an association between the alterations of perivascular ECM, extracellular proteolysis, and perineuronal/perisynaptic ECM, as a possible substrate of synaptic and cognitive alterations in CSVD.

Different inflammatory signatures based on CSF biomarkers relate to preserved or diminished brain structure and cognition.

Neuroinflammation is a hallmark of Alzheimer's disease (AD) and both positive and negative associations of individual inflammation-related markers with brain structure and cognitive function have been described. We aimed to identify inflammatory signatures of CSF immune-related markers that relate to changes of brain structure and cognition across the clinical spectrum ranging from normal aging to AD. A panel of 16 inflammatory markers, Aß42/40 and p-tau181 were measured in CSF at baseline in the DZNE DELCODE cohort (n = 295); a longitudinal observational study focusing on at-risk stages of AD. Volumetric maps of gray and white matter (GM/WM; n = 261) and white matter hyperintensities (WMHs, n = 249) were derived from baseline MRIs. Cognitive decline (n = 204) and the rate of change in GM volume was measured in subjects with at least 3 visits (n = 175). A principal component analysis on the CSF markers revealed four inflammatory components (PCs). Of these, the first component PC1 (highly loading on sTyro3, sAXL, sTREM2, YKL-40, and C1q) was associated with older age and higher p-tau levels, but with less pathological Aß when controlling for p-tau. PC2 (highly loading on CRP, IL-18, complement factor F/H and C4) was related to male gender, higher body mass index and greater vascular risk. PC1 levels, adjusted for AD markers, were related to higher GM and WM volumes, less WMHs, better baseline memory, and to slower atrophy rates in AD-related areas and less cognitive decline. In contrast, PC2 related to less GM and WM volumes and worse memory at baseline. Similar inflammatory signatures and associations were identified in the independent F.ACE cohort. Our data suggest that there are beneficial and detrimental signatures of inflammatory CSF biomarkers. While higher levels of TAM receptors (sTyro/sAXL) or sTREM2 might reflect a protective glia response to degeneration related to phagocytic clearance, other markers might rather reflect proinflammatory states that have detrimental impact on brain integrity.

Multimodal layer modelling reveals in vivo pathology in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a rapidly progressing neurodegenerative disease characterized by the loss of motor control. Current understanding of ALS pathology is largely based on post-mortem investigations at advanced disease stages. A systematic in vivo description of the microstructural changes that characterize early stage ALS, and their subsequent development, is so far lacking. Recent advances in ultra-high field (7 T) MRI data modelling allow us to investigate cortical layers in vivo. Given the layer-specific and topographic signature of ALS pathology, we combined submillimetre structural 7 T MRI data (qT1, QSM), functional localizers of body parts (upper limb, lower limb, face) and layer modelling to systematically describe pathology in the primary motor cortex (M1), in 12 living ALS patients with reference to 12 matched controls. Longitudinal sampling was performed for a subset of patients. We calculated multimodal pathology maps for each layer (superficial layer, layer 5a, layer 5b, layer 6) of M1 to identify hot spots of demyelination, iron and calcium accumulation in different cortical fields. We show preserved mean cortical thickness and layer architecture of M1, despite significantly increased iron in layer 6 and significantly increased calcium in layer 5a and superficial layer, in patients compared to controls. The behaviourally first-affected cortical field shows significantly increased iron in L6 compared to other fields, while calcium accumulation is atopographic and significantly increased in the low myelin borders between cortical fields compared to the fields themselves. A subset of patients with longitudinal data shows that the low myelin borders are particularly disrupted and that calcium hot spots, but to a lesser extent iron hot spots, precede demyelination. Finally, we highlight that a very slow progressing patient (Patient P4) shows a distinct pathology profile compared to the other patients. Our data show that layer-specific markers of in vivo pathology can be identified in ALS patients with a single 7 T MRI measurement after first diagnosis, and that such data provide critical insights into the individual disease state. Our data highlight the non-topographic architecture of ALS disease spread and the role of calcium, rather than iron accumulation, in predicting future demyelination. We also highlight a potentially important role of low myelin borders, that are known to connect to multiple areas within the M1 architecture, in disease spread. Finally, the distinct pathology profile of a very-slow progressing patient (Patient P4) highlights a distinction between disease duration and progression. Our findings demonstrate the importance of in vivo histology imaging for the diagnosis and prognosis of neurodegenerative diseases such as ALS.

