The medial temporal lobe (MTL) has distinct cortical subregions that are differentially vulnerable to pathology and neurodegeneration in diseases such as Alzheimer’s disease. However, previous protocols for segmentation of MTL cortical subregions on magnetic resonance imaging (MRI) vary substantially across research groups, and have been informed by different cytoarchitectonic definitions, precluding consistent interpretations. The Hippocampal Subfields Group aims to create a harmonized, histology-based protocol for segmentation of MTL cortical subregions that can reliably be applied to T2-weighted MRI with high in-plane resolution. Nissl-stained sections from the temporal lobes of three human specimens (66-90 years old; 2 female) were annotated by four expert neuroanatomists for the following MTL subregions: entorhinal cortex (ERC), Brodmann’s Area 35 (BA35; largely corresponding to “transentorhinal” cortex), Brodmann’s Area 36 (BA36), and parahippocampal cortex (PHC). On each histology section, the number of annotations and the spatial overlap of annotations were analyzed to determine the consensus of the anterior to posterior range of each structure. Gross anatomical landmarks, detectable on MRI and reliably corresponding with each range, were then selected to create an MRI ranging protocol. Feasibility of this MRI protocol was tested by two independent raters across four MRI scans (two healthy adults, two older adults), and agreement in range selection was assessed using Cohen’s kappa statistic. The proposed MTL ranging protocol is shown in Fig. 1 , and corresponding histology data substantiating the protocol is shown in Fig. 2 . MRI-visible gross anatomical landmarks that reliably corresponded with the anterior or posterior range of each subregion on histology included the anterior-most appearance of the collateral sulcus ( Fig. 3A ), hippocampal head ( Fig. 3B ), hippocampal body, and anterior calcarine fissure ( Fig. 3C ). This protocol demonstrated high feasibility when applied to MRI, with average kappa values of 0.75 ± 0.07, representing a “substantial” level of agreement of range selection. Future directions include obtaining consensus on this protocol from the larger research community through a Delphi procedure, and expansion of the protocol to include slice-by-slice segmentation guidelines for full delineation. This harmonized, histology-based protocol will facilitate critical research on MTL subregion vulnerability and their contributions to memory deficits in Alzheimer’s disease.

Subjective cognitive decline (SCD) is proposed as an indicator of transitional disease stage 2 in the Alzheimer’s disease (AD) continuum. However, molecular and particularly longitudinal fluid biomarker data for this stage are still limited. This study aimed to determine whether blood-based biomarkers in amyloid-positive individuals with SCD (A + SCD) support the notion of stage 2 as a distinct stage between stages 1 and 3 of AD and to identify those at high risk for clinical progression. In a prospective multicenter study (DELCODE) involving 457 participants across the AD continuum, we analyzed plasma phospho-tau 181 (p181) and neurofilament light chain (NfL) and assessed their association with longitudinal cognition, hippocampal atrophy, and AD clinical stage transition. The results showed that baseline plasma p181 levels were elevated and increased more rapidly in A + SCD individuals compared to amyloid-positive cognitively unimpaired (A + CU) individuals (stage 1). NfL levels rose across A + CU, A + SCD, and amyloid-positive mild cognitive impairment (A + MCI, stage 3). In A + SCD, but not in A + CU, higher p181 levels predicted cognitive decline (PACC5) and transition to MCI. In conclusion, plasma p181 provides molecular biomarker evidence supporting A + SCD as a pre-dementia AD stage (stage 2) distinct from A + CU (stage 1) and helps identify individuals at risk for cognitive decline early in the AD continuum.

Characterizing subtle cognitive changes in preclinical Alzheimer's disease (AD) is difficult using traditional neuropsychological assessments. Remote and unsupervised digital assessments can improve scalability, measurement reliability, and ecological validity, enabling the capture of subtle changes. We evaluate such tools for use in preclinical AD, or cognitively unimpaired individuals with abnormal levels of AD pathology. We screened 1,904 reports for studies remotely assessing cognition in preclinical AD samples. Twenty-three tools were identified and their usability, reliability, and validity, including construct and criterion validity based on in-person neuropsychological and Aβ/tau measures, was reported. We present a necessary update to a rapidly evolving field, following our previous review (Öhman et al., 2021) and address open questions of feasibility and reliability of remote testing in older adults. Future applications of such tools are discussed, including longitudinal monitoring of cognition, scalable case finding, and individualized prognostics in both clinical trials and healthcare contexts.

