bluuebunny/crossref_metadata_2025 huggingface dataset:
High Frequency Oscillations in Epileptic and Non‐Epileptic Alzheimer’s Disease Patients and the Effect of Levetiracetam on the Oscillations
Authors: Chenchu Vishnu Shandilya Mungamuru , Addo‐Osafo Kwaku , Ranasinghe Kamalini G , Shamas Mohamad , Staba Richard , Nagaragan Srikantan , Vossel Keith
Published: January 2025

Background

Altered network synchronization and rhythmic neural activity is observed in Alzheimer’s disease (AD). Spontaneous epileptiform activity and/or seizures occur in an estimated 60% of AD cases, and having AD increases the likelihood of seizures when compared with people without dementia. Thus, network hyperexcitability can be an early feature and helpful for diagnosis and treatment. However, it is unknown if biomarkers of epileptogenicity are detectible in AD, and if these biomarkers are affected by the anti‐seizure drug levetiracetam (LEV). One important biomarker of epileptogenicity is high‐frequency oscillations (HFOs).

Method

To measure HFOs, we used 10‐min magnetoencephalography (MEG) recordings (275‐channel, sampling rate 1200–2400 Hz) during awake resting periods in participants with AD and healthy controls. Recordings from 14 AD (6 non‐epileptic AD (NEAD, median age: 60.8, 2M/4F) and 8 having subclinical epileptic activity (EAD, median age: 54.9, 5M/3F)) and 8 control (median age: 71, 5M/3F) participants were analyzed using two software scripts: Delphos and a custom‐made script for detection of HFOs. LEV 125 mg twice‐a‐day or placebo was administered for 4 weeks in between two MEG recordings, and 4 weeks of washout before switching LEV/placebo phases for each participant.

Result

HFOs were categorized into ripples (80 to 250 Hz) and fast‐ripples (250 to 500 Hz). At baseline, AD participants, including both NEAD and EAD, had higher ripple rate (RR) and higher fast‐ripple rate (FR) than controls in several regions (p<0.05, paired t‐test/ANOVA‐Tukey). Additionally, compared to EAD, NEAD had higher RR in left‐frontal, left‐temporal, and cerebral fissure regions, and higher FR in left frontal regions (p<0.05, ANOVA‐Tukey). In both EAD and NEAD, LEV increased RR in left‐temporal and bi‐parietal regions, but decreased RR in the left central region (p<0.05, paired t‐test). In both AD groups, LEV increased FR in a few regions, but it decreased FR in right temporal region in NEAD.

Conclusion

AD had a high level of HFOs, with higher numbers observed in non‐ epileptic AD. LEV resulted in region‐specific increases in HFOs in both NEAD and EAD. Thus, HFOs can function as a biomarker of hyperexcitability in AD; however, their contribution to the epileptic phenotype in AD requires further investigation.
Haptoglobin related protein without signal peptide induces a new syndrome of renal salt wasting in Alzheimer’s disease
Authors: Maesaka John K , Imbriano Louis J , Candace Grant , Miyawaki Nobuyuki
Published: January 2025

Background

A new pathophysiologic approach to evaluating hyponatremic patients identified the different causes of hyponatremia, including non‐hyponatremic patients with renal salt wasting (RSW). RSW was considered a rare to nonexistent syndrome until we found 24 (38%) of 62 hyponatremic patients in a general medical ward to have RSW. We induced RSW in rats by injecting plasma from 18 AD patients suspected to have RSW. We utilized lithium as a marker of sodium transport in the proximal tubule. All 18 AD patients below a mini‐mental state examination (MMSE) score of 12 had increasing excretion of lithium from 33 to 58%.

Methods

The same renal clearance studies demonstrated natriuretic activity (NA) in AD serum. We subjected the serum with NA and normal control serum to proteomic analyses to identify the protein content in both sera.

Results

Fractional excretion (FE) of sodium and lithium increased from 0.2% to 0.69 % and 24.4 to 52.5% in the control and AD sera, respectively. FElithium progressively increased from 33% to as high as 58% as MMSE decreased from 12 to zero. Phenotype specific haptoglobin 1‐1, and 2‐2, kininogen, thrombospondin, PROZ, alpha‐1 microglobulin/bikunin, and retinol binding protein did not have NA. Haptoglobin related protein with signal peptide did not have NA but there was a robust dose response to haptoglobin related protein without signal peptide (HPRWSP). Am Jour Med Sci 2021;361:261‐268

Conclusion

It appears that every patient below an MMSE of 12 becomes progressively dehydrated. Studies are underway to determine whether HPRWSP can serve as a biomarker of RSW in Alzheimer’s disease and to determine the prevalence of RSW at different stages of dementia.
Life Review Depression Intervention Conducted by Asian and White American Caregivers: A Mixed‐Method Comparative Study
Authors: Miyawaki Christina E. , Bouldin Erin D. , McClellan Angela
Published: January 2025

Background

Approximately 10% of people living with Alzheimer’s dementia (PWD) experience depression, yet behavioral interventions remain scarce. We developed an innovative depression intervention, Caregiver‐Provided Life Review (C‐PLR) based on life review therapy. The purposes of this study were to evaluate the feasibility of training family caregivers in life review skills and evaluate the impact on depressive symptoms.

