Cerebrovascular Reactivity Across the Entire Brain in Cerebral Amyloid Angiopathy.

BACKGROUND AND OBJECTIVES: Reduced cerebrovascular reactivity is proposed to be a feature of cerebral amyloid angiopathy (CAA) but has not been measured directly. Employing a global vasodilatory stimulus (hypercapnia), this study assessed the relationships between cerebrovascular reactivity and MRI markers of CAA and cognitive function. METHODS: In a cross-sectional study, individuals with probable CAA, mild cognitive impairment, or dementia due to Alzheimer disease and healthy controls underwent neuropsychological testing and an MRI that included a 5% carbon dioxide challenge. Cerebrovascular reactivity was compared across groups controlling for age, sex, and the presence of hypertension, and its associations with MRI markers of CAA in participants with CAA and with cognition across all participants were determined using multivariable linear regression adjusting for group, age, sex, education, and the presence of hypertension. RESULTS: Cerebrovascular reactivity data (mean ± SD) were available for 26 participants with CAA (9 female; 74.4 ± 7.7 years), 19 participants with mild cognitive impairment (5 female; 72.1 ± 8.5 years), 12 participants with dementia due to Alzheimer disease (4 female; 69.4 ± 6.6 years), and 39 healthy controls (30 female; 68.8 ± 5.4 years). Gray and whiter matter reactivity averaged across the entire brain was lower in participants with CAA and Alzheimer disease dementia compared to healthy controls, with a predominantly posterior distribution of lower reactivity in both groups. Higher white matter hyperintensity volume was associated with lower white matter reactivity (standardized coefficient [ß], 95% CI -0.48, -0.90 to -0.01). Higher gray matter reactivity was associated with better global cognitive function (ß 0.19, 0.03-0.36), memory (ß 0.21, 0.07-0.36), executive function (ß 0.20, 0.02-0.39), and processing speed (ß 0.27, 0.10-0.45) and higher white matter reactivity was associated with higher memory (ß 0.22, 0.08-0.36) and processing speed (ß 0.23, 0.06-0.40). CONCLUSIONS: Reduced cerebrovascular reactivity is a core feature of CAA and its assessment may provide an additional biomarker for disease severity and cognitive impairment.

Diagnosing Alzheimer's Disease from Circulating Blood Leukocytes Using a Fluorescent Amyloid Probe.

BACKGROUND: Toxic amyloid-ß (Aß) peptides aggregate into higher molecular weight assemblies and accumulate not only in the extracellular space, but also in the walls of blood vessels in the brain, increasing their permeability, and promoting immune cell migration and activation. Given the prominent role of the immune system, phagocytic blood cells may contact pathological brain materials. OBJECTIVE: To develop a novel method for early Alzheimer's disease (AD) detection, we used blood leukocytes, that could act as "sentinels" after trafficking through the brain microvasculature, to detect pathological amyloid by labelling with a conformationally-sensitive fluorescent amyloid probe and imaging with confocal spectral microscopy. METHODS: Formalin-fixed peripheral blood mononuclear cells (PBMCs) from cognitively healthy control (HC) subjects, mild cognitive impairment (MCI) and AD patients were stained with the fluorescent amyloid probe K114, and imaged. Results were validated against cerebrospinal fluid (CSF) biomarkers and clinical diagnosis. RESULTS: K114-labeled leukocytes exhibited distinctive fluorescent spectral signatures in MCI/AD subjects. Comparing subjects with single CSF biomarker-positive AD/MCI to negative controls, our technique yielded modest AUCs, which improved to the 0.90 range when only MCI subjects were included in order to measure performance in an early disease state. Combining CSF Aß42 and t-Tau metrics further improved the AUC to 0.93. CONCLUSION: Our method holds promise for sensitive detection of AD-related protein misfolding in circulating leukocytes, particularly in the early stages of disease.

Cerebral Amyloid Angiopathy Is Associated With Emotional Dysregulation, Impulse Dyscontrol, and Apathy.

