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Introduction: Lower network segregation is associated with accelerated cognitive decline in Alzheimer's disease (AD), yet it is unclear whether less segregated brain networks facilitate connectivity‐mediated tau spreading. Methods: We combined resting state functional magnetic resonance imaging (fMRI) with longitudinal tau positron emission tomography (PET) in 42 betamyloid‐negative controls and 81 amyloid beta positive individuals across the AD spectrum. Network segregation was determined using resting‐state fMRI–assessed connectivity among 400 cortical regions belonging to seven networks. Results: AD subjects with higher network segregation exhibited slower brain‐wide tau accumulation relative to their baseline entorhinal tau PET burden (typical onset site of tau pathology). Second, by identifying patient‐specific tau epicenters with highest baseline tau PET we found that stronger epicenter segregation was associated with a slower rate of tau accumulation in the rest of the brain in relation to baseline epicenter tau burden. Discussion: Our results indicate that tau spreading is facilitated by a more diffusely organized connectome, suggesting that brain network topology modulates tau spreading in AD. Highlights: Higher brain network segregation is associated with attenuated tau pathology accumulation in Alzheimer's disease (AD).A patient‐tailored approach allows for the more precise localization of tau epicenters.The functional segregation of subject‐specific tau epicenters predicts the rate of future tau accumulation. [ABSTRACT FROM AUTHOR]

Objective: Polygenic variation accounts for a substantial portion of the risk of Alzheimer's disease (AD), but its effect on the rate of fibrillar‐tau accumulation as a key driver of dementia symptoms is unclear. Methods: We combined the to‐date largest number of genetic risk variants of AD (n = 85 lead single‐nucleotide polymorphisms [SNPs]) from recent genome‐wide association studies (GWAS) to generate a polygenic score (PGS). We assessed longitudinal tau‐positron emission tomography (PET), amyloid‐PET, and cognition in 231 participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Using the PGS, together with global amyloid‐PET, we predicted the rate of tau‐PET increases in Braak‐stage regions‐of‐interest and cognitive decline. We also assessed PGS‐risk enrichment effects on the required sample size in clinical trials targeting tau pathology. Results: We found that a higher PGS was associated with higher rates of tau‐PET accumulation, in particular at elevated amyloid‐PET levels. The tau‐PET increases mediated the association between PGS and faster cognitive decline. Risk enrichment through high PGS afforded sample size savings by 34%. Interpretation: Our results demonstrate that the PGS predicts faster tau progression and thus cognitive decline, showing utility to enhance statistical power in clinical trials. ANN NEUROL 2023;93:819–829 [ABSTRACT FROM AUTHOR]

Introduction: It is uncertain whether subjective cognitive decline (SCD) in individuals who seek medical help serves the identification of the initial symptomatic stage 2 of the Alzheimer's disease (AD) continuum. Methods: Cross‐sectional and longitudinal data from the multicenter, memory clinic–based DELCODE study. Results: The SCD group showed slightly worse cognition as well as more subtle functional and behavioral symptoms than the control group (CO). SCD–A+ cases (39.3% of all SCD) showed greater hippocampal atrophy, lower cognitive and functional performance, and more behavioral symptoms than CO–A+. Amyloid concentration in the CSF had a greater effect on longitudinal cognitive decline in SCD than in the CO group. Discussion: Our data suggests that SCD serves the identification of stage 2 of the AD continuum and that stage 2, operationalized as SCD‐A+, is associated with subtle, but extended impact of AD pathology in terms of neurodegeneration, symptoms and clinical progression. [ABSTRACT FROM AUTHOR]

Objective: Cerebral small vessel diseases (cSVDs) are a major cause of stroke and dementia. We used cutting‐edge 7T‐MRI techniques in patients with Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL), to establish which aspects of cerebral small vessel function are affected by this monogenic form of cSVD. Methods: We recruited 23 CADASIL patients (age 51.1 ± 10.1 years, 52% women) and 13 age‐ and sex‐matched controls (46.1 ± 12.6, 46% women). Small vessel function measures included: basal ganglia and centrum semiovale perforating artery blood flow velocity and pulsatility, vascular reactivity to a visual stimulus in the occipital cortex and reactivity to hypercapnia in the cortex, subcortical gray matter, white matter, and white matter hyperintensities. Results: Compared with controls, CADASIL patients showed lower blood flow velocity and higher pulsatility index within perforating arteries of the centrum semiovale (mean difference − 0.09 cm/s, p = 0.03 and 0.20, p = 0.009) and basal ganglia (mean difference − 0.98 cm/s, p = 0.003 and 0.17, p = 0.06). Small vessel reactivity to a short visual stimulus was decreased (blood‐oxygen‐level dependent [BOLD] mean difference −0.21%, p = 0.04) in patients, while reactivity to hypercapnia was preserved in the cortex, subcortical gray matter, and normal appearing white matter. Among patients, reactivity to hypercapnia was decreased in white matter hyperintensities compared to normal appearing white matter (BOLD mean difference −0.29%, p = 0.02). Interpretation: Multiple aspects of cerebral small vessel function on 7T‐MRI were abnormal in CADASIL patients, indicative of increased arteriolar stiffness and regional abnormalities in reactivity, locally also in relation to white matter injury. These observations provide novel markers of cSVD for mechanistic and intervention studies. ANN NEUROL 2023;93:29–39 [ABSTRACT FROM AUTHOR]

Background: In Alzheimer's disease (AD), younger symptom onset is associated accelerated cognitive decline and tau spreading, yet the drivers of faster disease manifestation in patients with earlier symptom onset are unknown. Earlier symptom onset is associated with stronger tau pathology in fronto‐parietal regions which typically harbor globally connected hubs that are central for cognition. Since tau spreads across connected regions, globally connected hubs may accelerate tau spreading due to their large number of connections to other brain regions. Thus, we hypothesized that a pattern shift of tau pathology towards globally connected brain hubs may facilitate tau spreading and earlier symptom manifestation in AD. Method: We included two independent samples with longitudinal Flortaucipir tau‐PET covering the AD spectrum (ADNI: n(controls/AD‐preclinical/AD‐symptomatic)=93/60/89, BioFINDER, n(controls/AD‐preclinical/AD‐symptomatic)=16/16/25). In addition, we included resting‐state fMRI from human connectome project participants (n=1000), applying a 200‐ROI brain atlas to obtain a global connectivity map for assessing brain hubs (Fig.1A‐D). Applying the same atlas to tau‐PET we transformed SUVRs to tau positivities using a pre‐established gaussian‐mixture modeling approach (Fig.1E‐F). By mapping tau‐PET positivities to the fMRI‐derived global connectivity map (Fig.1G‐L), we assessed the degree to which subject specific tau‐PET patterns were shifted towards globally connected hubs or non‐hubs, while adjusting for global tau levels. Using linear regression, we then tested whether a stronger shift of tau towards hubs was associated with earlier symptom manifestation and faster longitudinal tau accumulation. Result: In symptomatic AD patients, younger age was associated with a stronger shift of tau‐PET towards globally connected brain hubs (p[ADNI/BiOFINDER]=0.024/0.018, Fig.2A&B), and with higher global connectivity of epicenters with highest tau pathology (p[ADNI/BiOFINDER]<0.001/0.001, Fig.2C&D). In symptomatic AD, younger age (p[ADNI/BiOFINDER]=0.009/0.001) and a stronger shift of tau‐PET towards hubs predicted faster subsequent tau accumulation (p[ADNI/BiOFINDER]=0.004/0.002), supporting the view that that hubs facilitate tau spreading (Fig.3). Further, a stronger shift of tau‐PET towards globally connected brain hubs mediated the association between younger age and faster tau accumulation in symptomatic AD patients (p[ADNI/BiOFINDER]=0.039/0.046). Conclusion: Younger AD symptom onset is associated with stronger tau pathology in globally connected brain hubs, which facilitates faster tau spreading. [ABSTRACT FROM AUTHOR]

