Current advances in digital cognitive assessment for preclinical Alzheimer's disease

There is a pressing need to capture and track subtle cognitive change at the preclinical stage of Alzheimer's disease (AD) rapidly, cost-effectively, and with high sensitivity. Concurrently, the landscape of digital cognitive assessment is rapidly evolving as technology advances, older adult tech-adoption increases, and external events (i.e., COVID-19) necessitate remote digital assessment. Here, we provide a snapshot review of the current state of digital cognitive assessment for preclinical AD including different device platforms/assessment approaches, levels of validation, and implementation challenges. We focus on articles, grants, and recent conference proceedings specifically querying the relationship between digital cognitive assessments and established biomarkers for preclinical AD (e.g., amyloid beta and tau) in clinically normal (CN) individuals. Several digital assessments were identified across platforms (e.g., digital pens, smartphones). Digital assessments varied by intended setting (e.g., remote vs. in-clinic), level of supervision (e.g., self vs. supervised), and device origin (personal vs. study-provided). At least 11 publications characterize digital cognitive assessment against AD biomarkers among CN. First available data demonstrate promising validity of this approach against both conventional assessment methods (moderate to large effect sizes) and relevant biomarkers (predominantly weak to moderate effect sizes). We discuss levels of validation and issues relating to usability, data quality, data protection, and attrition. While still in its infancy, digital cognitive assessment, especially when administered remotely, will undoubtedly play a major future role in screening for and tracking preclinical AD

Context-specific activation of hippocampus and SN/VTA by reward is related to enhanced long-term memory for embedded objects

Animal studies indicate that hippocampal representations of environmental context modulate reward-related processing in the substantia nigra and ventral tegmental area (SN/VTA), a major origin of dopamine in the brain. Using functional magnetic resonance imaging (fMRI) in humans, we investigated the neural specificity of context-reward associations under conditions where the presence of perceptually similar neutral contexts imposed high demands on a putative hippocampal function, pattern separation. The design also allowed us to investigate how contextual reward enhances long-term memory for embedded neutral objects. SN/VTA activity underpinned specific context-reward associations in the face of perceptual similarity. A reward-related enhancement of long-term memory was restricted to the condition where the rewarding and the neutral contexts were perceptually similar, and in turn was linked to co-activation of the hippocampus (subfield DG/CA3) and SN/VTA. Thus, an ability of contextual reward to enhance memory for focal objects is closely linked to context-related engagement of hippocampal-SN/VTA circuitry

Big-Loop Recurrence within the Hippocampal System Supports Integration of Information across Episodes

Recent evidence challenges the widely held view that the hippocampus is specialized for episodic memory, by demonstrating that it also underpins the integration of information across experiences. Contemporary computational theories propose that these two contrasting functions can be accomplished by big-loop recurrence, whereby the output of the system is recirculated back into the hippocampus. We use ultra-high-resolution fMRI to provide support for this hypothesis, by showing that retrieved information is presented as a new input on the superficial entorhinal cortex—driven by functional connectivity between the deep and superficial entorhinal layers. Further, the magnitude of this laminar connectivity correlated with inferential performance, demonstrating its importance for behavior. Our findings offer a novel perspective on information processing within the hippocampus and support a unifying framework in which the hippocampus captures higher-order structure across experiences, by creating a dynamic memory space from separate episodic codes for individual experiences

Running-Induced Systemic Cathepsin B Secretion Is Associated with Memory Function

Peripheral processes that mediate beneficial effects of exercise on the brain remain sparsely explored. Here, we show that a muscle secretory factor, cathepsin B (CTSB) protein, is important for the cognitive and neurogenic benefits of running. Proteomic analysis revealed elevated levels of CTSB in conditioned medium derived from skeletal muscle cell cultures treated with AMP-kinase agonist AICAR. Consistently, running increased CTSB levels in mouse gastrocnemius muscle and plasma. Furthermore, recombinant CTSB application enhanced expression of brain-derived neurotrophic factor (BDNF) and doublecortin (DCX) in adult hippocampal progenitor cells through a mechanism dependent on the multifunctional protein P11. In vivo, in CTSB knockout (KO) mice, running did not enhance adult hippocampal neurogenesis and spatial memory function. Interestingly, in Rhesus monkeys and humans, treadmill exercise elevated CTSB in plasma. In humans, changes in CTSB levels correlated with fitness and hippocampus-dependent memory function. Our findings suggest CTSB as a mediator of effects of exercise on cognition