Frequent and remote cognitive assessment may improve sensitivity to subtle cognitive decline associated with preclinical Alzheimer’s disease (AD). Our objective was to evaluate the feasibility, reliability, and construct validity of repeated remote memory assessment in late middle-aged and older adults. Participants were recruited from longitudinal aging cohorts to complete medial temporal lobe-based memory paradigms (Object-In-Room Recall [ORR], Mnemonic Discrimination for Objects and Scenes [MDT-OS], Complex Scene Recognition [CSR]) using the neotiv application on a smartphone or tablet at repeated intervals over one year. Participants were randomized to a task schedule (biweekly or bimonthly burst) for a total of 24 ten-minute remote sessions. Feasibility metrics included participation, retention, compliance, and acceptability. Intraclass correlation coefficients (ICC) assessed test-retest reliability over an 8-week period. Analysis of covariance (ANCOVA) models including covariates of demographics, device type, and task schedule were used to evaluate relationships between neotiv baseline performance and traditional memory scores (Rey Auditory Verbal Learning Test [RAVLT]; Preclinical Alzheimer’s Cognitive Composite [PACC]). Of 280 potentially eligible adults, n = 180 consented (64% participation rate). Of 180 consented, n = 133 completed at least one session and n = 119 completed or nearly completed all sessions (retention rate = 66% for all consented and 89% for all completed 1+ session). Delayed retrieval sessions were completed within expected timeframes in 72% of sessions. Greater than 90% of respondents felt the application was easy to use, instructions were understood, and the frequency and length of remote sessions were appropriate. 60% enjoyed completing the tasks (34% felt neutral) and 40% preferred mobile tests to traditional cognitive testing (42% felt neutral). Test-retest reliability was moderate (ICC = 0.54-0.70). RAVLT and PACC were significantly associated with MDT-OS, CSR, and ORR performance ( p ’s <.001). Challenges to participation occurred primarily during enrollment; future studies may allocate additional support facilitating registration and initial task completion within the application. Acceptability of the mobile tasks was high. The mobile memory paradigms exhibited moderate test-retest reliability and were significantly related to gold-standard cognitive tests. Overall, findings support preliminary feasibility, reliability, and validity of the neotiv tasks in assessing memory function in cognitively healthy adults enriched for AD risk.

Traditional pen-and-paper neuropsychological assessments fail to capture subtle cognitive changes in the early stages of Alzheimer’s disease (AD). Remote and unsupervised digital assessments available on smartphones, tablets, and personal computers may offer a solution to this by increasing the amount and types of data available to researchers and clinicians, while simultaneously improving ecological validity and alleviating patient burden. As these remote and unsupervised digital cognitive assessment tools become more widely available, it is important that they are validated in a systematic way. In this review, we evaluate the validity of available remote tools, focusing on active assessment tools with which the patient interacts with (i.e., cognitive tests, active speech) that have been used to investigate subtle cognitive differences in preclinical AD, defined as clinically unimpaired individuals with biomarkers indicating increased risk of dementia due to AD. We performed a systematic literature review on PubMed, Web of Science, and PsycInfo using terms such as “digital,” “remote,” “unsupervised,” “cognition,” “aging,” and “Alzheimer’s,” which resulted in a total of 1,453 unique peer-reviewed articles and pre-prints. After filtering for tools that were remotely self-administered in humans, and excluding papers detailing findings in populations with other diseases than AD (e.g., multiple sclerosis, Parkinson’s disease) or papers reporting findings of intervention studies, 14 papers reporting the use or planned use of 14 tools to detect AD pathology in preclinical AD were selected (as of Jan. 2024). We evaluate each tool with regards to its use-case and usability, as well as various types of validity, and suggest a framework with which future tools may also be evaluated. Additionally, we discuss current directions in the field of remote and unsupervised digital cognitive assessment in early AD. With this review, we hope to show that the systematic and validated use of such tools will increase our understanding of subtle changes in cognition due to AD pathology, as well as make screening for clinical trials and treatment more accessible.

