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How beta-amyloid accumulation influences brain atrophy in Alzheimer's disease remains contentious with conflicting findings. We aimed to elucidate the correlations of regional longitudinal atrophy with cross-sectional regional and global amyloid in individuals with mild cognitive impairment and no cognitive impairment. We hypothesized that greater cortical thinning over time correlated with greater amyloid deposition, particularly within Alzheimer’s disease characteristic regions in mild cognitive impairment, and weaker or no correlations in those with no cognitive impairment. 45 patients with mild cognitive impairment and 12 controls underwent a cross-sectional [11C]-Pittsburgh Compound B PET and two retrospective longitudinal structural imaging (follow-up: 23.65 ± 2.04 months) to assess global/regional amyloid and regional cortical thickness, respectively. Separate linear mixed models were constructed to evaluate relationships of either global or regional amyloid with regional cortical thinning longitudinally. In patients with mild cognitive impairment, regional amyloid in the right banks of the superior temporal sulcus was associated with longitudinal cortical thinning in the right medial orbitofrontal cortex (p = 0.04 after False Discovery Rate correction). In the mild cognitive impairment group, greater right banks amyloid burden and less cortical thickness in the right medial orbitofrontal cortex showed greater visual and verbal memory decline over time, which was not observed in controls. Global amyloid was not associated with longitudinal cortical thinning in any locations in either group. Our findings indicate an increasing influence of amyloid on neurodegeneration and memory along the preclinical to prodromal spectrum. Future multimodal studies that include additional biomarkers will be well-suited to delineate the interplay between various pathological processes and amyloid and memory decline, as well as clarify their additive or independent effects along the disease deterioration.

Frontotemporal dementia is clinically and neuropathologically heterogeneous, but neuroinflammation, atrophy and cognitive impairment occur in all of its principal syndromes. Across the clinical spectrum of frontotemporal dementia, we assess the predictive value of in vivo neuroimaging measures of microglial activation and grey-matter volume on the rate of future cognitive decline. We hypothesized that inflammation is detrimental to cognitive performance, in addition to the effect of atrophy. Thirty patients with a clinical diagnosis of frontotemporal dementia underwent a baseline multimodal imaging assessment, including [11C]PK11195 PET to index microglial activation and structural MRI to quantify grey-matter volume. Ten people had behavioural variant frontotemporal dementia, 10 had the semantic variant of primary progressive aphasia and 10 had the non-fluent agrammatic variant of primary progressive aphasia. Cognition was assessed at baseline and longitudinally with the revised Addenbrooke's Cognitive Examination, at an average of 7-month intervals (for an average of ∼2 years, up to ∼5 years). Regional [11C]PK11195 binding potential and grey-matter volume were determined, and these were averaged within four hypothesis-driven regions of interest: bilateral frontal and temporal lobes. Linear mixed-effect models were applied to the longitudinal cognitive test scores, with [11C]PK11195 binding potentials and grey-matter volumes as predictors of cognitive performance, with age, education and baseline cognitive performance as covariates. Faster cognitive decline was associated with reduced baseline grey-matter volume and increased microglial activation in frontal regions, bilaterally. In frontal regions, microglial activation and grey-matter volume were negatively correlated, but provided independent information, with inflammation the stronger predictor of the rate of cognitive decline. When clinical diagnosis was included as a factor in the models, a significant predictive effect was found for [11C]PK11195 BPND in the left frontal lobe (−0.70, P = 0.01), but not for grey-matter volumes (P > 0.05), suggesting that inflammation severity in this region relates to cognitive decline regardless of clinical variant. The main results were validated by two-step prediction frequentist and Bayesian estimation of correlations, showing significant associations between the estimated rate of cognitive change (slope) and baseline microglial activation in the frontal lobe. These findings support preclinical models in which neuroinflammation (by microglial activation) accelerates the neurodegenerative disease trajectory. We highlight the potential for immunomodulatory treatment strategies in frontotemporal dementia, in which measures of microglial activation may also improve stratification for clinical trials.

