bluuebunny/crossref_metadata_2025 huggingface dataset:
Hearing loss and dementia in Peruvian populations
Authors: Custodio Nilton , Failoc‐Rojas Virgilio E , Chambergo‐Michilot Diego , Malaga Diego , Ore‐Gomez Maria Fernanda , RIVERA‐FERNANDEZ CLAUDIA , Soto‐Añari Marcio , Reyes‐Dumeyer Dolly , Casavilca‐Zambrano Sandro , Montesinos Rosa , Tosto Giuseppe
Published: December 2022

Background

Hearing loss is prevalent in older adults, affecting a third of this population. Hearing loss is a modifiable and treatable factor. It has been shown that hearing loss can lead to social isolation and later to dementia. In addition, the corresponding cortical area has a close relationship with auditory and cognitive processing. In this study we aimed to evaluate the association between dementia and hearing loss.

Method

A multicenter cross‐sectional study was carried out in three locations of different altitude in Peru: Lima, Arequipa and Puno. Participants over 50 years of age with an available informant were recruited in memory clinics. The Hughes Clinical Dementia Rating (CDR) was employed to rate dementia (0 being healthy, 0.5 being questionable dementia, and greater than 1 being dementia). The exposure variable was reported hearing loss, which was defined as current hearing problems for more than six months. A descriptive analysis was performed and to evaluate the association between these variables, multinomial logistic regression with robust variances was used to estimate prevalence ratios (PR) with 95% confidence intervals.

Results

We evaluated 295 patients. The mean age was 71.9 years. More than a half was female (68.8%). The prevalence of hearing loss was 19.6%. In the crude model, hearing loss were associated with increased prevalence of dementia, with older age and education being associated with higher and lower CDR scores, respectively. After adjusting for confounders and geographic clustering, the association between hearing loss and dementia showed a PR of 3.39 (95% CI: 1.11‐10.39) that in those without dementia.

Conclusion

In our cohort of Peruvian participants, we found that hearing loss was associated with dementia in line with previous investigations. Further follow‐up studies are needed to better assess and characterize this association.
Cognitive reserve moderates the relationship between hippocampal volume and cognitive decline – but not gait decline
Authors: Blumen Helena M , Jayakody Shanika Oshadi , Ayers Emmeline , Barzilai Nir , Milman Sofiya , Weiss Erica , Verghese Joe
Published: December 2022

Background

Cognitive reserve (CR) accounts for individual differences in the relationship between brain health and clinical status. Common proxies of CR include education, and physical and social leisure activities. Greater CR allows individuals to cope better with poor brain health, and thereby delay the onset of cognitive impairment and dementia. Yet, whether CR protects against age‐related gait and cognitive decline is not well‐understood. Here, we examined whether CR moderates the relationship between hippocampal volume (a common marker of brain health) and age‐related decline in gait and cognition.

Method

Data from 101 LonGenity participants without dementia (M Age=79.33±6.09 years; 56% women) who had completed one MRI, and up to 3 years of follow‐up testing (M follow‐up=1.83±0.54 years) was examined. Gait speed was assessed during normal pace walking. Cognition was assessed with 11 neuropsychological tests, and a global cognitive composite. CR proxies (from self‐report), included cognitive (years of education), physical (number of blocks walked per day), and social (volunteering, living with someone) activities. FreeSurfer 6.0 was used to obtain hippocampal volume from structural MRIs. Linear mixed‐effects models adjusted for sex, parental longevity, cognitive impairment, and comorbidities examined the relationship between hippocampal volume and age‐related gait and cognitive decline.

Result

Education moderated the relationship between hippocampal volume and decline in figure copy performance. The number of blocks walked per day moderated the relationship between hippocampal volume and decline in global cognition, Trail Making Test (TMT)‐A, TMT‐interference, digit symbol substitution and phonemic fluency performance. Living with someone moderated the relationship between hippocampal volume and decline in global cognition, TMT‐interference, and logical memory performance. None of the CR proxies moderated the relationship between hippocampal volume and gait speed decline.

Conclusion

Cognitive, physical, and social CR proxies moderated the relationship between hippocampal volume and age‐related cognitive decline – not age‐related gait decline. Follow‐up sensitivity analyses, however, suggested that some CR proxies (e.g. education) moderated the relationship between prefrontal volumes and age‐related gait decline – presumably because prefrontal regions are more consistently associated with gait speed. Future studies are need to confirm whether the relationship between CR and age‐related gait and cognitive decline depends on the brain health marker.
A digital biomarker for remote self‐assessment of Alzheimer’s Diseases: development and validation
Authors: Watermeyer Tamlyn J , Butler Joe , Matterson Ellie , Harper Emily G , Parra‐Rodriguez Mario A
Published: December 2022

Background

Online data‐collection provide an opportunity for Alzheimer's Disease research to collect large datasets crucial for understanding important public health concerns. However, the reliability of online tasks as compared to those administered in the lab is poorly examined. Our goal is to validate an online version of the short‐term memory‐binding task (STMBT), a potential digital biomarker sensitive to Alzheimer’s Disease (Parra et al., 2010), to understand if data collected online in two environments, at‐home and in the lab, is comparable.

Method

We created an online version of the STMBT task using Psytoolkit (Stoet 2010; Stoet 2017). Development involved piloting, group and user discussions to explore how such a novel tool could be best presented for self‐assessment. Useful insights led to refinement of the online tool (i.e., instruction videos, images, and text). The validation stage involves test‐retest reliability assessment of cognitively fit participants (aged >40 years) who complete the two conditions of this paradigm (i.e., shape only and binding). Task Environment (home and in the lab) and conditions (shape and binding) were fully counterbalanced. Measures of general cognitive abilities, anxiety and at‐home environment were also taken.

