Microvascular disease in cognitive impairment

Abstract

Background: Cerebral small vessel disease has been recognized as the greatest vascular contributor to dementia. Previously, small vessel disease was thought to be part of normal aging. With more advanced imaging techniques, however, it was noted that imaging manifestations of small vessel disease were more commonly seen in patients with dementia compared to cognitively healthy populations. Because of the !arge burden of small vessel disease in dementia, it has been hypothesized that these imaging markers may play an important role in the development of the disease, and may be an important pathway to target to slow clown or prevent the development of dementia, for which there is currently no cure.

Purpose: We aimed to explore various imaging markers of cerebral small vessel disease in a memory clinic population, and study their prevalence, detection on magnetic resonance imaging (MRI) and associations with clinical, imaging and genetic data as well as associations with cerebrospinal fluid (CSF) biomarkers.

Study I: We assessed cortical superficial siderosis in a memory clinic population. 1504 patients undergoing memory clinic investigation were emolled. All patients underwent brain MRI, including susceptibility weighted imaging (SWI) or T2*-weighted gradient-recalled echo sequence (T2*-GRE). A subset of patients were genotyped for Apolipoprotein E (APOE) (n=520) and had CSF analyzed for biomarkers (n=l039). The prevalence ofcortical superficial siderosis was 2.7% and was most commonly located in the occipital lobe. Cortical superficial siderosis was most frequent in vascular dementia, and associated with amyloid plaque pathology in the brain parenchyma, as well as a range of other small vessel disease imaging markers. Cortical superficial siderosis is a marker of cerebrovascular disease and associated with lower levels of CSF amyloid-beta and thus increased amyloid plaque burden in the brain parenchyma consistent with Alzheimer's disease.

Study II: We explored perivascular spaces in a memory clinic population in the same cohort as for study I. A total of 1504 patients were enrolled and all patients had brain MRI done, including SWI/T2*. APOE genotyping was performed for 520 patients and 1039 patients had CSF analyzed for biomarkers. Perivascular spaces were analyzed in the centrum semiovale and basal ganglia, and showed varying associations with other imaging markers of small vessel disease, suggesting differing etiologies. Perivascular spaces in the centrum semiovale were associated with markers of cerebral amyloid angiopathy, and perivascular spaces in the basal ganglia were associated with markers of hypertensive vasculopathy, however, an overlap between perivascular spaces in the two different regions was noted.

Study III: We aimed to investigate the association between metals in the CSF and cerebral microbleeds as well as cortical superficial siderosis in a memory clinic population. 194 patients with CSF analyses for both metals and routine biomarkers were enrolled and all patients had undergone brain MRI, and a subset of patients were genotyped for APOE (n=l02). Higher levels of CSF iron was associated with an increased number of cerebral microbleeds in APOE i::4 carriers. CSF iron and copper were associated with higher levels of P-tau and T-tau, reflecting increased neurofibrillary tangles in the brain and neurodegeneration, respectively. Metals, primarily iron and copper, may contribute to Alzheimer's disease pathology in the shape of neurofibrillary tangles and increased neurodegeneration.

Study IV: We sought to investigate the association between the APOE allele and various MRI markers of small vessel disease. 520 patients with APOE genotyping and brain MRI were enrolled, and a subset of patients had CSF analysis done (11=399). APOE i::4 were associated with markers of cerebral amyloid angiopathy, including lobar cerebral microbleeds, and APOE €2 was associated with markers of hypertensive vasculopathy, including deep and infratentorial microbleeds.

Study V: We aimed to investigate chronic cortical cerebral microinfarcts on 3 Tesla MRI in a memory clinic cohort. A total of 350 patients were enrolled, and all patients had brain MRI done, with a routine memory protocol performed including MPRAGE Tl-weighted sequences. 170 patients had CSF analyzed for biomarkers. Chronic cortical microinfarcts were shown to be common in a memory clinic population with a prevalence of 45% in the whole cohort and were associated with poor cognition as reflected by lower scores on the MMSE. Cortical microinfarcts were also associated with higher levels of P-tau. There were no associations between chronic cortical cerebral microinfarcts and other imaging markers of small vessel disease. Our study shows that cortical microinfarcts can be detected on 3 Tesla MRI and is a common manifestation of small vessel disease in cognitive impairment, and may have a role in the formation of neurofibrillary tangles as seen by the association with higher CSF P-tau levels.

Conclusions: Imaging manifestations of small vessel disease are common in a memory clinic population and show varying associations with small vessel disease imaging markers, clinical data, CSF biomarkers and the APOE allele, which in tum may reflect their differing roles in the pathogenesis of dementia.