Cerebral Microvascular Disease Research Articles

Silent cerebral microvascular disease and longitudinal risk of cognitive decline in atrial fibrillation

Abstract Background A relationship between silent stroke and cognitive disorder has recently been suggested in patients with nonvalvular atrial fibrillation (NVAF). This research is an exploratory research study to investigate the occurrence of asymptomatic cerebrovascular disorders with NVAF. Methods The SKAF (Silent cerebral microvascular disease and longitudinal risK of cognitive decline in Atrial Fibrillation) study is a prospective, investigator-initiated, multicenter, observational study of Japanese patients with NVAF aged 60 years or older. We had planned to enroll two hundred NVAF patients with no history of symptomatic stroke or dementia, and an anticoagulant therapy with edoxaban is being performed or an anticoagulant therapy is not being performed, and one hundred patients with sinus rhythm, for comparison. We collected patient characteristics, clinical course, the data of head MRI test and cognitive function test (Montreal Cognitive Assessment (MoCA)) at the baseline and the 24 months follow-up. The primary endpoint was the composite of silent ischemic stroke and micro-bleeding over a 24-month follow-up period. The secondary endpoint was cognitive decline over a 24-month follow-up period. Results The study was started in October 2016, with a planned 2-year recruitment period. As of January 31, 2018, a total of 326 patients were enrolled. Of those, 99 patients with sinus rhythm (SR group) and 214 patients with NVAF (NVAF group) were analyzed (male, 193 (62%) patients; age, 72.2±6.5 years). 156 of 195 (80%) patients with NVAF received the anticoagulant therapy with edoxaban. There was no significant difference of the primary composite for the endpoints between two groups (17.4% versus 17.4%; p=1.00). The incidences of silent ischemic stroke and micro-bleeding in SR and NVAF groups over a 24-month follow-up period were 9.3% and 10.8% (p= 0.833), and 8.1% and 9.2% (p=1.00), respectively. The NVAF group exhibited a significantly larger decline in cognition changes in MoCA score than SR group (-0.830 versus 0,000; p=0.0131). Notably, NVAF was found to be associated with cognitive decline. Conclusion The SKAF registry provided an equivalent risk of silent cerebral microvascular disease in patients with SR and NVAF. Clinically, NVAF had an impact on cognitive decline.

Association between uric acid and cognitive function in maintenance hemodialysis patient

Background: Chronic kidney disease (CKD) is an independent risk factor for cognitive dysfunction. Hyperuricemia is prevalent in CKD patients and has been associated with cognitive dysfunction. Hyperuricemia has been associated with an increased risk for cerebral microvascular disease. Aims and Objectives: The study aimed to evaluate the association between uric acid level and cognitive function in maintenance hemodialysis patients. Materials and Methods: The study was conducted on 90 maintenance hemodialysis patients. Serum uric acid (sUA) level was measured in patients on maintenance hemodialysis and cognitive performance was assessed by the Standardized Mini-Mental State Examination score. Results: There was a significant association between sUA level and cognitive function in hemodialysis patients. Patient with higher sUA levels was found to have poor cognitive function (P<0.05). There was a significant negative correlation between sUA and cognitive function which revealed an increase in sUA will decrease the cognitive function (P<0.05). In our study, there was a significant association between sUA and cognitive function in hemodialysis patients. Patients with hyperuricemia had poor cognitive function. Conclusion: In our study, there was a significant association between sUA and cognitive function in hemodialysis patients. Patients with hyperuricemia had poor cognitive function.

Abstract WP186: The Burden of White Matter Hyperintensities on Function Outcomes in Patients Treated for Acute Ischemic Stroke: A Post-Hoc Analysis of the IMS-III Trial