Late-life depression (LLD) is a risk factor for Alzheimer's disease (AD) dementia. Previous morphological studies have often associated LLD with atrophy within the medial temporal lobe (MTL), including the hippocampus. A number of previous studies have demonstrated the changes in several MTL subfields in LLD, such as the perirhinal cortex (PrC), cornu ammonis (CA), dentate gyrus (DG), subiculum and entorhinal cortex (EC), but with inconsistent results, which may be explained by the relatively low image resolution of the 3T scanner used in the previous studies. A total of 93 individuals over the age of 60 were included in this study, of which 23 LLD patients and 29 normal controls without a history of depression underwent T1 and T2tse scans on a 7-Tesla MRI scanner. Images were pre-processed and roughly segmented into CA1-3, DG, SUB, EC, and PrC (area 35, 36) using the Automated Segmentation Hippocampal Subfields (ASHS) and further separated into anterior and posterior (head and body). All segmented images were manually edited. Group comparisons of MTL subfield volumes were made, adjusting for age, sex, and years of education. Cognitive and clinical scores were correlated with the volume of each subfield. LLD and controls did not differ in total hippocampal volume. LLD showed reduced volume in the head portion of the right DG (p=0.05) and a trend towards reduced ratio between left and right EC (p=0.07). No other group differences were observed. Correlational analyses revealed a significant association between bilateral hippocampal volume and TMT-A speed, as well as the anxiety subscale of the Geriatric Depression Scale (GDS). Subfield analyses revealed significant associations between the anxiety subscale of the GDS and bilateral DG head volume (left: r=-0.36, p=0.006; right: r=-0.42, p=0.002) and between the left CA1 body and the cognition subscale of the GDS (r=0.29, p=0.03). Using ultra-high field MRI, we demonstrated an anterior-posterior differentiation along the hippocampal long axis in the involvement of cognitive and clinical symptoms in LLD. Future work should investigate the relationship between AD pathological changes and behavioral symptoms in LLD and whether MTL subfields may play a mediating role.

Frequent and remote cognitive assessment may improve sensitivity to subtle cognitive decline associated with preclinical Alzheimer’s disease (AD). However, repeated testing can result in unintended inflation of scores, due to practice effects. The objective of this study is to evaluate the extent of sessions with non-identical stimuli on performance and determine if study design or amyloid PET status moderates the impact of practice. Participants were recruited from longitudinal aging cohorts to complete medial temporal lobe-based memory paradigms (Object-In-Room Recall [ORR], Mnemonic Discrimination for Objects and Scenes [MDT-OS 1-back and 2-back], Complex Scene Recognition [CSR]) using the neotiv application at repeated intervals over one year. Participants were randomized to a task schedule (biweekly 1 task or bimonthly burst) for a total of 24 ten-minute remote sessions. In both groups, participants completed each task 6 times; the interval between identical tasks was eight weeks (Table 1). Linear mixed effects models were used to assess the impact of practice on task performance and the interaction of practice with (1) task schedule group or (2) amyloid status. Models contained person-level random intercepts and covariates of age, gender, education, and device type (tablet or smartphone). Task schedule group did not differ by demographic characteristics (Table 2, n = 133, mean age = 68.2, 67% female, 87% white, 97% cognitively unimpaired). The interaction of practice x task schedule group was only significant for the MDT-OS (Table 3, β = 0.01, p = 0.032). The main effect of practice was significant for the ORR (β = 0.20, p = 0.002) and CSR (β = 0.001, p<0.001) tasks. The interaction of practice x amyloid PET result was not significant in any models. The main effect of practice was significant in all models (Table 3, ORR: β = 0.21, p = 0.004; CSR: β = 0.01, p<0.001; MDT-OS: β = 0.01, p = 0.034). Practice effects were present, indicating that procedural practice benefited task scores, despite non-repeating stimuli. The MDT-OS group x practice interaction indicated that participants in the burst design group had lower scores at their initial MDT-OS visit, but increased performance with practice at a higher rate. No main effects or interaction of amyloid result was observed, possibly due to limited availability of data and few elevated participants.

