Concentrations of pro-inflammatory cytokines -interleukin-6 (IL-6) and interleukin-8 (IL-8) - are increased with age and in Alzheimer's disease (AD). It is not clear whether concentrations of IL-6 and IL-8 in the central nervous system predict later brain and cognitive changes over time nor whether this relationship is mediated by core AD biomarkers. Here, 219 cognitively healthy older adults (62-91 years), with baseline cerebrospinal fluid (CSF) measures of IL-6 and IL-8 were followed over time - up to 9 years - with assessments that included cognitive function, structural magnetic resonance imaging, and CSF measurements of phosphorylated tau (p-tau) and amyloid-β (Aβ-42) concentrations (for a subsample). Higher baseline CSF IL-8 was associated with better memory performance over time in the context of lower levels of CSF p-tau and p-tau/Aβ-42 ratio. Higher CSF IL-6 was related to less CSF p-tau changes over time. The results are in line with the hypothesis suggesting that an up-regulation of IL-6 and IL-8 in the brain may play a neuroprotective role in cognitively healthy older adults with lower load of AD pathology.

There is a limited understanding of age differences in functional connectivity during memory encoding. In the present study, a sample of cognitively healthy adult participants (n = 488, 18–81 years), a subsample of whom had longitudinal cognitive and brain structural data spanning on average 8 years back, underwent functional magnetic resonance imaging while performing an associative memory encoding task. We investigated (1) age-related differences in whole-brain connectivity during memory encoding; (2) whether encoding connectivity patterns overlapped with the activity signatures of specific cognitive processes, and (3) whether connectivity associated with memory encoding related to longitudinal brain structural and cognitive changes. Age was associated with lower intranetwork connectivity among cortical networks and higher internetwork connectivity between networks supporting higher level cognitive functions and unimodal and attentional areas during encoding. Task-connectivity between mediotemporal and posterior parietal regions—which overlapped with areas involved in mental imagery—was related to better memory performance only in older age. The connectivity patterns supporting memory performance in older age reflected preservation of thickness of the medial temporal cortex. The results are more in accordance with a maintenance rather than a compensation account.

It is unclear whether cerebrospinal fluid (CSF) biomarkers of neurodegeneration predict brain atrophy in cognitively healthy older adults, whether these associations can be explained by phosphorylated tau181 (p-tau) and the 42 amino acid form of amyloid-β (Aβ42) biomarkers, and which neural substrates may drive these associations. We addressed these questions in 2 samples of cognitively healthy older adults who underwent longitudinal structural MRI up to 7 years and had baseline CSF levels of heart-type fatty-acid binding protein (FABP3)=, total-tau, neurogranin, and neurofilament light (NFL) (n = 189, scans = 721). The results showed that NFL, total-tau, and FABP3 predicted entorhinal thinning and hippocampal atrophy. Brain atrophy was not moderated by Aβ42 and the associations between NFL and FABP3 with brain atrophy were independent of p-tau. The spatial pattern of cortical atrophy associated with the biomarkers overlapped with neurogenetic profiles associated with expression in the axonal (total-tau, NFL) and dendritic (neurogranin) components. CSF biomarkers of neurodegeneration are useful for predicting specific features of brain atrophy in older adults, independently of amyloid and tau pathology biomarkers.

Structural brain changes underlie cognitive changes and interindividual variability in cognition in older age. By using structural MRI data-driven clustering, we aimed to identify subgroups of cognitively unimpaired older adults based on brain change patterns and assess how changes in cortical thickness, surface area, and subcortical volume relate to cognitive change. We tested (1) which brain structural changes predict cognitive change (2) whether these are associated with core cerebrospinal fluid (CSF) Alzheimer's disease biomarkers, and (3) the degree of overlap between clusters derived from different structural modalities in 1899 cognitively healthy older adults followed up to 16 years. We identified four groups for each brain feature, based on the degree of a main longitudinal component of decline. The minimal overlap between features suggested that each contributed uniquely and independently to structural brain changes in aging. Cognitive change and baseline cognition were associated with cortical area change, whereas higher baseline levels of phosphorylated tau and amyloid-β related to changes in subcortical volume. These results may contribute to a better understanding of different aging trajectories.

Minor visual phenomena (MVP), such as visual illusions, pareidolias, feeling of presence, and passage hallucinations, are often experienced by patients with Lewy Body Disease (LBD), in addition to complex visual hallucinations (VH), even in the early stages of the disease. This systematic review aimed to provide an up-to-date literature review of the occurrence and prevalence of MVP in LBD and to assess their potential associations both with VH and visuoperceptual and visuospatial deficits. A systematic literature search was carried out in PubMed, Web of Science, APA PsycInfo, Scopus, and Cochrane Library, and a total of 44 articles were included. The included studies showed significant variability in the occurrence of MVP in the LBD population and in the assessment methods used, such as standardized scales (e.g., the noise pareidolia test), semi-structured interviews (e.g., the North-East Visual Hallucinations Interview), and clinical descriptions. Similarly to VH, MVP appears to be highly specific to LBD, helping in differential diagnosis from Alzheimer’s Disease. The overall relationship between MVP, VH, and visuoperceptual/visuospatial deficits remains unclear. Some studies found that MVP (especially pareidolic responses and presence of hallucinations) was positively correlated with VH, yet it is challenging to determine whether MVP can be considered a precursor of future VH development. Negative associations were reported between MVP (especially pareidolias) and visuoperceptual/visuospatial abilities. However, it is not clear whether these deficits serve as independent, exclusive factors in MVP occurrence or if they interact with VH as a contributing component. Gaining insight into the occurrence of these phenomena could prove beneficial for differential diagnosis, prognosis, and prediction of treatment outcomes in patients with LBD.

Structural brain changes underly cognitive changes in older age and contribute to inter-individual variability in cognition. Here, we assessed how changes in cortical thickness, surface area, and subcortical volume, are related to cognitive change in cognitively unimpaired older adults using structural magnetic resonance imaging (MRI) data-driven clustering. Specifically, we tested (1) which brain structural changes over time predict cognitive change in older age (2) whether these are associated with core cerebrospinal fluid (CSF) Alzheimer’s disease (AD) biomarkers phosphorylated tau (p-tau) and amyloid-β (Aβ42), and (3) the degree of overlap between clusters derived from different structural features. In total 1899 cognitively healthy older adults (50 - 93 years) were followed up to 16 years with neuropsychological and structural MRI assessments, a subsample of which (n = 612) had CSF p-tau and Aβ42 measurements. We applied Monte-Carlo Reference-based Consensus clustering to identify subgroups of older adults based on structural brain change patterns over time. Four clusters for each brain feature were identified, representing the degree of longitudinal brain decline. Each brain feature provided a unique contribution to brain aging as clusters were largely independent across modalities. Cognitive change and baseline cognition were best predicted by cortical area change, whereas higher levels of p-tau and Aβ42 were associated with changes in subcortical volume. These results provide insights into the link between changes in brain morphology and cognition, which may translate to a better understanding of different aging trajectories.