Objective: This study is a post-hoc analysis of the Interventional Management of Stroke (IMS) III trial investigating the burden of white matter hyperintensities (WMH), using the van Swieten Scale (VSS), on functional outcomes for acute ischemic stroke (AIS) patients treated with either intravenous thrombolysis (IVT) or IVT with mechanical thrombectomy (MT). Background: WMH are a well-established marker for underlying cerebral microvascular disease. VSS quantifies the disease burden from zero to four with higher numbers signifying more advanced disease. A higher burden of WMH is associated with poor functional outcomes after IVT. However, early studies regarding WMH and outcomes after MT have been conflicting. Methods: We included IMS-III trial patients in either treatment arm whose VSS was graded on initial brain CT and 90-day function outcomes were not missing. The primary study outcome was a 90-days modified Rankin Scale of 0-2, termed good outcome. Results: There was a total of 656 patients enrolled in the trial and 618 patients were included in this analysis. The VSS grades of WMH range from 0-4 and included 476 (77.02%), 56 (9.06%), 38 (6.15%), 24 (3.88%), and 24 (3.88%) patients, respectively. Overall, higher VSS grade was associated with a lower probability of achieving a good functional outcome, even after adjustments (Figure 1). Of the 142 patients with any degree of WMH, only 22.5% had a good functional outcome compared to 46.6% of 476 patients without WMH (Table 1). Conclusions: Patients enrolled in the IMS-III trial with any burden of WMH on brain CT had a statistically significant lower odds of a good functional outcome compared to patients without WMH.

Microbleed clustering in thalamus sign in CADASIL patients with NOTCH3 R75P mutation.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited cerebral microvascular disease characterized by the development of vascular dementia and lacunar infarctions. This study aimed to identify the genetic and clinical features of CADASIL in Japan. We conducted genetic analysis on a case series of patients clinically diagnosed with CADASIL. Clinical and imaging analyses were performed on 32 patients with pathogenic mutations in the NOTCH3 gene. To assess the presence of cerebral microbleeds (CMBs), we utilized several established rating scales including the Fazekas scale, Scheltens rating scale, and Microbleed Anatomical Rating Scale, based on brain MRI images. Among the 32 CADASIL patients, 24 cases were found carrying the R75P mutation in NOTCH3, whereas the remaining eight cases had other NOTCH3 mutations (R75Q, R110C, C134F, C144F, R169C, and R607C). The haplotype analysis of the R75P mutation uncovered the presence of a founder effect. A brain MRI analysis revealed that cases with the R75P mutation had a significantly higher total number of CMBs, particularly in the thalamus when compared to patients with other NOTCH3 mutations. Among 15 out of 24 cases with the R75P mutation, we observed a notable clustering of CMBs in the thalamus, termed microbleed clustering in thalamus sign (MCT sign). We propose that the MCT sign observed in NOTCH3 R75P-related CADASIL patients may serve as a potentially characteristic imaging feature. This finding offers further insights into the interactions between genotypes and phenotypes between NOTCH3 and CADASIL.

Abstract TP198: Periodontitis Enhances Cerebral Microhemorrhage Development In A Mouse Model Of Hypertension

Introduction: Periodontitis is a highly prevalent disorder that is increasingly recognized as a risk factor for cerebrovascular disease. In this study we examined the role of periodontitis in the development of cerebral microvascular disease. Methods: Hypertension was induced in aged (17 months old) male C57BL/6J mice via infusion of angiotensin II (ATII) at 1000 ng/kg/min via Alzet pump over 4 weeks. Periodontitis was induced by giving P. gingivalis -LPS (20 μg in 2 μL) injections between the first and second maxillary molars on both the right and left sides twice a week for six weeks. At end of six weeks, we collected mouse brains (N=5 each for Hypertension, Periodontitis, Hypertension + Periodontitis, and Control) and performed standard histology using Prussian blue staining to detect cerebral microhemorrhages (CMH) formation at 20x magnification. The average number, total area, and size of Prussian blue-positive deposits were quantified. Results: ATII-induced hypertension in animals (Systolic blood pressure: 113±2 mmHg to 156±3 mmHg, mean+SE, p<0.0001; Diastolic blood pressure: 82±2 mmHg to 119±3 mmHg, p<0.0001). Presence of hypertension produced significant increase in number of CMH compared to controls (1.97±0.29 per cm 2 vs. 1.24±0.20 per cm 2 , p<0.05). Presence of periodontitis did not alter the number of microhemorrhages (1.68±0.13 per cm 2 vs.1.97±0.29 per cm 2 ). However, size of microhemorrhages doubled in the presence of periodontitis with hypertension (10.58±2.55 μm 2 per cm 2 vs. 5.05±1.15 μm 2 per cm 2 , p<0.05). Conclusions: In this mouse model of ATII-induced hypertension, periodontitis appears to increase size of CMH rather than induce development of new lesions. These findings suggest a role for periodontitis in cerebrovascular disease by modifying and exacerbating pre-existing stroke risk factors rather than acting as an independent risk factor.