The advent of remote and unsupervised digital cognitive assessment facilitates the use of frequent assessments only days apart to examine learning rates. Learning rates have been shown to differentiate patients with Mild Cognitive Impairment (MCI) and preclinical Alzheimer’s disease (AD) from healthy individuals across a variety of cognitive measures. Here, we investigated whether impairments in learning rates in a mnemonic discrimination task were domain specific, as object and scene memory have been found to rely on anatomically distinct neural pathways that are differentially affected by AD. We examined learning rates over two weeks in the Mnemonic Discrimination Task for Objects and Scenes (MDT-OS) in N = 54 older adults (age = 67.1 ± 5.68) recruited through a memory clinic who were clinically cognitively unimpaired (CU, n = 44, n Aβ– = 28, n Aβ+ = 6) or had MCI (n = 10, n Aβ– = 3, n Aβ+ = 7). Five identical stimuli sets were completed at three-day intervals on participants’ own smartphone or tablet. Using linear mixed modeling, we found significant cognitive status-by-time interactions indicating that the MCI group showed reduced learning compared to the CU group in the Scene condition, though not the Object condition. However, a cognitive status-by-time-by-condition model indicated no significant effect of condition. We found no significant Aβ status-by-time interaction in either condition. However, an Aβ status-by-time-by-condition model revealed diminished learning in the Scene condition compared to the Object condition for the Aβ+ group but not the Aβ– group. In a sub-group analysis including only CU individuals, this three-way interaction effect remained significant. The current results suggest that individuals with MCI show diminished learning rates in mnemonic discrimination of scenes, compared to CU individuals. We identified ceiling effects in the Object condition, which may have contributed to a null finding. Additionally, we found that Aβ positivity was associated with reduced learning of scenes but not objects, both in the overall sample and in individuals with no clinical indication of cognitive impairment. In conclusion, learning rates in the MDT-OS may be a sensitive marker of AD in individuals who do not yet meet the clinical threshold for cognitive impairment.

The medial temporal lobe (MTL) cortex, located adjacent to the hippocampus, is crucial for memory and prone to the accumulation of certain neuropathologies such as Alzheimer’s disease neurofibrillary tau tangles. The MTL cortex is composed of several subregions which differ in their functional and cytoarchitectonic features. As neuroanatomical schools rely on different cytoarchitectonic definitions of these subregions, it is unclear to what extent their delineations of MTL cortex subregions overlap. Here, we provide an overview of cytoarchitectonic definitions of the cortices that make up the parahippocampal gyrus (entorhinal and parahippocampal cortices) and the adjacent Brodmann areas (BA) 35 and 36, as provided by four neuroanatomists from different laboratories, aiming to identify the rationale for overlapping and diverging delineations. Nissl-stained series were acquired from the temporal lobes of three human specimens (two right and one left hemisphere). Slices (50 µm thick) were prepared perpendicular to the long axis of the hippocampus spanning the entire longitudinal extent of the MTL cortex. Four neuroanatomists annotated MTL cortex subregions on digitized (20X resolution) slices with 5 mm spacing. Parcellations, terminology, and border placement were compared among neuroanatomists. Cytoarchitectonic features of each subregion are described in detail. Qualitative analysis of the annotations showed higher agreement in the definitions of the entorhinal cortex and BA35, while definitions of BA36 and the parahippocampal cortex exhibited less overlap among neuroanatomists. The degree of overlap of cytoarchitectonic definitions was partially reflected in the neuroanatomists’ agreement on the respective delineations. Lower agreement in annotations was observed in transitional zones between structures where seminal cytoarchitectonic features are expressed more gradually. The results highlight that definitions and parcellations of the MTL cortex differ among neuroanatomical schools and thereby increase understanding of why these differences may arise. This work sets a crucial foundation to further advance anatomically-informed human neuroimaging research on the MTL cortex.

Studies exploring the hippocampal subfield atrophy in Alzheimer’s disease (AD) have shown contradictory results. This review aims to disentangle such heterogeneity by investigating the dynamic changes of hippocampal subfields across the AD continuum. We systematically searched the PubMed and EMBASE databases for case-control studies. Selected studies included investigations of biomarker-based amyloid status and reported data on hippocampal subfield atrophy using advanced MRI techniques. Twelve studies were included. Despite high heterogeneity, a distinguishable pattern of vulnerability of hippocampal subfields can be recognized from the cognitively unimpaired phase to the dementia stage, shedding light on hippocampal changes with disease progression. Consistent findings revealed atrophy in the subiculum and presubiculum, along with a potential increase in volume in the cornu ammonis (CA) among the cognitively unimpaired group, a feature not observed in patients experiencing subjective cognitive decline. Atrophy in the subiculum, presubiculum, CA 1–4, and the dentate gyrus characterized the mild cognitive impairment stage, with a more pronounced severity in the progression to dementia.