[Cerebral Small Vessel Disease: Advances in Understanding its Pathophysiology]. / Zerebrale Mikroangiopathie: Fortschritte im Verständnis der Pathophysiologie.

Sporadic cerebral small vessel disease determines age- and vascular-risk-factor-related processes of the small brain vasculature. The underlying pathology develops in a stage-dependent manner - probably over decades - often already starting in midlife. Endothelial and pericyte activation precedes blood-brain barrier leaks, extracellular matrix remodeling and neuroinflammation, which ultimately result in bleeds, synaptic and neural dysfunction. Hemodynamic compromise of the small vessel walls promotes perivascular drainage failure and accumulation of neurotoxic waste products in the brain. Clinical diagnosis is mainly based on magnetic resonance imaging according to the Standards for Reporting Vascular Changes on Neuroimaging 2. Cerebral amyloid angiopathy is particularly stratified according to the Boston v2.0 criteria. Small vessel disease of the brain could be clinically silent, or manifested through a heterogeneous spectrum of diseases, where cognitive decline and stroke-related symptoms are the most common ones. Prevention and therapy are centered around vascular risk factor control, physically and cognitively enriched life style and, presumably, maintenance of a good sleep quality, which promotes sufficient perivascular drainage. Prevention of ischemic stroke through anticoagulation that carries at the same time an increased risk for large brain hemorrhages - particularly in the presence of disseminated cortical superficial siderosis - remains one of the main challenges. The cerebral small vessel disease field is rapidly evolving, focusing on the establishment of early disease stage imaging and biofluid biomarkers of neurovascular unit remodeling and the compromise of perivascular drainage. New prevention and therapy strategies will correspondingly center around the dedicated targeting of, e. g., cellular small vessel wall and perivascular tissue structures. Growing knowledge about brain microvasculature bridging neuroimmunological, neurovascular and neurodegenerative fields might lead to a rethink about apparently separate disease entities and the development of overarching concepts for a common line of prevention and treatment for several diseases.

Spatio-temporal dynamics of microglia phenotype in human and murine cSVD: impact of acute and chronic hypertensive states.

Vascular risk factors such as chronic hypertension are well-established major modifiable factors for the development of cerebral small vessel disease (cSVD). In the present study, our focus was the investigation of cSVD-related phenotypic changes in microglia in human disease and in the spontaneously hypertensive stroke-prone rat (SHRSP) model of cSVD. Our examination of cortical microglia in human post-mortem cSVD cortical tissue revealed distinct morphological microglial features specific to cSVD. We identified enlarged somata, an increase in the territory occupied by thickened microglial processes, and an expansion in the number of vascular-associated microglia. In parallel, we characterized microglia in a rodent model of hypertensive cSVD along different durations of arterial hypertension, i.e., early chronic and late chronic hypertension. Microglial somata were already enlarged in early hypertension. In contrast, at late-stage chronic hypertension, they further exhibited elongated branches, thickened processes, and a reduced ramification index, mirroring the findings in human cSVD. An unbiased multidimensional flow cytometric analysis revealed phenotypic heterogeneity among microglia cells within the hippocampus and cortex. At early-stage hypertension, hippocampal microglia exhibited upregulated CD11b/c, P2Y12R, CD200R, and CD86 surface expression. Detailed analysis of cell subpopulations revealed a unique microglial subset expressing CD11b/c, CD163, and CD86 exclusively in early hypertension. Notably, even at early-stage hypertension, microglia displayed a higher association with cerebral blood vessels. We identified several profound clusters of microglia expressing distinct marker profiles at late chronic hypertensive states. In summary, our findings demonstrate a higher vulnerability of the hippocampus, stage-specific microglial signatures based on morphological features, and cell surface protein expression in response to chronic arterial hypertension. These results indicate the diversity within microglia sub-populations and implicate the subtle involvement of microglia in cSVD pathogenesis.

Reduced dimension stimulus decoding and column-based modeling reveal architectural differences of primary somatosensory finger maps between younger and older adults.