Abstract TP223: Cerebral Microbleeds In Sickle Cell Disease

Introduction: Stroke due to sickle cell disease is often attributed to large vessel involvement in the disorder. The role of cerebral microvascular disease in sickle cell disease has received little attention. In this study, we examined development of cerebral microvascular lesions in a mouse model of sickle cell disease. We focused on cerebral microhemorrhages, the neuropathologic substrate of cerebral microbleeds. Methods: We studied microvascular disease in a well-characterized mouse model of humanized transgenic sickle (HbSS-BERK) and control (HbAA-BERK) mice expressing >99% human sickle hemoglobin (Hb) and normal human HbA, respectively. HbSS-BERK express human α and βS globins on a mixed genetic background. HbAA-BERK mice express normal human α and βA globin thus producing only normal human hemoglobin A, on the same mixed genetic background as HbSS-BERK. Seven- to nine-month-old mice (N=18 HbSS, N=12 HbAA) were examined. We collected mouse brains and performed standard histology using Prussian blue staining to detect CMH formation at 20x magnification. The average number, total area, and size of Prussian blue-positive deposits were quantified. In separate studies, Toluidine Blue staining was used to identify mast cells. Results: HbSS mice showed approximately 70% more cerebral microhemorrhages than controls (mean±SE of 1.17± 0.22 vs 0.69±0.13 number/cm 2, p=0.04). Lesion size did not differ between HbSS and control mice. Activated mast cells were identified in HbSS mouse brain but not in control mice. Conclusions: In this mouse model of sickle cell disease, HbSS mice demonstrated significantly increased development of cerebral microhemorrhages. These findings emphasize the potential importance of cerebral microvascular disease in sickle cell disease. Cerebral mast cell activation in sickle cell disease may be a novel target for investigation.

Arteriolar neuropathology in cerebral microvascular disease.

Cerebral microvascular disease (MVD) is an important cause of vascular cognitive impairment. MVD is heterogeneous in aetiology, ranging from universal ageing to the sporadic (hypertension, sporadic cerebral amyloid angiopathy [CAA] and chronic kidney disease) and the genetic (e.g., familial CAA, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy [CADASIL] and cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy [CARASIL]). The brain parenchymal consequences of MVD predominantly consist of lacunar infarcts (lacunes), microinfarcts, white matter disease of ageing and microhaemorrhages. MVD is characterised by substantial arteriolar neuropathology involving ubiquitous vascular smooth muscle cell (SMC) abnormalities. Cerebral MVD is characterised by a wide variety of arteriolar injuries but only a limited number of parenchymal manifestations. We reason that the cerebral arteriole plays a dominant role in the pathogenesis of each type of MVD. Perturbations in signalling and function (i.e., changes in proliferation, apoptosis, phenotypic switch and migration of SMC) are prominent in the pathogenesis of cerebral MVD, making 'cerebral angiomyopathy' an appropriate term to describe the spectrum of pathologic abnormalities. The evidence suggests that the cerebral arteriole acts as both source and mediator of parenchymal injury in MVD.

Cerebral microvascular disease and its associated cognitive dysfunction research progress

Cerebral microvascular disease and its associated cognitive dysfunction research progress