Result

Recruitment is on‐going, but preliminary data (n=10) has already proved informative. A repeated measures ANOVA looking at task‐accuracy with factors of Environment (home vs. lab) and Condition (shape vs. binding) revealed no significant effects of Environment: F(1, 9) = 0.308, p = .591; Condition: F(1, 9) = 2.202, p = .172); or Interaction: F(1, 9) = 0.308, p = .591). For the shape condition, all participants performed near ceiling regardless of testing environment. In the binding condition, we observed good‐to‐excellent test‐retest reliability between environments using single measures interclass correlation (ICC = 0.954, CI 0.83‐0.99, (F(9, 9) = 39.62, p <.001).

Conclusion

These preliminary results indicate the STMBT can provide reliable data when self‐administered using an online version of the task which has important implications for public health researchers. For our fully powered sample, we will provide summary of other measures.
Comparison of FreeSurfer inputs on estimates and reliability of volume and thickness measures
Authors: Ferreira‐Atuesta Carolina , Binder Sarah , Piendel Lydia A , Emerson Jacqueline M , Andrew‐Jaja Nancy , Sutkowski Jonathan , Hedden Trey
Published: December 2022

Background

Anatomical volume and cortical thickness are measures of neurodegeneration to track disease progression and evaluation of treatment efficacy. FreeSurfer software provides automatic structural parcellation and segmentation to estimate volume and thickness. T1‐weighted inputs are commonly used, but T2 or T2*FLAIR images can be added. This study compared FreeSurfer estimates for T1 only vs T1+T2 or T1+T2*FLAIR inputs with regard to reliability and its relation to amyloidosis.

Method

3‐Tesla MRI data were included for 379 scans (T1: 35%, T1+T2: 35%, T1+T2*FLAIR: 31% ‐ session 1: 39%, 2: 34%, 3: 27%) from 60 healthy older adults (mean age 71, 67% female). FreeSurfer‐derived estimates of volume and cortical thickness were obtained for T1, T1+T2, and T1+T2*FLAIR inputs. Kruskal Wallis tests followed by Dunn post hoc test were used to identify estimates that were significantly different across sequences. Two‐way mixed model analyses were performed on each estimate, including subject and session as grouping factors. Interclass correlation coefficients measured similarity and reliability. Amyloid‐PET SUVR levels were available for 54% of subjects. Bonferroni correction and estimated marginal means were used to correct for multiple comparisons.

Result

For volume estimates, 17% of pairwise combinations (7% T1+T2vsT1+T2*Flair, 6% T1vsT1+T2, and 4% T1vsT1+T2*FLAIR) showed significant differences between sequences adjusting for multiple comparisons. The cross‐sectional similarity between sequences had median ICC=0.87. Test‐retest reliability within sequences had median ICC=0.88 for T1, 0.87 for T1+T2 and 0.78 for T1+T2*FLAIR. For thickness estimates, 73% of pairwise combinations (27% T1+T2vsT1+T2*FLAIR, 23% T1vsT1+T2*FLAIR, and 22% T1vsT1+T2) showed significant differences between sequences after adjusting for multiple comparisons. The cross‐sectional similarity between sequences had median ICC=0.43. Test‐retest reliability within sequences had median ICC=0.78 for T1, 0.74 for T1+T2 and 0.30 for T1+T2*FLAIR. Amyloid SUVRs had non‐significant correlations with all ICC measures.

Conclusion

Overall, volumes had high similarity across sequence inputs and high test‐retest reliability. Thickness showed less reliability across sequences and sessions driven by low similarity and low reliability for T1+T2*FLAIR. Amyloid deposition did not impact reliability estimates. These results suggest that T1 only or T1+T2 inputs have high reliability across sessions and should be considered in clinical trials designs that measure change in volume or thickness.
Trajectory of Inflammatory biomarkers in the perioperative period and associations with postoperative decline in patients undergoing cardiac surgery
Authors: Evered Lisbeth A , Scott David A , Silbert Brendan S , O'Bryant Sid E. , Hall James
Published: December 2022

Background

Perioperative neurocognitive disorders (PND), including postoperative delirium (POD), are the most common complications of anesthesia and surgery in those 65y or more, especially following cardiac surgery. PND are associated with increased risk of poor recovery and long‐term outcomes including increased risk of morbidity, dementia and mortality. With no therapeutic targets currently available, prevention is the key to reducing PND. Whilst the pathophysiology of POD and PND remains to be elucidated, current hypotheses highlight the impact of inflammation on these outcomes. This study aimed to identify the trajectory of biomarkers throughout the perioperative period and associations with POD and PND to identify targets for therapeutic interventions to prevent POD and other PND.

Method

The RECOGNISED trial was a prospective trial investigating PND and inflammatory biomarkers across the perioperative period in patients undergoing cardiac surgery. Neuropsychological testing occurred at baseline, and 3 and 12 months postoperatively. Blood samples for inflammatory biomarkers were collected at baseline and 30 minutes, 6, 24 and 48 hours after commencement of surgery.

