bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effect of photobiological modulation therapy on cognitive impairment and cardiovascular structure in an APP/PS1 mouse model of Alzheimer’s Disease
Authors: Haghkar Mahdi , McDevitt Ross A , Zernetkina Valentina I , Grigorova Yulia N , Wei Wen , Syed Sunayana Begum , Fox Shanaya , Santos Carla Rocha Dos , Juhasz Ondrej , Morrell Christopher H , Lakatta Edward G , Fedorova Olga V 
Published: December 2023

AbstractBackgroundPhotobiological modulation (PBM) therapy, a form of low‐dose light therapy, is beneficial in treating various disease conditions including Alzheimer’s disease (AD). Double‐transgenic mice (APPswe/PS1dE9) develop progressive accumulation of amyloid‐β (Aβ) plaques, cognitive impairment, and alterations in cardiovascular structure and function, and represent a model of AD. Prior studies have shown that PBM therapy reduces the size and number of Aβ plaques in the neocortex and hippocampus in the mouse models of AD. The aim of this study was to investigate the effects of PBM on cardiovascular structure and function and cognitive function in the aged AD mice.MethodsSix‐month old female AD (APPswe/PS1dE9; AD‐PBM, n = 8) and wild type mice (WT‐PBM, n = 8) were exposed to near‐infrared light (wavelength 850 nm, 4.5 J/cm2, 3min/day, 5 days/week) for 6 months. Control mice (AD‐CNT, n = 6; WT‐CNT, n = 6) were placed under the PBM apparatus without turning the light on for 3min/day, 5 days/week. Cardiac parameters were measured by echocardiography. Gait analysis (DigiGait), home cage activity (HCA), and spatial working memory (indicated by alternation rate in cross maze test, CM) were assessed after 6 months of treatment. Group differences were identified by two‐way ANOVA.ResultsIn HCA test, the AD‐CNT mice exhibited circadian locomotor hyperactivity at night‐time relative to WT‐CNT mice (Figure 1A, B), which was reduced by PBM. AD‐CNT mice had lower alternation rates in CM, indicating spatial working memory impairment. PBM had minimal effect on this parameter (Table 1). The AD‐CNT vs. WT‐CNT mice manifested differences in several gait parameters, specifically, they demonstrated a lower fore propel time than WT‐CNT. PBM normalized this parameter in AD‐PBM mice to the level of WT‐CNT (Figure 1C). Both WT‐PBM and AD‐PBM mice had improved cardiovascular structure, which was demonstrated by lower relative wall thickness of left ventricle (LV) and LV mass, and higher LV volume at the end of diastole in PBM‐treated vs. correspondent CNT groups (Table 1, Figure 2).ConclusionPBM improved cardiovascular structure and AD‐associated cognitive impairment in the APP/PS1 mouse model. It is possible that more effective cardiovascular structure and function contributes to Aβ removal from the brain after PBM treatment.
Supported by NIA/NIH/IRP
Blood‐based Biomarkers, Kidney Disease, and Albuminuria in the Systolic Blood Pressure Intervention Trial (SPRINT)
Authors: Gaussoin Sarah A. , Pajewski Nicholas M. , Reboussin David M. , Williamson Jeff D. 
Published: December 2023

AbstractBackgroundThere is significant current interest in the use of non‐invasive blood biomarkers to characterize risk for, and progression to, Alzheimer’s’ disease (AD) and related dementias. Population‐based cohorts have examined the relationship between protein markers of AD and neurodegeneration, showing consistent associations with the presence of comorbidity, and in particular, chronic kidney disease (CKD). However, these studies have had limited racial diversity, and have not examined relationships with urinary albumin excretion.MethodWe assayed amyloid beta 40 (Aβ40), Aβ42, total tau, and neurofilament light chain (NfL) in stored blood samples from 508 participants (≥60 years) in SPRINT. We computed the ratio of Aβ42/Aβ40, and converted all measures to standardized Z‐scores in order to compare estimates. Using linear models, we examined the association of chronic kidney disease (CKD) with the blood measures, defined as a baseline estimated glomerular filtration rate (eGFR)<60 mL/min/1.73 m2. We also considered several additional analyses, including utilizing eGFR based on Cystatin‐C versus serum creatinine, as well as examining the relationship of albuminuria and race/ethnicity with the blood measures in participants without CKD at trial baseline.ResultParticipants (42.7% female, 31.9% non‐white) with a mean age of 69.9 years. There was a significant association between CKD and total tau, Nfl (p<0.001), but not with Aβ42/Aβ40 (p = 0.09). Participants with CKD exhibited higher levels of both total tau (least squares (LS) mean = 0.27, 95% CI: 0.12, 0.43) and NfL (LS mean = 0.67, 95% CI: 0.52, 0.83). Relationships were similar for eGFR based on cystatin C versus serum creatinine. After excluding participants with CKD (N = 352, 39.8% female, 34.1% non‐white, mean age of 68.8), there were not significant relationships between albuminuria with any of the biomarkers (p>0.05), nor was there a significant association between race/ethnicity and total tau, NfL, or Aβ42/Aβ40 (p>0.05).ConclusionIn a racially diverse subgroup of SPRINT participants, there were significant relationships between kidney function, defined via eGFR, with total tau and NfL, but not for the ratio of Aβ42/Aβ40. We did not observe any association between albuminuria and these blood measures of Alzheimer’s disease and non‐disease‐specific neurodegeneration.
Exploring the Potential of Fenamate NSAID Analogs for the Treatment of Alzheimer’s Disease
Authors: Shalaby Karim , Nguyen‐Tran Van , de la Fuente Alberto , Thompson Ian , Abdesselem Houari , Ouararhni Khalid , Karim Nasser 
Published: December 2023