Arterial hypertension, cognitive decline and cerebrovascular damage

Abstract Introduction Arterial hypertension has been associated with increased risk of cognitive dysfunction (CD) and dementia explained by the onset of cerebral microvascular disease. However, it is not well known which are true markers of cognitive decline and how to demonstrate them. Purpose We aimed to evaluate cognitive functions and study microvascular disease with cerebral localization in hypertensive patients. Methods Patients over 50 years with arterial hypertension were included. Cognitive status was assessed by using the Mini Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) tests. We selected 50 patients in two groups: 25 patients with mild CD (MoCA <26 points, MMSE >24 points), respectively 25 patients without CD (MoCA ≥26 points, MMSE ≥24 points). In these groups, magnetic resonance imaging (MRI) using GE Optima MR450w 1.5 Tesla of the brain was performed. MRI images with the RadiAnt program were studied and ImageJ was used to measure the area of the thalamus with a method developed by our team, by calculating the total area and hyperintense areas (microvascular damage) in number of pixels. For statistical analysis IBM-SPSS v.26 program was used. Results 585 consecutive hypertensive patients were enrolled, mean age 67.9±9.5 years, 52.1% women, mean blood pressure 135/80±20/11 mmHg (with antihypertensive treatment). The MoCA test identified cognitive impairment in 66.1% of participants (mean scores 20.66±3.9) while the MMSE in 17.1% (mean scores 20.64±3.0). In the subgroup of 50 patients, the mean age was 70.9±5.5 years for the CD group and 69.9±3.9 years for the group without CD (p=0.4, between 59–79 years). No significant difference was detected between groups in mean blood pressure, ambulatory blood pressure, and hypertension duration (18.0±12 years vs. 17.7, p=0.9). Cerebrovascular disease was detected in 48 patients by brain MRI. There was no statistically significant difference between the two groups. The most frequent changes were white matter hyperintensities in 89.6%, enlarged perivascular spaces in 77.1%, and lacunar infarcts in 52.1%. In three cases silent brain infarct was unmasked. In 45 patients, we applied the modified measurement of the thalamic area and a statistically significant difference was detected in the right thalamus area in patients with CD (p=0.009) compared to patients without CD (on the left side p=0.058). Conclusions CD and cerebral microvascular changes were frequently present in hypertensive patients with associated cardiovascular disease in the studied group. At the level of the thalamus with the method developed by our team, we demonstrated that microvascular alterations on the right side are associated with cognitive decline. The methodology developed for the quantitative measurement of the injured thalamic area proved to be objective and repeatable. The innovative method, the analysis of imaging data with pixels is a promising way to continue the research. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Hungarian Academy of Science

Abstract 87: Chronic Kidney Disease Induces Cerebral Microhemorrhages In Aged Mice

Introduction: Chronic kidney disease (CKD) is increasingly recognized as a risk factor of cerebral microvascular disease, but its association with common neuropathologic changes is not well understood. We investigated the relationship between CKD and development of cerebral microhemorrhages (CMH) in a mouse model of aging. We also examined the effect of CKD on endothelial cell function in an in vitro blood-brain barrier (BBB) model. Methods: CKD was produced in aged C57BL/6J mice using an adenine-induced tubulointerstitial nephritis model. We performed standard histology using Prussian blue staining to examine CMH formation. Correlations between CMH burden and serum creatinine levels were assessed. In cell culture studies, human brain microvascular endothelial cells (ihBMECs) derived from induced pluripotent stem cell line IMR90-4 were treated with serum from healthy or CKD patient donors for up to 3 days. Transendothelial electrical resistance (TEER) and tracer (sodium fluorescein) permeability across the ihBMEC monolayer were measured to assess the integrity of the in vitro BBB. Results: CKD induction in aged C57BL/6J mice caused a significant increase in both serum creatinine level (0.09±0.01 mg/dL to 0.43±0.03 mg/dL, p<0.001) and CMH number (p<0.05), without alteration of systolic or diastolic blood pressure. Number of CMH was positively correlated with serum creatinine level (r=0.41, p<0.001). Incubation of CKD serum with ihBMECs significantly reduced TEER by 26% (p<0.05) and increased sodium fluorescein permeability by 100% (p<0.01) across the ihBMEC monolayer. Conclusions: Adenine-induced CKD promotes the development of CMH in aged C57BL/6J mice independent of blood pressure, and extent of CMH development is directly proportional to degree of renal insufficiency. Moreover, serum-derived factors in CKD disrupt BBB integrity in vitro. These findings suggest CKD provokes microvascular injury at the capillary level, leading to CMH formation in this model.

