2-(4--(methylamino)phenyl)-6-hydroxybenzothiazole and Cerebral-Small-Vessel-Diseases

To examine the association between brain structural changes and β-amyloid deposition, and incident dementia in 183 elderly subjects without dementia (mean age 85.5 years) 2 years later.. Subjects had a brain structural MRI scan and a PET scan with (11)C-labeled Pittsburgh compound B (PiB) in 2009, and were evaluated clinically in 2011.. At baseline evaluation, of the 183 participants (146 cognitively normal [CN]); 37 mild cognitive impairment [MCI]), 139 (76%) were PiB+, had small hippocampal volume (<25th percentile), or had high white matter lesion (WML) volume (>75th percentile). Two years later, 111 (61%) were classified as CN, 51 (28%) as MCI, and 21 (11%) as dementia. At baseline, 51% of the CN participants and 67.5% of the MCI cases were PiB+. Thirty percent of the CN and 51% of the MCI cases had small hippocampi, and 24% of the CN and 40.5% of the MCI cases had abnormal WMLs. Of the 21 participants who progressed to dementia, 20 (95%) had at least one imaging abnormality. Only 3 (14%) were only PiB+, 1 (5%) had only small hippocampi, 1 (5%) had only WMLs, 1 (5%) was biomarker negative, and the other 16 had various pairs of imaging abnormalities. Continuous variables of PiB retention, left and right hippocampal volume, and WML volume were independent predictors of dementia in a logistic regression analysis controlling for age, sex, education level, and Mini-Mental State Examination scores.. The prevalence of β-amyloid deposition, neurodegeneration (i.e., hippocampal atrophy), and small vessel disease (WMLs) is high in CN older individuals and in MCI. A combination of 2 or 3 of these factors is a powerful predictor of short-term incidence of dementia.

Topics: Aged, 80 and over; Amyloid; Aniline Compounds; Brain; Cerebral Small Vessel Diseases; Cognitive Dysfunction; Dementia; Disease Progression; Double-Blind Method; Female; Geriatric Assessment; Ginkgo biloba; Humans; Longitudinal Studies; Male; Neurodegenerative Diseases; Phytotherapy; Plant Extracts; Positron-Emission Tomography; Predictive Value of Tests; Thiazoles

African Americans are at greater risk for developing Alzheimer's disease (AD) dementia than non-Hispanic whites. In addition to biological considerations (eg, genetic influences and comorbid disorders), social and environmental factors may increase the risk of AD dementia. This paper (1) assesses neuroimaging biomarkers of amyloid (A), tau (T), and neurodegeneration (N) for potential racial differences and (2) considers mediating effects of socioeconomic status (SES) and measures of small vessel and cardiovascular disease on observed race differences.. Imaging measures of AT(N) (amyloid and tau positron emission tomography [PET]) structural magnetic resonance imaging (MRI), and resting state functional connectivity (rs-fc) were collected from African American (n = 131) and white (n = 685) cognitively normal participants age 45 years and older. Measures of small vessel and cardiovascular disease (white matter hyperintensities [WMHs] on MRI, blood pressure, and body mass index [BMI]) and area-based SES were included in mediation analyses.. Compared to white participants, African American participants had greater neurodegeneration, as measured by decreased cortical volumes (Cohen's f. Modifiable factors, such as differences in social contexts and resources, particularly area-level SES, may contribute to observed racial differences in AD. Future studies should emphasize collection of relevant psychosocial factors in addition to the development of intentional diversity and inclusion efforts to improve the racial/ethnic and socioeconomic representativeness of AD studies. ANN NEUROL 2021;89:254-265.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Black or African American; Brain; Carbolines; Cerebral Small Vessel Diseases; Ethylene Glycols; Female; Functional Neuroimaging; Humans; Magnetic Resonance Imaging; Male; Mediation Analysis; Middle Aged; Neuroimaging; Positron-Emission Tomography; Radiopharmaceuticals; Social Class; tau Proteins; Thiazoles; White

To test the hypothesis that patients with concomitant lobar and deep intracerebral hemorrhages/microbleeds (mixed ICH) have predominantly hypertensive small vessel disease (HTN-SVD) rather than cerebral amyloid angiopathy (CAA), using in vivo amyloid imaging.. Eighty Asian patients with primary ICH without dementia were included in this cross-sectional study. All patients underwent brain MRI and. Patients with mixed ICH were younger (62.8 ± 11.7 vs 73.3 ± 11.9 years in CAA,. Patients with mixed ICH have much lower amyloid load than patients with CAA-ICH, while being similar to HTN-ICH. Overall, mixed ICH is probably caused by HTN-SVD, an important finding with clinical relevance.