Methods

Using a mixed‐method design, we trained Asian (n = 15) and White (n = 24) caregiver‐care recipient dyads. Eligible caregivers were family members who cared for PWD for ≥8 hours/week, completed caregiver training, six weekly life review sessions, and five weekly Fidelity check‐in calls with the research team. Care recipients experienced mild depression (≥5 on Geriatric Depression Scale) and dementia (≥13 on Telephone‐Montreal Cognitive Assessment). We collected pre‐ and post‐measures of care recipients’ depression (primary outcome), life satisfaction, caregivers’ burden, rewards of caregiving, and dyads’ relationship quality (secondary outcomes), and compared them using paired t‐tests. We evaluated feasibility by measuring fidelity check‐in scores to the C‐PLR training protocol during these calls.

Results

Thirty‐nine dyads completed the study. Asian (mean age = 52 years old) and White (59 years old) caregivers were working, female, and in good‐excellent health. Their care recipients (Asian = 82 years old; White = 80) were female and in poor‐fair health. Both Asian and White care recipients’ depression and dyads’ relationship scores from baseline to the end of the study significantly improved (Asian = 4.1 to 2.1, p<0.001; 12.5 to 13.4, p = 0.029; White = 4.1 to 3.1, p = 0.049; 13.8 to 14.5, p = 0.044, respectively). Asian (73%) and White (75%) caregivers’ fidelity scores were similarly high (p = 0.91) and rated as good‐excellent. Qualitative interviews of both caregivers supported the sentiments of the quantitative results. Furthermore, 73% of Asian dyads conducted the C‐PLR in their native language, however, it did not appear to influence any outcomes.

Conclusions

We found a significant impact of C‐PLR on depressive symptoms in both Asian and White PWD and their dyadic relationships. Both quantitative and qualitative results supported the feasibility of the C‐PLR training and the successful completion of the intervention. This study demonstrated that the C‐PLR intervention can be added to a list of successful non‐pharmaceutical interventions.
Home‐Based Multifocal Brain Circuit‐Based Neuromodulation Combining tACS and tDCS in Older Adults with Alzheimer’s Disease
Authors: Gilfix Talia , Zheng Judy , Davis Jonathan , Fox Rachel , Stein Benjamin , Yu Wanting , Morgan Jasmine , Syed Alisha , Syme Maggie L , Opitz Alexander , Manor Bradley , Pascual‐Leone Alvaro , Cappon Davide
Published: January 2025

Background

Alzheimer’s disease (AD) affects over 55 million people worldwide and is characterized by abnormal deposition of amyloid‐β and tau in the brain causing neuronal damage and disrupting transmission within brain circuits. Episodic memory loss, executive deficits, and depression are common symptoms arising from altered function in spatially distinct brain circuits that greatly contribute to disability. Transcranial electrical stimulation (tES) can target these circuits and has shown promise to relieve specific symptoms. However, previous trials focused on a single symptom and have been limited by poor quantification of induced electric fields (E‐field) in the intended cortical target(s). The studies aim to provide multi‐symptom relief to older adults with AD by combining two types of tES.

Method

Fourteen participants diagnosed with mild cognitive impairment (MCI) or early dementia due to AD were recruited as part of two studies (Table 1). Optimization of tES was performed by modeling the normal component of the induced E‐field (En) to target the left dorsolateral prefrontal cortex (DLPFC, Brodmann area 46) with transcranial direct current stimulation (tDCS) and to target the left angular gyrus (AG, Brodmann areas 39/40) with transcranial alternating current stimulation (tACS – 40 Hz) (Figure 1). Participants received daily stimulation sessions for four weeks at home, with baseline, post‐intervention, and 3‐month follow‐up assessments. E‐field modeling using MRIs evaluates behavioral effects' dependency on E‐field induced by tDCS and tACS in DLPFC and AG.

Result

Both studies showed excellent adherence to a home‐based, multi‐symptom tDCS/tACS intervention. To date, out of 280 scheduled sessions across 14 participants, 278 were completed, with a 99% adherence rate. The most common side effects were mild and transient (Table 2). Structural MRI scans were used to quantify E‐field modeling in target brain regions.

Conclusion

The studies demonstrate the safety, feasibility, and adherence of a remote‐supervised, caregiver‐led home‐based intervention combining tDCS and tACS to target two distinct brain networks and thus induce a more meaningful clinical impact by reducing distinct disabilities in AD. Quantifying the induced E‐field will provide data to assess the mediating effects of E‐field on treatment outcomes, yielding critical insights to enable future larger‐scale trials.
All‐cause mortality among veterans with mild cognitive impairment and Alzheimer’s dementia who have Intracerebral hemorrhage and subarachnoid hemorrhage
Authors: Aguilar Byron J. , Wang Ying , Arasa Vanesa Carlota Andreu , Berlowitz Dan , Mittler Brant , Morin Peter J , Reisman Joel , Abdennadher Myriam , Querfurth Henry W , Zhang Raymond , Monfared Amir Abbas Tahami , Zhang Quanwu , Xia Weiming , Aguilar Byron J.
Published: January 2025

Background

Cerebral amyloid angiopathy (CAA) is a significant contributor to hemorrhagic stroke, notably lobar intracerebral hemorrhage (ICH) and convexity subarachnoid hemorrhage (SAH), both of which have been observed in patients with MCI/AD. To evaluate all‐cause mortality among veterans with mild cognitive impairment (MCI) and Alzheimer’s dementia (AD) with/without Intracerebral hemorrhage and subarachnoid hemorrhage (ICH/SAH) in the United States (US) Veterans Affairs Healthcare System (VAHS).

