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Introduction: Sex disparities in stroke treatment have gained increasing interest, especially since women have worse post-stroke functional outcomes compared with men. Existing studies provide conflicting evidence, with some indicating women have longer delays and less often receive acute treatment, whereas others show no differences between men and women. We aimed to explore sex differences in acute treatment modalities and time metrics of patients with acute ischemic stroke (AIS) in a real-world setting. Second, we examined whether functional outcomes differed by sex and whether this was influenced by treatment timing., Methods: We analyzed data from the Dutch Acute Stroke Audit, a prospective consecutive registry of AIS patients from 72 hospitals in the Netherlands, between 2017 and 2020. We captured data on type of treatment administered (intravenous thrombolysis [IVT] and endovascular thrombectomy [EVT]), time metrics (onset-to-door time [OTDT], door-to-needle and door-to-groin times), and functional outcomes at 3 months (modified Rankin scale [mRS]). The association between sex and poor outcome (mRS 3-6) was assessed with Cox proportional hazard models stratified by type of treatment and adjusted for age, additionally for National Institutes of Health Stroke Scale (NIHSS) and OTDT., Results: Of the 58,632 patients, 26,941 (46%) were women. Compared with men, women were older (mean age 74.6 vs. 71.0, p < 0.001) and presented with slightly higher NIHSS scores (median 3 [IQR 2-7] vs. 3 [IQR 1-6], p < 0.001). Treatment modalities distribution (no treatment, IVT, EVT) was similar between women and men (64; 29; 10 vs. 63; 30; 9%, p = 0.16). Women had a slightly longer OTDT (median 145 vs. 139 min, p < 0.01). Women had increased odds of poor outcomes (OR 1.49 [95% CI: 1.43-1.56]). This was still statistically significant after adjusting for age and NIHSS score (OR 1.22 [95% CI: 1.16-1.28]). Neither treatment modality nor OTDT had an additional influence on this association., Conclusion: In this large real-world registry, we observed no differences in distribution of treatment modalities between sexes. We did find a minor pre-hospital delay in women and worse functional outcomes in women. The minor delay in OTDT does not fully explain the observed worse outcomes in women. Our results provide reassurance that no major sex biases are apparent in acute stroke management throughout participating Dutch centers., (© 2024 The Author(s). Published by S. Karger AG, Basel.)

Background and Purpose: Risk factors for stroke differ between women and men in general populations. However, little is known about sex differences in secondary prevention. We investigated if sex interacted with modifiable risk factors for stroke in a large arterial disease cohort., Methods: Within the prospective UCC-SMART study, 13,898 patients (35% women) with atherosclerotic disease or high-risk factor profile were followed up to 23 years for stroke incidence or recurrence. Hypertension, smoking, diabetes, overweight, dyslipidemia, high alcohol use, and physical inactivity were studied as risk factors. Association between these factors and ischemic and hemorrhagic stroke incidence or recurrence was studied in women and men using Cox proportional hazard models and Poisson regression models. Women-to-men relative hazard ratios (RHR) and rate differences (RD) were estimated for each risk factor. Left-truncated age was used as timescale., Results: The age-adjusted stroke incidence rate was lower in women than men (3.9 vs 4.4 per 1000 person-years), as was the age-adjusted stroke recurrence rate (10.0 vs 11.7). Hypertension and smoking were associated with stroke risk in both sexes. HDL cholesterol was associated with lower stroke incidence in women but not in men (RHR 0.49; CI 0.27-0.88; and RD 1.39; CI - 1.31 to 4.10). Overweight was associated with a lower stroke recurrence in women but not in men (RHR 0.42; CI 0.23-0.80; and RD 9.05; CI 2.78-15.32)., Conclusions: In high-risk population, sex modifies the association of HDL cholesterol on stroke incidence, and the association of overweight on stroke recurrence. Our findings highlight the importance of sex-specific secondary prevention., (© 2024. The Author(s).)

Introduction: White matter hyperintensities (WMH) are associated with key dementia etiologies, in particular arteriolosclerosis and amyloid pathology. We aimed to identify WMH locations associated with vascular risk or cerebral amyloid-β 1-42 (Aβ42)-positive status., Methods: Individual patient data (n = 3,132; mean age 71.5 ± 9 years; 49.3% female) from 11 memory clinic cohorts were harmonized. WMH volumes in 28 regions were related to a vascular risk compound score (VRCS) and Aß42 status (based on cerebrospinal fluid or amyloid positron emission tomography), correcting for age, sex, study site, and total WMH volume., Results: VRCS was associated with WMH in anterior/superior corona radiata (B = 0.034/0.038, p < 0.001), external capsule (B = 0.052, p < 0.001), and middle cerebellar peduncle (B = 0.067, p < 0.001), and Aß42-positive status with WMH in posterior thalamic radiation (B = 0.097, p < 0.001) and splenium (B = 0.103, p < 0.001)., Discussion: Vascular risk factors and Aß42 pathology have distinct signature WMH patterns. This regional vulnerability may incite future studies into how arteriolosclerosis and Aß42 pathology affect the brain's white matter., Highlights: Key dementia etiologies may be associated with specific patterns of white matter hyperintensities (WMH). We related WMH locations to vascular risk and cerebral Aβ42 status in 11 memory clinic cohorts. Aβ42 positive status was associated with posterior WMH in splenium and posterior thalamic radiation. Vascular risk was associated with anterior and infratentorial WMH. Amyloid pathology and vascular risk have distinct signature WMH patterns., (© 2024 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Background: We hypothesize that Alzheimer's disease (AD)-related pathology may accelerate cognitive decline in patients with cardiovascular diseases., Objective: To investigate the association between blood-based biomarkers of AD, astrocyte activation, and neurodegeneration and cognitive decline., Methods: From the multi-center Heart-Brain study, we included 412 patients with heart failure, carotid occlusive disease or vascular cognitive impairment (age:68.6±9.0) and 128 reference participants (65.7±7.5). Baseline amyloid-β42/40 (Aβ42/40), phosphorylated-tau181 (pTau181), glial fibrillary acidic protein (GFAP), and neurofilament light (NfL) were determined using SiMoA (Quanterix). Memory, attention, language, and executive functioning were evaluated (follow-up:2.1±0.3 years). We applied linear mixed models with terms for biomarker, time and biomarker*time interactions, adjusted for age, sex, education, and site, to assess associations between biomarkers and cognitive decline., Results: Among patients, Aβ42/40 was not associated with cognitive performance at baseline. However, lower Aβ42/40 was associated with steeper decline in global cognition (β±SE:0.04±0.02). Higher pTau181 was associated with worse baseline performance on global cognition (-0.14±0.04) and memory (-0.31±0.09) and with steeper decline in global cognition (-0.07±0.02), memory (-0.09±0.04), attention (-0.05±0.02), and language (-0.10±0.03). Higher GFAP was associated with worse baseline performance on global cognition (-0.22±0.05), memory (-0.43±0.10), attention (-0.14±0.06), language (-0.15±0.05), and executive functioning (-0.15±0.05) and steeper decline in global cognition (-0.05±0.01). Higher NfL was associated with worse baseline performance on global cognition (-0.16±0.04), memory (-0.28±0.09), attention (-0.20±0.06), and executive functioning (-0.10±0.04), but was not associated with performance over time. In reference participants, no associations were found., Conclusions: Our findings suggest that blood-based biomarkers of AD-related pathology predict cognitive decline in patients with cardiovascular diseases.