Topics: Aged; Aged, 80 and over; Aniline Compounds; Brain; Cerebral Amyloid Angiopathy; Cerebral Hemorrhage; Cerebral Small Vessel Diseases; Cross-Sectional Studies; Female; Humans; Intracranial Hemorrhage, Hypertensive; Magnetic Resonance Imaging; Male; Middle Aged; Positron-Emission Tomography; Taiwan; Thiazoles

Recent evidence suggests that combining individual imaging markers of cerebral small vessel disease (SVD) may more accurately reflect its overall burden and better correlate with clinical measures.. We wished to establish the clinical relevance of the total SVD score in a memory clinic population by investigating the association with SVD score and cognitive performance, cortical atrophy, and structural network measures, after adjusting for amyloid-β burden.. We included 243 patients with amnestic mild cognitive impairment (MCI), Alzheimer's disease dementia, subcortical vascular MCI, or subcortical vascular dementia. All underwent MR and [11C] PiB-PET scanning and had standardized cognitive testing. Multiple linear regression was used to evaluate the relationships between SVD score and cognition, cortical thickness, and structural network measures. Path analyses were performed to evaluate whether network disruption mediates the effects of SVD score on cortical thickness and cognition.. Total SVD score was associated with the performance of frontal (β - 4.31, SE 2.09, p = 0.040) and visuospatial (β - 0.95, SE 0.44, p = 0.032) tasks, and with reduced cortical thickness in widespread brain regions. Total SVD score was negatively correlated with nodal efficiency, as well as changes in brain network organization, with evidence of reduced integration and increasing segregation. Path analyses showed that the associations between SVD score and frontal and visuospatial scores were partially mediated by decreases in their corresponding nodal efficiency and cortical thickness.. Total SVD burden has clinical relevance in a memory clinic population and correlates with cognition, and cortical atrophy, as well as structural network disruption.

Topics: Aged; Aged, 80 and over; Aniline Compounds; Atrophy; Cerebral Cortex; Cerebral Small Vessel Diseases; Cognition Disorders; Cohort Studies; Female; Humans; Image Processing, Computer-Assisted; Magnetic Resonance Imaging; Male; Neural Pathways; Neuropsychological Tests; Positron-Emission Tomography; Thiazoles

Late life depression is related to pathologic burdens, such as cerebral small vascular disease (CSVD) and amyloid, which are associated with brain network changes and cortical thinning. To examine the associations of various CSVD imaging markers, amyloid, and network changes with depression in cognitively impaired patients, we prospectively recruited 228 cognitively impaired patients having various degrees of amyloid and CSVD who underwent diffuse tensor image and PiB PET. Greater CSVD burden was associated with greater Geriatric Depression Scale (GDS) (white matter hyperintensities, WMH: p = 0.025, lacunes: p < 0.001) but not with amyloid (p = 0.095), and cortical thinning (p = 0.630) was not associated with greater GDS. The changes in white matter networks were related to GDS with decreasing integration (global efficiency: p < 0.001) and increasing segregation (clustering coefficient: p = 0.009). The network changes mediated the relationships of WMH and lacunes with GDS. Our findings provide insight to better understand how CSVD burdens contribute to depression in cognitively impaired patients having varying degrees of amyloid and vascular burdens.