Method

Veterans with MCI or AD were identified based on having clinical notes or diagnostic codes in the VAHS database (2010‐2019). ICH and SAH were identified with ICD‐10 codes I61.x and I60.x, respectively. Survival curves were generated, and Poisson regression was used to adjust for baseline characteristics.

Result

A total of 853,791 veterans with MCI/AD were included, with a mean age of 74 years, of which 96% were male, 5% Hispanic, 15% Black, and 74% White; 32% had MCI and 68% had AD. Approximately 0.6% of the overall sample had ICH/SAH. The observed mortality rates per 1000 person‐years were 130 for males and 60 for females and 138 for AD vs 102 for MCI. Mortality rates for Veterans with MCI/AD with and without ICH was 102 and 127, and with and without SAH was 83 and 127, respectively. Kaplan‐Meier curves showed a higher survival probability for Veterans with ICH/SAH events vs those without the events (P<0.01) and for AD vs MCI (P< 0.01; Figure). The mortality risk was lower for MCI than AD overall (IRR = 0.83, P< 0.01). The death rate in veterans with MCI/AD was statistically significantly lower for those with vs without ICH/SAH even after adjustment (IRR = 0.85, p<0.01). Death rate was higher in non‐Hispanic vs Hispanic (IRR = 1.23, P<0.01) and for White vs Black veterans (IRR = 1.05, P<0.01).

Conclusion

In US VAHS, AD was associated with an increased risk of death than MCI; ICH/SAH did not increase mortality risk. After adjustment, mortality rates were found to be 23% higher for non‐Hispanic vs Hispanic groups and 5% higher for White vs Black groups. Those findings will be further examined by incorporating Medicare data for Veterans who had dual eligibility for both VA and Medicare coverage.
Health‐related Quality of Life in People living with Dementia – Over and Underestimation of Proxy‐ratings
Authors: Buchholz Maresa , Engel Lidia , Weber Niklas , Michalowsky Bernhard
Published: January 2025

Background

Proxy ratings primarily provided by informal caregivers are usually administered if patients living with dementia (PlwD) are cognitively unable to rate health independently. The literature is limited by the use of typically agreement statistics, reporting that proxies generally underestimate PlwD health. Additional analyses of self‐ and proxy‐rated discrepancies in individual responses that focus on HRQoL dimensions are lacking. We examined discrepancies between self‐ and proxy‐rated health in PlwD on an individual response level.

Method

We analyzed baseline data of n = 174 dyads (PlwD and their caregivers) of a cluster‐randomized, controlled intervention trial. HRQoL was assessed with the EQ‐5D‐5L from a self‐ and proxy‐proxy perspective together with sociodemographic and clinical data. The EQ‐5D‐5L consists of five dimensions (“mobility”, “self‐care”, “usual activity”, “pain/discomfort”, “anxiety/depression”), each with five response options. Initially, we calculated agreement statistics (weighted kappa) for each dimension. For individual response levels, we analyzed the degree of inconsistencies between self‐ and proxy ratings ranging from 0 (identical responses in all dimensions) to 5 (different responses in all five dimensions). We grouped the PlwD into “no problems” and “problems” depending on the EQ‐5D‐5L response of each dimensions to compare the response distances between PlwD and caregivers.

Result

PlwD had a mean age of 80.1 years (49.1% female) with a MMSE mean score of 19.2; informal caregivers were, on average, 67.9 years old (67.8% female). Every third PlwD lived alone. In general, PlwD rated their HRQoL better than proxies (EQ‐5D‐5L indices: 0.75±0.25 vs 0.68±0.23; p<0.01). Nine dyads (5%) showed identical ratings, whereas 95% rated their health differently. Weighted kappa coefficients were lowest for the dimension usual activity (0.23) and highest for pain/discomfort (0.40). Among the grouped PlwD without and with problems, proxies estimated PlwD HRQoL worse (underestimation) or better (overestimation), respectively. This was due to a central‐tendency‐bias of caregivers, two times more frequently selecting mid‐response options, particularly apparent in mobility, usual activities, and self‐care.

Conclusion

The two trends of contrary response behaviour (over‐ and underestimation & central tendency bias) could be caused by uncertainties of caregivers, underlining the challenge of using both perspectives interchangeably. Further research is needed when using HRQoL measures as proxy instruments.
Worry differentially affects the impact of placental growth factor on processing speed in older adults with amnestic Mild Cognitive Impairment
Authors: Lam Jovian C , Savettiere Adriana , Louras Peter , Fairchild Jennifer Kaci
Published: January 2025

Background

Placental growth factor (PIGF) is an angiogenic, pro‐inflammatory biomarker that is overexpressed in cardiovascular diseases. Recent literature has linked PIGF to the identification of cognitive impairment with white matter burden. Worry is associated with an increased risk for cardiovascular disease, accelerated aging and subsequent reduced brain volume, and decline in cognition. Given these associations, worry presents as a potential link to PIGF and cognitive impairments, though no research to date has examined its relationship to PIGF and cognition. Thus, current study aims to examine the possible moderating role of worry on PIGF and cognitive function (e.g., processing speed) in older adults with amnestic mild cognitive impairment (aMCI).