The medial temporal lobe (MTL) is hypothesized to be relatively spared in early-onset Alzheimer’s disease (EOAD). Yet, detailed examination of MTL subfields and drivers of atrophy in amnestic EOAD is lacking. BioFINDER-2 participants with memory impairment, abnormal amyloid-β and tau-PET were included. Forty-one amnestic EOAD individuals ≤65 years and, as comparison, late-onset AD (aLOAD, ≥70 years, n = 154) and amyloid-β-negative cognitively unimpaired controls were included. MTL subregions and biomarkers of (co-)pathologies were measured. AD groups showed smaller MTL subregions compared to controls. Atrophy patterns were similar across AD groups: aLOAD showed thinner entorhinal cortices than aEOAD; aEOAD showed thinner parietal regions than aLOAD. aEOAD showed lower white matter hyperintensities than aLOAD. No differences in MTL tau-PET or transactive response DNA binding protein 43-proxy positivity were found. We found evidence for MTL atrophy in amnestic EOAD and overall similar levels to aLOAD of MTL tau pathology and co-pathologies.

Remote monitoring of cognition holds the promise to facilitate case-finding in clinical care and the individual detection of cognitive impairment in clinical and research settings. In the context of Alzheimer’s disease, this is particularly relevant for patients who seek medical advice due to memory problems. Here, we develop a remote digital memory composite (RDMC) score from an unsupervised remote cognitive assessment battery focused on episodic memory and long-term recall and assess its construct validity, retest reliability, and diagnostic accuracy when predicting MCI-grade impairment in a memory clinic sample and healthy controls. A total of 199 participants were recruited from three cohorts and included as healthy controls ( n = 97), individuals with subjective cognitive decline ( n = 59), or patients with mild cognitive impairment ( n = 43). Participants performed cognitive assessments in a fully remote and unsupervised setting via a smartphone app. The derived RDMC score is significantly correlated with the PACC5 score across participants and demonstrates good retest reliability. Diagnostic accuracy for discriminating memory impairment from no impairment is high (cross-validated AUC = 0.83, 95% CI [0.66, 0.99]) with a sensitivity of 0.82 and a specificity of 0.72. Thus, unsupervised remote cognitive assessments implemented in the neotiv digital platform show good discrimination between cognitively impaired and unimpaired individuals, further demonstrating that it is feasible to complement the neuropsychological assessment of episodic memory with unsupervised and remote assessments on mobile devices. This contributes to recent efforts to implement remote assessment of episodic memory for case-finding and monitoring in large research studies and clinical care.

Memory clinic patients are a heterogeneous population representing various aetiologies of pathological ageing. It is not known whether divergent spatiotemporal progression patterns of brain atrophy, as previously described in Alzheimer's disease patients, are prevalent and clinically meaningful in this group of older adults. To uncover distinct atrophy subtypes, we applied the Subtype and Stage Inference (SuStaIn) algorithm to baseline structural MRI data from 813 participants enrolled in the DELCODE cohort (mean ± standard deviation, age = 70.67 ± 6.07 years, 52% females). Participants were cognitively unimpaired (n = 285) or fulfilled diagnostic criteria for subjective cognitive decline (n = 342), mild cognitive impairment (n = 118) or dementia of the Alzheimer's type (n = 68). Atrophy subtypes were compared in baseline demographics, fluid Alzheimer's disease biomarker levels, the Preclinical Alzheimer Cognitive Composite (PACC-5) as well as episodic memory and executive functioning. PACC-5 trajectories over up to 240 weeks were examined. To test whether baseline atrophy subtype and stage predicted clinical trajectories before manifest cognitive impairment, we analysed PACC-5 trajectories and mild cognitive impairment conversion rates of cognitively unimpaired participants and those with subjective cognitive decline. Limbic-predominant and hippocampal-sparing atrophy subtypes were identified. Limbic-predominant atrophy initially affected the medial temporal lobes, followed by further temporal regions and, finally, the remaining cortical regions. At baseline, this subtype was related to older age, more pathological Alzheimer's disease biomarker levels, APOE ε4 carriership and an amnestic cognitive impairment. Hippocampal-sparing atrophy initially occurred outside the temporal lobe, with the medial temporal lobe spared up to advanced atrophy stages. This atrophy pattern also affected individuals with positive Alzheimer's disease biomarkers and was associated with more generalized cognitive impairment. Limbic-predominant atrophy, in all participants and in only unimpaired participants, was linked to more negative longitudinal PACC-5 slopes than observed in participants without or with hippocampal-sparing atrophy and increased the risk of mild cognitive impairment conversion. SuStaIn modelling was repeated in a sample from the Swedish BioFINDER-2 cohort. Highly similar atrophy progression patterns and associated cognitive profiles were identified. Cross-cohort model generalizability, at both the subject and the group level, was excellent, indicating reliable performance in previously unseen data. The proposed model is a promising tool for capturing heterogeneity among older adults at early at-risk states for Alzheimer's disease in applied settings. The implementation of atrophy subtype- and stage-specific end points might increase the statistical power of pharmacological trials targeting early Alzheimer's disease.