Background: Progression of fibrillar tau is a key driver of neurodegeneration and cognitive decline in Alzheimer's disease (AD), however which factors predict the rate of tau accumulation at the patient‐level is unclear. Here we propose to employ a polygenic score (PGS) for the prediction of tau accumulation and cognitive changes in AD, which could be useful for selection of individuals with faster tau progression in clinical trials. Methods: We included 231 ADNI participants with longitudinal measurements of tau‐PET, amyloid‐PET, cognitive data and genotype data. We computed a PGS based on 85 independent lead SNPs from two recent large GWAS (DOI:10.1101/2020.10.01.20200659; DOI:10.1038/s41588‐021‐00921‐z), excluding all APOE variants. Using linear mixed effect models, we computed the individual rates of change in each of the biomarkers. In linear regression models we tested whether PGS can predict the rate of tau‐PET changes in Braak‐stage ROIs (Figure 1A) and cognitive changes. In order to assess whether amyloid mediates the effect of PGS on tau accumulation we performed sensitivity analyses in subgroups categorized by amyloid status as well as tested the interaction between the PGS and global amyloid‐PET. We further estimated sample size required for detection of hypothetical treatment effect on the rate tau accumulation using power analysis. Results: Higher PGS was associated with higher accumulation rates of tau‐PET in cortical regions (Braak 3+4:β=0.306, pFDR<0.001; Braak 5+6:β=0.262, pFDR<0.001; Figure 1B). A higher PGS was further associated with faster decline in episodic memory (β=‐0.223, pFDR<0.001; Figure 1C) and global cognition (β=0.280, pFDR<0.001; Figure 1C). The observed effects of PGS on cognitive changes were mediated by higher tau‐PET accumulation (Figure 2). We found a synergistic effect between PGS and elevated amyloid‐PET levels on the rate of tau‐PET accumulation such that the PGS effects on tau‐PET accumulation were stronger particularly at elevated amyloid levels (Figure 3). Selection of individuals with highest PGS yielded a 32‐33% saving in required sample size to detect a treatment effect on tau accumulation. Conclusion: Higher polygenic score is associated with faster tau accumulation and may be a useful tool for risk stratification in disease‐modifying treatments on tau. [ABSTRACT FROM AUTHOR]

Objective: Ischemic stroke etiology remains undetermined in 30% of cases. We explored the genetic architecture of stroke classified as undetermined to test if mechanisms and risk factors underlying large‐artery atherosclerotic (LAAS), cardioembolic (CES), and small‐vessel stroke (SVS) contribute to its pathogenesis. Methods: We analyzed genome‐wide data from 16,851 ischemic stroke cases and 32,473 controls. Using polygenic risk scores for LAAS, CES, and SVS, we assessed the genetic overlap with stroke of undetermined source and used pairwise genomewide association study (GWAS‐PW) to search for shared loci. We then applied Mendelian randomization (MR) to identify potentially causal risk factors of stroke of undetermined source. Results: Genetic risk for LAS, CES, and SVS was associated with stroke of undetermined source pointing to overlap in their genetic architecture. Pairwise analyses revealed 19 shared loci with LAAS, 2 with CES, and 5 with SVS that have been implicated in atherosclerosis‐related phenotypes. Genetic liability to both carotid atherosclerosis and atrial fibrillation was associated with stroke of undetermined source, but the association with atrial fibrillation was attenuated after excluding cases with incomplete diagnostic workup. MR analyses showed effects of genetically determinants of blood pressure, diabetes, waist‐to‐hip ratio, inflammatory pathways (IL‐6 signaling, MCP‐1/CCL2 levels), and factor XI levels on stroke of undetermined source. Interpretation: Stroke of undetermined source shares genetic and vascular risk factors with other stroke subtypes, especially LAAS, thus highlighting the diagnostic limitations of current subtyping approaches. The potentially causal associations with carotid atherosclerosis and atherosclerotic risk factors might have implications for prevention strategies targeting these mechanisms. ANN NEUROL 2022;91:640–651 [ABSTRACT FROM AUTHOR]

Introduction: The BIN1 rs744373 single nucleotide polymorphism (SNP) is a key genetic risk locus for Alzheimer’s disease (AD) associated with tau pathology. Because tau typically accumulates in response to amyloid beta (Aβ), we tested whether BIN1 rs744373 accelerates Aβ-related tau accumulation. Methods: We included two samples (Alzheimer’s Disease Neuroimaging Initiative [ADNI], n = 153; Biomarkers for Identifying Neurodegenerative Disorders Early and Reliably [BioFINDER], n = 63) with longitudinal 18F-Flortaucipir positron emission tomography (PET), Aβ biomarkers, and longitudinal cognitive assessments. We assessed whether BIN1 rs744373 was associated with faster tau-PET accumulation at a given level of Aβ and whether faster BIN1 rs744373-associated tau-PET accumulation mediated cognitive decline. Results: BIN1 rs744373 risk-allele carriers showed faster global tau-PET accumulation (ADNI/BioFINDER, P < .001/P < .001). We found significant Aβ by rs744373 interactions on global tau-PET change (ADNI: β/standard error [SE] = 0.42/0.14, P = 0.002; BioFINDER: β/SE = –0.35/0.15, P = .021), BIN1 risk-allele carriers showed accelerated tau-PET accumulation at higher Aβ levels. In ADNI, rs744373 effects on cognitive decline were mediated by faster global tau-PET accumulation (β/SE = 0.20/0.07, P = .005). Discussion: BIN1-associated AD risk is potentially driven by accelerated tau accumulation in the face of Aβ. [ABSTRACT FROM AUTHOR]