Background Cerebral amyloid angiopathy (CAA) causes cognitive decline, but it is not known whether it is associated with neuropsychiatric symptoms (NPS). Methods and Results Participants with CAA, mild cognitive impairment, mild dementia due to Alzheimer's disease, and normal cognition were recruited from stroke and dementia clinics and community advertising. NPS were captured using the Neuropsychiatric Inventory Questionnaire short form. The number and total severity (number multiplied by severity of each symptom [mild, moderate, or severe]) of NPS were analyzed using generalized linear regression with a negative binomial link and multiple linear regression, adjusting for age, sex, and education. A total of 109 participants (43 with CAA, 15 with Alzheimer's disease, 28 with mild cognitive impairment, and 23 with normal cognition) (mean age 71.1 [SD=7.6]; 53.2% male) were included. The most frequent NPS in CAA were depression/dysphoria (48.8%), irritability/lability (37.2%), agitation/aggression (37.2%), apathy/indifference (34.9%), and anxiety (32.6%). In adjusted models, patients with CAA had 3.2 times (95% CI, 1.7-6.0) more NPS symptoms and 3.1 units (95% CI, 1.0-5.1) higher expected severity score. The number of NPS was similar to patients with mild cognitive impairment (3.2 times higher than controls) but less than in patients with Alzheimer's disease dementia (4.1 times higher than controls). Within patients with CAA, there were 1.20 times (95% CI, 1.01-1.32) more NPS per 1% increase in white matter hyperintensity as a percentage of intracranial volume. Conclusions NPS are common in CAA, with a similar prevalence as in mild cognitive impairment. The association of the total number of NPS with higher white matter hyperintensity volume suggests that white matter damage may underlie some of these symptoms.

Cortical Thickness and Its Association with Clinical Cognitive and Neuroimaging Markers in Cerebral Amyloid Angiopathy.

BACKGROUND: Cerebral amyloid angiopathy (CAA) contributes to brain neurodegeneration and cognitive decline, but the relationship between these two processes is incompletely understood. OBJECTIVE: The purpose of this study is to examine cortical thickness and its association with cognition and neurodegenerative biomarkers in CAA. METHODS: Data were collected from the Functional Assessment of Vascular Reactivity study and the Calgary Normative Study. In total, 48 participants with probable CAA, 72 cognitively normal healthy controls, and 24 participants with mild dementia due to AD were included. Participants underwent an MRI scan, after which global and regional cortical thickness measurements were obtained using FreeSurfer. General linear models, adjusted for age and sex, were used to compare cortical thickness globally and in an AD signature region. RESULTS: Global cortical thickness was lower in CAA compared to healthy controls (mean difference (MD) -0.047 mm, 95% confidence interval (CI) -0.088, -0.005, p = 0.03), and lower in AD compared to CAA (MD -0.104 mm, 95% CI -0.165, -0.043, p = 0.001). In the AD signature region, cortical thickness was lower in CAA compared to healthy controls (MD -0.07 mm, 95% CI -0.13 to -0.01, p = 0.02). Within the CAA group, lower cortical thickness was associated with lower memory scores (R2 = 0.10; p = 0.05) and higher white matter hyperintensity volume (R2 = 0.09, p = 0.04). CONCLUSION: CAA contributes to neurodegeneration in the form of lower cortical thickness, and this could contribute to cognitive decline. Regional overlap with an AD cortical atrophy signature region suggests that co-existing AD pathology may contribute to lower cortical thickness observed in CAA.

Understanding the impact of the COVID-19 pandemic on well-being and virtual care for people living with dementia and care partners living in the community.

The COVID-19 pandemic has necessitated public health measures that have impacted the provision of care for people living with dementia and their families. Additionally, the isolation that results from social distancing may be harming well-being for families as formal and informal supports become less accessible. For those living with dementia and experiencing agitation, social distancing may be even harder to maintain, or social distancing could potentially aggravate dementia-related neuropsychiatric symptoms. To understand the lived experience of social and physical distancing during the COVID-19 pandemic in Canada, we remotely interviewed 21 participants who normally attend a dementia specialty clinic in Calgary, Alberta, during a period where essential businesses were closed and health care had abruptly transitioned to telemedicine. A reflexive thematic analysis was used to analyze the interview and field note data. The impacts of the public health measures in response to the pandemic emerged through iterative analysis in three main categories of experience: (1) personal, (2) health services, and (3) health status (of both persons living with dementia and care partner). Isolation and mental health needs emerged as important impacts to family experiences. This in-depth understanding of the needs and experiences of the pandemic for people living with dementia suggests that innovative means are urgently needed to facilitate provision of remote medicine and also social interaction and integration.

