Raoul P. Kloppenborg

Type 2 diabetes mellitus, hypertension, dyslipidemia and obesity: A systematic comparison of their impact on cognition

Vascular risk factors, such as type 2 diabetes mellitus, hypertension, dyslipidemia and obesity, have been associated with an increased risk of cognitive dysfunction, particularly in the elderly. The aim of this systematic review was to compare these risk factors with regard to the nature and magnitude of the associated cognitive decrements. Cross-sectional and longitudinal studies that assessed cognitive functioning in non-demented persons in relation to diabetes/impaired glucose metabolism (k = 36), hypertension (k = 24), dyslipidemia (k = 7) and obesity (k = 6) and that adjusted or matched for age, gender and education were included. When possible, effect sizes (Cohens d) were computed per cognitive domain. Diabetes and hypertension were clearly associated with cognitive decrements; the results for obesity and dyslipidemia were less consistent. Effect sizes were moderate (median approximately -0.3) for all risk factors. Decline was found in all cognitive domains, although the effects on cognitive speed, mental flexibility and memory were most consistent. Methodological aspects of included studies and implications of these findings are discussed.

Presence and progression of white matter hyperintensities and cognition A meta-analysis

Objective: We aimed to quantify the effects of white matter hyperintensities (WMHs) on specific cognitive functions with particular attention to WMH progression and localization. Methods: PubMed (January 1990–July 2013) and bibliographies from included articles were used. Studies that were included (1) used MRI; (2) had a population-based or case-control design with a healthy control group that could be used for analysis; (3) matched/adjusted for age, sex, and education; and (4) addressed ≥1 predefined cognitive domains with ≥1 validated neuropsychological tests. Data were independently extracted by 2 investigators. Pearson r was extracted/calculated and used as the common metric for the effect size across studies. Results: Twenty-three cross-sectional and 14 longitudinal studies were included with a total of 8,685 and 7,731 participants. Presence of WMHs was significantly associated with concurrent cognitive deficits in all examined domains: general intelligence (Fisher z −0.10, 95% confidence interval [CI] −0.19 to −0.04), memory (−0.08, −0.13 to −0.06), processing speed (−0.11, −0.17 to −0.07), attention and executive functions (−0.11, −0.16 to −0.07), and perception/construction (−0.15, −0.21 to −0.07). Similar effect sizes were observed for cognitive decline over time. WMH progression was associated with greater cognitive decline, particularly for general intelligence (Fisher z −0.31, 95% CI −0.5 to −0.02) and attention and executive functions (−0.32, −0.34 to −0.28). Conclusions: The small but robust and consistent effects of WMHs on all cognitive domains suggest a more global effect on cognition than previously thought. Progression of WMHs was associated with even worse cognitive functioning, most pronounced in attention and executive functioning.

Cerebral Small Vessel Disease and Risk of Death, Ischemic Stroke, and Cardiac Complications in Patients With Atherosclerotic Disease The Second Manifestations of ARTerial Disease-Magnetic Resonance (SMART-MR) Study

Background and Purpose— Cerebral small vessel disease may be related to vascular and nonvascular pathology. We assessed whether lacunar infarcts and white matter lesions on MRI increased the risk of vascular and nonvascular death and future vascular events in patients with atherosclerotic disease. Methods— Brain MRI was performed in 1309 patients with atherosclerotic disease from the Second Manifestations of ARTerial disease-Magnetic Resonance (SMART-MR) study. Infarcts were scored visually and volumetric assessment of white matter lesion was performed. Patients were followed for a median of 4.5 years (range, 0.2 to 7.1 years) for death, ischemic stroke, and ischemic cardiac complications. Results— Cox regression models showed that presence of lacunar infarcts (n=229) increased the risk of vascular (hazard ratio, 2.6; 95% CI, 1.4 to 4.9) and nonvascular death (hazard ratio, 2.7; 95% CI, 1.3 to 5.3), adjusted for age, sex, vascular risk factors, nonlacunar infarcts, and white matter lesion. These risks were similar for patients with silent lacunar infarcts. White matter lesion volume (relative to total intracranial volume) increased the risk of vascular death (hazard ratio per milliliter increase, 1.03; 95% CI, 1.01 to 1.05) and white matter lesions in the upper quintile compared with lower quintiles increased risk of ischemic stroke (hazard ratio, 2.6; 95% CI, 1.3 to 4.9). Conclusions— Cerebral small vessel disease, with or without a history of cerebrovascular disease, is associated with increased risk of death and ischemic stroke in patients with atherosclerotic disease.