Background: Higher segregation of functional networks in the brain has been associated with better cognitive abilities in aging (Chan, PNAS, 2014) and higher cognitive resilience against Alzheimer's disease (Ewers, Brain, in press). Here, we elucidated for the first time the genetic and environmental (i.e. cardiovascular) determinants of system segregation (SyS) in two large population‐based cohorts. Method: We included 16,635 UK Biobank (UKB) participants (45‐81y, discovery‐sample) and 2,414 Rotterdam‐Study participants (52‐90y, replication‐sample). Resting‐state‐fMRI SyS was computed as the ratio of between‐network to within‐network connectivity, where networks (N=55) were defined by independent component analysis. Genome‐wide association study (GWAS) of SyS was performed in UKB, controlling for twenty principal components, age, sex, genotype‐array and assessment center. For out‐of‐sample prediction, a polygenic risk score (PRS) of SyS was tested in Rotterdam‐Study participants. In both cohorts, we determined the effect of cardiovascular health (adherence to Life's simple 7) on SyS. We estimated age‐dependent and ‐independent effects of SyS on cognition (multi‐domain factor score) in both cohorts and, in a subsample of 2,113 UKB participants, on cognitive decline over time. To explore causal effects, Mendelian Randomization (MR) analyses were performed. Result: GWAS of SyS in UKB yielded 659 genome‐wide significant single‐nucleotide polymorphisms (SNPs; P<5e‐08, h2=0.144, Fig. 1). Nine independent risk loci were detected implicated 59 genes. Lead SNPs with highest likelihood to have deleterious consequences were located near the INPP5A and PLCE1 genes. In Rotterdam‐Study participants, PRS explained 1.4% of variance in SyS. We found overall better cardiovascular health to be associated with higher SyS, while higher blood pressure alone was a significant predictor of lower SyS (UKB:βstd=‐0.059(0.007), P<0.001; Rotterdam‐Study:βstd(SE)=‐0.060(0.020), P=0.003; Fig. 2). MR analysis in UKB confirmed that genetically elevated levels of blood pressure were associated with lower SyS (β(CI95%)=‐0.003(‐0.002,‐0.001), P=0.002). We found higher SyS to be associated with better cognition across all ages in UKB (βstd(SE)=‐0.031(0.012), P=0.005) and in older, but not younger Rotterdam‐Study participants (βstd(SE)=0.038(0.016), P=0.0026, Fig. 3). In MR analysis, genetically elevated levels of SyS were associated with better cognition (β(CI95)=0.104(0.03‐0.18), P=0.008). Conclusion: The current study highlights the importance of cardiovascular health for maintaining segregated brain systems what in turn was shown to benefit cognitive functions during aging. [ABSTRACT FROM AUTHOR]

Background: The development of in vivo amyloid (Aβ) and tau biomarkers has greatly facilitated diagnosing AD (Jack et al., 2018), however, reliable prognosis of AD‐related cognitive decline remains a critical yet unmet challenge. Here, especially tau biomarkers may offer great potential for individualized risk prediction of clinical AD progression, since the progressive spread of tau tracks clinical status more closely than Aβ deposition (Ossenkoppele et al., 2016; Wang et al., 2016). Thus, positron emission tomography (PET) of tau may be a better predictor for future cognitive decline and clinical progression than amyloid‐PET. Here, we examined whether tau‐PET‐based Braak‐staging outperforms amyloid‐PET as a predictor of future cognitive decline and clinical progression in older adults with and without cognitive impairment. Method: We included 396 cognitively normal to AD dementia subjects with Flutemetamol/Florbetapir‐amyloid‐PET, Flortaucipir‐tau‐PET and longitudinal cognitive assessments. Annual change rates in global cognition (i.e. MMSE, ADAS13) and episodic memory (i.e. ADNI‐MEM) were calculated via linear mixed models. We determined global amyloid‐PET (i.e. Centiloid) plus global and Braak‐stage‐specific tau‐PET SUVRs, which were stratified as positive(+)/negative(‐) at pre‐established cut‐offs. Using Braak‐stage‐specific binarized tau‐PET SUVRs, we classified subjects as BraakI+/BraakI‐IV+/BraakI‐VI+/Braakatypical+. In bootstrapped linear regression, we assessed whether global tau‐PET explained more variance in subsequent cognitive decline than Centiloid. Using ANCOVAs, we tested whether advanced Braak‐stage predicted faster future cognitive decline. All models were controlled for age, sex, education, clinical diagnosis, and baseline cognition. Lastly, we determined Braak‐stage‐specific conversion risk to mild cognitive impairment (MCI) or dementia. Result: Higher global tau‐PET SUVR at baseline explained more variance in subsequent cognitive decline across ∼2 years of follow up compared to baseline amyloid‐PET, consistently for MMSE, ADAS13, and memory (all p<0.001; Fig. 1). The association between global tau‐PET and subsequent cognitive changes remained consistent when additionally controlling for baseline amyloid‐PET. Advancing Braak‐stage was associated with gradually worsening future cognitive decline, independent of Centiloid (p<0.001; Fig. 2), and elevated clinical conversion risk to MCI or AD dementia (e.g. 15.38% for BraakI+, 23.81% for BraakI‐IV+, 45.45% for BraakI‐VI+; Fig. 3). Conclusion: Tau‐PET clearly outperforms amyloid‐PET in predicting future cognitive decline, where tau‐PET‐based Braak‐staging may be used for estimating patient‐specific risk for clinical AD progression. [ABSTRACT FROM AUTHOR]

Introduction: Midlife clustering of vascular risk factors has been associated with late‐life dementia, but causal effects of individual biological and lifestyle factors remain largely unknown. Methods: Among 229,976 individuals (mean follow‐up 9 years), we explored whether midlife cardiovascular health measured by Life's Simple 7 (LS7) is associated with incident all‐cause dementia and whether the individual components of the score are causally associated with dementia. Results: Adherence to the biological metrics of LS7 (blood pressure, cholesterol, glycemic status) was associated with lower incident dementia risk (hazard ratio = 0.93 per 1‐point increase, 95% confidence interval [CI; 0.89–0.96]). In contrast, there was no association between the composite LS7 score and the lifestyle subscore (smoking, body mass index, diet, physical activity) and incident dementia. In Mendelian randomization analyses, genetically elevated blood pressure was associated with higher risk of dementia (odds ratio = 1.31 per one‐standard deviation increase, 95% CI [1.05–1.60]). Discussion: These findings underscore the importance of blood pressure control in midlife to mitigate dementia risk. [ABSTRACT FROM AUTHOR]