The primary somatosensory cortex (SI) contains fine-grained tactile representations of the body, arranged in an orderly fashion. The use of ultra-high resolution fMRI data to detect group differences, for example between younger and older adults' SI maps, is challenging, because group alignment often does not preserve the high spatial detail of the data. Here, we use robust-shared response modeling (rSRM) that allows group analyses by mapping individual stimulus-driven responses to a lower dimensional shared feature space, to detect age-related differences in tactile representations between younger and older adults using 7T-fMRI data. Using this method, we show that finger representations are more precise in Brodmann-Area (BA) 3b and BA1 compared to BA2 and motor areas, and that this hierarchical processing is preserved across age groups. By combining rSRM with column-based decoding (C-SRM), we further show that the number of columns that optimally describes finger maps in SI is higher in younger compared to older adults in BA1, indicating a greater columnar size in older adults' SI. Taken together, we conclude that rSRM is suitable for finding fine-grained group differences in ultra-high resolution fMRI data, and we provide first evidence that the columnar architecture in SI changes with increasing age.

Blend Sign and Haemorrhage Location and Volume Predict Late Recurrence and Mortality in Intracerebral Haemorrhage Patients.

BACKGROUND: Studies on risk factors for primary intracerebral haemorrhage (ICH) focus on short-term predictive values of distinct clinical parameters or computed tomography (CT) markers and disregard the others. We, therefore, studied independent predictive values of demographic, clinical, and CT markers regarding ICH expansion, late ICH recurrence, and late mortality. METHODS: In a retrospective study of 288 patients with primary ICH, ICH localization (158 lobar, 81 deep, and 49 cerebellar), volume, blend sign, spot sign, finger-like projections, and subarachnoid haemorrhages were evaluated. ICH localization-specific differences for demographic (age, sex), clinical parameters (vascular risk factors, antiplatelet, and anticoagulation therapy), and CT markers were evaluated using logistic regression. We applied Cox proportional hazards modelling using these parameters to predict risk factors for ICH expansion, late ICH recurrence, and late mortality. RESULTS: The blend sign in lobar ICH relates to increased risk of ICH expansion (HR2.3), late ICH recurrence (HR2.3), and mortality (HR1.6). Age, conditions requiring antiplatelet medication, deep ICH localization, volume, and blend sign represented the most important independent factors impacting overall mortality. CONCLUSIONS: Blend sign at baseline ICH is a manifestation of underlying detrimental vascular processes that signal increased ICH expansion risk, although is also indicative of long-term risks for late recurrent ICH and late mortality.

Classifying flow cytometry data using Bayesian analysis helps to distinguish ALS patients from healthy controls.

Introduction: Given its wide availability and cost-effectiveness, multidimensional flow cytometry (mFC) became a core method in the field of immunology allowing for the analysis of a broad range of individual cells providing insights into cell subset composition, cellular behavior, and cell-to-cell interactions. Formerly, the analysis of mFC data solely relied on manual gating strategies. With the advent of novel computational approaches, (semi-)automated gating strategies and analysis tools complemented manual approaches. Methods: Using Bayesian network analysis, we developed a mathematical model for the dependencies of different obtained mFC markers. The algorithm creates a Bayesian network that is a HC tree when including raw, ungated mFC data of a randomly selected healthy control cohort (HC). The HC tree is used to classify whether the observed marker distribution (either patients with amyotrophic lateral sclerosis (ALS) or HC) is predicted. The relative number of cells where the probability q is equal to zero is calculated reflecting the similarity in the marker distribution between a randomly chosen mFC file (ALS or HC) and the HC tree. Results: Including peripheral blood mFC data from 68 ALS and 35 HC, the algorithm could correctly identify 64/68 ALS cases. Tuning of parameters revealed that the combination of 7 markers, 200 bins, and 20 patients achieved the highest AUC on a significance level of p < 0.0001. The markers CD4 and CD38 showed the highest zero probability. We successfully validated our approach by including a second, independent ALS and HC cohort (55 ALS and 30 HC). In this case, all ALS were correctly identified and side scatter and CD20 yielded the highest zero probability. Finally, both datasets were analyzed by the commercially available algorithm 'Citrus', which indicated superior ability of Bayesian network analysis when including raw, ungated mFC data. Discussion: Bayesian network analysis might present a novel approach for classifying mFC data, which does not rely on reduction techniques, thus, allowing to retain information on the entire dataset. Future studies will have to assess the performance when discriminating clinically relevant differential diagnoses to evaluate the complementary diagnostic benefit of Bayesian network analysis to the clinical routine workup.