INTRODUCTION:Remote unsupervised cognitive assessments have the potential to complement and facilitate cognitive assessment in clinical and research settings. METHODS:Here, we evaluate the usability, validity, and reliability of unsupervised remote memory assessments via mobile devices in individuals without dementia from the Swedish BioFINDER-2 study and explore their prognostic utility regarding future cognitive decline. RESULTS:Usability was rated positively; remote memory assessments showed good construct validity with traditional neuropsychological assessments and were significantly associated with tau-positron emission tomography and downstream magnetic resonance imaging measures. Memory performance at baseline was associated with future cognitive decline and prediction of future cognitive decline was further improved by combining remote digital memory assessments with plasma p-tau217. Finally, retest reliability was moderate for a single assessment and good for an aggregate of two sessions. DISCUSSION:Our results demonstrate that unsupervised digital memory assessments might be used for diagnosis and prognosis in Alzheimer's disease, potentially in combination with plasma biomarkers. HIGHLIGHTS:Remote and unsupervised digital memory assessments are feasible in older adults and individuals in early stages of Alzheimer's disease. Digital memory assessments are associated with neuropsychological in-clinic assessments, tau-positron emission tomography and magnetic resonance imaging measures. Combination of digital memory assessments with plasma p-tau217 holds promise for prognosis of future cognitive decline. Future validation in further independent, larger, and more diverse cohorts is needed to inform clinical implementation.

Mnemonic discrimination (MD), the ability to distinguish between similar experiences in memory, is essential for memory precision. We hypothesized that training mnemonic discrimination should improve memory precision by increasing the neural activity differences between a new experience and a similar familiar experience (repeat). Participants performed a 2-week, web-based training program. For group 1, memory similarity was adapted to performance. Group 2 trained non-adaptively and group 3 served as active control. Adaptivity improved training gain and led to transfer to other memory tasks. Surprisingly, training reduced neural activity differences between new (lure) and similar familiar (repeat) experiences. Thus, instead of enhancing neural activity to lures and decreasing neural activity to repeats, training led to increased activity to repeats. In several brain regions this pattern was associated with improved MD. These findings highlight an unexpected neural mechanism underpinning improved memory precision in recognition memory. ### Competing Interest Statement The authors have declared no competing interest.