Background: Klotho‐VS heterozygosity (KL‐VShet) is associated with reduced risk of developing Alzheimer's disease (AD). However, whether KL‐VShet is associated with lower levels of pathologic tau, the key AD pathology driving cognitive decline, is unknown. Here, we tested the interaction between KL‐VShet and beta‐amyloid, the key driver of tau pathology, on PET‐assessed neurofibrillary tau in elderly controls and patients across the AD continuum. Method: In the ADNI cohort, we identified 144 KL‐VShet carriers (55‐90y, 53% women, 38% ApoE4+, 24% MCI) and 407 KL‐VShet non‐carriers (55‐90y, 51% women, 37% ApoE4+, 29% MCI) with tau‐sensitive ([18F]flortaucipir) and Aβ‐sensitive ([18F]florbetapir or [18F]florbetaben) PET acquisitions as well as genetic and clinical information available. A subgroup of 200 participants (52 KL‐VShet carriers) underwent a second tau‐PET after 1.63 years on average. We assessed the KL‐VShet x amyloid‐PET interaction effect on tau‐PET SUVR levels or annual change rates derived from an inferior temporal and global cortical ROI. Mediation analysis was used to determine whether KL‐VShet was associated with better memory performance (ADNI‐MEM), and whether this association was mediated by reduced tau‐PET levels. All analyses were controlled for age, sex, diagnosis, education and ApoE4. Result: We found a significant interaction effect indicating that KL‐VShet carriers compared to non‐carriers had lower inferior temporal (β=‐0.12, P=0.009, effect size (Cohen's f)=0.112) and global (β=‐0.13, P=0.008, effect size=0.114) tau‐PET levels per centiloid (CL) unit increase in amyloid‐PET (Fig 1a,b). Longitudinally assessed annual change rates of inferior temporal tau‐PET were also lower in KL‐VShet carriers per unit increase in baseline amyloid‐PET (β =‐0.22, P=0.039, effect size=0.148; Fig 1c,d). Post‐hoc correlation analysis revealed that the KL‐VShet effect on tau‐PET was stronger in Klotho mRNA‐expressing brain regions (Fig. 2). Importantly, KL‐VShet was associated with better memory performance (β=0.13, p=0.040, effect size=0.104) in amyloid‐positive participants and this association was significantly mediated by lower tau‐PET levels. Conclusion: Our findings provide evidence for a protective role of KL‐VShet against amyloid‐related tau pathology and tau‐related memory impairments in elderly individuals at risk of AD dementia. Hence, Klotho may be an attractive treatment target to slow the progression of AD. [ABSTRACT FROM AUTHOR]

Background: The BIN1 rs744373 SNP is a key risk locus for Alzheimer's disease (AD). Cross‐sectional studies showed BIN1 rs744373 to be associated with higher tau pathology, i.e. a key AD pathological hallmark that is associated with Aβ. Whether carriage of the BIN1 rs744373 risk SNP accelerates the association between Ab and the rate of tau accumulation is unclear. Here, we examined whether BIN1 rs744373 risk‐allele‐carriers show faster Aβ‐related tau accumulation and thus faster cognitive decline. Method: We included two independent samples (ADNI, n=153; BioFINDER, n=63) characterized with longitudinal 18F‐Flortaucipir tau‐PET (mean follow‐up ∼2years), Aβ‐biomarkers (i.e. Ab‐PET in ADNI vs. cerebrospinal fluid Aβ1‐42 in BioFINDER) and longitudinal cognitive assessments (i.e. ADNI only). We assessed whether BIN1 rs744373 was associated with faster tau accumulation at a given level of Aβ and whether BIN1 rs744373‐associated tau accumulation mediated faster cognitive decline. Result: BIN1 rs744373 risk‐allele‐carriers showed faster global tau‐PET accumulation (ADNI/BioFINDER, p<0.001/p<0.001, Fig. 1A&B). We found significant Aβ by rs744373 interactions on global tau‐PET accumulation rates (ADNI: b/SE=0.42/0.14, p=0.002; BioFINDER: b/SE=‐0.35/0.15, p=0.021, Fig. 1C&D), showing accelerated tau accumulation in BIN1 risk‐allele‐carriers at higher Aβ‐levels. In ADNI, rs744373‐effects on cognitive decline were mediated by faster global tau‐PET accumulation (b/SE=0.20/0.07, p=0.005, Fig. 2). Conclusion: BIN1 rs744373 risk‐allele carriers show accelerated Aβ‐related tau accumulation rates and cognitive decline. These findings suggest that BIN1‐associated risk for AD dementia is specifically driven by accelerated tau accumulation, suggesting that BIN1 may be specifically involved in the progression of tau pathology. [ABSTRACT FROM AUTHOR]

We have provided an overview on the profound impact of COVID‐19 upon older people with Alzheimer's disease and other dementias and the challenges encountered in our management of dementia in different health‐care settings, including hospital, out‐patient, care homes, and the community during the COVID‐19 pandemic. We have also proposed a conceptual framework and practical suggestions for health‐care providers in tackling these challenges, which can also apply to the care of older people in general, with or without other neurological diseases, such as stroke or parkinsonism. We believe this review will provide strategic directions and set standards for health‐care leaders in dementia, including governmental bodies around the world in coordinating emergency response plans for protecting and caring for older people with dementia amid the COIVD‐19 outbreak, which is likely to continue at varying severity in different regions around the world in the medium term. [ABSTRACT FROM AUTHOR]

Objective: Early discrimination of patients with ischemic stroke (IS) from stroke mimics (SMs) poses a diagnostic challenge. The circulating metabolome might reflect pathophysiological events related to acute IS. Here, we investigated the utility of early metabolic changes for differentiating IS from SM.Methods: We performed untargeted metabolomics on serum samples obtained from patients with IS (N = 508) and SM (N = 349; defined by absence of a diffusion weighted imaging [DWI] positive lesion on magnetic resonance imaging [MRI]) who presented to the hospital within 24 hours after symptom onset (median time from symptom onset to blood sampling = 3.3 hours; interquartile range [IQR] = 1.6-6.7 hours) and from neurologically normal controls (NCs; N = 112). We compared diagnostic groups in a discovery-validation approach by applying multivariable linear regression models, machine learning techniques, and propensity score matching. We further performed a targeted look-up of published metabolite sets.Results: Levels of 41 metabolites were significantly associated with IS compared to NCs. The top metabolites showing the highest value in separating IS from SMs were asymmetrical and symmetrical dimethylarginine, pregnenolone sulfate, and adenosine. Together, these 4 metabolites differentiated patients with IS from SMs with an area under the curve (AUC) of 0.90 in the replication sample, which was superior to multimodal cranial computed tomography (CT; AUC = 0.80) obtained for routine diagnostics. They were further superior to previously published metabolite sets detected in our samples. All 4 metabolites returned to control levels by day 90.Interpretation: A set of 4 metabolites with known biological effects relevant to stroke pathophysiology shows unprecedented utility to identify patients with IS upon hospital arrival, thus encouraging further investigation, including multicenter studies. ANN NEUROL 2020;88:736-746. [ABSTRACT FROM AUTHOR]