Method

Participants included sixty‐six community‐dwelling older Veterans (Mage = 70.97 ± 8.66 years) who met criteria for aMCI. The sample was primarily male (95%), White (74%), and well‐educated (56% with bachelors or above). Composite scores reflective of processing speed were created using participants’ performances on the following measures: Symbol Digit Modalities Test, Stroop Color and Word subtests, and Trail Making Test A. Worry was measured by the Penn State Worry Questionnaire. Plasma PIGF levels were analyzed using SomaScan® disease‐specific panels. Hierarchical linear regressions were used to examine the moderating effect of worry on the relationship between PIGF and processing speed, while controlling for age.

Result

Results indicated an overall significant model F(4,61) = 8.28, p < .01, ΔR2 = .03 and main effect of PIGF (β = ‐2.12e‐03, t = ‐2.28, p = .03) on processing speed. There was also a significant interaction between worry and PIGF (β = ‐1.30e‐04, t = ‐2.02, p < .05). Follow‐up analyses indicated a significant association between PIGF and processing speed in individuals with higher levels (+ 1 SD) of worry (β = ‐.01, t = ‐3.34, p < .01).

Conclusion

The current results present a novel finding that worry intensifies the inverse relationship of PIGF and processing speed. Importantly, the current study reinforces a biopsychological link to cognition and a more nuanced consideration when examining biomarkers and risk factors of cognitive impairment.
Perivascular Space Analysis: A Possible Tool for Predicting Cerebral Amyloid Angiopathy in Pathology‐Confirmed Cases
Authors: Fotouhi Maryam , Sheikh‐Bahaei Nasim , Choupan Jeiran
Published: January 2025

Background

Diagnosis of cerebral amyloid angiopathy (CAA) presents a significant challenge in determining whether to propose anti‐amyloid treatment plans. The identification of perivascular spaces (PVS) through MRI serves as a possible strategy to elucidate the physiopathological interconnections between the brain's clearance mechanisms and the accumulation of amyloid. This study endeavors to the association between PVS morphology and CAA pathology.

Methods

T1‐weighted and T2‐FLAIR MRI data were obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Demographic details (sex, age, post‐mortem interval) and ADNI pathologic scores were gathered. Histological images provided scores for cerebral amyloid angiopathy. Leveraging our on the last premortem MRI, we automatically mapped regional PVS in white matter and basal ganglia. analysis was then employed to investigate whether premortem regional PVS volume fractions serve as predictors for postmortem CAA pathology, accounting for age, sex, and post‐mortem interval.

Results

The investigation revealed notable predictive associations between specific occipital regions' PVS volume fractions and the presence of amyloid angiopathy pathology, after multiple comparison correction. Specifically, the study identified the right cuneus PVS volume fraction as a robust predictor for the manifestation of amyloid angiopathy pathology (t=3.12, p=0.001). Similarly, the left precuneus PVS volume fraction emerged as a statistically significant predictor (t=2.78, p=0.005).

Conclusion

This study presents a noteworthy advancement in amyloid angiopathy diagnosis, employing standard MRI analysis of perivascular spaces. The identified correlation offers a pragmatic means to enhance diagnostic accuracy without complexity. This research underscores the potential applicability of PVS analysis in routine clinical practice for early CAA detection, contributing significantly to the practical improvement of CAA diagnostics.

Reference: 1. Sepehrband, F., Barisano, G., Sheikh‐Bahaei, N. et al. Image processing approaches to enhance perivascular space visibility and quantification using MRI. Sci Rep 9, 12351 (2019). https://doi.org/10.1038/s41598‐019‐48910‐x
Reducing Pre‐screening Cognitive Assessment Variability to improve Enrollment in clinical trials
Authors: Toll Nicholas
Published: January 2025

Background

A standard practice at our research site has been the administration by a clinician of cognitive pre‐screeners to the subjects in our initial visit. The administration of these assessments, along with the examination of medical histories, is designed to evaluate a patient’s current cognitive abilities and assist with their placement in the most appropriate study. However, as the number of clinicians increased, variation regarding administration of the cognitive screener was noted, resulting in a likelihood of increased rate of screen failures.

Method

To reduce the rate of screen failures at our research site and to increase the specificity of pre‐screening we implemented an improvement process to have one trained individual administering all of the standard cognitive pre‐screenings.

Result

This design resulted in a 25% reduction of outcomes variability due to multiple examiners, as unique responses are more likely to be interpreted in a similar manner. The methodology reduced practice effects as cognitive screening questions may be inadvertently discussed prior to the screener (e.g., month, date, place) during interview with the subject and caregiver. Additionally, the process eliminates any potential for relationship bias, as the trained individual has no prior relationship to the subject, as well as assist the clinician in tailoring the interview to specific qualifying studies.

Conclusion

The improvement process reduced the number of screen failure allowing our site to take another step in the long and difficult collaborative process involved with the creation and approval of novel medications.
Developing a novel claim‐based algorithm to identify incident and prevalent dementia using Medicare claims of the Atherosclerosis Risk in Communities (ARIC) cohort
Authors: Wang Tiansheng , Pate Virginia , Kim Dae , Power Melinda C , Garden Gwenn A , Palta Priya , Knopman David S. , Jonson‐Funk Michelle , Stürmer Til , Kucharska‐Newton Anna M.
Published: January 2025

Background

Pharmacoepidemiologic studies assessing drug effectiveness for Alzheimer’s disease and related dementias (ADRD) are increasingly popular given the critical need for effective therapies for ADRD. To meet the urgent need for robust dementia ascertainment from real‐world data, we aimed to develop a novel algorithm for identifying incident and prevalent dementia in claims.