Endovascular thrombectomy (EVT) success to treat acute ischemic stroke varies with factors like stroke etiology and clot composition, which can differ between sexes. We studied if sex-specific blood cell characteristics (BCCs) are related to recanalization success. We analyzed electronic health records of 333 EVT patients from a single intervention center, and extracted 71 BCCs from the Sapphire flow cytometry analyzer. Through Sparse Partial Least Squares Discriminant Analysis, incorporating cross-validation and stability selection, we identified BCCs associated with successful recanalization (TICI 3) in both sexes. Stroke etiology was considered, while controlling for cardiovascular risk factors. Of the patients, successful recanalization was achieved in 51% of women and 49% of men. 21 of the 71 BCCs showed significant differences between sexes  (pFDR-corrected < 0.05). The female-focused recanalization model had lower error rates than both combined [t(192.4) = 5.9, p < 0.001] and male-only models [t(182.6) = - 15.6, p < 0.001]. In women, successful recanalization and cardioembolism were associated with a higher number of reticulocytes, while unsuccessful recanalization and large artery atherosclerosis (LAA) as cause of stroke were associated with a higher mean corpuscular hemoglobin concentration. In men, unsuccessful recanalization and LAA as cause of stroke were associated with a higher coefficient of variance of lymphocyte complexity of the intracellular structure. Sex-specific BCCs related to recanalization success varied and were linked to stroke etiology. This enhanced understanding may facilitate personalized treatment for acute ischemic stroke., (© 2023. The Author(s).)

Background: Poststroke cognitive impairment (PSCI) occurs in about half of stroke survivors. Cumulative evidence indicates that functional outcomes of stroke are worse in women than men. Yet it is unknown whether the occurrence and characteristics of PSCI differ between men and women., Methods: Individual patient data from 9 cohorts of patients with ischemic stroke were harmonized and pooled through the Meta-VCI-Map consortium (n=2343, 38% women). We included patients with visible symptomatic infarcts on computed tomography/magnetic resonance imaging and cognitive assessment within 15 months after stroke. PSCI was defined as impairment in ≥1 cognitive domains on neuropsychological assessment. Logistic regression analyses were performed to compare men to women, adjusted for study cohort, to obtain odds ratios for PSCI and individual cognitive domains. We also explored sensitivity and specificity of cognitive screening tools for detecting PSCI, according to sex (Mini-Mental State Examination, 4 cohorts, n=1814; Montreal Cognitive Assessment, 3 cohorts, n=278)., Results: PSCI was found in 51% of both women and men. Men had a lower risk of impairment of attention and executive functioning (men: odds ratio, 0.76 [95% CI, 0.61-0.96]), and language (men: odds ratio, 0.67 [95% CI, 0.45-0.85]), but a higher risk of verbal memory impairment (men: odds ratio, 1.43 [95% CI, 1.17-1.75]). The sensitivity of Mini-Mental State Examination (<25) for PSCI was higher for women (0.53) than for men (0.27; P =0.02), with a lower specificity for women (0.80) than men (0.96; P =0.01). Sensitivity and specificity of Montreal Cognitive Assessment (<26.) for PSCI was comparable between women and men (0.91 versus 0.86; P =0.62 and 0.29 versus 0.28; P =0.86, respectively)., Conclusions: Sex was not associated with PSCI occurrence but affected domains differed between men and women. The latter may explain why sensitivity of the Mini-Mental State Examination for detecting PSCI was higher in women with a lower specificity compared with men. These sex differences need to be considered when screening for and diagnosing PSCI in clinical practice.

Introduction: Impact of white matter hyperintensities (WMH) on cognition likely depends on lesion location, but a comprehensive map of strategic locations is lacking. We aimed to identify these locations in a large multicenter study., Methods: Individual patient data (n = 3525) from 11 memory clinic cohorts were harmonized. We determined the association of WMH location with attention and executive functioning, information processing speed, language, and verbal memory performance using voxel-based and region of interest tract-based analyses., Results: WMH in the left and right anterior thalamic radiation, forceps major, and left inferior fronto-occipital fasciculus were significantly related to domain-specific impairment, independent of total WMH volume and atrophy. A strategic WMH score based on these tracts inversely correlated with performance in all domains., Discussion: The data show that the impact of WMH on cognition is location-dependent, primarily involving four strategic white matter tracts. Evaluation of WMH location may support diagnosing vascular cognitive impairment., Highlights: We analyzed white matter hyperintensities (WMH) in 3525 memory clinic patients from 11 cohorts The impact of WMH on cognition depends on location We identified four strategic white matter tracts A single strategic WMH score was derived from these four strategic tracts The strategic WMH score was an independent determinant of four cognitive domains., (© 2022 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Introduction: The spatial distribution of white matter hyperintensities (WMH) on MRI is often considered in the diagnostic evaluation of patients with cognitive problems. In some patients, clinicians may classify WMH patterns as "unusual", but this is largely based on expert opinion, because detailed quantitative information about WMH distribution frequencies in a memory clinic setting is lacking. Here we report voxel wise 3D WMH distribution frequencies in a large multicenter dataset and also aimed to identify individuals with unusual WMH patterns., Methods: Individual participant data (N = 3525, including 777 participants with subjective cognitive decline, 1389 participants with mild cognitive impairment and 1359 patients with dementia) from eleven memory clinic cohorts, recruited through the Meta VCI Map Consortium, were used. WMH segmentations were provided by participating centers or performed in Utrecht and registered to the Montreal Neurological Institute (MNI)-152 brain template for spatial normalization. To determine WMH distribution frequencies, we calculated WMH probability maps at voxel level. To identify individuals with unusual WMH patterns, region-of-interest (ROI) based WMH probability maps, rule-based scores, and a machine learning method (Local Outlier Factor (LOF)), were implemented., Results: WMH occurred in 82% of voxels from the white matter template with large variation between subjects. Only a small proportion of the white matter (1.7%), mainly in the periventricular areas, was affected by WMH in at least 20% of participants. A large portion of the total white matter was affected infrequently. Nevertheless, 93.8% of individual participants had lesions in voxels that were affected in less than 2% of the population, mainly located in subcortical areas. Only the machine learning method effectively identified individuals with unusual patterns, in particular subjects with asymmetric WMH distribution or with WMH at relatively rarely affected locations despite common locations not being affected., Discussion: Aggregating data from several memory clinic cohorts, we provide a detailed 3D map of WMH lesion distribution frequencies, that informs on common as well as rare localizations. The use of data-driven analysis with LOF can be used to identify unusual patterns, which might serve as an alert that rare causes of WMH should be considered., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: FB is supported by the NIHR biomedical research center at UCLH. MD received honoraria for lectures from Bayer Vital and Sanofi Genzyme, Consultant for Hovid Berhad and Roche Pharma. RWP received honoraria from GE Healthcare and is co-lead of Neurofilament light consortium. CHS is supported by an Alzheimer's Society Fellowship. The remaining authors have nothing to disclose., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: Examine the association between neuropsychiatric symptoms (NPS) and clinical outcome in memory clinic patients with vascular brain injury., Design/setting: TRACE-VCI prospective memory clinic cohort with follow-up (2.1 ± 0.5 years)., Participants: Five hundred and seventy-five memory clinic patients with vascular brain injury on MRI (i.e. possible Vascular Cognitive Impairment [VCI]). Severity of cognitive impairment ranged from no objective cognitive impairment to mild cognitive impairment (MCI) and dementia., Measurements: We used Neuropsychiatric Inventory (total score and score on hyperactive, psychotic, affective, and apathetic behavior domains) to measure NPS. We assessed the association between NPS and institutionalization, mortality and cognitive deterioration (increase ≥0.5 on Clinical Dementia Rating scale) with Cox proportional hazards models and logistic regression analyses., Results: NPS were present in 89% of all patients, most commonly in the hyperactive and apathetic behavior domain. Across the whole cohort, affective behavior was associated with institutionalization (HR: 1.98 [1.01-3.87]), mainly driven by the dementia subgroup (HR: 2.06 [1.00-4.21]). Apathetic behavior was associated with mortality and cognitive deterioration (HR: 2.07 [1.10-3.90],OR: 1.67 [1.12-2.49], respectively), mainly driven by the MCI subgroup (HR: 4.93 [1.07-22.86],OR: 3.25 [1.46-7.24], respectively). Conversely, hyperactive behavior was related to lower mortality (HR: 0.54 [0.29-0.98]), again particularly driven by the MCI subgroup (HR:0.17 [0.04-0.75]). Psychotic behavior was associated with cognitive deterioration in patients with no objective cognitive impairment (OR: 3.10 [1.09-8.80]) and with institutionalization in MCI (HR: 12.45 [1.28-121.14])., Conclusion: NPS are common and have prognostic value in memory clinic patients with possible VCI. This prognostic value depends on the severity of cognitive impairment., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