Topics: Aged; Amyloid; Aniline Compounds; Brain; Cerebral Small Vessel Diseases; Cognitive Dysfunction; Depression; Diffusion Tensor Imaging; Female; Humans; Male; Organ Size; Phenanthrolines; Positron-Emission Tomography; Prospective Studies; Psychiatric Status Rating Scales; Radiopharmaceuticals; Thiazoles

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid; Amyloidogenic Proteins; Aniline Compounds; Cerebral Small Vessel Diseases; Cognitive Dysfunction; Female; Humans; Male; Middle Aged; Occipital Lobe; Positron-Emission Tomography; Thiazoles

We investigated the amyloid and vascular burden in Pittsburgh compound B (PiB)-negative subcortical vascular mild cognitive impairment (svMCI) and PiB-negative subcortical ischemic vascular dementia (SIVD) to elucidate the potential roles of amyloid deposition and small vessel disease (SVD). Thirty-eight svMCI patients and 42 SIVD patients were enrolled. The regional PiB uptake values and SVD markers were obtained and compared between groups. Additionally, correlations among amyloid burden, SVD, and cognition were made. Patients with PiB-negative SIVD showed more amyloid deposition than those with PiB-negative svMCI, particularly in the cuneus, lingual gyrus, supramarginal, and angular gyri. Despite subthreshold levels for amyloid deposition, our findings showed a marked regional difference in amyloid uptake between svMCI and SIVD, particularly in posteriorly located brain areas. However, lacune, a proxy for vascular burden, showed a broader association with cognition and had more impacts on developing dementia than amyloid burden. The topographical pattern of amyloid deposition and its impact on clinical status in pure subcortical vascular cognitive impairment were different from those in Alzheimer's disease.

Topics: Aged; Aged, 80 and over; Amyloidogenic Proteins; Aniline Compounds; Brain; Brain Mapping; Cerebral Small Vessel Diseases; Cognition; Cognitive Dysfunction; Dementia, Vascular; Female; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Neuroimaging; Thiazoles; Tomography, X-Ray Computed

SEE COHEN DOI101093/AWW183 FOR A SCIENTIFIC COMMENTARY ON THIS ARTICLE: Amyloid-β and cerebral small vessel disease are the two major causes of cognitive impairment in the elderly. However, the underlying mechanisms responsible for precisely how amyloid-β and cerebral small vessel disease affect cognitive impairment remain unclear. We investigated the effects of amyloid-β and lacunes on downstream imaging markers including structural network and cortical thickness, further analysing their relative impact on cognitive trajectories. We prospectively recruited a pool of 117 mild cognitive impairment patients (45 amnestic type and 72 subcortical vascular type), from which 83 patients received annual follow-up with neuropsychological tests and brain magnetic resonance imaging for 3 years, and 87 patients received a second Pittsburgh compound B positron emission tomography analysis. Structural networks based on diffusion tensor imaging and cortical thickness were analysed. We used linear mixed effect regression models to evaluate the effects of imaging markers on cognitive decline. Time-varying Pittsburgh compound B uptake was associated with temporoparietal thinning, which correlated with memory decline (verbal memory test, unstandardized β = -0.79, P < 0.001; visual memory test, unstandardized β = -2.84, P = 0.009). Time-varying lacune number was associated with the degree of frontoparietal network disruption or thinning, which further affected frontal-executive function decline (Digit span backward test, unstandardized β = -0.05, P = 0.002; Stroop colour test, unstandardized β = -0.94, P = 0.008). Of the multiple imaging markers analysed, Pittsburgh compound B uptake and the number of lacunes had the greatest association with memory decline and frontal-executive function decline, respectively: Time-varying Pittsburgh compound B uptake (standardized β = -0.25, P = 0.010) showed the strongest effect on visual memory test, followed by time-varying temporoparietal thickness (standardized β = 0.21, P = 0.010) and time-varying nodal efficiency (standardized β = 0.17, P = 0.024). Time-varying lacune number (standardized β = -0.25, P = 0.014) showed the strongest effect on time-varying digit span backward test followed by time-varying nodal efficiency (standardized β = 0.17, P = 0.021). Finally, time-varying lacune number (β = -0.22, P = 0.034) showed the strongest effect on time-varying Stroop colour test followed by time-varying frontal thickness (standardized β =