Method

We developed algorithm candidates by different timing/frequency of dementia diagnosis/treatment to identify dementia from inpatient/outpatient/prescription claims for 6,515 and 3,997 participants from Visits 5 (2011‐2013; mean age 75.8 (SD 5.3) years) and 6 (2016‐2017; mean age 79.8 (SD 4.8) years) of the ARIC cohort with ≥ 1‐year continuous Medicare Part A & B enrollment prior to each visit. We evaluated algorithm performance (sensitivity/specificity/positive predictive value (PPV)/negative predictive value (NPV)) against the gold standard of the ARIC dementia classification based on an extensive battery of neurocognitive tests administered at each visit. We compared performance of the new algorithm with that of three existing algorithms (Jain, Bynum, Lee) and their relaxed forms (4‐year window, dementia diagnosis plus a depression diagnosis or dementia evaluation procedure, ignoring code position) to identify incident (n = 90 at V6) and prevalent dementia (n = 190 at V5; n = 160 at V6).

Result

The newly developed primary algorithm requires presence of a dementia diagnosis code followed by another diagnosis code within 1 year (under condition that the following non‐specific ICD‐9 diagnostic codes, 290.40, 290.41, 290.11, 290.3, should appear no more than once), or a subsequent dementia treatment prescription within 90 days (requiring Medicare Part D enrollment ≥ 6 months). The PPV of the new algorithm in the identification of incident dementia was PPV of 72.7%, with a specificity of 99.1%, outperforming existing algorithms. Its sensitivity of 38.7% and NPV of 96.2% were comparable to those achieved by existing algorithms. Sensitivity analysis restricting to ICD‐10 diagnostic codes increased the PPV and attenuated its sensitivity by 6%. Similar comparative performance was observed in the identification of prevalent dementia.

Conclusion

A novel algorithm for identifying dementia from Medicare claims, developed using linked ARIC‐Medicare data, outperforms previous algorithms and stands as a valuable tool in the assessment of ADRD drugs from real‐world data.
Psychometric properties of the Psychological Consequences of Screening Questionnaire (PCQ) adapted for cognitive screening
Authors: Lovett Rebecca , Filec Sarah , Hurtado Jeimmy , Kwasny Mary , Sideman Alissa Bernstein , Persell Stephen , Possin Katherine L , Wolf Michael S
Published: January 2025

Background

Context‐specific measures with high content validity are needed to adequately determine psychosocial effects related to screening for cognitive impairment. The objective of this investigation was to examine psychometric properties of the Psychological Consequences of Screening Questionnaire (PCQ), a measure of psychological impact of medical screening, adapted for cognitive screening in primary care.

Methods

Two‐hundred adults aged ≥65 recently completing routine, standardized cognitive screening as part of their Medicare Annual Wellness Visit were administered the adapted PCQ measure, comprised of negative (PCQ‐Neg) and positive (PCQ‐Pos) scales. Measure distribution, acceptability, internal consistency, factor structure, and content validity (construct, discriminative, criterion) were analyzed.

Results

Participants had a mean age of 73.3, were primarily female and socioeconomically advantaged. Nearly all received a normal cognitive screening result (99.5%). Overall PCQ scores were low (PCQ‐Neg: M 1.27; PCQ‐Pos: M 7.63). Both scales demonstrated floor effects. Acceptability was satisfactory, although the PCQ‐Pos had slightly more item missingness. Both scales had Cronbach alpha’s >0.80 and a single factor structure. Spearman correlations between the PCQ‐Neg with general measures of psychological distress ranged from 0.26 to 0.37 (p’s <0.001); correlation with a measure of well‐being was ‐0.19 (p<0.01). The PCQ‐Neg discriminated between those with and without a subjective cognitive complaint (M 2.73 vs. 0.89, p <0.001), and was associated with medical visit satisfaction (r = ‐0.24, p<0.001). The PCQ‐Pos predicted willingness for future screening (M 8.00 vs 3.00, p = 0.03).

Conclusions

The adapted PCQ‐Neg scale is an overall valid measure of negative psychological consequences of cognitive screening; findings for the PCQ‐Pos scale were more variable. Future studies are needed to further understand PCQ performance among more diverse samples and those with abnormal test results following cognitive screening.
The interaction between dietary habits, BDNF, CCK, and gut microbiota in the pathophysiology of Alzheimer’s disease
Authors: Montgomery Caitlin E , Hipsley Jessica Arango , Schuh Olivia , Shah Anjali , Khanna Deepesh
Published: January 2025

Background

Research heavily suggests that brain‐derived neurotrophic factor (BDNF), vital for neuronal growth and plasticity, and cholecystokinin (CCK), a satiety hormone that regulates BDNF levels, are altered in Alzheimer’s Disease pathophysiology. Factors such as dysbiosis of gut microbiota and poor food habits may affect CCK and BDNF release and brain function. The objective is to evaluate the effects of dietary habits, gut microbiota, and exercise on BDNF and CCK release in Alzheimer’s Disease patients.

Methods

A comprehensive review on how BDNF and CCK levels are affected in Alzheimer’s patients was conducted using databases like PubMed and Google Scholar. Search string keywords included “Alzheimer’s,” “BDNF,” “CCK,” paired with “exercise,” “diet,” and “gut microbiota.” The inclusion criteria included original articles published from 2012‐2024 from peer‐reviewed journals and studies exploring CCK and BDNF interaction with diet, exercise, and gut microbiota. Eligible studies were excluded if BDNF and CCK levels were associated with diseases other than Alzheimer’s. Papers were not restricted to the US population.