Result

Patients were aged 70y (6) and 24% were male. IL‐6 levels increased at every postoperative time point compared with baseline, with a maximum increase at 6h (1.6 (4.4) vs 113.8 (154.2), p<0.001). IL‐10 levels also increased at every postoperative timepoint, with maximum increase at 6h (0.32 (0.23) vs 10.5 (17.5), p < 0.001). IL‐18 levels were significantly increased at 24 and 48h, with peak increase at 24h (111.9 (51.6) vs 133.8 (54.7), p < 0.001). TNF‐α levels were significantly increased at 30 minutes and 6h postoperatively, with maximal increase at 6h (6.1 (1.7) vs 12.8 (7.9), p < 0.001). Patients with POD experienced a significantly greater increase in IL‐6 at 6h compared to patients without POD. There was no association between peak IL‐10, IL‐18 or TNF‐ α levels and POD. Associations between these biomarkers and other PND will be discussed.

Conclusion

These results demonstrate significant increases in both pro‐inflammatory and anti‐inflammatory biomarkers during the perioperative period. IL‐6 levels at 6h were predictive of POD, confirming the role of inflammation in the development of POD. IL‐6 may be a useful target for therapeutic interventions to prevent POD.
Subclinical β‐amyloid peptides impair homeostatic synaptic potentiation in hippocampal neurons in 5XFAD mice
Authors: Catron Mackenzie A. , Howe Rachel K. , John Emily K. St. , Potesta Cobie Victoria , Shostak Alena , Schrag Matthew , Zhou Chengwen
Published: December 2022

Background

Alzheimer’s disease (AD) patients exhibit early symptoms of non‐rapid eye movement sleep (NREM) reduction and relatively REM sleep increase, which influences homeostatic synaptic plasticity (HSP) in cortical and subcortical neurons. Meanwhile, β‐amyloid peptides can suppress synaptic plasticity in hippocampus to impair learning/memory in animal studies.

Method

In accordance with IACUC of Vanderbilt University Medical center, coronal brain slices were prepared from wt and hemi 5xFAD mice at postnatal days (P)30, 60‐90 and 120‐150. Whole‐cell patch‐clamp recordings were made from hippocampal CA1 pyramidal neurons to record spontaneous excitatory synaptic currents (sEPSCs) at 32°C (clamped at ‐55.8mV, chloride reversal potentials). Slow‐wave oscillations (SWOs, 0.5 Hz, 10 min) were induced by injecting sinusoidal currents into neurons to simulate neuronal activity (up/down state) during NREM sleep. 200 µM β‐amyloid peptides were used in ACSF for this study.

Result

Compared with age‐matched wt littermates at P30 and P60‐90, sEPSCs in hippocampal neurons from hemi 5xFAD mice (n = 4 mice) exhibited larger amplitudes and higher frequency. However, at P120‐150, sEPSCs in neurons from hemi 5xFAD mice (n = 5 mice) became smaller than wt littermates (n = 4 mice), suggesting that excitatory synapses in hemi 5xFAD mice may be altered along the ageing course. Moreover, following SWO induction, HSP could be induced in neurons from wt littermates at all postnatal ages (n = 5 mice) and post‐SWO sEPSCs in neurons were increased. However, HSP could not be induced in neurons from hemi 5xFAD mice at P120‐150, except P30 and P60‐90. Moreover, 200 µM β‐amyloid peptides can suppress this synaptic potentiation in neurons from hemi 5XFAD mice at P90 (n = 4 mice).

Conclusion

Reduced NREM sleep activity in hemi 5xFAD mice can impair sEPSCs and HSP in hippocampal CA1 neurons along the ageing course, and subclinical β‐amyloid peptides can suppress this sleep‐related homeostatic synaptic potentiation, which contributes to cognitive deficits in AD patients.
Childhood measures of socioeconomic status and cognitive decline in the LifeAfter90 Study
Authors: Peterson Rachel L. , Gilsanz Paola , George Kristen M. , Meunier Claire C. , Soh Yenee , Corrada Maria M. , Glymour M. Maria , Whitmer Rachel A. , Lor Yi
Published: December 2022

Background

Childhood socioeconomic status (SES) is associated with cognitive functioning in adulthood. It is not known if this relationship endures in the oldest old. We examined the associations of subjective and objective childhood SES with baseline cognition and cognitive decline in the LifeAfter90 (LA90) cohort.

Method

LA90 is an ongoing diverse cohort of individuals aged 90+ without dementia diagnoses at recruitment. In our analytic sample (n = 341), we operationalized objective childhood SES as maternal education (range 0‐20 years); paternal education was substituted in 14% of cases missing maternal education. Subjective childhood SES was assessed using the MacArthur Scale of Subjective Social Status in which participants ranked their childhood SES using an unnumbered 10‐rung ladder picture (coded continuously with 1 = lowest SES and 10 = highest SES). Executive function (EF), semantic memory (SM), and verbal episodic memory (VEM) were assessed using the Spanish and English Neuropsychological Assessment Scales and z‐standardized to baseline. Mixed effects models estimated the associations between each childhood SES marker and level and change in each cognitive domain, adjusting for baseline age, time since baseline, gender, race and ethnicity, practice effects, and interview mode (phone vs. in‐person). We tested for the association between childhood SES measures and cognitive change by interacting SES measures with time.

Result

Participants completed an average of 3 visits (range 1‐6) each 6 months apart. On average, participants were about 93 years old (SD = 2.2), and 63% were female (Table 1). Mean parental education was 9.8 years (SD = 4.6; range = 0‐20); mean ladder score was 7.1 (SD = 2.4). Higher objective childhood SES was associated with better baseline EF (Figure 1: β = 0.03; 95% CI = 0.02, 0.05) and SM (β = 0.03; 95% CI = 0.02, 0.05). Having higher subjective childhood SES was associated with a slower decline in EF (Table 2: β = 0.02; 95% CI = 0.01, 0.04).