Resilience is a psychological construct broadly defined as positive adaptation in response to adversity (Fletcher & Sarkar, 2013). Resilient people do not despair or distract themselves from difficulties, but instead face them head-on. What makes some individuals more resilient than others is thought to rely on psychological mechanisms such as abilities to cognitively and emotionally cope with negative emotions. The corpus callosum provides interhemispheric connections, specifically to cognitive pathways, which allow for faster processing and reflection and has been identified as a key neural substrate of resilience (Edwards, Sherr, Barkovich, & Richards, 2014; Etkin, Egner, & Kalisch, 2011). Galinowski et al. (2015) have shown greater anatomical connectivity within the anterior body of the corpus callosum in resilient adolescents with high exposure to lifetime stress compared with non-resilient adolescents exposed to the same level of stress and healthy control adolescents from the same community. Converging neuroimaging evidence has further shown reduced volume of the corpus callosum in stress-related and major psychiatric disorders such as depression and treatment-resistant schizophrenia (Sun, Maller, Daskalakis, Furtado, & Fitzgerald, 2009). These studies highlight an association between resilience and structural integrity of the corpus callosum, with particular emphasis on the cognitive resources it subserves (Galinowski et al., 2015). Other characteristics typically used in the conceptualization of resilience are extraversion, openness to experience, self-efficacy and agreeability (Fletcher & Sarkar, 2013; Galinowski et al., 2015). However, protective factors are largely built on the assumption that resilient individuals actively work through the problems they face (Luthar, 2006; Luthar & Cicchetti, 2000; Luthar, Cicchetti, & Becker, 2000). Here, we call into question this widely held assertion by presenting a case of a fully functioning middle-aged man, T.C., who is not only unaware of his congenital absence of the corpus callosum, but also refutes key traits that are commonly associated with the concept of resilience.

Supplemental material, sj-pdf-1-jcb-10.1177_0271678X231173587 for Differential association of cerebral blood flow and anisocytosis in APOE ε4 carriers at midlife by Maria-Eleni Dounavi, Elijah Mak, Peter Swann, Audrey Low, Graciela Muniz-Terrera, Anna McKeever, Marianna Pope, Guy B Williams, Katie Wells, Brian Lawlor, Lorina Naci, Paresh Malhotra, Clare Mackay, Ivan Koychev, Karen Ritchie, Li Su, Craig W Ritchie and John T O’Brien: on behalf of the SVDs@target consortium in Journal of Cerebral Blood Flow & Metabolism

Sensitive and specific antemortem biomarkers of neurodegenerative disease and dementia are crucial to the pursuit of effective treatments, required both to reliably identify disease and to track its progression. Atrophy is the structural magnetic resonance imaging (MRI) hallmark of neurodegeneration. However in most cases it likely indicates a relatively advanced stage of disease less susceptible to treatment as some disease processes begin decades prior to clinical onset. Among emerging metrics that characterise brain shape rather than volume, fractal dimension (FD) quantifies shape complexity. FD has been applied in diverse fields of science to measure subtle changes in elaborate structures. We review its application thus far to structural MRI of the brain in neurodegenerative disease and dementia. We identified studies involving subjects who met criteria for mild cognitive impairment, Alzheimer's Disease, Vascular Dementia, Lewy Body Dementia, Frontotemporal Dementia, Amyotrophic Lateral Sclerosis, Parkinson's Disease, Huntington's Disease, Multiple Systems Atrophy, Spinocerebellar Ataxia and Multiple Sclerosis. The early literature suggests that neurodegenerative disease processes are usually associated with a decline in FD of the brain. The literature includes examples of disease-related change in FD occurring independently of atrophy, which if substantiated would represent a valuable advantage over other structural imaging metrics. However, it is likely to be non-specific and to exhibit complex spatial and temporal patterns. A more harmonious methodological approach across a larger number of studies as well as careful attention to technical factors associated with image processing and FD measurement will help to better elucidate the metric's utility.