La retina, una ventana de la enfermedad cerebrovascular en la diabetes

Cerebrovascular disease is one of the complications of long-term diabetes mellitus. While the structure and function of the great cerebral vessels may be more easily studied, the cerebral microcirculation is difficult to assess. However, a simple eye fundus examination with an ophthalmoscope enables to visualize the microvascular abnormalities that characterize diabetic retinopathy, which isth e most common microvascular complication of diabetes. The anatomical and functional similarity between retinal and cerebral microcirculation supports the hypothesis that alterations in retinal vascular reactivity could be considered as an early marker of cerebral microvascular dysfunction in diabetes. The initiating factor of diabetic angiopathies is endothelial dysfunction. Endothelial dysfunction results in a reduced bioavailability of nitric oxide (NO), as a consequence of decreased NO synthesis and/or increased production of free oxygen radicals that are NO scavengers. Diabetes also stimulates the production of endothelial-derived contractile factors such as superoxide anions and hydroxyl radicals, endothelin and certain cyclooxygenase (COX) derivatives. COX activation is related to a high level of oxidative stress. Oxidative stress participates in the inflammatory response involved in the diabetic vascular dysfunction. These pathogenic mechanisms have been shown in both cerebral and retinal arteries, mainly through in vitro vascular reactivity studies, suggesting that diabetes induces a profound change in microvascular regulatory mechanisms. The association between the degree of retinal perfusion, brain injuries and altered cognitive function indicates a certain parallelism in the degree of impairment of both retinal and brain circulations. In addition, prospective studies conclude that diabetic retinopathy predicts ischemic cerebrovascular disease independently of other risk factors, supporting the importance of cerebral microvascular disease in diabetics. Further research on the vascular abnormalities is needed to understand the pathogenic mechanisms underlying retinopathies and cerebrovascular disease in diabetes. In the near future, the use of fully automated methods to detect signs of retinopathy will not only facilitate the efficient evaluation of vascular changes in the retina but will also help to reduce cerebral vascular morbidity and mortality.

Cerebral perfusion and the risk of cognitive decline and dementia in community dwelling older people.

The arterial spin labeling-spatial coefficient of variation (sCoV) is a new vascular magnetic resonance imaging (MRI) parameter that could be a more sensitive marker for dementia-associated cerebral microvascular disease than the commonly used MRI markers cerebral blood flow (CBF) and white matter hyperintensity volume (WMHV). 195 community-dwelling older people with hypertension were invited to undergo MRI twice, with a three-year interval. Cognition was evaluated every two years for 6-8 years using the mini-mental state examination (MMSE). We assessed relations of sCoV, CBF and WMHV with cognitive decline during follow-up. We also registered dementia diagnoses, up to 9 years after the first scan. In an additional analysis, we compared these MRI parameters between participants that did and did not develop dementia. 136/195 completed the second scan. sCoV and CBF were not associated with MMSE changes during 6-8 years of follow-up. Higher WMHV was associated with declining MMSE scores (-0.02 points/year/ml, 95%CI=-0.03 to -0.00). ScOv and CBF did not differ between participants who did (n=15) and did not (n=180) develop dementia, whereas higher WMHV was reported in participants who developed dementia after the first MRI (13.3 vs 6.1mL, p<0.001). There were no associations between longitudinal change in any of the MRI parameters and cognitive decline or subsequent dementia. Global sCoV and CBF were less sensitive longitudinal markers of cognitive decline and dementia compared to WMHV in community-dwelling older people with hypertension. Larger longitudinal MRI perfusion studies are needed to identify possible (regional) patterns of cerebral perfusion preceding cognitive decline and dementia diagnosis.

Prevalence of cerebral small vessel disease in a Fabry disease cohort

ObjectiveTo characterize the prevalence of brain ischemia and cerebral small vessel disease in a cohort of patients with Fabry disease (FD) seen at an academic medical center. BackgroundFD is an inherited X-linked lysosomal storage disorder with central nervous system involvement. Limited data are available in the literature on the cerebrovascular neuroimaging findings in FD, and the reported prevalence of stroke symptoms and cerebral small vessel disease has varied widely. Design/methodsBrain MRI was performed in 21 patients with FD followed at University of California Irvine Medical Center. Stroke symptoms were assessed and quantification of cerebral microvascular disease was performed using small vessel disease (SVD) score. Lacunes and deep white matter hyperintensities were scored on a four-point scale of 0 (absent) and 1–3 to account for increasing severity; microbleeds were scored 0 (absent) or 1 (present). The total SVD score is the sum of the three components and ranges from 0 to 7. ResultsNearly 43% (9/21) of our FD cohort (aged 32–81 years, mean = 50) had a SVD score of one or higher, all of whom were aged 50 or more years. The most common MRI-defined SVD was white matter hyperintensities (9/9, 100%), followed by microbleeds (6/9, 66%), and lacunes (3/9, 33%). The three patients with previous strokes had some of the highest SVD scores reported in the cohort (scores 3–5). ConclusionsIn this cohort, the prevalence of SVD (43%) was three times higher than prevalence of stroke symptoms. SVD score was highest in the those who had experienced a stroke. These findings emphasize the importance of routine MRI screening of patients with FD in order to identify and treat high risk patients.