We aim to investigate the frequency and type of sleep problems in memory clinic patients with subjective cognitive decline (SCD) and their association with cognition, mental health, brain magnetic resonance imaging (MRI), and cerebrospinal fluid (CSF) biomarkers. Three hundred eight subjects (65 ± 8 years, 44% female) were selected from the Subjective Cognitive Impairment Cohort (SCIENCe) project. All subjects answered two sleep questionnaires, Berlin Questionnaire (sleep apnea) and Pittsburgh Sleep Quality Index (sleep quality) and underwent a standardized memory clinic work-up. One hundred ninety-eight (64%) subjects reported sleep problems, based on 107 (35%) positive screenings on sleep apnea and 162 (53%) on poor sleep quality. Subjects with sleep problems reported more severe depressive symptoms, more anxiety, and more severe SCD. Cognitive tests, MRI, and CSF biomarkers did not differ between groups. Our results suggest that improvement of sleep quality and behaviors are potential leads for treatment in many subjects with SCD to relieve the experienced cognitive complaints., Competing Interests: LE has been invited speaker at Center for Innovation Medical Technology of the NAS of Ukraine. NDP is consultant to Boehringer Ingelheim, Aribio, and Amylyx. He is co‐PI of a study with Fuji Film Toyama Chemical. NDP received a speaker fee from Biogen. NDP served on the DSMB of Abbvie's M15‐566 trial. NDP is CEO and co‐owner of Brain Research Center, the Netherlands. CET was involved in Alz Res therapy Medidact Neurology and received travel support from Roche. LV received a small fee for the development of an online course on shared decision‐making, by EACH, the international organization for communication in health care (paid to her). PS has received consultancy fees (paid to the institution) from AC Immune, Alkermes, Alnylam, Alzheon, Anavex, Biogen, Brainstorm Cell, Cortexyme, Denali, EIP, ImmunoBrain Checkpoint, GemVax, Genentech, Green Valley, Novartis, Novo Nordisk, PeopleBio, Renew LLC, Roche. He is PI of studies with AC Immune, CogRx, FUJI‐film/Toyama, IONIS, UCB, and Vivoryon. PhS is a part‐time employee of Life Sciences Partners Amsterdam. PhS serves on the board of Brain Research Center and New Amsterdam Pharma. PhS served on the DSMB of Genentech SAB. WF is consultant to Oxford Health Policy Forum CIC, Roche, and Biogen MA Inc. and has been an invited speaker at Boehringer Ingelheim, Biogen MA Inc, Danone, Eisai, WebMD Neurology (Medscape). All funding is paid to her institution. WF holds the Pasman chair. WF has performed contract research for Biogen MA Inc and Boehringer Ingelheim. All funding is paid to her institution. The other authors (HMAH, KAB, JLE, MLK) have nothing to disclose., (© 2022 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer's Association.)

Background: Fundamental aspects of human identity may play a role in the presentation of stroke symptoms and, consequently, stroke recognition. Strokes must be recognized and treated expeditiously, as delays result in poorer outcomes. It is known that sex plays a role in the presentation of symptoms, such that non-traditional symptoms are more commonly observed among women. However, factors such as geographical location and race/ethnicity, and the interactions between these various factors, need to be considered. This will provide an intersectional approach., Methods: A systematic review and meta-analysis of the literature was conducted to investigate differences in the presentation of stroke symptoms between sexes. Using PubMed and Embase, a search involving the components sex, symptoms and stroke was completed and yielded 26 full-text manuscripts., Results: Our findings indicate that there is substantial overlap in stroke symptom presentation in men and women. Nonetheless, some differences in the clinical manifestations of stroke were observed. In addition, it was discovered that only three studies were conducted outside of North America and Europe. Furthermore, only two studies reported symptoms based on both sex and racial/ethnic group., Conclusion: These findings indicate a research gap and call for increased research in order to uncover the possible interactions between sex and race/ethnicity in an intersectional approach. Resultantly, stroke recognition could be improved and greater equity in healthcare can be achieved., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Hosman, Engels, den Ruijter and Exalto.)