Alzheimer's pathology targets distinct memory networks in the ageing brain

Alzheimer’s disease researchers have been intrigued by the selective regional vulnerability of the brain to amyloid-β plaques and tau neurofibrillary tangles. Post-mortem studies indicate that in ageing and Alzheimer’s disease tau tangles deposit early in the transentorhinal cortex, a region located in the anterior-temporal lobe that is critical for object memory. In contrast, amyloid-β pathology seems to target a posterior-medial network that subserves spatial memory. In the current study, we tested whether anterior-temporal and posterior-medial brain regions are selectively vulnerable to tau and amyloid-β deposition in the progression from ageing to Alzheimer’s disease and whether this is reflected in domain-specific behavioural deficits and neural dysfunction. 11C-PiB PET and 18F-flortaucipir uptake was quantified in a sample of 131 cognitively normal adults (age: 20–93 years; 47 amyloid-β-positive) and 20 amyloid-β-positive patients with mild cognitive impairment or Alzheimer’s disease dementia (65–95 years). Tau burden was relatively higher in anterior-temporal regions in normal ageing and this difference was further pronounced in the presence of amyloid-β and cognitive impairment, indicating exacerbation of ageing-related processes in Alzheimer’s disease. In contrast, amyloid-β deposition dominated in posterior-medial regions. A subsample of 50 cognitively normal older (26 amyloid-β-positive) and 25 young adults performed an object and scene memory task while functional MRI data were acquired. Group comparisons showed that tau-positive (n = 18) compared to tau-negative (n = 32) older adults showed lower mnemonic discrimination of object relative to scene images [t(48) = −3.2, P = 0.002]. In a multiple regression model including regional measures of both pathologies, higher anterior-temporal flortaucipir (tau) was related to relatively worse object performance (P = 0.010, r = −0.376), whereas higher posterior-medial PiB (amyloid-β) was related to worse scene performance (P = 0.037, r = 0.309). The functional MRI data revealed that tau burden (but not amyloid-β) was associated with increased task activation in both systems and a loss of functional specificity, or dedifferentiation, in posterior-medial regions. The loss of functional specificity was related to worse memory. Our study shows a regional dissociation of Alzheimer’s disease pathologies to distinct memory networks. While our data are cross-sectional, they indicate that with ageing, tau deposits mainly in the anterior-temporal system, which results in deficits in mnemonic object discrimination. As Alzheimer’s disease develops, amyloid-β deposits preferentially in posterior-medial regions additionally compromising scene discrimination and anterior-temporal tau deposition worsens further. Finally, our findings propose that the progression of tau pathology is linked to aberrant activation and dedifferentiation of specialized memory networks that is detrimental to memory function

A protocol for manual segmentation of medial temporal lobe subregions in 7 Tesla MRI

Recent advances in MRI and increasing knowledge on the characterization and anatomical variability of medial temporal lobe (MTL) anatomy have paved the way for more specific subdivisions of the MTL in humans. In addition, recent studies suggest that early changes in many neurodegenerative and neuropsychiatric diseases are better detected in smaller subregions of the MTL rather than with whole structure analyses. Here, we developed a new protocol using 7 Tesla (T) MRI incorporating novel anatomical findings for the manual segmentation of entorhinal cortex (ErC), perirhinal cortex (PrC; divided into area 35 and 36), parahippocampal cortex (PhC), and hippocampus; which includes the subfields subiculum (Sub), CA1, CA2, as well as CA3 and dentate gyrus (DG) which are separated by the endfolial pathway covering most of the long axis of the hippocampus. We provide detailed instructions alongside slice-by-slice segmentations to ease learning for the untrained but also more experienced raters. Twenty-two subjects were scanned (19–32 yrs, mean age = 26 years, 12 females) with a turbo spin echo (TSE) T2-weighted MRI sequence with high-resolution oblique coronal slices oriented orthogonal to the long axis of the hippocampus (in-plane resolution 0.44 × 0.44 mm2) and 1.0 mm slice thickness. The scans were manually delineated by two experienced raters, to assess intra- and inter-rater reliability. The Dice Similarity Index (DSI) was above 0.78 for all regions and the Intraclass Correlation Coefficients (ICC) were between 0.76 to 0.99 both for intra- and inter-rater reliability. In conclusion, this study presents a fine-grained and comprehensive segmentation protocol for MTL structures at 7 T MRI that closely follows recent knowledge from anatomical studies. More specific subdivisions (e.g. area 35 and 36 in PrC, and the separation of DG and CA3) may pave the way for more precise delineations thereby enabling the detection of early volumetric changes in dementia and neuropsychiatric diseases

Hippocampal vascularization patterns: A high-resolution 7 Tesla time-of-flight magnetic resonance angiography study