Reader Response: White Matter Hyperintensities Mediate the Association of Nocturnal Blood Pressure With Cognition.

Chesebro et al.1 report dysfunctional circadian variation of systolic blood pressure—reverse dipping, that is, night/day BP > 1—among the hypertensive subset (mean age 64 years) of their Venezuelan cohort, and they link this to periventricular white matter hyperintensities and decreased memory. In 2019, we reported associations between reverse dipping of diastolic blood pressure and both cerebral microvascular disease and decreased cognition—overall cognitive status and test of language—in an elderly (aged 90+ years) California cohort.2 We found this association for all participants—which included 64% hypertensives by history and 45% by measurement—and for all white matter disease, rather than just periventricular disease. Although the location of white matter disease may be relevant, previous work suggests periventricular, deep, and total white matter hyperintensities are highly correlated.3 We also described linkage of reverse dipping with cerebral microbleeds. The findings of these 2 groups, working independently of each other in 2 very different populations, emphasize the likely validity of the primary findings. An important implication of these articles relates to the timing of hypertension medications and whether patients may benefit from a nighttime dosing regimen.4 In addition, tract-specific location analysis of white matter hyperintensities may be fruitful for further investigation.5

Characteristics, outcomes, and risk factors of ICANS after axicabtagene ciloleucel: Does age matter?

e19556 Background: CD19 chimeric antigen receptor T cell therapy possesses unique side effects including cytokine release syndrome (CRS) and immune effector cell associated neurotoxicity syndrome (ICANS). Age is a major risk factor for ICANS. However, whether ICANS in older patients is different compared to younger patients is unknown. Herein, we report clinical course, outcomes and risk factors for ICANS in older patients with large B cell lymphoma (LBCL) treated with axicabtagene ciloleucel (axi-cel). Methods: We comprehensively reviewed detailed clinical courses of ICANS in 78 adult patients with LBCL treated with axi-cel between June 2016 and October 2020. Incidence, manifestation, risk factors, treatment, and outcomes of ICANS were compared between patients age ≥60 (n=32) and &lt;60 (n=46) years old. Results: Baseline characteristics were comparable between older and younger patients except higher proportion of high international prognostic index and underlying cerebral microvascular disease in older patients. ICANS was observed in 16 patients in the older and 24 patients in the younger age group, with a 30-day incidence of 52% and 50%, respectively. Median time to CRS and ICANS were similar between 2 age groups. The most common initial neurological findings included aphasia, dysgraphia and encephalopathy in both age groups. Table summarizes the characteristics, clinical course and interventions of ICANS in older and younger patients. In Cox regression model, the presence of CRS was the only factor associated with ICANS in both age groups. Age, history of central nervous system involvement and cerebral microvascular disease were not associated with ICANS. Importantly, all patients had complete resolution of ICANS. No elderly patients in our cohort experienced seizure as a manifestation of ICANS. Conclusions: In our study, older age was not a risk factor for ICANS. CRS was the only factor associated with ICANS in both younger and older patients. Incidence, clinical course and neurological outcomes of ICANS in older patients treated with axi-cel were comparable to younger patients. [Table: see text]

Restless Legs Syndrome Shows Increased Silent Postmortem Cerebral Microvascular Disease With Gliosis.