Background: Little is known about the trajectories of cognitive decline in relation to different types of vascular brain injury in patients presenting at a memory clinic with Vascular Cognitive Impairment (VCI)., Methods: We included 472 memory clinic patients (age 68 (±8.2) years, 44% female, MMSE 25.9 (±2.8), 210 (44.5%) dementia) from the prospective TRACE-VCI cohort study with possible VCI, defined as cognitive complaints and vascular brain injury on MRI and at least 1 follow-up cognitive assessment (follow-up time 2.5 (±1.4) years, n  = 1172 assessments). Types of vascular brain injury considered lacune(s) (≥1; n = 108 patients (23%)), non-lacunar infarct(s) (≥1; n = 54 (11%)), white matter hyperintensities (WMH) (none/mild versus moderate/severe ( n = 211 patients (45%)) and microbleed(s) (≥1; n = 202 patients (43%)). We assessed cognitive functioning at baseline and follow-up, including the Rey Auditory Verbal Learning Test (RAVLT), Trail Making Test (TMT) A and B, category naming task and MMSE. The association of different types of vascular brain injury with cognitive decline was evaluated with linear mixed models, including one type of vascular brain injury (dichotomized), time and vascular brain injury*time, adjusted for sex, age, dementia status (yes/no), education (Verhage scale) and medial temporal lobe atrophy (MTA) score (dichotomized as ≥ 1.5)., Results: Across the population, performance declined over time on all tests. Linear mixed models showed that lacune(s) were associated with worse baseline TMTA (Beta(SE)) (8.3 (3.8), p  = .03) and TMTB (25.6 (10.3), p = .01), albeit with a slower rate of decline on MMSE, RAVLT and category naming. By contrast, patients with non-lacunar infarct(s) showed a steeper rate of decline on TMTB (29.6 (7.7), p = .00), mainly attributable to patients with dementia (62.9 (15.5), p = .00)., Conclusion: Although different types of vascular brain injury have different etiologies and different patterns, they show little differences in cognitive trajectories depending on type of vascular brain injury., Competing Interests: None., (© 2022 The Author(s).)

Background and Aim: Cognitive dysfunction is increasingly recognized as an important comorbidity of type 2 diabetes (T2D). We aimed to establish if the risk of accelerated cognitive decline (ACD) is higher in females with T2D than males., Methods and Results: 3163 participants (38% female) with T2D from the cognition substudy of CAROLINA® (NCT01243424) were included (mean age 64.4 ± 9.2 years; T2D duration 7.6 ± 6.1 years). The cognitive outcome was occurrence of ACD at end of follow-up, defined as a regression based index score ≤16th percentile on either the Mini-Mental State Examination (MMSE) or a composite measure of attention and executive functioning (Trail Making and Verbal Fluency Test). Potential confounders, were taken into account at an individual patient level. Logistic regression analysis was used to investigate ACD risk by sex. We assessed potential mediators for sex differences in ACD using Causal Mediation Analysis (CMA). After a median follow-up duration of 6.1 ± 0.7 years, 361 (30.0%) females compared to 494 (25.2%) males exhibited ACD (OR 1.27 [95%CI 1.08-1.49], p = .003). Depressive symptoms, which were more common in females (24.3% vs 12.5%), mediated between sex and ACD (mediation effect 20.3%, p = 0.03). There were no other significant mediators., Conclusion: Females with T2D had a higher risk of ACD compared to males. This was partly explained by depressive symptoms. After evaluation of vascular and diabetes-related risk factors, complications and treatment, a major share of the higher risk of ACD in females remained unexplained. Our results highlight the need for further research on causes of sex-specific ACD in T2D., Competing Interests: Declaration of competing interest The authors declare that there are no relationships or activities that might bias, or be perceived to bias, their work. OEJ was previously employed by Boehringer Ingelheim., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: In the Netherlands, a digital decision support system for telephone triage at out-of-hours services in primary care (OHS-PC) is used. Differences in help-seeking behavior between men and women when transient ischemic attack (TIA) or stroke is suspected could potentially affect telephone triage and allocation of urgency. Aim: To assess patient and call characteristics and allocated urgencies between women and men who contacted OHS-PC with suspected TIA/stroke. Methods: A cross-sectional study of 1,266 telephone triage recordings of subjects with suspected neurological symptoms calling the OHS-PC between 2014 and 2016. The allocated urgencies were derived from the electronic medical records of the OHS-PC and the final diagnosis from the patient's own general practitioner, including diagnoses based on hospital specialist letters. Results: Five hundred forty-six men (mean age = 67.3 ± 17.1) and 720 women (mean age = 69.6 ± 19.5) were included. TIA/stroke was diagnosed in 294 men (54%) (mean age = 72.3 ± 13.6) and 366 women (51%) (mean age = 78.0 ± 13.8). In both genders, FAST (face-arm-speech test) symptoms were common in TIA/stroke (men 78%, women 82%) but also in no TIA/stroke (men 63%, women 62%). Men with TIA/stroke had shorter call durations than men without TIA/stroke (7.10 vs. 8.20 min, p = 0.001), whereas in women this difference was smaller and not significant (7.41 vs. 7.56 min, p = 0.41). Both genders were allocated high urgency in 75% of the final TIA/stroke cases. Conclusion: Overall, patient and call characteristics are mostly comparable between men and women, and these only modestly assist in identifying TIA/stroke. There were no gender differences in allocated urgencies after telephone triage in patients with TIA/stroke., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Exalto, van Doorn, Erkelens, Smit, Rutten, Kappelle and Zwart.)

Background: Emerging evidence shows sex differences in manifestations of vascular brain injury in memory clinic patients. We hypothesize that this is explained by sex differences in cardiovascular function., Objective: To assess the relation between sex and manifestations of vascular brain injury in patients with cognitive complaints, in interaction with cardiovascular function., Methods: 160 outpatient clinic patients (68.8±8.5 years, 38% female) with cognitive complaints and vascular brain injury from the Heart-Brain Connection study underwent a standardized work-up, including heart-brain MRI. We calculated sex differences in vascular brain injury (lacunar infarcts, non-lacunar infarcts, white matter hyperintensities [WMHs], and microbleeds) and cardiovascular function (arterial stiffness, cardiac index, left ventricular [LV] mass index, LV mass-to-volume ratio and cerebral blood flow). In separate regression models, we analyzed the interaction effect between sex and cardiovascular function markers on manifestations of vascular brain injury with interaction terms (sex*cardiovascular function marker)., Results: Males had more infarcts, whereas females tended to have larger WMH-volumes. Males had higher LV mass indexes and LV mass-to-volume ratios and lower CBF values compared to females. Yet, we found no interaction effect between sex and individual cardiovascular function markers in relation to the different manifestations of vascular brain injury (p-values interaction terms > 0.05)., Conclusion: Manifestations of vascular brain injury in patients with cognitive complaints differed by sex. There was no interaction between sex and cardiovascular function, warranting further studies to explain the observed sex differences in injury patterns.