Results

Literature suggests BDNF levels significantly increase with exercise in Alzheimer’s disease patients. BDNF levels decrease in mice fed a high‐fat diet that reflects the Western diet. Research on the connection between gut microbiota and Alzheimer’s disease has also been explored in human and mice studies. A study conducted on human participants showed serum BDNF levels to significantly increase at Week 12 in the probiotic’s treatment group in contrast to the placebo group (−3.32 ± 2.35 ng/mL). A study on healthy mice that were given fecal microbiota transplantation from 5XFAD mice with major features of Alzheimer’s Disease amyloid pathology demonstrated elevated proinflammatory cytokines and decreased neurogenesis in the brain. Studies exploring CCK levels found that higher CCK was significantly associated with greater gray matter volume in areas of the brain that play a role in memory primarily spanning cingulate cortex and parahippocampal gyrus. In Alzheimer’s patients, CCK levels were found to be significantly lower.

Conclusion

Findings collectively suggest the complex interactions between diet, exercise, and neurocognitive outcomes, with both dietary interventions and physical activity, positively influence synaptic plasticity, cognitive performance, and biomarkers associated with neurodegenerative diseases.
An End‐to‐End Model for Visualization and Highlight of Alzheimer's Disease Progression
Authors: Zhang Juexin , Weng Ying , Xiao Weizhong
Published: January 2025

Background

Subtle cognitive decline in the prodromal stages of Alzheimer's disease (AD), encompassing both significant memory concerns (SMC) and mild cognitive impairment (MCI), presents a crucial diagnostic hurdle. This challenge stems from the inherent difficulty in both detecting the nuanced neurocognitive aberrations and visualizing the corresponding brain alterations, particularly within the hippocampus, on conventional magnetic resonance imaging (MRI). Consequently, current clinical diagnostic procedures remain arduous and necessitate substantial clinical expertise. Considering these limitations, the development of automated deep learning‐based methods for visualizing early‐stage AD‐related brain changes holds immense promise.

Method

We propose a generative model capable to synthesize high quality MRIs for both retroactive and predictive visualization of a given MRI. Furthermore, our model also indicates the morphological changes of a given MRI. Our model is comprised of three interconnected components: a classifier, a generative model, and a morphological feature identifier. Initially, a convolutional neural network (CNN) classifier categorizes the input MRI into its corresponding stage within the disease progression spectrum. Subsequently, the generative model, constructed to capture the nuances of disease‐related morphological evolution, synthesizes MRIs that simulate the brain's structural configuration at other potential stages of the disease. Finally, the morphological feature identifier, through a process of automated segmentation, delineates areas exhibiting significant morphological deviations and highlights those regions deemed most pertinent for further clinical evaluation.

Result

We employed T1‐weighted MRIs from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) public dataset to test our model. Our synthetic MR images achieved high visual fidelity, as well as indistinguishable from real images for human observers, and yielded high peak signal‐to‐noise ratio (PSNR) and structural similarity index measure (SSIM) scores. Moreover, our model can precisely highlight morphological deviations.

Conclusion

To facilitate diagnosis and intervention in early AD, we put forward a generative model to synthesize other stages of a given MRI. This allows clinicians to visualize potential disease progression pathways and clearly observe morphological changes in vulnerable brain regions. Our model can also highlight key anatomical alterations to help AD analysis and offer valuable insights into promise for early AD management.
The Effect of Social Isolation on Cognitive Performance and Brain Morphology among the Urban Elderly Indian Cohort: A Cross‐Sectional Analysis
Authors: Lingegodwa Abhishek Mensegere , Singh Sadhana , Stezin Albert , Partha Ajith , N M Divya , C M Amitha , HS Deva Kumar , Narayanasamy Rajitha , R Meghana , Menon Meenakshi , vishwanath Vindhya , HS Sunitha , Velavarajan Goutham , Arvind Prathima , Agrawal Deepashri , Malo Palash K , Mondal Banashree , Hameed Shafeeq K Shahul , Sundarakumar Jonas S. , Issac Thomas Gregor
Published: January 2025

Background

Social isolation among the elderly is increasing and its detrimental effect on cognition is not fully understood. We aimed to study the effects of social isolation on cognitive performance and brain morphology among the urban elderly.

Method

In this cross‐sectional analysis of 1484 participants from the Tata Longitudinal Study of Aging (TLSA) based in urban Bangalore, we administered the social network index questionnaire to identify participants experiencing social isolation. Cognitive performance was assessed using the Addenbrooke Cognitive Examination III (ACE III) battery and brain cortical volumes were obtained after subcortical volumetry was performed on T1 images (Siemens 3T Magnetom Prisma Fit) using the Freesurfer software (v 7.2.0). Multiple linear regression analysis was performed with social network diversity score (low scores indicating less involvement in social roles) as the independent variable and, ACE III total, subdomains, and brain volumes as dependent variables controlling for age, gender, education, blood pressure, cholesterol, physical activity, and depression were used as covariates.

Result

In this study 727 (49%) were males, the mean age (SD) was 62.6 (9.6), the majority of them belonged to upper and middle socio‐economic strata (96.3%) and the mean (SD) education was 14 (4.2) years. People who have poor social network diversity scores performed poorly in ACE total (β=1.056, p<0.001), attention (β=0.119, p=0.006), memory (β=0.437, p<0.001), fluency (β=0.169, p=0.005), language (β=0.161, p=0.001), and visuospatial domain (β=0.169, p=0.001) (Table 1). Those with lower social network scores had lower total grey matter volume (β=9474.99, p<0.001), and higher white matter hyperintensities (β=‐0.469, p<0.001).