BackgroundPatients with restless legs syndrome (RLS) have increased silent microvascular disease by magnetic resonance imaging. However, there has been no previous autopsy confirmation of these magnetic resonance imaging findings. RLS is also frequently associated with inflammatory and immunologically mediated medical disorders. The postmortem cortex in patients with RLS was therefore evaluated for evidence of microvascular and immunological changes.Methods and ResultsTen microvascular injury samples of precentral gyrus in 5 patients with RLS (3 men, 2 women; mean age, 81 years) and 9 controls (2 men, 7 women; mean age, 90 years) were studied by hematoxylin and eosin stains in a blinded fashion. None of the subjects had a history of stroke or neurologic insults. In a similar manner, the following immunohistochemistry stains were performed: (1) glial fibrillary acidic protein (representing gliosis, reactive change of glial cells in response to damage); (2) CD3 (a T‐cell marker); (3) CD19 (a B‐cell marker); (4) CD68 (a macrophage marker); and (5) CD117 (a mast cell marker). Patients with RLS had significantly greater silent microvascular disease (P=0.015) and gliosis (P=0.003). T cells were increased in RLS compared with controls (P=0.009) and tended to colocalize with microvascular disease (P=0.003). Other markers did not differ. There was no correlation between microvascular lesion load and RLS severity or duration.ConclusionsPatients with RLS had statistically significantly more silent cerebral microvascular disease and gliosis than controls compatible with previous magnetic resonance imaging studies and with studies showing a link between RLS and hypertension, clinical stroke, and cardiovascular disease. T‐cell invasion may be a secondary phenomenon.

Diabetic Retinopathy and Cognitive Decline in Older People with Type 2 Diabetes

Objective: Cerebral microvascular disease associated with type 2 diabetes (T2D) may exacerbate the effects of aging on cognitive function. A considerable homology exists between the retinal and cerebral microcirculations. An hypothesized association between diabetic retinopathy (DR) and cognitive decline was examined in older people with T2D. Research design and methods: In our study 54 men and women aged 60-75 years with T2D underwent standard standard retinal examination and a battery of cognitive function tests. A general cognitive ability score (g) was generated by principal components analysis. The Mill-Hill Vocabulary Scale was used to estimate premorbid cognitive ability. DR was graded using Diabetic Retinopathy Scale. Results: A significant relationship was observed with increasing severity of DR (none, mild, and moderate to severe) for most cognitive measures. Participants with moderate-to-severe retinopathy had the worst g and the worst performances on the individual tests. There was a significant interaction between sex and retinopathy for g. In male subjects, the associations of retinopathy with g (and with tests of verbal fluency and processing speed but not memory and nonverbal reasoning) persisted (P < 0.05) when further adjusted for vocabulary (to estimate lifetime cognitive decline), depression, cardiovascular risk factors, and macrovascular disease. Conclusions: DR was independently associated with estimated lifetime cognitive decline in older men with type 2 diabetes, supporting the hypothesis that cerebral microvascular disease may contribute to their observed accelerated age-related cognitive decline. A sex interaction with stronger findings in men requires further confirmation.

The Decreased Complexity of Blood Pressure Dynamics Is Associated With Higher White Matter Lesions in Older Adults

White matter lesions (WML) are highly prevalent in older adults and thought to represent cerebral microvascular disease, contributing to slow gait and dementia. Hypertension is associated with WML. However, the underlying mechanism of this association is unclear. The complex beat-to-beat BP fluctuations represent the influence of BP regulatory mechanisms over multiple time scales. The association between WML and abnormalities in BP regulation may be manifest as a loss of complexity in BP dynamics. The aim of this study is thus to explore the relationships between hypertension, BP complexity, and WML in older adults. Twenty-two older adults with hypertension (SBP>140 mmHg) and 19 age-matched older adults without hypertension (i.e., control) completed this study. Their whole-brain WML were assessed by two neurologists using the Fazekas Scale. Greater score reflects higher WML grade. Each participant completed a 10-minute BP assessment when sitting quietly following the MRI. The continuous SBP and DBP series were recorded, and the complexity of them was quantified using multiscale entropy (MSE). Lower MSE reflects lower complexity. Compared to the controls, hypertensives had significantly greater Fazekas scores (i.e., higher WML grade) (F=4.8, p=0.02) and lower complexity of SBP and DBP (F>3.7, p<0.01), after adjusting for age. Across two cohorts, those with lower SBP and DBP complexity had higher Fazekas score (r<-0.51, p<0.01), and this association was independent of age and group. These results suggest that WML are associated with a loss of complexity in BP dynamics. Future longitudinal studies are needed to examine the causal relationship between WML and BP.