Steroid responsive encephalopathy in cerebral amyloid angiopathy: a case report and review of evidence for immunosuppressive treatment

Cerebral amyloid angiopathy (CAA) is a common but often asymptomatic disease, characterized by deposition of amyloid in cerebral blood vessels. We describe the successful treatment of CAA encephalopathy with dexamethasone in a patient with CAA-related inflammation causing subacute progressive encephalopathy and seizures, which is an increasingly recognized subtype of CAA. The two pathological subtypes of CAA-related inflammation are described and a review of the literature is performed concerning immunosuppressive treatment of CAA-related inflammation with special attention to its pathological subtypes. Immunosuppressive therapy appears to be an appropriate treatment for CAA encephalopathy.

Cerebral small-vessel disease and progression of brain atrophy The SMART-MR study

ABSTRACT Objectives: To investigate whether severity and progression of periventricular and deep white matter lesions (WML) and lacunar infarcts were associated with progression of brain atrophy. Methods: Within the SMART-MR study, a prospective cohort on MRI changes in patients with symptomatic atherosclerotic disease, 565 patients (57 ± 9 years) without large infarcts had vascular screening and 1.5 T MRI at baseline and after a mean follow-up of 3.9 years. With automated brain segmentation, total brain, cortical gray matter, ventricular, and WML volumes were estimated and expressed relative to intracranial volume (%). Lacunar infarcts were rated manually. Results: Using linear regression analyses adjusted for demographics and vascular risk factors, periventricular WML volume at baseline was associated with greater decrease in cortical gray matter volume (B = −1.73%, 95% confidence interval [CI] −3.15% to −0.30%, per 1% WML volume increase) and greater increase in ventricular volume (B = 0.12%, 95% CI 0.04% to 0.20%). Progression of periventricular WML volume corresponded with a greater decrease in cortical gray matter volume (B = −0.45%, 95% CI −0.9% to 0%) and greater increase in ventricular volume (B = 0.15%, 95% CI 0.1% to 0.2%). Presence of lacunar infarcts was associated with greater decline in total brain volume (B = −0.25%, 95% CI −0.49% to −0.01%) and progression of lacunar infarcts with a greater decrease of total brain (B = −0.30%, 95% CI −0.59% to 0.01%) and cortical gray matter volume (B = −0.81%, 95% CI −1.43% to −0.20%). Conclusions: In patients with symptomatic atherosclerotic disease, presence and progression of periventricular WML and lacunar infarcts is associated with greater progression of brain atrophy independent of vascular risk factors.

Homocysteine and cerebral small vessel disease in patients with symptomatic atherosclerotic disease. The SMART-MR study

OBJECTIVE High homocysteine level is a risk factor for atherosclerosis and has been associated with lacunar infarcts (LIs), white matter lesions (WML) and cognitive dysfunction. It is unclear whether homocysteine is associated with cerebral small vessel disease (cSVD) on top of pre-existent atherosclerosis. We evaluated the association between homocysteine and cSVD in a large cohort of patients with symptomatic atherosclerotic disease. METHODS Within the SMART-MR study, a prospective cohort study of patients with symptomatic atherosclerotic disease, we estimated cross-sectional associations of total plasma homocysteine (THCY) and hyperhomocysteinemia (HHCY) with WML volume and presence of LI, using automated brain segmentation in MRIs of 1232 patients and cognitive function in 763 patients. WML were expressed as a logarithmic transformed percentage of total brain volume. RESULTS Linear regression analyses adjusted for age, sex, vascular risk factors and extent of atherosclerosis showed that THCY and HHCY were significantly associated with larger WML volumes (B=0.01%: 95% CI 0.002-0.02%, and B=0.21%: 95% CI 0.04-0.39%). Increasing THCY was significantly associated with an increased risk of LIs (OR 1.04, 95% CI 1.01-1.07, per 1 μmol). Moreover, HHCY was associated with worse cognitive function (B=-0.12: 95% CI -0.22 to -0.01). CONCLUSION In patients with symptomatic atherosclerotic disease, higher homocysteine levels are associated with higher WML volume, presence of LI and slightly worse cognitive function.

Homocysteine and progression of generalized small-vessel disease The SMART-MR Study

Objectives: Assuming the involvement of homocysteine in a generalized small-vessel disease, we investigated the association of homocysteine levels with progression of white matter lesions, lacunar infarcts, and kidney disease. Methods: Within the SMART-MR (Second Manifestations of ARTerial disease–Magnetic Resonance) Study, a prospective cohort study on brain aging in patients with symptomatic atherosclerotic disease, 663 patients (aged 57 ± 9 years) had vascular screening and 1.5-tesla MRI at baseline and after a mean follow-up of 3.9 years. Multiple regression analysis was used to estimate the longitudinal association between total homocysteine level, defined as a continuous variable and as hyperhomocysteinemia (the highest quintile of homocysteine), and progression of white matter lesion volume, lacunar infarcts, and estimated glomerular filtration rate. Results: After adjusting for age, sex, follow-up time, and vascular risk factors, hyperhomocysteinemia was significantly associated with increased risk of white matter lesion progression (odds ratio 2.4, 95% confidence interval [CI] 1.5–4.1) and lower estimated glomerular filtration rate at follow-up (B = −3.4 mL/min, 95% CI −5.9 to −0.9) and borderline significantly associated with new lacunar infarcts (odds ratio 1.8, 95% CI 0.9–3.4). Conclusions: Our findings implicate a role for homocysteine in the development of a generalized small-vessel disease in which both brain and kidney are affected.