Microglia activation is the brain's major immune response to amyloid plaques in Alzheimer's disease (AD). Both cerebrospinal fluid (CSF) levels of soluble TREM2 (sTREM2), a biomarker of microglia activation, and microglia PET are increased in AD; however, whether an increase in these biomarkers is associated with reduced amyloid‐beta (Aβ) accumulation remains unclear. To address this question, we pursued a two‐pronged translational approach. Firstly, in non‐demented and demented individuals, we tested CSF sTREM2 at baseline to predict (i) amyloid PET changes over ∼2 years and (ii) tau PET cross‐sectionally assessed in a subset of patients. We found higher CSF sTREM2 associated with attenuated amyloid PET increase and lower tau PET. Secondly, in the AppNL‐G-F mouse model of amyloidosis, we studied baseline 18F‐GE180 microglia PET and longitudinal amyloid PET to test the microglia vs. Aβ association, without any confounding co‐pathologies often present in AD patients. Higher microglia PET at age 5 months was associated with a slower amyloid PET increase between ages 5‐to‐10 months. In conclusion, higher microglia activation as determined by CSF sTREM2 or microglia PET shows protective effects on subsequent amyloid accumulation. Synopsis: TREM2 is a protein almost exclusively expressed by microglia in the brain. This study investigates the association between soluble TREM2 (sTREM2) levels in cerebrospinal fluid and the longitudinal Aβ accumulation in human and mouse. In patients with Aβ pathology, higher cerebrospinal fluid (CSF) levels of sTREM2 are associated with lower rates of Aβ accumulation.Higher CSF sTREM2 levels are associated with lower neurofibrillary tangles.In the Aβ mouse model, higher microglia activation at baseline is associated with lower rates of Aβ accumulation between 5 and 10 months of age, when Aβ deposition primarily takes place. [ABSTRACT FROM AUTHOR]

Introduction: Both beta‐amyloid (Ab) deposition and decline in white matter integrity, are brain alterations observed in Alzheimer's disease (AD) and start to occur by the fourth and fifth decades. However, the association between both brain alterations in asymptomatic subjects is unclear. Methods: Amyloid positron emission tomography (PET) and diffusion tensor imaging (DTI) were obtained in 282 cognitively normal subjects (age 30‐89 years). We assessed the interaction of age by abnormal amyloid PET status (Florbetapir F‐18 PET >1.2 standard uptake value ratio [SUVR]) on regional mean diffusivity (MD) and global white matter hyperintensity (WMH) volume, controlled for sex, education, and hypertension. Results: Subjects with abnormal amyloid PET (n = 87) showed stronger age‐related increase in global WMH and regional MD, particularly within the posterior parietal regions of the white matter. Discussion: Sporadic Aβ deposition is associated with white matter alterations in AD predilection areas in an age‐dependent manner in cognitively normal individuals. [ABSTRACT FROM AUTHOR]

Objective: To systematically investigate causal relationships between obesity and cerebrovascular disease and the extent to which hypertension and hyperglycemia mediate the effect of obesity on cerebrovascular disease.Methods: We used summary statistics from genome-wide association studies for body mass index (BMI), waist-to-hip ratio (WHR), and multiple cerebrovascular disease phenotypes. We explored causal associations with 2-sample Mendelian randomization (MR) accounting for genetic covariation between BMI and WHR, and we assessed what proportion of the association between obesity and cerebrovascular disease was mediated by systolic blood pressure (SBP) and blood glucose levels, respectively.Results: Genetic predisposition to higher BMI did not increase the risk of cerebrovascular disease. In contrast, for each 10% increase in WHR there was a 75% increase (95% confidence interval [CI] = 44-113%) in risk for large artery ischemic stroke, a 57% (95% CI = 29-91%) increase in risk for small vessel ischemic stroke, a 197% increase (95% CI = 59-457%) in risk of intracerebral hemorrhage, and an increase in white matter hyperintensity volume (β = 0.11, 95% CI = 0.01-0.21). These WHR associations persisted after adjusting for genetic determinants of BMI. Approximately one-tenth of the observed effect of WHR was mediated by SBP for ischemic stroke (proportion mediated: 12%, 95% CI = 4-20%), but no evidence of mediation was found for average blood glucose.Interpretation: Abdominal adiposity may trigger causal pathological processes, partially independent from blood pressure and totally independent from glucose levels, that lead to cerebrovascular disease. Potential targets of these pathological processes could represent novel therapeutic opportunities for stroke. ANN NEUROL 2020;87:516-524. [ABSTRACT FROM AUTHOR]

Introduction: Developing cross‐validated multi‐biomarker models for the prediction of the rate of cognitive decline in Alzheimer's disease (AD) is a critical yet unmet clinical challenge. Methods: We applied support vector regression to AD biomarkers derived from cerebrospinal fluid, structural magnetic resonance imaging (MRI), amyloid‐PET and fluorodeoxyglucose positron‐emission tomography (FDG‐PET) to predict rates of cognitive decline. Prediction models were trained in autosomal‐dominant Alzheimer's disease (ADAD, n = 121) and subsequently cross‐validated in sporadic prodromal AD (n = 216). The sample size needed to detect treatment effects when using model‐based risk enrichment was estimated. Results: A model combining all biomarker modalities and established in ADAD predicted the 4‐year rate of decline in global cognition (R2 = 24%) and memory (R2 = 25%) in sporadic AD. Model‐based risk‐enrichment reduced the sample size required for detecting simulated intervention effects by 50%–75%. Discussion: Our independently validated machine‐learning model predicted cognitive decline in sporadic prodromal AD and may substantially reduce sample size needed in clinical trials in AD. [ABSTRACT FROM AUTHOR]

Objective: To determine the contribution of acute infarcts, evidenced by diffusion-weighted imaging positive (DWI+) lesions, to progression of white matter hyperintensities (WMH) and other cerebral small vessel disease (SVD) markers.Methods: We performed monthly 3T magnetic resonance imaging (MRI) for 10 consecutive months in 54 elderly individuals with SVD. MRI included high-resolution multishell DWI, and 3-dimensional fluid-attenuated inversion recovery, T1, and susceptibility-weighted imaging. We determined DWI+ lesion evolution, WMH progression rate (ml/mo), and number of incident lacunes and microbleeds, and calculated for each marker the proportion of progression explained by DWI+ lesions.Results: We identified 39 DWI+ lesions on 21 of 472 DWI scans in 9 of 54 subjects. Of the 36 DWI+ lesions with follow-up MRI, 2 evolved into WMH, 4 evolved into a lacune (3 with cavity <3mm), 3 evolved into a microbleed, and 27 were not detectable on follow-up. WMH volume increased at a median rate of 0.027 ml/mo (interquartile range = 0.005-0.073), but was not significantly higher in subjects with DWI+ lesions compared to those without (p = 0.195). Of the 2 DWI+ lesions evolving into WMH on follow-up, one explained 23% of the total WMH volume increase in one subject, whereas the WMH regressed in the other subject. DWI+ lesions preceded 4 of 5 incident lacunes and 3 of 10 incident microbleeds.Interpretation: DWI+ lesions explain only a small proportion of the total WMH progression. Hence, WMH progression seems to be mostly driven by factors other than acute infarcts. DWI+ lesions explain the majority of incident lacunes and small cavities, and almost one-third of incident microbleeds, confirming that WMH, lacunes, and microbleeds, although heterogeneous on MRI, can have a common initial appearance on MRI. ANN NEUROL 2019;86:582-592. [ABSTRACT FROM AUTHOR]