Aim: To investigate the relationship between the diabetes-specific dementia risk score (DSDRS) and concurrent and future cognitive impairment (CI) in type 2 diabetes (T2D)., Methods: DSDRS were calculated for participants with T2D aged ≥60 years from the CARMELINA-cognition substudy (ClinicalTrials.gov Identifier: NCT01897532). Cognitive assessment included Mini-Mental State Examination (MMSE) and a composite attention and executive functioning score (A&E). The relation between baseline DSDRS and probability of CI (MMSE < 24) and variation in cognitive performance was assessed at baseline (n = 2241) and after 2.5 years follow-up in patients without baseline CI (n = 1312)., Results: Higher DSDRS was associated with a higher probability of CI at baseline (OR = 1.17 per point, 95% CI 1.12-1.22) and follow-up (OR = 1.24 per point, 95% CI 1.14-1.35). Moreover, in patients without baseline CI, higher DSDRS was also associated with lower baseline cognitive performance (MMSE: F(1, 1930) = 47.07, p < .0001, R 2  = 0.02); A&E z-score: (F(1, 1871) = 33.44 p < .0001, R 2  = 0.02) and faster cognitive decline at follow-up (MMSE: F(3, 1279) = 38.41, p < .0001; A&E z-score: F(3, 1206) = 148.48, p < .0001)., Conclusions: The DSDRS identifies patients with T2D at risk of concurrent as well as future CI. The DSDRS may thus be a supportive tool in screening strategies for cognitive dysfunction in patients with T2D., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: G.J.B.'s institution receives study grants from Boehringer Ingelheim. O.E.J. is an employee of Boehringer Ingelheim. No other potential conflicts of interest relevant to this article were reported., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: We aimed to establish sex differences in vascular brain damage of memory clinic patients with possible vascular cognitive impairment (VCI)., Methods: A total of 860 memory clinic patients (aged 67.7 ± 8.5; 46% female) with cognitive complaints and vascular brain damage (ie, possible VCI) from the prospective TRACE-VCI (Utrecht-Amsterdam Clinical Features and Prognosis in Vascular Cognitive Impairment) cohort study with 2-year follow-up were included. Age-adjusted female-to-male differences were calculated with general linear models, for demographic variables, vascular risk factors, clinical diagnosis, cognitive performance, and brain magnetic resonance imaging markers., Results: We found no difference in age nor distribution of clinical diagnoses between females and males. Females performed worse on the MMSE (Mini-Mental State Examination) and CAMCOG (Cognitive and Self-Contained Part of the Cambridge Examination for Mental Disorders of the Elderly). Females had a larger white matter hyperintensity volume, while males more often showed (lacunar) infarcts. There was no difference in microbleed prevalence. Males had smaller normalized total brain and gray matter volumes. During follow-up, occurrence of cognitive decline and institutionalization was comparable, but mortality was higher in males., Discussion: Our results suggest that susceptibility and underlying etiology of VCI might differ by sex. Males seem to have more large vessel brain damage compared to females that have more small vessel brain damage., (© 2020 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Introduction: Prognostication in memory clinic patients with vascular brain injury (eg possible vascular cognitive impairment [VCI]) is often uncertain. We created a risk score to predict poor clinical outcome., Methods: Using data from two longitudinal cohorts of memory clinic patients with vascular brain injury without advanced dementia, we created (n = 707) and validated (n = 235) the risk score. Poor clinical outcome was defined as substantial cognitive decline (change of Clinical Dementia Rating ≥1 or institutionalization) or major vascular events or death. Twenty-four candidate predictors were evaluated using Cox proportional hazard models., Results: Age, clinical syndrome diagnosis, Disability Assessment for Dementia, Neuropsychiatric Inventory, and medial temporal lobe atrophy most strongly predicted poor outcome and constituted the risk score (C-statistic 0.71; validation cohort 0.78). Of note, none of the vascular predictors were retained in this model. The 2-year risk of poor outcome was 6.5% for the lowest (0-5) and 55.4% for the highest sum scores (10-13)., Discussion: This is the first, validated, prediction score for 2-year clinical outcome of patients with possible VCI., (© 2020 the Alzheimer's Association.)

Introduction: It is unknown whether different types of small vessel disease (SVD), differentially relate to brain atrophy and if co-occurring Alzheimer's disease pathology affects this relation., Methods: In 725 memory clinic patients with SVD (mean age 67 ± 8 years, 48% female) we compared brain volumes of those with moderate/severe white matter hyperintensities (WMHs; n = 326), lacunes (n = 132) and cerebral microbleeds (n = 321) to a reference group with mild WMHs (n = 197), also considering cerebrospinal fluid (CSF) amyloid status in a subset of patients (n = 488)., Results: WMHs and lacunes, but not cerebral microbleeds, were associated with smaller gray matter (GM) volumes. In analyses stratified by CSF amyloid status, WMHs and lacunes were associated with smaller total brain and GM volumes only in amyloid-negative patients. SVD-related atrophy was most evident in frontal (cortical) GM, again predominantly in amyloid-negative patients., Discussion: Amyloid status modifies the differential relation between SVD lesion type and brain atrophy in memory clinic patients., Competing Interests: There are no conflicts of interest for any of the authors., (© 2020 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, Inc. on behalf of Alzheimer's Association.)

Background: We investigated the association between white matter hyperintensity location and depressive symptoms in a memoryclinic population using lesion–symptom mapping., Methods: We included 680 patients with vascular brain injury from the TRACE-VCI cohort (mean age ± standard deviation: 67 ± 8 years; 52% female): 168 patients with subjective cognitive decline, 164 with mild cognitive impairment and 348 with dementia. We assessed depressive symptoms using the Geriatric Depression Scale. We applied assumptionfree voxel-based lesion–symptom mapping, adjusted for age, sex, total white matter hyperintensity volume and multiple testing. Next, we applied exploratory region-of-interest linear regression analyses of major white matter tracts, with additional adjustment for diagnosis., Results: Voxel-based lesion–symptom mapping identified voxel clusters related to the Geriatric Depression Scale in the left corticospinal tract. Region-of-interest analyses showed no relation between white matter hyperintensity volume and the Geriatric Depression Scale, but revealed an interaction with diagnosis in the forceps minor, where larger regional white matter hyperintensity volume was associated with more depressive symptoms in subjective cognitive decline (β = 0.26, p < 0.05), but not in mild cognitive impairment or dementia., Limitations: We observed a lack of convergence of findings between voxel-based lesion–symptom mapping and region-of-interest analyses, which may have been due to small effect sizes and limited lesion coverage despite the large sample size. This warrants replication of our findings and further investigation in other cohorts., Conclusion: This lesion–symptom mapping study in depressive symptoms indicates the corticospinal tract and forceps minor as strategic tracts in which white matter hyperintensity is associated with depressive symptoms in memory-clinic patients with vascular brain injury. The impact of white matter hyperintensity on depressive symptoms is modest, but it appears to depend on the location of white matter hyperintensity and disease severity., Competing Interests: N. Prins serves on the advisory board of Boehringer Ingelheim and Probiodrug, and on Abbvie’s DSMB M15-566 trial; has provided consultancy services for Sanofi, Takeda and Kyowa Kirin Pharmaceutical Development; receives research support from Alzheimer Nederland (project number WE.03-2012-02); and is the CEO and co-owner of Brain Research Centre, Amsterdam, the Netherlands. P. Scheltens has acquired grant support (for the institution) from GE Healthcare and Piramal; and in the past 2 years he has received consultancy/speaker fees (paid to the institution) from Medavante, Novartis, Probiodrug, Biogen, Roche, Toyama and EIP Pharma. F. Barkhof serves as a consultant for Biogen-Idec, Janssen Alzheimer Immunotherapy, Bayer-Schering, Merck-Serono, Roche, Novartis, Genzyme and Sanofi-aventis; has received sponsoring from EU-H2020, NWO, SMSR, TEVA, Novartis, Toshiba and Imi; and serves on the editorial boards of Radiology, Brain, Neuroradiology, MSJ and Neurology. Research programs of W.M. van der Flier have been funded by ZonMW, NWO, EU-FP7, Alzheimer Nederland, Cardiovasculair Onderzoek Nederland, Stichting Dioraphte, Gieskes-Strijbis fonds, Pasman Stichting, Boehringer Ingelheim, Piramal Imaging, Roche BV, Janssen Stellar, Biogen and Combinostics; all funding is paid to her institution. G. Biessels has been funded by the Dutch Heart Association, ZonMW, the Netherlands Organisation for Health Research and Development and European Union Horizon 2020. No other competing interests declared., (© 2019 Joule Inc. or its licensors)