Conclusion

Social isolation negatively affects global cognition and its subdomains and shows significant changes in brain volumes. Addressing social isolation among the elderly using policy measures should be mandated to decrease the load of cognitive impairment in the population.
Factor Structure and Internal Consistency of the Alzheimer's Disease Center's Neuropsychological Test Battery in the Uniform Data Set Version 3: The Nigeria Sample
Authors: Ucheagwu Valentine A , Ugokwe‐Joseph Rita Nonyelum , Ossai Jesse , Odilora Chiamaka , Giordani Bruno
Published: January 2025

Background

Harmonized neuropsychological battery for research in Alzheimer’s disease and related dementia (ADRD) in sub‐Sahara Africa is very important if we are to understand ADRD phenotype and mechanisms in the region and how they relate and differ from other regions. No study in Nigeria has examined factor structure (construct validity) at both exploratory and confirmatory levels of harmonized neuropsychological battery for research in Nigeria. This study was a move in this direction using already established neuropsychological test battery the Uniform Data Set Neuropsychological Battery version 3 (UDSNB 3.0) of the Alzheimer’s Disease Center United States.

Method

UDSNB 3.0 fully completed by 349 older adults (220 females) between the 65 – 85 years were used to test for construct validity. Exploratory and confirmatory factor analyses as well as Cronbach Alpha internal consistencies were analyzed.

Result

Principal axis factor analysis (PA) method with orthogonal rotation (varimax with Keiser normalization) and eigenvalue greater than 1 was used for exploratory factor analysis (EFA). Four factors were extracted: first – Executive function/language (Phonemic and category fluencies, number span tasks – forward and backward and multilingual naming test) accounted for 17.23% of the variance, second – Memory (Craft Story immediate and recall) accounted for 16.30%, third factor – Visual spatial (Benson Complex Figure Immediate, recall and recognition) accounting 11.59% and fourth factor – Processing speed accounting 5.64%. Confirmatory factor analysis (CFA) did not fit the four factor exploratory model: CMIN/DF = 4.23; CFI= 0.75; RMSEA=0.12. However, a good model fit was established: CMIN/DF= 2.13; CFI=0.94; RMSEA=0.07, when executive function was unbundled into working memory (Number Span – forward and backward) and language (phonemic and category fluencies) and recognition task of the Benson Complex Figure removed from the model. Moderate internal consistencies were found among the subtests.

Conclusion

UDSNB 3.0 showed good model fit on a five factor structure : Working memory, language, memory, visual spatial and processing speed. These domains could be measured in Nigeria older adults using UDSNB 3.0 cognitive tasks.
Sex differences in the relationship between cognition and brain structure in midlife individuals at risk for future dementia
Authors: Qi Qing , Deng Feng , Dounavi Maria‐Eleni , Muniz‐Terrera Graciela , Koychev Ivan , Malhotra Paresh , O'Brien John T , Ritchie Craig W , Lawlor Brian , Naci Lorina
Published: January 2025

Background

Two‐thirds of Alzheimer’s Disease (AD) cases occur in women. Compared to men, women exhibit more rapid cognitive decline and brain atrophy in the presence of AD‐related neuropathology (Gamache et al., 2020). It is now acknowledged that AD processes are present decades before the onset of clinical symptoms (Jack et al., 2013). However, whether there are sex differences in cognition‐brain structure coupling and how AD risk affects their relationships in midlife remain unclear. In this study, we investigated associations between sex, AD risk, brain structure and cognition.

Method

Structural Magnetic Resonance Imaging and detailed neuropsychological assessments were obtained for 614 cognitively healthy individuals (40‐59 years, 233 M/ 381 F) from the PREVENT‐Dementia study. Dementia risk factors were assessed by Apolipoprotein E [APOE] ε4 allele status, and the Cardiovascular Risk Factors Aging and Dementia (CAIDE) score. Multiple linear regression model was used to investigate the associations between sex, AD risk, brain structure and cognition.

Result

CAIDE was negatively associated with global cortical thickness, and negatively associated with episodic and relational memory (Figure 1). We didn’t find a significant association between global cortical thickness and cognition (Figure 2a) but found a sex‐specific coupling of global cortical thickness and episodic and relational memory (Figure 2b). Such sex‐specific coupling between global cortical thickness and cognition was absent in APOE ε4 carriers, and only shown in APOE ε4 non‐carriers (Figure 2c, 2d). Furthermore, among the selected AD signature regions, cognition was decoupled from the precuneus cortical thickness in APOE ε4 carriers, and only coupled with cortical thickness of precuneus in APOE ε4 non‐carriers (Figure 2e, 2f).