Peripheral Nerve Ultrasound for the Differentiation between ALS, Inflammatory, and Hereditary Polyneuropathies.

Background and Objectives: Ultrasound (US) is a non-invasive tool for the in vivo detection of peripheral nerve alterations. Materials and Methods: In this study, we applied nerve US to assist the discrimination between the spectrum of amyotrophic lateral sclerosis (ALS, n = 11), chronic inflammatory demyelinating polyradiculoneuropathy (CIDP, n = 5), and genetically confirmed Charcot-Marie-Tooth disease (CMT, n = 5). All participants and n = 15 controls without neurological diseases underwent high-resolution US of the bilateral tibial nerve. The nerve cross-sectional area (CSA) and nerve microvascular blood flow were compared between the groups and related to cerebrospinal fluid (CSF) measures, clinical symptoms, and nerve conduction studies. The analyses are part of a larger multimodal study on the comparison between US and 7 Tesla (7T) magnetic resonance neurography (MRN). Results: The patients and controls were matched with respect to their demographical data. CMT had the longest disease duration, followed by CIDP and ALS. CSA was related to age, weight, and disease duration. CSA was larger in CMT and CIDP compared to ALS and controls. The blood flow was greatest in CIDP, and higher than in CMT, ALS, and controls. In ALS, greater CSA was correlated with greater CSF total protein and higher albumin quotient. The US measures did not correlate with clinical scores or nerve conduction studies in any of the subgroups. Conclusion: Our results point towards the feasibility of CSA and blood flow to discriminate between ALS, CIDP, and CMT, even in groups of small sample size. In ALS, larger CSA could indicate an inflammatory disease subtype characterized by reduced blood-nerve barrier integrity. Our upcoming analysis will focus on the additive value of 7T MRN in combination with US to disentangle the spectrum between more inflammatory or more degenerative disease variants among the disease groups.

Layer-specific vulnerability is a mechanism of topographic map aging.

Topographic maps form a critical feature of cortical organization, yet are poorly described with respect to their microstructure in the living aging brain. We acquired quantitative structural and functional 7T-MRI data from younger and older adults to characterize layer-wise topographic maps of the primary motor cortex (M1). Using parcellation-inspired techniques, we show that quantitative T1 and Quantitative Susceptibility Maps values of the hand, face, and foot areas differ significantly, revealing microstructurally distinct cortical fields in M1. We show that these fields are distinct in older adults and that myelin borders between them do not degenerate. We further show that the output layer 5 of M1 shows a particular vulnerability to age-related increased iron, while layer 5 and the superficial layer show increased diamagnetic substance, likely reflecting calcifications. Taken together, we provide a novel 3D model of M1 microstructure, where body parts form distinct structural units, but layers show specific vulnerability toward increased iron and calcium in older adults. Our findings have implications for understanding sensorimotor organization and aging, in addition to topographic disease spread.

Brain microvascular disease and functional network connectivity-a call for a stage-based approach.

This scientific commentary refers to 'Functional connectivity in older adults-the effect of cerebral small vessel disease' by Drenth et al. (https://doi.org/10.1093/braincomms/fcad126).

Arterial hypertension and ß-amyloid accumulation have spatially overlapping effects on posterior white matter hyperintensity volume: a cross-sectional study.