Objective: To determine the occurrence of acute cerebral microinfarcts (ACMIs) in memory clinic patients and relate their presence to vascular risk and cognitive profile, CSF and neuroimaging markers, and clinical outcome., Methods: The TRACE-VCI study is a memory clinic cohort of patients with vascular brain injury on MRI (i.e., possible vascular cognitive impairment [VCI]). We included 783 patients (mean age 67.6 ± 8.5, 46% female) with available 3T diffusion-weighted imaging (DWI). ACMIs were defined as supratentorial DWI hyperintensities <5 mm with a corresponding hypo/isointense apparent diffusion coefficient signal and iso/hyperintense T2*-weighted signal., Results: A total of 23 ACMIs were found in 16 of the 783 patients (2.0%). Patients with ACMIs did not differ in vascular risk or cognitive profile, but were more often diagnosed with vascular dementia (odds ratio [OR] 5.1; 95% confidence interval [CI] 1.4-18.9, p = 0.014). ACMI presence was associated with lower levels of β-amyloid ( p < 0.004) and with vascular imaging markers (lacunar infarcts: OR 3.5, CI 1.3-9.6, p = 0.015; nonlacunar infarcts: OR 4.1, CI 1.4-12.5, p = 0.012; severe white matter hyperintensities: OR 4.8, CI 1.7-13.8, p = 0.004; microbleeds: OR 18.9, CI 2.5-144.0, p = 0.0001). After a median follow-up of 2.1 years, the risk of poor clinical outcome (composite of marked cognitive decline, major vascular event, death, and institutionalization) was increased among patients with ACMIs (hazard ratio 3.0; 1.4-6.0, p = 0.005)., Conclusion: In patients with possible VCI, ACMI presence was associated with a high burden of cerebrovascular disease of both small and large vessel etiology and poor clinical outcome. ACMIs may thus be a novel marker of active vascular brain injury in these patients., (© 2019 American Academy of Neurology.)

Background: Type 2 diabetes mellitus (T2DM) increases the risk of vascular cognitive impairment (VCI). It is unknown which type of vascular lesions and co-morbid etiologies, in particular Alzheimer's disease pathology, are associated with T2DM in patients with VCI, and how this relates to cognition and prognosis., Objective: To compare brain MRI and cerebrospinal fluid (CSF) markers, cognition, and prognosis in patients with possible VCI with and without T2DM., Methods: We included 851 memory clinic patients with vascular brain injury on MRI (i.e., possible VCI) from a prospective cohort study (T2DM: n = 147, 68.4±7.9 years, 63% men; no T2DM: n = 704, 67.6±8.5 years, 52% men). At baseline, we assessed between-group differences in brain MRI abnormalities, CSF markers of Alzheimer's disease, and cognitive profile. After two years follow-up, we compared occurrence of cognitive decline, stroke, and death., Results: The distribution of clinical diagnoses did not differ between patients with and without T2DM. T2DM patients had more pronounced brain atrophy (total and white matter volume), and more lacunar infarcts, whereas microbleeds were less common (all p < 0.05). CSF amyloid-β levels were similar between the groups. T2DM patients performed worse on working memory (effect size: - 0.17, p = 0.03) than those without, whereas performance on other domains was similar. During follow-up, risk of further cognitive decline was not increased in T2DM.∥Conclusion: In patients with possible VCI, presence of T2DM is related to more pronounced brain atrophy and a higher burden of lacunar infarcts, but T2DM does not have a major impact on cognitive profile or prognosis.∥.

Background: Memory clinic patients frequently present with different forms of vascular brain injury due to different etiologies, often co-occurring with Alzheimer's disease (AD) pathology., Objective: We studied how cognition was affected by different forms of vascular brain injury, possibly in interplay with AD pathology., Methods: We included 860 memory clinic patients with vascular brain injury on magnetic resonance imaging (MRI), receiving a standardized evaluation including cerebrospinal fluid (CSF) biomarker analyses (n = 541). The cognitive profile of patients with different forms of vascular brain injury on MRI (moderate/severe white matter hyperintensities (WMH) (n = 398), microbleeds (n = 368), lacunar (n = 188) and non-lacunar (n = 96) infarct(s), macrobleeds (n = 16)) was assessed by: 1) comparison of all these different forms of vascular brain injury with a reference group (patients with only mild WMH (n = 205) without other forms of vascular brain injury), using linear regression analyses also stratified for CSF biomarker AD profile and 2) multivariate linear regression analysis., Results: The cognitive profile was remarkably similar across groups. Compared to the reference group effect sizes on all domains were <0.2 with narrow 95% confidence intervals, except for non-lacunar infarcts on information processing speed (age, sex, and education adjusted mean difference from reference group (β: - 0.26, p = 0.05). Results were similar in the presence (n = 300) or absence (n = 241) of biomarker co-occurring AD pathology. In multivariate linear regression analysis, higher WMH burden was related to a slightly worse performance on attention and executive functioning (β: - 0.08, p = 0.02) and working memory (β: - 0.08, p = 0.04)., Conclusion: Although different forms of vascular brain injury have different etiologies and different patterns of cerebral damage, they show a largely similar cognitive profile in memory clinic patients regardless of co-occurring AD pathology.

Cerebral small vessel disease (CSVD) occurs often in memory clinic patients. Apart from cognitive deficits, these patients can express physical decline, which predicts adverse health outcomes. In this study, we investigated the cooccurrence of clinically relevant impairments in physical performance and CSVD in memory clinic patients. We included 131 patients with vascular brain injury, mild cognitive impairment or Alzheimer disease with available 3T MRI and physical performance scores. CSVD was visually rated according to 3 subtypes and as a total burden score, composed of the presence of white matter hyperintensities (WMH), lacunar infarcts (LI), and cerebral microbleeds (MB). Physical performance was assessed with the Short Physical Performance Battery (SPPB), covering gait speed, balance, and chair stand performance. CSVD markers and impaired physical performance both occurred often. High total CSVD burdens cooccurred with impaired chair stand performances [odds ratio (OR) 2.67; 95% confidence interval (CI) (1.12-6.34)]. WMH cooccurred with impaired SPPB scores (OR, 3.76; 95% CI, 1.68-8.44), impaired gait speeds (OR, 4.11; 95% CI, 1.81-9.31) and impaired chair stand performances (OR, 5.62; 95% CI, 2.29-13.80). In memory clinic patients, high burdens of CSVD, particularly WMH, often cooccur with impairments in physical performance. The presence of WMH should alert clinicians to the presence of these, clinically relevant, physical impairments.