Background: In Alzheimer's disease (AD), the functional connectome plays a key role in the trans‐neuronal spreading of tau pathology, a key driver of cognitive decline. The functional connectome is comprised of segregated, but communicating networks which lose segregation with age, resulting in an overall more diffuse connectome. Prior neuroimaging studies have found an association between weaker network segregation and faster symptom manifestation in AD, however, it is unclear if this association occurs because of a more diffuse connectome facilitating connectivity‐mediated tau spreading. Method: To investigate if network segregation is linked with accelerated tau spreading, we combined resting‐state fMRI with longitudinal Flortaucipir tau‐PET in 36 healthy controls and 57 biomarker‐defined AD subjects spanning the preclinical to dementia spectrum. Network segregation (the between to within‐network connectivity balance) was estimated at the subject level with resting‐state‐fMRI‐determined connectivity between 400 cortical regions of interest belonging to seven major networks. Result: Results revealed that higher baseline entorhinal tau‐PET (Braak I) was associated with accelerated tau accumulation in the rest of the brain (Braak III‐VI) in the AD and pooled sample, yet subjects with stronger network segregation exhibited an attenuated effect (Fig.1A). Additionally, through modelling patient‐specific tau epicentres we similarly demonstrated that subjects with high epicentre segregation exhibited an attenuated tau accumulation rate in the remaining brain (Fig1B). Conclusion: In line with the concept that tau spreads trans‐neuronally, our findings suggest that a more diffuse network topology facilitates tau expansion and further emphasises the critical role of the functional connectome in routing the spread of tau. [ABSTRACT FROM AUTHOR]

Background: Fibrillar tau progresses from initial epicenters of high tau accumulation to closely connected cortical regions during the course of Alzheimer's disease (AD). Myelin ensheaths the interregional axonal connections, where ontogenetically late and thinly myelinated fibers are more susceptible to damage and may propel the propagation of fibrillar tau, as suggested by post‐mortem data (https://doi.org/10.1093/brain/awv236). Here we tested for the first time, in two independent samples of AD patients whether 1) regions connected to epicenters by more thickly myelinated fiber tracts show lower rates of tau‐PET accumulation, and 2) differences in regional amyloid‐PET levels explain the association between myelin and tau‐PET accumulation. Methods: We included two independently recruited samples with longitudinal AV1451‐tau‐PET of amyloid‐PET positive non‐demented and demented individuals (ADNI: n = 123, mean FU = 1.53[0.69‐3.95] years; BioFINDER: n = 39, mean FU = 1.87[1.21‐2.78] years). Adopting our previously established connectivity‐based prediction approach (https://doi.org/10.1126/sciadv.abd1327), we first determined tau epicenters by selecting the top 10% ROIs with highest tau‐PET uptake. Next, we computed for each tau epicenter the connectivity‐based distance to the ROIs in the remainder of the brain, based on resting‐state fMRI data from the Human Connectome Project (HCP). To determine the myelin levels in the underlying fiber tracts, we reconstructed fiber‐tracts for each epicenter‐to‐ROI pair based on DWI data from HCP and extracted regional myelin‐water‐fraction (MWF) values for each tract from an overlaid myelin‐water‐imaging atlas (https://doi.org/10.1111/jon.12657). In order to test whether fiber tract myelination attenuates the connectivity‐based tau‐spreading, we tested the interaction between epicenter connectivity‐based distance and MWF in the corresponding fiber‐tracts on the rate of tau‐PET accumulation in the connected regions. In a sensitivity analysis restricted to the sufficiently powered ADNI‐sample, we controlled the interaction analysis for regional amyloid‐PET levels within target ROIs. Results: We found a significant interaction of connectivity‐based distance by fiber‐tract MWF on the rate of tau‐PET accumulation (ADNI: β = 2.08, p = 0.009; BioFINDER: β = 1.876, p = 0.028; Figure 1), such that regions connected by highly myelinated fiber‐tracts showed lower rates of connectivity‐dependent tau accumulation. When controlling for regional amyloid‐PET levels, the interaction remained significant (ADNI: β = 2.23, p = 0.006). Conclusion: Higher fiber‐tract myelination is associated with lower rates of tau progression in AD, independent of beta‐amyloid. [ABSTRACT FROM AUTHOR]

Cerebral small vessel disease (cSVD) comprises pathological processes of the small vessels in the brain that may manifest clinically as stroke, cognitive impairment, dementia, or gait disturbance. It is generally accepted that endothelial dysfunction, including blood‐brain barrier (BBB) failure, is pivotal in the pathophysiology. Recent years have seen increasing use of imaging, primarily dynamic contrast‐enhanced magnetic resonance imaging, to assess BBB leakage, but there is considerable variability in the approaches and findings reported in the literature. Although dynamic contrast‐enhanced magnetic resonance imaging is well established, challenges emerge in cSVD because of the subtle nature of BBB impairment. The purpose of this work, authored by members of the HARNESS Initiative, is to provide an in‐depth review and position statement on magnetic resonance imaging measurement of subtle BBB leakage in clinical research studies, with aspects requiring further research identified. We further aim to provide information and consensus recommendations for new investigators wishing to study BBB failure in cSVD and dementia. [ABSTRACT FROM AUTHOR]

Increasing evidence recognizes Alzheimer's disease (AD) as a multifactorial and heterogeneous disease with multiple contributors to its pathophysiology, including vascular dysfunction. The recently updated AD Research Framework put forth by the National Institute on Aging–Alzheimer's Association describes a biomarker‐based pathologic definition of AD focused on amyloid, tau, and neuronal injury. In response to this article, here we first discussed evidence that vascular dysfunction is an important early event in AD pathophysiology. Next, we examined various imaging sequences that could be easily implemented to evaluate different types of vascular dysfunction associated with, and/or contributing to, AD pathophysiology, including changes in blood‐brain barrier integrity and cerebral blood flow. Vascular imaging biomarkers of small vessel disease of the brain, which is responsible for >50% of dementia worldwide, including AD, are already established, well characterized, and easy to recognize. We suggest that these vascular biomarkers should be incorporated into the AD Research Framework to gain a better understanding of AD pathophysiology and aid in treatment efforts. [ABSTRACT FROM AUTHOR]

We conducted a European‐only and transancestral genome‐wide association meta‐analysis in 72,147 stroke patients and 823,869 controls using data from UK Biobank (UKB) and the MEGASTROKE consortium. We identified an exonic polymorphism in NOS3 (rs1799983, p.Glu298Asp; p = 2.2E‐8, odds ratio [OR] = 1.05, 95% confidence interval [CI] = 1.04–1.07) and variants in an intron of COL4A1 (rs9521634; p = 3.8E‐8, OR = 1.04, 95% CI = 1.03–1.06) and near DYRK1A (rs720470; p = 6.1E‐9, OR = 1.05, 95% CI = 1.03–1.07) at genome‐wide significance for stroke. Effect sizes of known stroke loci were highly correlated between UKB and MEGASTROKE. Using Mendelian randomization, we further show that genetic variation in the nitric oxide synthase–nitric oxide pathway in part affects stroke risk via variation in blood pressure. Ann Neurol 2018;84:934–939 [ABSTRACT FROM AUTHOR]