Cerebrovascular reactivity in cerebral amyloid angiopathy, Alzheimer disease, and mild cognitive impairment.

OBJECTIVE: To assess cerebrovascular reactivity in response to a visual task in participants with cerebral amyloid angiopathy (CAA), Alzheimer disease (AD), and mild cognitive impairment (MCI) using fMRI. METHODS: This prospective cohort study included 40 patients with CAA, 22 with AD, 27 with MCI, and 25 healthy controls. Each participant underwent a visual fMRI task using a contrast-reversing checkerboard stimulus. Visual evoked potentials (VEPs) were used to compare visual cortex neuronal activity in 83 participants. General linear models using least-squares means, adjusted for multiple comparisons with the Tukey test, were used to estimate mean blood oxygen level-dependent (BOLD) signal change during the task and VEP differences between groups. RESULTS: After adjustment for age and hypertension, estimated mean BOLD response amplitude was as follows: CAA 1.88% (95% confidence interval [CI] 1.60%-2.15%), AD 2.26% (1.91%-2.61%), MCI 2.15% (1.84%-2.46%), and control 2.65% (2.29%-3.00%). Only patients with CAA differed from controls (p = 0.01). In the subset with VEPs, group was not associated with prolonged latencies or lower amplitudes. Lower BOLD amplitude response was associated with higher white matter hyperintensity (WMH) volumes in CAA (for each 0.1% lower BOLD response amplitude, the WMH volume was 9.2% higher, 95% CI 6.0%-12.4%) but not other groups (p = 0.002 for interaction) when controlling for age and hypertension. CONCLUSIONS: Mean visual BOLD response amplitude was lowest in participants with CAA compared to controls, without differences in VEP latencies and amplitudes. This suggests that the impaired visual BOLD response is due to reduced vascular reactivity in CAA. In contrast to participants with CAA, the visual BOLD response amplitude did not differ between those with AD or MCI and controls.

Cross-sectional and longitudinal differences in peak skeletonized white matter mean diffusivity in cerebral amyloid angiopathy.

OBJECTIVES: To test the hypotheses that peak skeletonized mean diffusivity (PSMD), a measure of cerebral white matter microstructural disruption, is 1) increased in patients with cerebral amyloid angiopathy (CAA) compared to normal control (NC), mild cognitive impairment (MCI), and Alzheimer's disease (AD); 2) associated with neuropsychological test performance among CAA patients; and 3) increased more quickly over one year in CAA than in AD, MCI, and NC. METHODS: Ninety-two participants provided a medical history, completed a neuropsychological assessment, and had a magnetic resonance (MR) exam including diffusion tensor imaging (DTI) from which PSMD was calculated. A 75-minute neuropsychological test battery was used to derive domain scores for memory, executive function, and processing speed. Multivariable analyses controlling for age and sex (and education, for cognitive outcomes) were used to test the study hypotheses. RESULTS: PSMD was higher in the CAA group (mean 4.97 × 10-4 mm2/s) compared to NC (3.25 × 10-4 mm2/s), MCI (3.62 × 10-4 mm2/s) and AD (3.89 × 10-4 mm2/s) groups (p < .01). Among CAA patients, higher PSMD was associated with slower processing speed (estimated -0.22 standard deviation (SD) change in processing speed z score per SD increase in PSMD, 95% CI -0.42 to -0.03, p = .03), higher WMH volume [ß = 0.74, CI 0.48 to 1.00], and higher CAA SVD score [ß = 0.68, CI 0.24 to 1.21] but was not associated with MMSE, executive function, memory, CMB count, or cortical thickness. PSMD increased over 1-year in all groups (p < .01) but without rate differences between groups (p = .66). CONCLUSIONS: PSMD, a simple marker of diffuse global white matter heterogeneity, is increased in CAA. Our findings further support a role for white matter disruption in causing cognitive impairment in CAA.

Cortical Microinfarcts on 3T Magnetic Resonance Imaging in Cerebral Amyloid Angiopathy.