BACKGROUND: White matter hyperintensities (WMH) in subjects across the Alzheimer's disease (AD) spectrum with minimal vascular pathology suggests that amyloid pathology-not just arterial hypertension-impacts WMH, which in turn adversely influences cognition. Here we seek to determine the effect of both hypertension and Aß positivity on WMH, and their impact on cognition. METHODS: We analysed data from subjects with a low vascular profile and normal cognition (NC), subjective cognitive decline (SCD), and amnestic mild cognitive impairment (MCI) enrolled in the ongoing observational multicentre DZNE Longitudinal Cognitive Impairment and Dementia Study (n = 375, median age 70.0 [IQR 66.0, 74.4] years; 178 female; NC/SCD/MCI 127/162/86). All subjects underwent a rich neuropsychological assessment. We focused on baseline memory and executive function-derived from multiple neuropsychological tests using confirmatory factor analysis-, baseline preclinical Alzheimer's cognitive composite 5 (PACC5) scores, and changes in PACC5 scores over the course of three years (ΔPACC5). RESULTS: Subjects with hypertension or Aß positivity presented the largest WMH volumes (pFDR < 0.05), with spatial overlap in the frontal (hypertension: 0.42 ± 0.17; Aß: 0.46 ± 0.18), occipital (hypertension: 0.50 ± 0.16; Aß: 0.50 ± 0.16), parietal lobes (hypertension: 0.57 ± 0.18; Aß: 0.56 ± 0.20), corona radiata (hypertension: 0.45 ± 0.17; Aß: 0.40 ± 0.13), optic radiation (hypertension: 0.39 ± 0.18; Aß: 0.74 ± 0.19), and splenium of the corpus callosum (hypertension: 0.36 ± 0.12; Aß: 0.28 ± 0.12). Elevated global and regional WMH volumes coincided with worse cognitive performance at baseline and over 3 years (pFDR < 0.05). Aß positivity was negatively associated with cognitive performance (direct effect-memory: - 0.33 ± 0.08, pFDR < 0.001; executive: - 0.21 ± 0.08, pFDR < 0.001; PACC5: - 0.29 ± 0.09, pFDR = 0.006; ΔPACC5: - 0.34 ± 0.04, pFDR < 0.05). Splenial WMH mediated the relationship between hypertension and cognitive performance (indirect-only effect-memory: - 0.05 ± 0.02, pFDR = 0.029; executive: - 0.04 ± 0.02, pFDR = 0.067; PACC5: - 0.05 ± 0.02, pFDR = 0.030; ΔPACC5: - 0.09 ± 0.03, pFDR = 0.043) and WMH in the optic radiation partially mediated that between Aß positivity and memory (indirect effect-memory: - 0.05 ± 0.02, pFDR = 0.029). CONCLUSIONS: Posterior white matter is susceptible to hypertension and Aß accumulation. Posterior WMH mediate the association between these pathologies and cognitive dysfunction, making them a promising target to tackle the downstream damage related to the potentially interacting and potentiating effects of the two pathologies. TRIAL REGISTRATION: German Clinical Trials Register (DRKS00007966, 04/05/2015).

Implications of quantitative susceptibility mapping at 7 Tesla MRI for microbleeds detection in cerebral small vessel disease.

Background: Cerebral microbleeds (MBs) are a hallmark of cerebral small vessel disease (CSVD) and can be found on T2*-weighted sequences on MRI. Quantitative susceptibility mapping (QSM) is a postprocessing method that also enables MBs identification and furthermore allows to differentiate them from calcifications. Aims: We explored the implications of using QSM at submillimeter resolution for MBs detection in CSVD. Methods: Both 3 and 7 Tesla (T) MRI were performed in elderly participants without MBs and patients with CSVD. MBs were quantified on T2*-weighted imaging and QSM. Differences in the number of MBs were assessed, and subjects were classified in CSVD subgroups or controls both on 3T T2*-weighted imaging and 7T QSM. Results: 48 participants [mean age (SD) 70.9 (8.8) years, 48% females] were included: 31 were healthy controls, 6 probable cerebral amyloid angiopathy (CAA), 9 mixed CSVD, and 2 were hypertensive arteriopathy [HA] patients. After accounting for the higher number of MBs detected at 7T QSM (Median = Mdn; Mdn7T-QSM = 2.5; Mdn3T-T2 = 0; z = 4.90; p < 0.001) and false positive MBs (6.1% calcifications), most healthy controls (80.6%) demonstrated at least one MB and more MBs were discovered in the CSVD group. Conclusions: Our observations suggest that QSM at submillimeter resolution improves the detection of MBs in the elderly human brain. A higher prevalence of MBs than so far known in healthy elderly was revealed.