Conclusion

Objective measures of childhood SES were associated with baseline cognition and subjective childhood SES was associated with slower EF decline among the oldest‐old. High childhood SES may increase chances of surviving past age 90, a selection bias which would attenuate the associations we observed. Our results suggest the long arm of childhood may extend throughout the first century of life.
BIN1 K358R variant in 5xFAD mice ameliorates AB pathology and microgliosis
Authors: Tran Katelynn , Milinkeviciute Giedre , Tran Kristine M , Phan Jimmy , Da Cunha Celia , Javonillo Dominic I , Kawauchi Shimako , Tenner Andrea J , LaFerla Frank , MacGregor Grant R , Green Kim N
Published: December 2022

Background

Genome‐Wide Association Studies (GWAS) identified bridging integrator 1 (BIN1) as the most important susceptibility loci for late‐onset Alzheimer's disease (LOAD), second to apolipoprotein E (APOE). BIN1 is an important regulator of endocytosis and membrane dynamics. Neuronal BIN1 localizes to pre‐synaptic termini where it functions in excitatory synaptic transmission via regulation of neurotransmitter vesicle dynamics. In humans, the gene produces multiple isoforms with 7 brain specific isoforms. A missense variant in Bin1 (K358R) has been linked to increased risk of development of LOAD. Here, we introduced this variant in mice and evaluated its effects on plaque genesis and subsequent damage.

Method

To create the Bin1K358R allele, CRISPR/Cas9 endonuclease‐mediated genome editing of Bin1 was used to introduce a K426R mutation. This mutant allele models a SNP (rs138047593) found in human BIN1 that encodes a missense mutation associated with increased risk of sporadic Alzheimer's disease. The K358R variant in human BIN1 (K542R in the BIN1‐202 isoform) is located within the C‐terminal SH3 domain. Generated BIN1 K358R mice were crossed with 5xFAD mouse models, creating four groups (wild type (WT), BIN1K358R homozygous (HO), 5xFAD, and 5xFAD/BIN1 K358R HO), then aged to 4 months for analysis of AD‐related pathology. Coronal brain sections were immunolabeled to visualize dense‐core plaques (Thioflavin‐S), microglia (IBA1), reactive astrocytes (GFAP), axonal and neuritic damage (neurofilament light chain (NfL) and LAMP1, respectively). Confocal images of hippocampal and cortical regions were analyzed using Imaris software. In addition, Aβ and NfL levels were quantified in the brain tissue and plasma NfL measured using Meso Scale Discovery technology.

Result

BIN1 K358R introduced in the 5xFAD background significantly reduces plaque densities and associated microgliosis in the hippocampal region, which matches insoluble Aβ42 levels. In contrast, GFAP levels are significantly increased in 5xFAD/BIN1 K358R mice compared to 5xFAD mice. Despite reduced plaque densities, dystrophic neurite area as measured by LAMP1 staining, as well as plasma NfL, are equivalent between 5xFAD/BIN1 K358R and 5xFAD mice, suggesting increased damage per plaque.

Conclusion

BIN1 K358R reduces Aβ plaque deposition, but exacerbates the damage caused by those plaques, as determined by the surrounding halo of dystrophic neurites, and plasma NfL.
The WW‐FINGERS‐SARS‐CoV‐2 initiative: a multinational survey to assess the effects of the COVID‐19 Pandemic on Lifestyle and Psychosocial factors relevant to Brain Health
Authors: Mangialasche Francesca , Rocha Ana Sabsil Lopez , Lehtisalo Jenni , Solomon Alina , Middleton Lefkos T , Thunborg Charlotta , Levak Nicholas , de Jager Celeste A , Price Geraint J , Rydström Anders , Ngandu Tiia , Kivipelto Miia ,   WW‐FINGERS‐SARS‐CoV‐2 initiative
Published: December 2022

Background

global population aging and forecasted trends of modifiable risk factors for dementia and Alzheimer’s disease (AD) make prevention of these conditions an urgent priority. The World‐Wide FINGERS (WW‐FINGERS) global network of multidomain trials for dementia risk reduction and prevention is at the forefront of efforts to find effective and sustainable solutions for diverse population. The COVID‐19 pandemic has caused changes in the mental and physical health of older adults, which can influence dementia risk and prevention opportunities.

Methods

The WW‐FINGERS‐SARS‐CoV‐2 survey was developed to assess direct and indirect effects of the COVID‐19 pandemic in older adults. The questionnaire measures changes in lifestyle factors (e.g., diet, physical activity), management of chronic noncommunicable diseases (e.g., diabetes, hypertension), and psychosocial factors ‐including depressive symptoms, sleep disorders, social isolation‐ that are relevant to cognition. Both a pen‐and‐paper and a digital version of the survey have been developed in several languages. The digital version is supported through REDCap (Research Electronic Data Capture), which is used also for harmonized data collection.

Results

30 countries are participating in the survey. As for January 2022, data have been collected from 20 countries, with 23000+ participants. Local adaptations and piloting were done to optimize implementation in clinical‐based and population‐based settings. Participants are in the at‐risk spectrum for dementia: from normal cognition to pre‐dementia cognitive symptoms. Timing of the survey implementation varies across populations, allowing to capture short, medium and long‐term effects of the pandemic and restrictions measures. Some countries have used the survey to recruit participants in multimodal prevention trials. An updated report of the survey status and main results will be presented.