Objective: Retinopathy impacts over one-third of those with diabetes mellitus and is associated with impaired cognitive performance and cerebrovascular lesions in middle-aged adults with type 1 diabetes. However, the association between diabetic retinopathy (DR) and risk of dementia in type 1 diabetes is unknown. We investigated the association between DR and incident dementia in a large, elderly population with type 1 diabetes., Methods: A cohort of 3742 patients with type 1 diabetes aged 50 years and above was followed from January 1, 1996 to September 30, 2015 for incident dementia. DR diagnoses were identified from electronic medical records. Age as timescale Cox proportional hazard models evaluated associations between time-updated DR and dementia risk. Models were adjusted for demographics, severe glycemic events, glycosylated hemoglobin, and vascular comorbidities., Results: Among 3742 patients with type 1 diabetes (47% female, 21% nonwhite), 182 (5%) were diagnosed with dementia during a mean follow-up of 6.2 years. No significant association was found between DR and incident dementia in the main analyses [adjusted Hazard Ratio=1.12; 95% confidence interval, 0.82-1.54), nor among subgroup restricted to those aged 60 years and above or 70 years and above., Conclusions: DR was not associated with risk of dementia, suggesting that pathophysiological processes underlying dementia may be different in type 1 versus type 2 diabetes.

Background: Cerebral microinfarcts (CMIs) are small ischemic lesions that are a common neuropathological finding in patients with stroke or dementia. CMIs in the cortex can now be detected in vivo on 3 Tesla MRI., Objective: To determine the occurrence of CMIs and associated clinical features in patients with possible vascular cognitive impairment (VCI)., Method: 182 memory-clinic patients (mean age 71.4±10.6, 55% male) with vascular injury on brain MRI (i.e., possible VCI) underwent a standardized work-up including 3 Tesla MRI and cognitive assessment. A control group consisted of 70 cognitively normal subjects (mean age 70.6±4.7, 60% male). Cortical CMIs and other neuroimaging markers of vascular brain injury were rated according to established criteria., Result: Occurrence of CMIs was higher (20%) in patients compared to controls (10%). Among patients, the presence of CMIs was associated with male sex, history of stroke, infarcts, and white matter hyperintensities. CMI presence was also associated with a diagnosis of vascular dementia and reduced performance in multiple cognitive domains., Conclusion: CMIs on 3 Tesla MRI are common in patients with possible VCI and co-occur with imaging markers of small and large vessel disease, likely reflecting a heterogeneous etiology. CMIs are associated with worse cognitive performance, independent of other markers of vascular brain injury.

Background: The metabolic syndrome (MetS) refers to a cluster of cardiovascular risk factors that is associated with an increased risk of cognitive impairment and dementia. It is unclear however, if the presence of the MetS is associated with a particular clinical profile or a different prognosis in patients with cognitive complaints or early dementia., Objectives: To compare 1) the clinical profile and 2) the prognosis of patients attending a memory clinic according to the presence or absence of MetS., Design: Longitudinal cohort., Setting: Memory clinic., Participants: We included and followed 86 consecutive patients (average age of 66.7 (SD 9.7)) from the Amsterdam Dementia Cohort with an MMSE>22., Measurements: Clinical profile (neuropsychological examination, brain MRI, cerebrospinal fluid (CSF) biomarkers, clinical diagnosis) on an initial standardized diagnostic assessment was compared according to MetS status. Progression to dementia was assessed in initially nondemented patients (subjective complaints n=40, mild cognitive impairment n=24, follow-up available in 59)., Results: 35 (41%) patients met the MetS criteria. Demographics were similar between patients with or without the MetS. At baseline, diagnosis, cognitive performance, severity of degenerative or vascular abnormalities on MRI, and CSF amyloid and tau levels did not differ between the groups (all p>0.05). Among nondemented patients, however, MetS was associated with worse performance on executive function, attention & speed and visuoconstructive ability (z-scores, p<0.05). During a mean follow-up of 3.4years a similar proportion of patients with (4; 17%) and without (6; 17%) the MetS progressed to dementia (p=0.45)., Conclusion: Among nondemented patients presenting at a memory clinic MetS was associated with slightly worse cognitive performance (worse on tasks assessing executive functions, visuo-constructive ability, attention & speed), but conversion rate to dementia was not increased., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Objective: The objective of this study was to obtain external validation of the only available midlife dementia risk score cardiovascular risk factors , aging and dementia study (CAIDE) constituting age, education, hypertension, obesity, and hyperlipidemia in a larger, more diverse population. Our second aim was to improve the CAIDE risk score by additional midlife risk factors., Methods: This retrospective cohort study was conducted in an integrated health care delivery system. A total of 9480 Kaiser Permanente members who participated in a health survey study (age range, 40-55 years) from 1964 to 1973 were included in this study. Dementia diagnoses from primary care and medical specialist visits were collected from January 1, 1994 to January 16, 2006, using International Classification of Diseases 9 codes 290.0, 290.1 for "possible dementia," and 331.0 and 290.4 for "specialist confirmed dementia." Risk model prediction and validation were examined with the C statistic, net reclassification improvement, and integrated discrimination improvement. Dementia risk per sum score was calculated with Kaplan-Meier estimates., Results: A total of 2767 participants (25%) were diagnosed with any type of dementia, of which 1011 diagnoses (10.7%) were specialist-confirmed diagnoses. Average time between midlife examination and end of follow-up was 36.1 years. The CAIDE risk score replicated well with a C statistic of 0.75, quite similar to the original CAIDE C statistic of 0.78. The CAIDE score also predicted well within different race strata. Other midlife risk factors (central obesity, depressed mood, diabetes mellitus, head trauma, lung function, and smoking) did not improve predictability. The risk score allowed stratification of participants into those with 40-year low (9%) and high (29%) dementia risk., Conclusions: A combination of modifiable vascular risk factors in midlife is highly predictive of the likelihood of dementia decades later. Possible dementia prevention strategies should point to a life course perspective on maintaining vascular health., (Copyright © 2014 The Alzheimer's Association. Published by Elsevier Inc. All rights reserved.)