Vessel distance mapping: A novel methodology for assessing vascular-induced cognitive resilience.

The association between cerebral blood supply and cognition has been widely discussed in the recent literature. One focus of this discussion has been the anatomical variability of the circle of Willis, with morphological differences being present in more than half of the general population. While previous studies have attempted to classify these differences and explore their contribution to hippocampal blood supply and cognition, results have been controversial. To disentangle these previously inconsistent findings, we introduce Vessel Distance Mapping (VDM) as a novel methodology for evaluating blood supply, which allows for obtaining vessel pattern metrics with respect to the surrounding structures, extending the previously established binary classification into a continuous spectrum. To accomplish this, we manually segmented hippocampal vessels obtained from high-resolution 7T time-of-flight MR angiographic imaging in older adults with and without cerebral small vessel disease, generating vessel distance maps by computing the distances of each voxel to its nearest vessel. Greater values of VDM-metrics, which reflected higher vessel distances, were associated with poorer cognitive outcomes in subjects affected by vascular pathology, while this relation was not observed in healthy controls. Therefore, a mixed contribution of vessel pattern and vessel density is proposed to confer cognitive resilience, consistent with previous research findings. In conclusion, VDM provides a novel platform, based on a statistically robust and quantitative method of vascular mapping, for addressing a variety of clinical research questions.

Extracellular Matrix Changes in Subcellular Brain Fractions and Cerebrospinal Fluid of Alzheimer's Disease Patients.

The brain's extracellular matrix (ECM) is assumed to undergo rearrangements in Alzheimer's disease (AD). Here, we investigated changes of key components of the hyaluronan-based ECM in independent samples of post-mortem brains (N = 19), cerebrospinal fluids (CSF; N = 70), and RNAseq data (N = 107; from The Aging, Dementia and TBI Study) of AD patients and non-demented controls. Group comparisons and correlation analyses of major ECM components in soluble and synaptosomal fractions from frontal, temporal cortex, and hippocampus of control, low-grade, and high-grade AD brains revealed a reduction in brevican in temporal cortex soluble and frontal cortex synaptosomal fractions in AD. In contrast, neurocan, aggrecan and the link protein HAPLN1 were up-regulated in soluble cortical fractions. In comparison, RNAseq data showed no correlation between aggrecan and brevican expression levels and Braak or CERAD stages, but for hippocampal expression of HAPLN1, neurocan and the brevican-interaction partner tenascin-R negative correlations with Braak stages were detected. CSF levels of brevican and neurocan in patients positively correlated with age, total tau, p-Tau, neurofilament-L and Aß1-40. Negative correlations were detected with the Aß ratio and the IgG index. Altogether, our study reveals spatially segregated molecular rearrangements of the ECM in AD brains at RNA or protein levels, which may contribute to the pathogenic process.

Brain Vascular Health in ALS Is Mediated through Motor Cortex Microvascular Integrity.

Brain vascular health appears to be critical for preventing the development of amyotrophic lateral sclerosis (ALS) and slowing its progression. ALS patients often demonstrate cardiovascular risk factors and commonly suffer from cerebrovascular disease, with evidence of pathological alterations in their small cerebral blood vessels. Impaired vascular brain health has detrimental effects on motor neurons: vascular endothelial growth factor levels are lowered in ALS, which can compromise endothelial cell formation and the integrity of the blood-brain barrier. Increased turnover of neurovascular unit cells precedes their senescence, which, together with pericyte alterations, further fosters the failure of toxic metabolite removal. We here provide a comprehensive overview of the pathogenesis of impaired brain vascular health in ALS and how novel magnetic resonance imaging techniques can aid its detection. In particular, we discuss vascular patterns of blood supply to the motor cortex with the number of branches from the anterior and middle cerebral arteries acting as a novel marker of resistance and resilience against downstream effects of vascular risk and events in ALS. We outline how certain interventions adapted to patient needs and capabilities have the potential to mechanistically target the brain microvasculature towards favorable motor cortex blood supply patterns. Through this strategy, we aim to guide novel approaches to ALS management and a better understanding of ALS pathophysiology.