Conclusion

The WW‐FINGERS‐SARS‐CoV2 survey is a joint global action of the WW‐FINGERS network which can inform better care of older adults in the context of a pandemic. The survey is also a valuable tool for pre‐screening of participants for prevention trials, and results can inform adaptions to ensure successful recruitment and adherence in forthcoming multidomain trials for dementia prevention in older adults.
The COVID‐19 pandemic on Patients With Dementia and Family Caregivers‐report from the Memory clinic
Authors: Stefanova Elka , Šarčević Maksim , Aleksić Predrag , Živković Aleksa , Despotović Jelica , Jezdić Filip , Matijaš Kristina , Stojkovic Tanja , Stojmenovic Gorana Mandic , Kostic Vladimir S
Published: December 2022

Background

The aim of the present study was to examine cognitive‐behavioral changes that may be related to the lockdown and the quarantine during the COVID‐19 pandemic in Serbian patients with mild cognitive impairment (MCI), and Alzheimer dementia (AD). The caregivers’ distress was also evaluated.

Method

The 2089 registered patients with cognitive deficits, between December 2018 until January 2020 in Belgrade Memory clinic registry, University Clinical Center was contacted by telephone within the survey, 2 months after the lockdown declaration. Either the patients or their caregivers were asked to answer on: Caregiver Questionnaire, the Kingston Caregiver Stress Scale, Patient Questionnaire, Neuropsychiatric Questionnaire, and Clinical Dementia rating scale for caregiver and patients.

Result

The study included 1002 (females 56.%) patients either with AD (n = 389) or MCI (n = 604) who have got completed data set for analyses. Unfortunately, 74 patients died in the pandemic time, and 225 subjects rejected to participate, and the rest were not reached due to wrong phone number, or missed contact record. Caregivers reported a worsening in cognitive functions in 55.1% of AD patients, and increased neuropsychiatric symptoms were reported in 59.8% as worsening of preexisting symptoms (41.9%) or as new onset (21%). The most common were depression, apathy, sleep disorders and anxiety. The prevalence of these symptoms was the same as before the pandemic, but there was a change in their frequency and intensity. Approximately 15.9% of patients with MCI showed the onset of new behavioral symptoms, sleep disorder and anxiety were the predominant new symptoms. The transition from MCI to dementia was recorded in 24%. Due to increased patients’ neuropsychiatric burden stress‐related symptoms were experienced by two‐thirds of caregivers.

Conclusion

Pandemic quarantine induces a significant increase of neuropsychiatric symptoms in approximately half of patients and stress‐related symptoms in two‐thirds of caregivers. Health services need to plan a post‐pandemic strategy in order to address these emerging needs.
Digital Cognitive Training in MCI and Early AD: Real World Evidence and Insights from a Large Online Cohort
Authors: Schafer Robert J , Osman Allen M , Jaffe Paul I , Kerlan Kelsey , Ng Nicole F , Offidani Emanuela , Doraiswamy P. Murali
Published: December 2022

Background

The 21st Century Cures Act highlights the value of evidence obtained outside of traditional clinical trials (real world evidence, RWE) to enhance trial design and support health care decision making. Increasing use of computers and smartphones has accelerated the generation of RWE and enabled digital therapies including computerized cognitive training (CCT). CCT offers promise for improving cognitive outcomes in MCI and AD, but its effectiveness has not been fully established. Toward this end, we examined RWE on the effectiveness of CCT in MCI/AD using a large online dataset.

Method

We analyzed de‐identified data from a cohort of 82,984 individuals who participated in an online CCT program (Lumosity). Of these, 3514 reported a diagnosis of MCI or AD while the rest served as controls (N = 79,470). Participants completed the NeuroCognitive Performance Test (NCPT), a validated, computerized, online neuropsychological battery. A subset also completed a survey assessing real‐world cognitive functioning (RWC survey). Measures on both instruments were examined at baseline and after varying doses of CCT.

Result

At baseline, the MCI/AD cohort was significantly impaired on all eight NCPT cognitive subtests and the NCPT composite measure of global cognition compared to demographics‐matched controls (p<0.0001, N = 3514 MCI/AD, 79,470 healthy). The MCI/AD cohort was also impaired on the RWC survey (p<0.0001 for the composite score), particularly on items related to concentration or forgetfulness. Engagement with CCT varied among MCI/AD subjects with 2+ assessment timepoints (N = 1934), with an average of 340 CCT games played (SD = 482) over 112 days between assessments (SD = 104). The change from baseline in the NCPT composite measure increased with amount of CCT (p<0.0001, Cohen’s d = 0.31). RWC survey items also improved with training in a subset who completed them at multiple timepoints (p = 0.0530, N = 162).

Conclusion

This study provides RWE for the efficacy of CCT in MCI/AD on both objective and patient rated cognitive outcomes. The study also provides insights into dose effects. Such RWE will help optimize CCT interventions to improve cognitive symptoms of MCI and AD.
Understanding the role of amyloid on cerebral microvasculature in Alzheimer’s disease: A pre‐clinical Intra Voxel Incoherent Motion (IVIM) study
Authors: Shahid Syed Salman , Yen Jui‐Hung , Paraiso Hallel C , Wu Yu‐Chien , Yu Ivorine
Published: December 2022

Background

Vascular perturbation is emerging as an important contribution to Alzheimer’s disease (AD) trajectory. However, the role of microvascular alterations in pathophysiological processes remains unclear. We hypothesized a direct link between β‐amyloid (Aβ) and the cerebral microvasculature, leading to vascular stress, deteriorated blood‐brain barrier, and impaired microcirculation. The early detection of changes in the microvasculature can be used as an early biomarker to study underlying disease mechanisms. This study used intra‐voxel incoherent motion (IVIM) technique to quantitatively map functional capillaries related to blood volume fraction as surrogate marker for microvasculature alterations in an Alzheimer’s disease mouse model.