Background and Purpose- Cerebral microinfarcts are small ischemic lesions that are found in cerebral amyloid angiopathy (CAA) patients at autopsy. The current study aimed to detect cortical microinfarcts (CMI) on in vivo 3 Tesla (3T) magnetic resonance imaging (MRI) in CAA patients, to study the progression of CMI over a 1-year period, and to correlate CMI with markers of CAA-related vascular brain injury and cognitive functioning. Methods- Thirty-five CAA patients (mean age, 74.2±7.6 years), 13 Alzheimer disease (AD) patients (67.0±5.8 years), and 26 healthy controls (67.2±9.5 years) participated in the study. All participants underwent a standardized clinical and neuropsychological assessment as well as 3T MRI. CMI were rated according to standardized criteria. Results- CMI were present in significantly more CAA patients (57.1%; median number: 1, range 1-9) than in Alzheimer disease (7.7%) or in healthy controls (11.5%; P<0.001). Incident CMI were observed after a 1-year follow-up. CMI did not correlate with any other MRI marker of CAA nor with cognitive function. Conclusions- In vivo CMI are a frequent finding on 3T MRI in CAA patients, and incident CMI are observable after 1-year follow-up. CMI can be regarded as a new MRI marker of CAA, potentially distinct from other well-established markers. Future larger cohort studies with longitudinal follow-up are needed to elucidate the relationship between CMI and possible causes and clinical outcomes in CAA.

Cerebral Amyloid Angiopathy Is Associated With Executive Dysfunction and Mild Cognitive Impairment.

BACKGROUND AND PURPOSE: Autopsy studies suggest that cerebral amyloid angiopathy (CAA) is associated with cognitive impairment and risk for dementia. We analyzed neuropsychological test data from a prospective cohort study of patients with CAA to identify the prevalence of cognitive impairment and its associations with brain magnetic resonance imaging features and the apolipoprotein E genotype. METHODS: Data were analyzed from 34 CAA, 16 Alzheimer's disease, 69 mild cognitive impairment, and 27 ischemic stroke participants. Neuropsychological test results were expressed as z scores in relation to normative data provided by the test manuals and then grouped into domains of memory, executive function, and processing speed. RESULTS: Mean test scores in CAA participants were significantly lower than norms for memory (-0.44±1.03; P=0.02), executive function (-1.14±1.07; P<0.001), and processing speed (-1.06±1.12; P<0.001). Twenty-seven CAA participants (79%) had mild cognitive impairment based on low cognitive performance accompanied by cognitive concerns. CAA participants had similarly low executive function scores as Alzheimer's disease, but relatively preserved memory. CAA participants' scores were lower than those of ischemic stroke controls for executive function and processing speed. Lower processing speed scores in CAA were associated with higher magnetic resonance imaging white matter hyperintensity volume. There were no associations with the apolipoprotein E ε4 allele. CONCLUSIONS: Mild cognitive impairment is very prevalent in CAA. The overall cognitive profile of CAA is more similar to that seen in vascular cognitive impairment rather than Alzheimer's disease. White matter ischemic lesions may underlie some of the impaired processing speed in CAA.

Constructing the meaning of survivor with former pediatric brain tumor patients.

Although the term survivor is frequently used in cancer discourse, the meaning of survivor and how people identify with this term can be difficult to understand. The purpose of this qualitative study is to explore the meaning of the term survivor from the perspective of young adults who have experienced a pediatric brain tumor (PBT). A constructivist grounded theory was utilized in this study with 6 young adults who had a PBT. This study also used semistructured interviews with participants who also completed reflective journals, which were focused on the survivor concept. Data were analyzed through coding strategies and constant comparative methods. Findings present 4 major themes of process: (a) reviewing the illness experience, (b) qualifying as a survivor, (c) thinking positive, and (d) being changed. These themes are important to consider in the construction, interpretation, and understanding of how the majority of this population do not identify with the current social use of the term survivor. Clearly, there is a need for a clearer understanding of survivor and how it specifically applies to those who have had a PBT. Everyone should remain conscious and consider how a broad, generalizing term such as survivor may influence a person's attitude and advocacy toward their health.