Conclusion

We found inherent sex‐specific differences in the coupling between brain structure and cognition. Our results suggest that these sex‐specific differences are being eroded by APOE ε4 carriership in mid‐life. Longitudinal follow‐up in this cohort will shed light on the long‐term sex‐specific impact of APOE genotype on brain structure and cognition in preclinical populations with risk for AD.
Changes in plasma biomarker levels are predictive of amyloid pathology and memory decline in cognitively unimpaired individuals
Authors: den Braber Anouk , Rousset Rebecca Z. , Verberk Inge M.W. , Boonkamp Lynn , Tomassen Jori , van der Landen Sophie M. , Collij Lyduine E. , Barkhof Frederik , van de Giessen Elsmarieke , Wilson David H , Miller Mike , Pijnenburg Yolande A.L. , van der Flier Wiesje M. , de Geus Eco J.C. , Visser Pieter Jelle , Teunissen Charlotte
Published: January 2025

Background

Plasma levels of amyloid‐β1‐42/1‐40, and glial fibrillary acidic protein (GFAP) have demonstrated predictive potential for amyloid pathology in the early stages of Alzheimer’s disease (AD) development. Utilizing baseline and up to 6‐year follow‐up plasma, positron emission tomography (PET) and cognitive data from cognitively unimpaired individuals, we here aim to test whether early changes in plasma biomarker levels associate with change in amyloid status and cognitive decline.

Methods

From the EMIF‐AD PreclinAD study we selected individuals with normal cognition and longitudinal plasma, PET and cognitive data available (nbaseline=200, table 1). Amyloid‐status was determined using visual assessment of dynamic [18F]flutemetamol‐PET scans. Plasma levels of amyloid‐β1‐40, amyloid‐β1‐42, neurofilament light (NfL), and GFAP were measured using the neurology 4‐plex E Simoa assay (Quanterix). Linear mixed models were applied to examine longitudinal changes in plasma biomarker levels, and their association with longitudinal changes in amyloid‐status and cognition.

Results

At baseline 13.3%, and at 4‐year follow‐up 25.9% of participants were amyloid‐positive. Twenty‐one participants converted from a negative to positive amyloid‐status. At baseline, GFAP levels were higher and amyloid‐β1‐42/1‐40 lower in amyloid‐positive compared to negative individuals (β(SE)=0.43(0.14), β(SE)=‐0.75(0.21), p<0.005, respectively). In the total cohort, plasma levels of GFAP and NfL increased over time, whereas amyloid‐β1‐42/1‐40 remained stable (Figure 1). Although overall stable, plasma amyloid‐β1‐42/1‐40 decreased in participants that converted from a negative to positive amyloid‐status over time (β(SE)=‐0.04(0.02), p=0.02). Alongside, an increase in GFAP levels was observed in participants that converted from a negative to positive amyloid‐status compared to stable negative participants (Figure 1). No group differences were observed for NfL. A longitudinal increase in GFAP levels was associated with memory decline in stable amyloid positive individuals (GFAP*time*amyloid‐group status: β(SE)=‐0.09(0.02), p<0.001, Figure 2).

Conclusions

Early changes in plasma GFAP and amyloid‐β1‐42/1‐40 are associated with changes in amyloid‐status in cognitively unimpaired individuals. Further, increases in plasma GFAP levels over time are predictive of future memory decline in amyloid‐positive individuals. These results support the potential of plasma GFAP and, to a lesser extent, amyloid‐β1‐42/1‐40 as diagnostic and prognostic markers for AD in early stages of disease development.
Association of microstructural changes with vascular disease and Alzheimer’s Disease
Authors: Sun Pan , He Zhengbo , Li Anqi , Zhu Yalin , Cai Yue ,   ADNI, Guo Tengfei
Published: January 2025

Background

Non‐invasive diffusion‐weighted imaging (DWI) can be used to assess cortical microstructure through cortical mean diffusivity (cMD). However, it is still unclear about the dynamic changes of cMD, as well as how it relates to vascular disease and Alzheimer’s disease (AD).

Method

We identified 318 cognitively unimpaired (CU) and 305 cognitively impaired (CI) participants with DWI image, β‐amyloid (Aβ) positron emission tomography (PET) image from the Alzheimer’s Disease Neuroimaging Initiative cohort. The 623 participants were separated into A‐CU, A‐CI, A+CU, and A+CI groups. Microstructural changes reflected by cMD were processed with a surface‐based diffusion tensor imaging (DTI) approach. Aβ PET was processed using cortical summary composite standardized uptake value ratio (SUVR) and converted to the Centiloid following the standard equation from the ADNI website. Tau PET SUVR was extracted in the composite temporal‐metaROI. T2‐flair‐based magnetic resonance imaging (MRI) was utilized for white matter hyperintensity (WMH) total number calculation with an in‐house developed algorithm and toolbox. T1 MRI image was processed using Freesurfer, and the cMD value in the 68 Desikan‐Killiany atlas regions of interest was extracted. Linear mixed effect (LME) models were used to calculate slopes of cMD for all participants with longitudinal DWI and WMH data. Generalized linear models (GLM) were used to compare baseline and slope of cMD among subgroups, adjusting for age, sex, APOE‐ε4, and education.

Result

Compared to the commonly used macrostructure indicators of cortical thickness and gray matter volume, the micro‐structural indicator cMD exhibited high sensitivity of group‐level alteration crosse‐sectionally and longitudinally for both vascular disease and AD (Figure 1). cMD was negatively correlated with Aβ in the A‐CI group but positively related to tau in the A+CI group. Tau PET was associated with faster increases of cMD only in the A+CI group (Figure 2). In contrast, cMD and WMH were linked with each other in both cross‐sectional and longitudinal datasets in Aβ negative individuals (Figure 3).

Conclusion

The findings suggest that cortical microstructure alternation reflected by cMD may be a promising biomarker for neurodegenerative disease compared to the cortical thickness and gray matter volume, particularly for vascular disease.