Method

Male 5xFAD mice at 6‐months‐old and age‐matched littermates were scanned using high‐resolution IVIM optimized DWI. The DWI and anatomical images were acquired on a horizontal bore 9.4T Biospec micro‐MRI system equipped with a 1H cryogenic coil. 2D T2‐weightd images were acquired with a voxel size of 60x60x300 µm3 and DWIs were acquired with a voxel size of 120x120x300 µm3. Hippocampal subfields (CA1, CA2, CA3, DG, and Subiculum) in (Badhwar hippocampal) atlas space were transformed to individual T2W space and then linearly transformed to DWI space. IVIM maps (Apparent diffusion coefficient [D], pseudo‐diffusion coefficient [D*], and perfusion fraction [fIVIM]) were calculated (voxel‐wise) using a bi‐exponential IVIM model. The mean fIVIM of individual subfields were used for group‐wise comparison, and the Hedges’g were used for effect‐size analysis.

Result

Our preliminary results showed regional differences in microvascular perfusion fraction between control (n=6) and 5xFAD (n=8) mice at 6 months of age. fIVIM was significantly lower in DG (p<0.05; Hedge’s g =‐1.4; 95% CI: ‐2.552, ‐0.202) and in Subiculum (p<0.05; Hedge’s g=‐1.3; 95% CI: ‐2.54, ‐0.194) of 5xFAD compared to wild‐type mice. The fIVIM remains unchanged in other subfields. The decreased fIVIM suggested that deficits in the capillary network of DG and Subiculum develop early

Conclusion

These findings support the sensitivity of IVIM to detect circulatory deficits in the hippocampal microvasculature associated with Aβ pathology. The IVIM may provide new insight into cerebral small vessel health in an early AD stage without a contrast agent administration and can be readily translated to the clinic.
Influence of fecal microbiota transplantation on gut microbiota composition in transgenic mice modeling amyloid‐β plaques and neurofibrillary tangles
Authors: Borsom Emily M , Keefe Christopher R , Hirsch Allyson H , Conn Kathryn A , Orsini Gabrielle M , Jaramillo Sierra A , Bolyen Evan K , Dillon Matthew R , Lee Keehoon , Caporaso J. Gregory , Cope Emily K
Published: December 2022

Background

The gut microbiota, the aggregates of all microbial cells that inhabit the gut, bidirectionally communicates with the brain through cytokines, hormones, metabolites, and neurotransmitters via the gut microbiota‐brain axis. The gut microbiota is thought to contribute to the development of Alzheimer’s disease (AD), which is characterized by plaque deposition, neurofibrillary tangles, and neuroinflammation. We hypothesize that manipulation of the gut microbiota will alter development of AD pathologies and neuroinflammation via the gut microbiota‐brain axis.

Method

We performed fecal microbiota transplants (FMT) from aged (52‐64 weeks) 3xTg‐AD mice, which are modeling plaques and neurofibrillary tangles, to young 3xTg‐AD (n=5) or wild‐type mice (n=10) via oral gavage. Phosphate buffered saline (PBS) was gavaged into 3xTg‐AD (n=5) and wild‐type mice (n=10) as a control. At 8 weeks, mice were gavaged with FMT or PBS for 5 consecutive days, followed by fortnightly maintenance transplants for 24 weeks. The V4 region of the 16S rRNA gene was sequenced on the Illumina MiSeq. Data were analyzed using QIIME 2. Reverse transcriptase qPCR was used to assess microgliosis, astrocytosis, and Th1/Th2 inflammation in the hippocampus of the FMT cohort at 24 weeks of age.

Result

We observed a shift in microbiota composition of FMT‐treated mice when compared to control (PBS‐treated) mice. Bacteroides acidifaciens was increased in 3xTg‐AD and wild‐type mice receiving FMT. We demonstrate partial engraftment of the gut microbiota from aged 3xTg‐AD mice in all FMT‐treated mice, demonstrated by a Random Forest model, which correctly predicts treatment groups based on gut microbiota composition (Accuracy Ratio over baseline assignment: 2.6).

Conclusion

We demonstrate the ability to transplant an aged gut microbiome into young mice. Future shallow shotgun metagenomic sequencing will be used to determine the species‐ and strains‐ that engraft in the GI tract. Additionally, targeted reverse transcription RT‐qPCR and immunostaining for plaques and hyperphosphorylated tau in the hippocampus will be used to assess how FMTs alter AD pathologies. These studies will contribute to our understanding of how features of the gut microbiota may contribute to AD development.
Enhancing Sensitivity of Immunomagnetic Detection of Alzheimer’s Disease Biomarkers with Magnetic Nanoparticles and Anti‐Biofouling Coating
Authors: Li Yuancheng , Mao Hui
Published: December 2022

Background

Immunomagnetic capturing/detection of biomarkers, including immunoprecipitation‐mass‐spectrometry (IP‐MS) and single molecule array (Simoa®), is a key technology in biofluidic‐based in vitro diagnosis of Alzheimer’s disease (AD). However, proteins and other biomolecules in samples can non‐specifically absorb on the surface of biomarker‐targeting ligand functionalized capturing agents, such as commercial magnetic beads (Dynabeads®). Such “biofouling” effect leads to the formation of a “protein corona” that not only attenuates the detection specificity, sensitivity and reproducibility by blocking the binding of targeted biomarkers, but also creates strong “contaminating” background signals. This report introduces a polyethylene glycol‐block‐allyl glycidyl ether (PEG‐b‐AGE) polymer coated magnetic iron oxide nanoparticle (IONP) rendering anti‐biofouling capability to improve the sensitivity of blood‐sample‐based AD biomarker detection.