Introduction: Diffusion tensor imaging detects early tissue alterations in Alzheimer's disease and cerebral small vessel disease (SVD). However, the origin of diffusion alterations in SVD is largely unknown. Methods: To gain further insight, we applied free water (FW) imaging to patients with genetically defined SVD (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy [CADASIL], n = 57), sporadic SVD (n = 444), and healthy controls (n = 28). We modeled freely diffusing water in the extracellular space (FW) and measures reflecting fiber structure (tissue compartment). We tested associations between these measures and clinical status (processing speed and disability). Results: Diffusion alterations in SVD were mostly driven by increased FW and less by tissue compartment alterations. Among imaging markers, FW showed the strongest association with clinical status (R2 up to 34%, P <.0001). Findings were consistent across patients with CADASIL and sporadic SVD. Discussion: Diffusion alterations and clinical status in SVD are largely determined by extracellular fluid increase rather than alterations of white matter fiber organization. [ABSTRACT FROM AUTHOR]

Introduction White matter hyperintensities (WMHs) increase the risk of Alzheimer's disease (AD). Whether WMHs are associated with the decline of functional neural networks in AD is debated. Method Resting-state functional magnetic resonance imaging and WMH were assessed in 78 subjects with increased amyloid levels on AV-45 positron emission tomography (PET) in different clinical stages of AD. We tested the association between WMH volume in major atlas-based fiber tract regions of interest (ROIs) and changes in functional connectivity (FC) between the tracts' projection areas within the default mode network (DMN). Results WMH volume within the inferior fronto-occipital fasciculus (IFOF) was the highest among all tract ROIs and associated with reduced FC in IFOF-connected DMN areas, independently of global AV-45 PET. Higher AV-45 PET contributed to reduced FC in IFOF-connected, temporal, and parietal DMN areas. Conclusions High fiber tract WMH burden is associated with reduced FC in connected areas, thus adding to the effects of amyloid pathology on neuronal network function. [ABSTRACT FROM AUTHOR]

Objective: To establish a fully automated, robust imaging marker for cerebral small vessel disease (SVD) and related cognitive impairment that is easy to implement, reflects disease burden, and is strongly associated with processing speed, the predominantly affected cognitive domain in SVD.Methods: We developed a novel magnetic resonance imaging marker based on diffusion tensor imaging, skeletonization of white matter tracts, and histogram analysis. The marker (peak width of skeletonized mean diffusivity [PSMD]) was assessed along with conventional SVD imaging markers. We first evaluated associations with processing speed in patients with genetically defined SVD (n = 113). Next, we validated our findings in independent samples of inherited SVD (n = 57), sporadic SVD (n = 444), and memory clinic patients with SVD (n = 105). The new marker was further applied to healthy controls (n = 241) and to patients with Alzheimer's disease (n = 153). We further conducted a longitudinal analysis and interscanner reproducibility study.Results: PSMD was associated with processing speed in all study samples with SVD (p-values between 2.8 × 10(-3) and 1.8 × 10(-10) ). PSMD explained most of the variance in processing speed (R(2) ranging from 8.8% to 46%) and consistently outperformed conventional imaging markers (white matter hyperintensity volume, lacune volume, and brain volume) in multiple regression analyses. Increases in PSMD were linked to vascular but not to neurodegenerative disease. In longitudinal analysis, PSMD captured SVD progression better than other imaging markers.Interpretation: PSMD is a new, fully automated, and robust imaging marker for SVD. PSMD can easily be applied to large samples and may be of great utility for both research studies and clinical use. Ann Neurol 2016;80:581-592. [ABSTRACT FROM AUTHOR]

Objective: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), the most common inherited small-vessel disease, is associated with vascular aggregation of mutant Notch3 protein, dysfunction of cerebral vessels, and dementia. Pericytes, perivascular cells involved in microvascular function, express Notch3. Therefore, we hypothesize that these cells may play a role in the pathogenesis of CADASIL. Methods: Two-, 7-, and 12-month-old CADASIL mutant mice (TgNotch3(R169C) ) and wild-type controls were examined regarding Notch3 aggregation in pericytes, the coverage of cerebral vessels by pericytes, pericyte numbers, capillary density, blood-brain barrier (BBB) integrity, astrocytic end-feet, and the expression of astrocytic gap junction and endothelial adherens junction protein using immunostaining and Western blot analysis. In addition, we examined cerebrovascular CO2 reactivity using laser Doppler fluxmetry and in vivo microscopy. Results: With increasing age, mutated Notch3 aggregated around pericytes and smooth muscle cells. Notch3 aggregation caused significant reduction of pericyte number and coverage of capillaries by pericyte processes (p < 0.01). These changes were associated with detachment of astrocytic end-feet from cerebral microvessels, leakage of plasma proteins, reduction in expression of endothelial adherens junction protein, and reduced microvascular reactivity to CO2 . Smooth muscle cells were not affected by Notch3 accumulation. Interpretation: Our results show that pericytes are the first cells affected by Notch3 aggregation in CADASIL mice. Pericyte pathology causes opening of the BBB and microvascular dysfunction. Therefore, protecting pericytes may represent a novel therapeutic strategy for vascular dementia. [ABSTRACT FROM AUTHOR]

ABSTRACT OBJECTIVES Single case reports suggest that black blood MRI (T1-weighted fat and blood suppressed sequences with and without contrast injection; BB-MRI) may visualize intracranial vessel wall contrast enhancement (CE) in primary angiitis of the central nervous system (PACNS). In this single-center observational pilot study we prospectively investigated the value of BB-MRI in the diagnosis of large artery PACNS. METHODS Patients with suspected large artery PACNS received a standardized diagnostic program including BB-MRI. Vessel wall CE was graded (grade 0-2) by two experienced readers blinded to clinical data and correlated to the final diagnosis. RESULTS Four of 12 included patients received a final diagnosis of PACNS. All of them showed moderate (grade 1) to strong (grade 2) vessel wall CE at the sites of stenosis. A moderate (grade 1) vessel wall CE grade was also observed in 6 of the remaining 8 patients in whom alternative diagnoses were made: arteriosclerotic disease ( n= 4), intracranial dissection ( n= 1), and Moyamoya disease ( n= 1). CONCLUSIONS Our pilot study demonstrates that vessel wall CE is a frequent finding in PACNS and its mimics. Larger trials will be necessary to evaluate the utility of BB-MRI in the diagnostic workup of PACNS. [ABSTRACT FROM AUTHOR]