Considerable evidence suggests a close relationship between vascular and degenerative pathology in the human hippocampus. Due to the intrinsic fragility of its vascular network, the hippocampus appears less able to cope with hypoperfusion and anoxia than other cortical areas. Although hippocampal blood supply is generally provided by the collateral branches of the posterior cerebral artery (PCA) and the anterior choroidal artery (AChA), different vascularization patterns have been detected postmortem. To date, a methodology that enables the classification of individual hippocampal vascularization patterns in vivo has not been established. In this study, using high-resolution 7 Tesla time-of-flight angiography data (0.3 mm isotropic resolution) in young adults, we classified individual variability in hippocampal vascularization patterns involved in medial temporal lobe blood supply in vivo. A strong concordance between our classification and previous autopsy findings was found, along with interesting anatomical observations, such as the variable contribution of the AChA to hippocampal supply, the relationships between hippocampal and PCA patterns, and the different distribution patterns of the right and left hemispheres. The approach presented here for determining hippocampal vascularization patterns in vivo may provide new insights into not only the vulnerability of the hippocampus to vascular and neurodegenerative diseases but also hippocampal vascular plasticity after exercise training

Amidst an amygdala renaissance in Alzheimer’s disease

Laura E. M. Wisse and David Berron contributed equally to this work. Accepted manuscripts: Accepted manuscripts are PDF versions of the author’s final manuscript, as accepted for publication by the journal but prior to copyediting or typesetting. They can be cited using the author(s), article title, journal title, year of online publication, and DOI. They will be replaced by the final typeset articles, which may therefore contain changes. The DOI will remain the same throughout.Supplementary material: Supplementary material is available at Brain online at: https://doi.org/10.1093/brain/awad411 .Copyright © The Author(s) 2023. The amygdala was highlighted as an early site for neurofibrillary tau tangle pathology in Alzheimer’s disease in the seminal Braak & Braak article (1991). This knowledge has, however, only received traction recently with advances in imaging and image analysis techniques. Here, we provide a cross-disciplinary overview of pathology and neuroimaging studies on the amygdala. These studies provide strong support for an early role of the amygdala in Alzheimer’s disease and the utility of imaging biomarkers of the amygdala in detecting early changes and predicting decline in cognitive functions and neuropsychiatric symptoms in early stages. We summarize the animal literature on connectivity of the amygdala, demonstrating that amygdala nuclei that show the earliest and strongest accumulation of neurofibrillary tangle pathology are those that are connected to brain regions that also show early neurofibrillary tangle accumulation. Additionally, we propose an alternative pathway of neurofibrillary tangle spreading within the medial temporal lobe between the amygdala and the anterior hippocampus. The proposed existence of this pathway is strengthened by novel experimental data on human functional connectivity. Finally, we summarize the functional roles of the amygdala, highlighting the correspondence between neurofibrillary tangle accumulation and symptomatic profiles in Alzheimer’s disease. In summary, these findings provide a new impetus for studying the amygdala in Alzheimer’s disease and a unique perspective to guide further study on neurofibrillary tangle spreading and the occurrence of neuropsychiatric symptoms in Alzheimer’s disease.This work is supported by grants from the Swedish Research Council (2022-00900) and the Crafoord Foundation (LW). This study is supported by MultiPark - A Strategic Research Area at Lund University (LW). This work is supported by the National Institutes of Health: U19-AG033655, P30-AG066507, P41-EB031771, R01-EB020062, T32-GM13677, U19-MH114821, R01-NS074980-10S1, RF1MH126732, RF1MH128875, F30AG077736 (MM and KS) and the Kavli Neuroscience Discovery Institute (MM and KS) as well as the Kavli Foundation and the KG. Jebsen Foundation (MPW). This work is further supported by the Elly Bergren Foundation and regional research support by the Division of Psychiatry, Habilitation and Medical aid, Region Skåne (MJ). This work was partly supported by the National Institute for Health and Care Research 23 Exeter Biomedical Research Centre

The impact of ageing reveals distinct roles for human dentate gyrus and CA3 in pattern separation and object recognition memory

© 2017 The Author(s). Both recognition of familiar objects and pattern separation, a process that orthogonalises overlapping events, are critical for effective memory. Evidence is emerging that human pattern separation requires dentate gyrus. Dentate gyrus is intimately connected to CA3 where, in animals, an autoassociative network enables recall of complete memories to underpin object/event recognition. Despite huge motivation to treat age-related human memory disorders, interaction between human CA3 and dentate subfields is difficult to investigate due to small size and proximity. We tested the hypothesis that human dentate gyrus is critical for pattern separation, whereas, CA3 underpins identical object recognition. Using 3 T MR hippocampal subfield volumetry combined with a behavioural pattern separation task, we demonstrate that dentate gyrus volume predicts accuracy and response time during behavioural pattern separation whereas CA3 predicts performance in object recognition memory. Critically, human dentate gyrus volume decreases with age whereas CA3 volume is age-independent. Further, decreased dentate gyrus volume, and no other subfield volume, mediates adverse effects of aging on memory. Thus, we demonstrate distinct roles for CA3 and dentate gyrus in human memory and uncover the variegated effects of human ageing across hippocampal regions. Accurate pinpointing of focal memory-related deficits will allow future targeted treatment for memory loss