Topics: Aged; Amyloid beta-Peptides; Aniline Compounds; Cerebral Cortex; Cerebral Small Vessel Diseases; Cognitive Dysfunction; Executive Function; Female; Humans; Longitudinal Studies; Magnetic Resonance Imaging; Male; Memory Disorders; Positron-Emission Tomography; Stroke, Lacunar; Thiazoles

To determine whether amyloid and hypertensive cerebral small vessel disease (hCSVD) changes synergistically affect the progression of lobar microbleeds in patients with subcortical vascular mild cognitive impairment (svMCI).. Among 72 patients with svMCI who underwent brain MRI and [. Over 3 years, 31 of 52 patients (59.6%) had incident cerebral microbleeds (CMBs) in the lobar and deep regions. Both baseline and longitudinal changes in lacune numbers were associated with increased numbers of lobar and deep microbleeds, while baseline and longitudinal changes in PiB uptake ratio were associated only with the progression of lobar microbleeds, especially in the temporal, parietal, and occipital areas. Regional white matter hyperintensity severity was also associated with regional lobar CMBs in the parietal and occipital regions. There were interactive effects between baseline and longitudinal lacune number and PiB retention on lobar microbleed progression. Increased lobar, but not deep, CMBs were associated with decreased scores in the digit span backward task and Rey-Osterrieth Complex Figure Test.. Our findings suggest that amyloid-related pathology and hCSVD have synergistic effects on the progression of lobar microbleeds, providing new clinical insight into the interaction between amyloid burden and hCSVD on CMB progression and cognitive decline with implications for developing effective prevention strategies.

Topics: Aged; Amyloidosis; Aniline Compounds; Apolipoproteins E; Brain; Cerebral Hemorrhage; Cerebral Small Vessel Diseases; Disease Progression; Female; Follow-Up Studies; Humans; Incidence; Longitudinal Studies; Magnetic Resonance Imaging; Male; Neuropsychological Tests; Positron-Emission Tomography; Prospective Studies; Radiopharmaceuticals; Thiazoles; White Matter

We sought to determine the incidence and associations of lobar microbleeds (LMBs) in a longitudinal cohort with (11)C-Pittsburgh compound B (PiB) PET imaging.. One hundred seventy-four participants from the observational Australian Imaging, Biomarkers and Lifestyle Study of Ageing (97 with normal cognition [NC], 37 with mild cognitive impairment [MCI], and 40 with Alzheimer disease [AD] dementia) were assessed at 3 time points over 3 years with 3-tesla susceptibility-weighted MRI and (11)C-PiB PET. MRIs were inspected for microbleeds, siderosis, infarction, and white matter hyperintensity severity, blind to clinical and PiB findings. Neocortical PiB standardized uptake value ratio, normalized to cerebellar cortex, was dichotomized as positive or negative (PiB+/-, standardized uptake value ratio >1.5). Annualized LMB incidence was calculated, and logistic regression was used to determine the association of incident LMBs with PiB, APOE ε4+ status, and cerebrovascular disease.. LMBs were present in 18.6% of NC, 24.3% of MCI, and 40% of AD participants (p < 0.05 vs NC). LMB incidence was 0.2 ± 0.6 per year in NC participants, 0.2 ± 0.5 in MCI, and 0.7 ± 1.4 in AD (p < 0.03 vs NC) and was 6-fold higher in PiB+ than PiB-NC. Incident LMBs were associated with age, APOE ε4+, PiB+, and baseline LMBs. Incidence of multiple LMBs was also associated with lacunar infarction and white matter hyperintensity severity.. Older age, baseline LMBs, higher β-amyloid burden, and concomitant cerebrovascular disease may all confer higher risk of incident LMBs. This should be considered when designing protocols for amyloid-modifying clinical trials.

Topics: Adult; Aged; Aged, 80 and over; Alzheimer Disease; Amyloid; Aniline Compounds; Australia; Brain; Cerebral Small Vessel Diseases; Female; Humans; Incidence; Intracranial Hemorrhages; Magnetic Resonance Imaging; Male; Middle Aged; Positron-Emission Tomography; Thiazoles