Spinocerebellar ataxia type 3 (SCA3) is the most common autosomal dominant ataxia worldwide. First targeted gene therapy trials have started, offering the intriguing scenario of preventive treatment. SCA3 is associated with progressive regional brain atrophy that starts before clinical manifestation. We aimed to identify the spatiotemporal progression pattern of brain atrophy of SCA3 with a focus on early disease stages. T1-weighted MRI scans of 300 SCA3 mutation carriers and 317 controls were analyzed. Subtype and Stage Inference (SuStaIn) was used to identify the sequence of volume loss across selected brain regions. We observed one distinct sequence of brain atrophy events in SCA3 without evidence for the existence of alternative cascades. Atrophy started in the most caudal parts of the brainstem. Almost all preataxic SCA3 mutation carriers clustered in the first atrophy stages. Certainty of sequence estimation was highest for early atrophy stages with prominent involvement of the pons and cerebellar white matter. Brain atrophy in SCA3 follows a clear and distinct sequence ascending from the lower brainstem with an early involvement of white matter. Knowledge of this sequence might support the stratification of SCA3 mutation carriers with an imminent clinical onset for early interventions.### Competing Interest StatementJF received consultancy frees from Vico Therapeutics, unrelated to the present manuscript, and funding from the Advanced Clinician Scientist Programme (ACCENT, funding code 01EO2107, the ACCENT Program is funded by the German Federal Ministry of Education and Research (BMBF)) as well as a fellow of the Hertie Network of Excellence in Clinical Neuroscience. TK is receiving research support from the German Federal Ministry of Education and Research (BMBF) and Servier. ### Funding StatementThis publication is an outcome of ESMI, an EU Joint Programme - Neurodegenerative Disease Research (JPND) project (see www.jpnd.eu). The project is supported through the following funding organisations under the aegis of JPND: Germany, Federal Ministry of Education and Research (BMBF; funding codes 01ED1602A/B); Netherlands, The Netherlands Organisation for Health Research and Development; United Kingdom, Medical Res earch Council (MR/N028767/1). At the US sites this work was in part supported by the National Ataxia Foundation and the National Institute of Neurological Disorders and Stroke (NINDS) grant R01NS080816. The Center for Magnetic Resonance Research is supported by the National Institute of Biomedical Imaging and Bioengineering (NIBIB) grant P41 EB027061, the Institutional Center Cores for Advanced Neuroimaging award P30 NS076408 and S10 OD017974 grant. JF received consultancy frees from Vico Therapeutics, unrelated to the present manuscript, and funding from the Advanced Clinician Scientist Programme (ACCENT, funding code 01EO2107, the ACCENT Program is funded by the German Federal Ministry of Education and Research (BMBF)) as well as a fellow of the Hertie Network of Excellence in Clinical Neuroscience. TK is receiving research support from the German Federal Ministry of Education and Research (BMBF) and Servier. MCF is funded by Friedreichs research alliance (FARA, USA) and Fundacao de Amparo a pesquisa do Estado de Sao Paulo (grants # 2021/06739-4 and 2013/07559-3). TJRR is funded by Friedreichs research alliance (FARA, USA). No further conflicting interests were disclosed related to this manuscript. ### Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:Ethics committee/IRB of the University Hospital Bonn gave ethical approval for this work. Ethics committee/IRB of the University of Campinas gave ethical approval for this work. In addition, the ethics committee/IRB of the Xiangya Hospital, Central South University in China (Reference number: 202310206) gave ethical approval for this work. Ethics committee/IRB of the Radboud University Medical Center Nijmegen gave ethical approval for this work. Ethics committee/IRB of the Salpetrier University Hospital Paris gave ethical approval for this work. Ethics committee/IRB of the University Hospital Tuebingen gave ethical approval for this work. Ethics committee/IRB of the UCL London gave ethical approval for this work.Ethics committee/IRB of the University of Minnesota gave ethical approval for this work. Ehtics committee/IRB of the University Hospital Essen gave ethical approval for this work. Ethics committee/IRB of the University Hospital Heidelberg gave ethical approval for this work. Ethics committee/IRB of the University Medical Center Groningen gave ethical approval for this work. Ethics committee/IRB of the Johns Hopkins University School of Medicine, Baltimore, gave ethical approval for this work, as well as the Massachusetts General Hospital. Ethics committee/IRB of the RWTH Aachen gave ethical approval for this work. Ethics committee/IRB of the University of Cantabria gave ethical approval for this work. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.YesAll data produced in the present study are available upon reasonable request to the authors.

Ultra-high field (UHF) imaging provides substantial benefits for the structural and functional investigation of the human medial temporal lobe. The medial temporal lobe is a complex system of many subregions that is critically involved in many cognitive functions and vulnerable to neurodegenerative processes. Here, we first lay out the benefits of UHF imaging for visualizing anatomical features with high resolution to delineate subregions. We provide examples of structural imaging studies that critically rely on UHF imaging. Second, we point out how UHF functional imaging advances the investigation of the functional organization of the medial temporal lobe and its involvement in cognitive processes. Examples are given for how UHF imaging is used here to reveal critical mechanisms and information flow on the subregional and layer-specific levels. Finally, we highlight motion and signal dropout as challenges of structural and functional UHF and conclude with perspectives for UHF imaging in the future.