Objective: It is unclear, if the association between abnormalities in glucose metabolism (dysglycemia) and impaired cognitive functioning is primarily driven by degenerative or vascular brain damage. We therefore examined the relation between dysglycemia and brain volume and vascular lesions on MRI in a memory clinic population., Methods: The relations between markers of glycemia (HbA1c and fasting glucose levels) and normalized brain volume, medial temporal lobe atrophy and vascular lesions (white matter hyperintensities, lacunes) were assessed in 274 consecutive patients attending a memory clinic, using linear regression analyses., Results: Clinical diagnoses were subjective complaints (n=117), mild cognitive impairment (n=62), Alzheimer's disease (n=61) and other type of dementia (n=34). Twenty patients had a history of diabetes. Across the whole study population there was no relation between HbA1c or fasting glucose and the brain MRI measurements, after adjustments for age, sex and diagnostic group. Secondary analyses after stratification by diabetes status, diagnosis and median age (67 years) did not change the results., Conclusion: In this memory clinic population, dysglycemia was not associated with either brain volume or vascular lesions. Apparently, dysglycemia is not associated with a specific class of brain pathology in patients with cognitive complaints., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: Persons with type 2 diabetes are at an increased risk of dementia compared to those without, but the etiology of this increased risk is unclear., Objective: Cerebral microvascular disease may mediate the link between diabetes and dementia. Given the anatomical and physiological similarities between cerebral and retinal microvessels, we examined the longitudinal association between diabetic retinal disease and dementia in patients with type 2 diabetes., Methods: Longitudinal cohort study of 29,961 patients with type 2 diabetes aged ≥60 years. Electronic medical records were used to collect diagnoses and treatment of severe diabetic retinal disease (i.e., diabetic proliferative retinopathy and macular edema) between 1996-1998 and dementia diagnoses for the next ten years (1998-2008). The association between diabetic retinal disease and dementia was evaluated by Cox proportional hazard models adjusted for sociodemographics, as well as diabetes-specific (e.g., diabetes duration, pharmacotherapy, HbA1c, hypoglycemia, hyperglycemia) and vascular (e.g., vascular disease, smoking, body mass index) factors., Results: 2,008 (6.8%) patients had severe diabetic retinal disease at baseline and 5,173 (17.3%) participants were diagnosed with dementia during follow-up. Those with diabetic retinal disease had a 42% increased risk of incident dementia (demographics adjusted Hazards Ratio (HR) = 1.42, 95% Confidence Interval (CI) 1.27, 1.58); further adjustment for diabetes-specific (HR 1.29; 95% CI 1.14, 1.45) and vascular-related disease conditions (HR 1.35; 95% CI 1.21, 1.52) attenuated the relation slightly., Conclusion: Diabetic patients with severe diabetic retinal disease have an increased risk of dementia. This may reflect a causal link between microvascular disease and dementia.

Background: Although patients with type 2 diabetes are twice as likely to develop dementia as those without this disease, prediction of who has the highest future risk is difficult. We therefore created and validated a practical summary risk score that can be used to provide an estimate of the 10 year dementia risk for individuals with type 2 diabetes., Methods: Using data from two longitudinal cohorts of patients with type 2 diabetes (aged ≥60 years) with 10 years of follow-up, we created (n=29,961) and validated (n=2413) the risk score. We built our prediction model by evaluating 45 candidate predictors using Cox proportional hazard models and developed a point system for the risk score based on the size of the predictor's β coefficient. Model prediction was tested by discrimination and calibration methods. Dementia risk per sum score was calculated with Kaplan-Meier estimates., Findings: Microvascular disease, diabetic foot, cerebrovascular disease, cardiovascular disease, acute metabolic events, depression, age, and education were most strongly predictive of dementia and constituted the risk score (C statistic 0·736 for creation cohort and 0·746 for validation cohort). The dementia risk was 5·3% (95% CI 4·2-6·3) for the lowest score (-1) and 73·3% (64·8-81·8) for the highest (12-19) sum scores., Interpretation: To the best of our knowledge, this is the first risk score for the prediction of 10 year dementia risk in patients with type 2 diabetes mellitus. The risk score can be used to increase vigilance for cognitive deterioration and for selection of high-risk patients for participation in clinical trials., Funding: Kaiser Permanente Community Benefit, National Institute of Health, Utrecht University, ZonMw, and Fulbright., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

The risk of dementia is increased in people with type 2 diabetes mellitus (T2DM). This review gives an update on the relation between T2DM and specific dementia subtypes - i.e. Alzheimer's disease and vascular dementia - and underlying pathologies. We will show that while epidemiological studies link T2DM to Alzheimer's disease as well as vascular dementia, neuropathological studies attribute the increased dementia risk in T2DM patients primarily to vascular lesions in the brain. Risk factors for dementia among patients with T2DM are also addressed. Currently, there is evidence that microvascular complications, atherosclerosis and severe hypoglycemic events increase dementia risk. However, for a more complete understanding of risk factors for dementia in T2DM a life time perspective is needed. This should identify which individuals are at increased risk, what are vulnerable periods in life, and what are windows of opportunity for treatment. Currently, there are no DM specific treatments for dementia, but we will review observations from clinical trials that tried to prevent cognitive decline through intensified glycemic control and address other clinical implications of the association between T2DM and dementia., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Objectives: To determine the association between markers of glycemia and cerebrospinal fluid (CSF) amyloid beta 1-42 (Abeta42) and tau levels in patients attending a memory clinic., Design: Cross-sectional study., Setting: Memory clinic., Participants: Two hundred forty-five consecutive patients attending a memory clinic. Clinical diagnoses were subjective cognitive complaints (n=91), mild cognitive impairment (n=62), Alzheimer's disease (n=58), and other dementia (n=34). Twenty-one patients had diabetes mellitus., Measurements: Glycosylated hemoglobin (HbA1c); fasting blood glucose levels; and CSF levels of Abeta42, total tau, and p-tau 181., Results: In regression analyses across the whole study sample adjusted for age, sex, and diagnostic group, there was no relationship between HbA1c or fasting glucose and CSF tau, p-tau 182, or Abeta42 levels. Stratification for diabetes mellitus did not change the results., Conclusion: These observations do not support the hypothesis that the association between dysglycemia and impaired cognitive functioning is mediated through aberrant amyloid or tau metabolism.

Background: White matter lesions (WML) and brain atrophy are often found on MRI in the elderly. Shared vascular risk factors may be an explanation for their concomitance. However, disturbances of white matter integrity could also be involved in the pathogenesis of brain atrophy. Our objective was to systematically review studies that investigated the relation between WML and brain atrophy on MRI, and to investigate whether there is sufficient evidence to indicate that this relation is independent of shared risk factors., Methods: We searched PubMed for studies published in English between 1980 and October 2007, combining search terms for WML and brain atrophy. Articles that studied the relation between WML and brain atrophy were included if they met the following criteria: (1) original study, (2) MRI used for imaging, (3) assessment methods for WML and brain atrophy specified, and (4) a sample size of at least 20 participants. We recorded type and age of the study population, type and assessment of WML and brain atrophy, and variables for which adjustments were made in the analyses., Results: We identified 48 studies that met our inclusion criteria. A significant relation between WML and brain atrophy was found in 37 out of 48 studies. The source of the study population (e.g. clinic or population based) did not affect this relation. However, only 10 studies adjusted for shared risk factors, of which 9 found an association., Conclusions: The majority of studies found an association between WML and brain atrophy, but it is not yet clear if this association is independent of shared risk factors., (Copyright (c) 2009 S. Karger AG, Basel.)