Method

Non‐specifically adsorbed proteins on Dynabeads® and anti‐biofouling IONP after incubating with human serum were quantified to evaluate biofouling effect. Dynabeads® and IONP were conjugated with antibodies, and compared for the detection of fluorescent dye FITC‐labeled AD biomarkers spiked in human serum (10 to 2000 pg/mL), including Aβ40, Aβ42, and phosphorylated tau (p‐tau181), which were quantified by fluorescence. To compare the detection in the settings of current platforms, spiked Aβ40 and Aβ42 in human serum were measured by IP‐MS using antibody‐conjugated Dynabeads® and IONP as the capturing agents. Antibodies in assay kits of Simoa® were used to conjugated with Dynabeads® and IONP to compare the detection of five AD biomarkers spiked in human serum in the Simoa® setting. Additionally, plasma samples from 21 AD patients were tested for Aβ40 and Aβ42 measurement using antibody‐conjugated IONP and Dynabeads® by IP‐MS.

Result

Anti‐biofouling IONP demonstrated a ∼20‐fold reduction in serum protein adsorption, comparing to Dynabeads®. Dynabeads® and IONP demonstrated comparable detection sensitivity (captured/spiked, %) when spiked AD biomarkers at the concentration of ∼200‐2000 pg/mL. However, in samples with spiked AD biomarkers at ∼10‐100 pg/mL, Dynabeads® showed a decreased sensitivity up to 29% comparing to IONP. When Aβ40 and Aβ42 in patient plasma samples were immunoprecipitated by IONP or Dynabeads and analyzed by mass‐spectrometry, IONP showed 1.8‐ to 23.5‐folds greater signal‐to‐noise ratio (peak intensity/baseline) than Dynabeads®.

Conclusion

Anti‐biofouling IONP demonstrated improved sensitivity in blood‐based AD biomarker detections over Dynabeads®.
M2 microglia activation and proNGF inhibition : Possible Mechanisms Behind Cognitive Improvements by Low‐Dose Ionizing Radiation on Alzheimer's Disease; A Literature Review
Authors: Alifa Hasna Noor
Published: December 2022

Background

Recent studies showed that Low‐Dose Ionizing Radiation (LDIR) may induce significant cognitive improvements on Alzheimer's disease (AD). The mechanism behind it is still remain unclear.

Method

In this review, numerous research papers and clinical studies results from the last 10 years related to LDIR exposure on AD as a treatment, immunochemistry in AD, and neurogenesis are collected. The results of the studies are then comprehensively analyzed to find any associations that could explain or give clues on how LDIR exposure may induce significant cognitive improvements in AD.

Result

There is evidence that LDIR modulates microglia phenotypes by switching phenotype M1 to M2. The anti‐inflammatory M2 microglia may associated in amyloid plaques and tau tangles reduction that showed in many studies on LDIR for AD treatment. Further study shows that LDIR also promotes proNGF inhibition that may triggers neurogenesis.

Conclusion

LDIR shows that it may be a promising novel treatment for AD retrospectively via immunomodulation and triggers neurogenesis.
Beta‐amyloid regions related to amyloid positivity using a feature selection method.
Authors: Ko Hyunwoong
Published: December 2022

Background

Cerebral beta‐amyloid (Aβ) is a hallmark of AD. Few studies have revealed which of the regional Aβ markers are associated with abnormal levels of Aβ status. The aim of the current study was to identify multivariate regional Aβ markers predicting Aβ positivity (Aβ+).

Method

Seven hundred and sixty‐five participants from the ADNI‐2 cohort at baseline visit were included in the study. We used regional Aβ uptake as predictors in a predictive model. Flobetapir PET images were classified as Aβ‐positive if the standard uptake value ratio was over 1.1. The least absolute shrinkage and selection operator (LASSO) model with 1,000 bootstrap was implemented to identify regional Aβ traits to predict cortical amyloid burden from participants.

Result

Out of 116 predictors, 27 markers in cortical thickness significantly predicted Aβ+ among participants at baseline. After bootstrapping, 2 phenotypes had 95% confidence intervals that did not overlap zero: left precuneus (β = 0.684) and right rostral middle frontal region (β = 0.605).

Conclusion

These results demonstrated that several brain regions are related to abnormal levels of cerebral Aβ. These markers suggest robust sign that may capture AD pathology. To this end, this research was supported by the MSIT (Ministry of Science and ICT), Korea, under the ITRC (Information Technology Research Center) support program (IITP‐2022‐2017‐0‐01630) supervised by the IITP (Institute for Information & communications Technology Promotion).
Metacognition in older African American adults during the COVID‐19 pandemic
Authors: Kero Katherine , Woodard John L. , Giordani Bruno , Daugherty Ana M. , Shair Sarah , Hanna Sophie , DiCerbo Loraine M. , Kavcic Voyko
Published: December 2022

Background

There is a critical need to identify older adults in the earliest stages of cognitive decline for targeted dementia reduction interventions. Subjective memory concerns often drive older adults to seek objective memory assessments. However, there is often poor agreement between subjective complaints and objective measures. Previous research suggests that self‐appraised memory decline may be more sensitive to mild cognitive impairment than objective measures, but factors influencing the relationship between self‐perceived and actual functioning are unclear. Subjective memory appraisal may be susceptible to negative affective perceptions such as anxiety. Anxiety has increased substantially during the pandemic, suggesting the heightened potential for it to distort subjective perceptions, thereby increasing demands for cognitive assessments. This study investigated whether the discrepancy between subjective cognitive concerns and objective cognitive performance is related to anxiety in a sample of older African American adults.