Objective:Frequent and remote cognitive assessment may improve sensitivity to subtle cognitive decline associated with preclinical Alzheimer’s disease (AD). The objective of this study was to evaluate the feasibility and acceptability of repeated remote memory assessment in late middle-aged and older adults.Participants and Methods:We recruited participants from a longitudinal aging cohort to complete three medial temporal lobe-based memory paradigms (Object-In-Room Recall [ORR], Mnemonic Discrimination for Objects and Scenes [MDT-OS], Complex Scene Recognition [CSR]) using the neotiv application at repeated intervals over one year. We conducted initial telephone calls to perform screening, consent, and download instructions. Participants were assigned 24 remote sessions on a smartphone or tablet and were alerted via push notification when an assignment was ready to complete. Participants were randomly assigned to: (1) complete memory tests every other week or (2) complete memory tests for multiple days within one week every other month. Each remote session lasts approximately 10 minutes and includes one memory paradigm and brief usability/acceptability questionnaires followed by a delayed retrieval session 90 minutes later. Feasibility metrics examined included participation, retention, compliance, and usability/acceptability.Results:Of 150 participants recruited, 113 consented and were enrolled into the study (participation rate = 75%). Current retention rate is 75%, with 85/113 currently active (n=73) or completed (n=12). Of the 85 active or completed participants, the mean age is 68.7 (range = 4882), 64% are women, 70% used a smartphone (30% tablet), 84 are cognitively unimpaired and 1 has mild cognitive impairment. The primary threat to retention was participants consenting into the study but never registering in the app or completing their first scheduled assignment. After enrollment, 130 telephone calls were made by study staff to facilitate registration into the app or to remind participants to complete tasks. 74-80% of participants completed delayed retrieval tasks within 30 minutes of push notification, but average retrieval time was 125137 minutes post-learning trials. Regarding acceptability/usability, 94% agreed the application was easy to use, 56% enjoyed completing the mobile memory tests (36% felt neutral), 40% prefer remote mobile memory tests to standard in-person paper and pencil tests, and 50% understood the test instructions. 87% felt the frequency of tests assigned was “just right” (13% “too often”) and 90% felt the test length was “just right” (7% too short, 3% too long). Participants who completed all 24 sessions to date (n=12) all endorsed being “satisfied” or “very satisfied” with the platform and visit schedule, as well as recommended continued use of this type of cognitive testing.Conclusions:Remote memory assessment using smartphones and tablets is feasible and acceptable for cognitively unimpaired late middle-aged and older adults. Follow-up by study staff was needed to ensure adequate retention. Comprehension of instructions and compliance with completing delayed retrieval tasks within the expected timeframe was lower than expected. These feedback will be incorporated into an updated version of the app to improve compliance and retention. Longitudinal data collection is ongoing and results will be updated with a larger sample. Results will be compared across frequency schedule groups.

Remotely administered, unsupervised smartphone-based cognitive tests have the potential for scalable and cost-effective screening of Alzheimer’s disease (AD) in clinical trials and primary care. Previous work has provided initial evidence for the feasibility and validity of these tools in clinical and community settings. However, more studies investigating the utility of these cognitive tests are warranted, particularly regarding user experience and the association with AD biomarkers. To date, 198 participants (CDR 0 = 85%, CDR 0.5 = 15%, Mini-Mental State Examination = 29, average age = 77) have enrolled in this smartphone sub-study, a part of the Swedish population-based Gothenburg H70 Birth Cohort Studies. After participating for at least 12 months, the user experience of smartphone-based cognitive tests (two memory tests, MDT-OS and ORR-LDR) was assessed. Furthermore, we investigated their associations with volumetric brain changes based on magnetic resonance imaging (MRI) and cerebrospinal fluid (CSF) biomarkers (Aβ42/Aβ40 ratio, T-tau, P-tau, NFL, and neurogranin). The latter will be analyzed in a subsample (n = 45 for CSF and n = 110 for MRI) of all participants. Voxel-based analyses are being performed in SPM12. Most study participants found the app easy and enjoyable to use, the instructions easy to understand, and they generally favored performing tests in their home environment. Low CSF Aβ42/Aβ40 ratio at age 70 was associated with worse performance on the ORR-LDR at age 77 (R = .43, p<.002), while measures of t-tau, p-tau, NFL, and neurogranin at age 70 were not. Voxel-wise associations between smartphone-based cognitive tests and MRI measures will be reported at the conference. Our results suggest that using smartphone-based cognitive tests in a remote unsupervised setting has the potential to identify aspects of early AD in a community-based setting. The positive user experience is promising for acceptance of these novel tools for cognition assessment. Next steps include analyses of the relation with neuroimaging-based biomarkers.