Greater apathy is associated with faster rate of cognitive decline in older adults with type 2 diabetes

AbstractBackgroundAlthough depression is known to be highly associated with cognitive impairment and dementia, it is unclear how its different dimensions affect cognition. Here, we examined the relationships between baseline dimensions of depression with cognitive decline in a sample of initially non‐demented older adults with type 2 diabetes (T2D) participating in the Israel Diabetes and Cognitive Decline (IDCD) study.MethodsSubjects [n=1023; mean age= 71.6 (SD= 4.6); 41.1% female] completed the 15‐item geriatric depression scale (GDS) at baseline and a neuropsychological battery approximately every 18 months. Cognitive domains included episodic memory, attention/working memory, executive functions, and language/semantic categorization. Global cognition was the average of the four domains z‐scores. The GDS dimensions were defined as Dysphoric Mood, Withdrawal–Apathy–Vigor (WAV), Anxiety, Hopelessness and Memory Complaint, based on previous studies. Mixed regression models adjusting for age, sex, and education assessed associations of baseline depression dimensions with cognitive decline.ResultsCross‐sectionally, there were numerous associations between depression dimensions and cognitive outcomes (Table 1). Overtime, WAV was significantly associated with greater decline in global cognition (p=0.004), executive function (p=0.002) and episodic memory (p=0.039). Dysphoric mood was associated with a faster rate of episodic memory decline (p=0.022). Anxiety was not associated with neither cross sectional nor longitudinal cognitive outcomes. Adjusting for cardiovascular risk factors did not alter substantively the results.ConclusionSimilar to non‐diabetic populations, different dimensions of depression in T2D elderly were associated with variable cognitive outcomes. Longitudinally, among the aspects of depression, apathy was consistently associated with greater rate of cognitive decline. This highlights the possibility of shared mechanisms between depression and dementia, an example of which could be cerebral microvascular disease, which is highly prevalent in T2D patients.

Cognitive indices correlate with [18F]GTP1 tau PET signal and white matter hyperintensities in prodromal‐to‐mild Alzheimer's disease: Baseline data from the Tauriel Study

AbstractBackgroundIn prior cross‐sectional studies using [18F]GTP1 or other tau PET tracers across a spectrum of Alzheimer’s disease (AD) severity, tau PET signal has independently correlated with cognition, even after adjustments for β‐amyloid (Aβ) load and atrophy. However, it remains uncertain how robust these correlations are in more homogeneous patient populations (e.g., clinical trial participants) and after adjustment for MRI white‐matter hyperintensities (WMH). We sought to address this question by examining baseline data from the Phase 2 Tauriel study (NCT03289143), which is investigating the safety and efficacy of semorinemab (an anti‐tau antibody) in prodromal‐to‐mild AD.MethodWe analyzed data from a subset of Tauriel participants who underwent baseline [18F]GTP1 tau PET imaging and met criteria for probable AD dementia (n=244) or mild cognitive impairment (MCI; n=137), with MMSE of 20‐30, global Clinical Dementia Rating (CDR) of 0.5 or 1, significant Aβ pathology (PET or CSF), and significant episodic memory impairment on the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Other screening/baseline assessments included the 13‐item version of the Alzheimer’s Disease Assessment Scale‐Cognitive Subscale (ADAS‐Cog13) and MRI (WMH scored with Fazekas scale). Relationships between cognitive indices, whole cortical gray (WCG) [18F]GTP1 SUVR, WMH, and age were assessed using Pearson correlations and multiple linear regression.ResultUnivariate analyses revealed significant correlations between all cognitive indices [MMSE, CDR Sum of Boxes, ADAS‐Cog13, and RBANS] and [18F]GTP1 SUVR across the whole cortical gray (WCG; p’s&lt;0.001). Significant univariate correlations were also seen between WMH and ADAS‐Cog13 scores (p=0.035) and between age and RBANS scores (p&lt;0.001). Multivariate linear regression analyses that included all three factors consistently identified both WCG [18F]GTP1 SUVR and WMH as independent predictors of cognitive performance across all indices (p’s&lt;0.05), with a much larger proportion of variance attributable to WCG [18F]GTP1 SUVR.ConclusionAmongst participants with prodromal‐to‐mild AD enrolled in the Tauriel study, [18F]GTP1 tau PET signal was more strongly associated with baseline cognitive performance than the extent of WMH. These data suggest that even in AD participants with co‐morbid cerebral microvascular ischemic disease, therapeutic interventions targeting tau have the potential to ameliorate subsequent cognitive decline.