Homocysteine, progression of ventricular enlargement, and cognitive decline. The Second Manifestations of ARTerial disease-Magnetic Resonance Study

Homocysteine may be a modifiable risk factor for cognitive decline and brain atrophy, particularly in older persons. We examined whether homocysteine increased the risk for cognitive decline and brain atrophy, and evaluated the modifying effect of age.

Cerebellar infarct patterns: The SMART-Medea study

Objective Previous studies on cerebellar infarcts have been largely restricted to acute infarcts in patients with clinical symptoms, and cerebellar infarcts have been evaluated with the almost exclusive use of transversal MR images. We aimed to document the occurrence and 3D-imaging patterns of cerebellar infarcts presenting as an incidental finding on MRI. Methods We analysed the 1.5 Tesla MRI, including 3D T1-weighted datasets, of 636 patients (mean age 62 ± 9 years, 81% male) from the SMART-Medea study. Cerebellar infarct analyses included an assessment of size, cavitation and gliosis, of grey and white matter involvement, and of infarct topography. Results One or more cerebellar infarcts (mean 1.97; range 1–11) were detected in 70 out of 636 patients (11%), with a total amount of 138 infarcts identified, 135 of which showed evidence of cavitation. The average mean axial diameter was 7 mm (range 2–54 mm), and 131 infarcts (95%) were smaller than 20 mm. Hundred-thirty-four infarcts (97%) involved the cortex, of which 12 in combination with subcortical white matter. No infarcts were restricted to subcortical branches of white matter. Small cortical infarcts involved the apex of a deep (pattern 1) or shallow fissure (pattern 2), or occurred alongside one (pattern 3) or opposite sides (pattern 4) of a fissure. Most (87%) cerebellar infarcts were situated in the posterior lobe. Conclusions Small cerebellar infarcts proved to be much more common than larger infarcts, and preferentially involved the cortex. Small cortical infarcts predominantly involved the posterior lobes, showed sparing of subcortical white matter and occurred in characteristic topographic patterns.

Cerebellar Cortical Infarct Cavities Correlation With Risk Factors and MRI Markers of Cerebrovascular Disease

Background and Purpose— Small cerebellar infarct cavities have been recently found on magnetic resonance imaging (MRI) to preferentially involve the cerebellar cortex, but epidemiological studies are lacking. We aimed to determine the prevalence and risk factor profiles of cerebellar cortical infarct cavities (⩽1.5 cm) as well as their association with MRI markers of cerebrovascular disease and functioning. Methods— We analyzed the 1.5 Tesla MRI of 636 patients (mean age, 62±9 years; 81% men) from the Second Manifestations of Arterial Disease-Memory, Depression and Aging (SMART-Medea) study. Logistic regression analyses were performed to estimate the associations of age, sex, vascular risk factors, MRI markers of cerebrovascular disease, and functioning with cerebellar cortical cavities, adjusted for age and sex. Results— Cerebellar cortical infarct cavities occurred on MRI in 10% of patients and were significantly associated with age, intima-media thickness (odds ratio [OR], 2.0; 95% confidence interval [CI], 1.1–3.7), high levels of homocysteinemia (OR, 1.8; 95% CI, 1.0–3.3), cortical infarcts (OR, 2.9; 95% CI, 1.6–5.4), gray matter lacunes of presumed vascular origin (OR, 3.0; 95% CI, 1.6–5.8), brain stem infarcts (OR, 5.1; 95% CI, 1.9–13.6), and decreased brain parenchymal fraction (OR, 0.84; 95% CI, 0.74–0.94), but not with white matter hyperintensities (OR, 1.2; 95% CI, 0.8–1.8) or white matter lacunes of presumed vascular origin (OR, 1.1; 95% CI, 0.5–2.5). They were also associated with worse physical functioning (OR 0.96; 95% CI, 0.94 to 0.99) but not with mental functioning. Conclusions— Cerebellar cortical infarct cavities are far more common than previously assumed based on symptomatic case series and are associated with markers of atherothromboembolic cerebrovascular disease.