The 2012 Eibsee meeting on 'Cellular Mechanisms of Neurodegeneration' addressed the need to integrate research on classical neurodegenerative mechanisms with investigations that relate to the immunological, glial and vascular sequels that accompany and often propagate neuronal injury. We report on the central topics that were addressed and discuss future directions towards establishing 'systems neurology' as a new integrated research field. [ABSTRACT FROM AUTHOR]

Objective Recent studies have identified a major locus for risk for coronary artery disease and myocardial infarction on chromosome 9p21.3. Stroke, in particular, ischemic stroke caused by atherosclerotic disease, shares common mechanisms with myocardial infarction. We investigated whether the 9p21 region contributes to ischemic stroke risk. Methods In an initial screen, 15 single nucleotide polymorphisms (SNPs) covering the critical genetic interval on 9p21 were genotyped in samples from Southern Germany (1,090 cases, 1,244 control subjects) and the United Kingdom (758 cases, 872 control subjects, 3 SNPs). SNPs significantly associated with ischemic stroke or individual stroke subtypes in either of the screening samples were subsequently genotyped in 2,528 additional cases and 2,189 additional control subjects from Europe and North America. Results Genotyping of the screening samples demonstrated associations between seven SNPs and atherosclerotic stroke (all p < 0.05). Analysis of the full sample confirmed associations between six SNPs and atherosclerotic stroke in multivariate analyses controlling for demographic variables, coronary artery disease, myocardial infarction, and vascular risk factors (all p < 0.05). The odds ratios for the lead SNP (rs1537378-C) were similar in the various subsamples with a pooled odds ratio of 1.21 (95% confidence interval, 1.07-1.37) under both fixed- and random-effects models ( p = 0.002). The point estimate for the population attributable risk is 20.1% for atherosclerotic stroke. Interpretation The chromosome 9p21.3 region represents a major risk locus for atherosclerotic stroke. The effect of this locus on stroke appears to be independent of its relation to coronary artery disease and other stroke risk factors. Our findings support a broad role of the 9p21 region in arterial disease. Ann Neurol 2009;65:531-539 [ABSTRACT FROM AUTHOR]

Transient ischemia has been shown to damage the basal lamina of the cerebral microvasculature. Other studies proved statins to be beneficial to non-cerebral microvessels. The aim of this study was to determine whether pravastatin pretreatment ameliorates microvascular basal lamina damage following transient ischemia. Using the suture model, we subjected 15 rats to focal ischemia (3 h) and reperfusion (24 h). Rats received pravastatin (20 mg/kg/day) or saline for 4 weeks prior to the experiment. The outcome was determined by a behavior test and the infarct size. Collagen type IV, a marker for an intact basal lamina, and hemoglobin extravasation were measured by Western blot analysis. A ratio (in percentage) between ischemic and contralateral hemispheres was calculated. Pravastatin pretreatment resulted in a significantly better neurological outcome and reduced infarct size (15 ± 0.5 and 59 ± 10 mm3, respectively) compared with controls (12.25 ± 0.4 and 167 ± 13 mm3, respectively, P < 0.01 for both). In controls, loss of collagen type IV was seen in the basal ganglia and in the cortex (43 ± 4 and 64 ± 5%, respectively). Pravastatin prevented significant collagen loss (basal ganglia: 106 ± 17%; cortex: 112 ± 14%, P < 0.01 for both) and significantly reduced the hemoglobin extravasation compared with controls in the basal ganglia (198 ± 49 vs. 553 ± 47%, P < 0.01). Pravastatin pretreatment resulted in a reduction of microvascular basal lamina damage and hemoglobin extravasation following transient ischemia. Pravastatin seems to protect the cerebral microvascular system. [ABSTRACT FROM AUTHOR]

The article presents several studies related to Hemiplegic and Basilar-Type migraine. The study titled "Haploinsufficiency of ATP1A2 Encoding the Na+/K+ Pump Alpha2 Subunit Associated with Familial Hemiplegic Migraine Type 2" concludes that L764P and W887R are causative in the two Italian families. The study titled "Alterations in the Alpha2 Isoform of Na,K-AtPase Associated with Familial Hemiplegic Migraine Type 2" shows that spectrum of molecular phenotypes associated with FHM2 is broad.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary vascular disease that usually begins with migraine, followed by repeated strokes and progressive dementia. We describe an unusual clinical presentation of this condition in members of a Chilean family with an established NOTCH3 mutation. We report early clinical, neuropsychological, transcranial ultrasound, magnetic resonance imaging (MRI), cerebral blood flow, and skin biopsy findings on these patients. Of the patients, 2 presented with facial dystonia, 1 of whom had abnormal single photon emission computed tomography and transcranial ultrasound studies after normal brain MRI scans. Our report emphasizes that CADASIL must be considered in the study of patients with secondary dystonia. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to an article about familial carpal tunnel syndrome.

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a progressive adult-onset tremor/ataxia syndrome caused by premutations in the FMR1 gene. In cranial MRI, the most characteristic findings are bilateral T2 hyperintense lesions within the middle cerebellar peduncles. Here we present a sibpair of two affected brothers presenting with very different symptoms (typical FXTAS versus essential tremor-like), disease progression, and MRI findings, illustrating broad intrafamilial variability of FXTAS. Also, their family history suggests further evidence of possible manifestation of FXTAS in women. © 2005 Movement Disorder Society [ABSTRACT FROM AUTHOR]

Focal cerebral ischemia leads to the gradual disruption of the extracellular matrix. A key role in the turnover of the extracellular matrix is played by the system of matrix metalloproteinases (MMPs). In this study we describe changes of the MMP inducer protein (EMMPRIN) following experimental cerebral ischemia (induced for 3 h and followed by 24 h reperfusion, suture model) in rats. Extracellular EMMPRIN was measured by Western blot of the ischemic and nonischemic basal ganglia and cortex separately. Compared with the contralateral nonischemic area, the ischemic hemisphere showed a significant increase in EMMPRIN: basal ganglia, 158% ± 4% ( P < 0.05); cortex, 128% ± 25% ( P < 0.05). Immunohistochemistry was used to localize EMMPRIN on cerebral microvessels. EMMPRIN-positive microvascular structures were quantified by automatic morphometric video-imaging analysis and a significant increase in the number of cerebral microvessels staining positive for EMMPRIN in the ischemic basal ganglia was shown. The significant loss of microvascular basal lamina antigen collagen type IV in ischemic cortex and basal ganglia was calculated by Western blot. Measured by gelatin zymography, we demonstrated an MMP-2 and MMP-9 increase in the ischemic brain regions ( P < 0.05). For the first time the MMP activation system EMMPRIN was shown to be relevant in cerebral ischemia. These results raise the possibility that the increased expression of EMMPRIN, the increase in MMPs and the damage of the basal lamina following cerebral ischemia are connected and part of a network of related changes. [ABSTRACT FROM AUTHOR]