Method

Telephone screenings were administered to 206 older African Americans (aged 64‐94 years) during the first year of the pandemic as part of a more extensive study. Demographic data, objective memory (Telephone Interview for Cognitive Status [TICS]), subjective memory (Cognitive Change Questionnaire [CCQ]), and anxiety (Generalized Anxiety Disorder‐7 [GAD‐7]) were measured, along with survey questions about affective and stress responses to COVID‐19 experiences.

Result

Objective TICS scores were predictive of subjective CCQ executive function scores (F(1, 197) = 4.37, p = .038, R2 = .022). Discrepancy scores were calculated as the standardized residual variance between objective and subjective measures. Discrepancy scores were correlated with anxiety (r = .396, p<.001), indicating that higher anxiety was related to an overestimation of cognitive difficulty relative to the level of objective cognitive resources.

Conclusion

Objective and subjective measures of cognition are related. However, discrepancies exist between objectively‐measured and self‐perceived cognition. Elevation in anxiety level is associated with greater overestimation of cognitive difficulties relative to one’s objective level of cognition. As pandemic‐related stressors have worsened anxiety for some, individuals with higher anxiety may also have depreciated their self‐appraisal of cognitive abilities in the present climate. Clinicians should consider anxiety as a possible contributing factor when assessing subjective cognitive difficulties.
A decade of gene discovery by the Alzheimer’s Disease Sequencing Project
Authors: Schellenberg Gerard D. , Blue Elizabeth E ,   Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
Published: December 2022

Background

Alzheimer’s disease (AD) is caused in part by variation in genes and genetic regulatory elements. Early work identified autosomal dominant mutations in APP, PSEN1 and PSEN2 that cause AD, and large effect size variants in APOE. However, most of AD genetic risk is caused by variants that result in a modest change in risk. These variants are spread across many genetic elements. In 2009, genome‐wide association studies (GWAS) began to identify these AD loci (> 60 sites). While these studies continue to be productive, GWAS lacks the resolution to identify the critical AD genes and causative variants responsible for risk/protective signals. In 2012, the Alzheimer’s Disease Sequencing Project (ADSP) was initiated to use Next Generation Sequencing methods for AD gene discovery. Sequence data has single nucleotide resolution with the potential to identify causative common and rare variants and to detect structural variants (SVs; insertions, deletions, copy number variation, etc.).

Method

The ADSP is a collaborative network of investigators that assembles cohorts for sequencing, processes the data, and performs genetic analysis. In the past 10 years, the ADSP generated whole exome (WES) and whole‐genome‐sequence (WGS) data for 20,504 case and 43,004 control subjects. Subjects sequenced are or clinically diagnosed or neuropathologically confirmed AD cases and cognitively normal elderly subjects. Subjects include non‐Hispanic whites, Hispanics, African Americans, and Asians. In progress are WGS data for an additional ∼20,000 subjects. Sequence data are harmonized by the Genome Center for Alzheimer Disease and shared with the research community via the National Institute on Aging Genetics Data Storage site.

Result

Analysis of WES and WGS data nominates 46 AD genes and regions of interest (PMID: 35005195). These genes implicate known and novel AD pathways providing new insight into AD pathogenesis and novel therapeutic targets. SVs were detected in ABCA7 and NCK2. The ADSP includes functional genomics studies to connect risk variants to specific genes and to understand the function of these variants. Analysis methods also includes artificial intelligence/machine learning approaches.

Conclusion

The genes and pathways identified by the ADSP are a rich source of validated targets for future therapeutic development.
Genetic Insights from the ADSP into Drug Discovery In Alzheimer’s Disease
Authors: Goate Alison , George‐Hyslop Peter St ,   Alzheimer’s Disease Sequencing Project
Published: December 2022

Background

A major goal of the NAPA plan initiated in 2013 is the development of novel drugs for the treatment and prevention of Alzheimer’s disease (AD). It is widely recognized that drug targets with genetic support are more likely to successfully make it through the drug development pipeline than those without genetic support. The target may be a genetic risk factor for AD or within a genetically regulated network implicated by an AD genetic risk factor. Thus, one of the primary goals of the Alzheimer’s disease sequencing project (ADSP) is to identify and validate putative novel drug targets and to work with the community to advance testing of these candidates.

Methods

Since 2013 the ADSP has performed genome wide association studies of both common and rare variants to identify novel AD risk genes in diverse human populations.

Results

Genomic analyses have demonstrated that these AD risk alleles are enriched with regulatory regions, in microglial enhancers and the PU.1 regulatory network. The ADSP has also made a major effort in including different ancestries into AD research and utilized the differences in AD risk between ancestries for major genetic risk factors (like ApoE) to identified potential therapeutic targets. A key challenge for common variants associated with AD is to link them to specific genes, and to understand the subsequent biological processes that lead to AD. This is a major focus of the Functional Genetics Consortium within the ADSP. Rare coding variants have directly implicated specific genes, which also provide support for the central role of microglial function in AD risk, e.g. Trem2, ABI3, PLCg2. The genetics of endophenotypes (e.g. sTrem2) and of protein quantitative trait loci offer alternative approaches to link genetics to biology.

Conclusions

Together, common and rare variants identify myeloid cell efferocytosis as a key disease risk hub. An alternative approach to drug discovery is the use of in silico approaches to match disease relevant signatures to existing drugs to enable drug repurposing. To date this approach has focused on transcriptomic signatures and implicates several biological pathways including the integrated stress response.