AbstractBackgroundAlzheimer’s disease (AD) is the most common form of dementia, and its prevalence continues to increase with absence of available interventions. Drug repurposing accelerates the drug discovery process as therapeutics with known safety and toxicology profiles are considered. Although the blood‐brain barrier (BBB) prevents uptake of most pharmaceuticals, our laboratory previously showed that tolfenamic acid (TA), a fenamate non‐steroidal anti‐inflammatory drug (NSAID) with known anti‐cancer effects, can cross the BBB and slow the progression of AD (Zawia et al, 2018).MethodIn the present study, we test 2‐(2‐Cyanophenylthio) benzoic acid (CBA) and Niflumic acid (NA), small molecule analogs of TA that showed better safety and efficacy at targeting neurodegenerative pathways in vitro, and a similar mechanism of action to TA. We aimed to examine the effects of the analogs on in mice using proteomic and transcriptomic analyses.Single dose study of TA, CBA, and NA was carried out in C57BL/6 mice following oral administration at 100 mg/kg. Differential expression of genes and proteomic biomarkers in mice cortices were analyzed between each treatment group and a corresponding control group.ResultsAnalysis of the number of perturbed genes revealed that the drugs demonstrate limited off‐target effects. Bioinformatic analyses revealed that the therapeutics targeted cancer and neurodegenerative pathways including autophagy, inflammation, and neuronal trafficking. CBA and NA shared common downstream targets and pathways suggesting that they may have a similar mode of action.ConclusionWe found a set of differentially expressed genes that have been linked to processes involved in AD pathogenesis such as the production and clearance of neurotoxic Aβ peptides, tau phosphorylation, regulation of oxidative stress, and inflammatory processes. These results suggest that the drugs may influence pathways related to the pathogenesis of AD and support the potential of drug repurposing of fenamate NSAIDs such as TA, and its analogs CBA and NA, as a strategy for cancer and neurodegenerative disease therapy. Further research is needed to confirm the effect of the analogs on AD biomarkers and their efficacy as therapeutics for AD.
Redefinition of dementia care in Italy in the era of anti‐amyloid agents for Alzheimer’s disease: an Expert Opinion and practical guideline
Authors: Filippi Massimo , Cecchetti Giordano , Cagnin Annachiara , Marra Camillo , Nobili Flavio , Parnetti Lucilla , Agosta Federica 
Published: December 2023

AbstractBackgroundCurrent evidence from clinical trials testing anti‐beta amyloid (Aβ) monoclonal antibodies (mAbs) in patients with early Alzheimer’s disease (AD) suggests a likely authorization in Europe in the next years, requiring a huge change of dementia care in all countries.MethodA group of prominent AD clinical experts in Italy met to discuss patients’ selection for immunotherapies and management strategies. The current diagnostic‐therapeutical standards in Italy were taken as the starting‐point.ResultImmunotherapies’ prescription must follow a biological diagnosis of AD, defined through the assessment of both amyloidopathy and tauopathy biomarkers. Their high risk/benefit ratio, moreover, needs a highly specialized diagnostic assessment, which should be dispensed by a neurologist. The Expert Panel suggests a reorganization of dementia and cognitive decline centers (CDCD) for the diagnosis of AD in Italy into 3 levels of increasing complexity, with specific tasks and requirements/resources: 1) community centers, with at least 1 neurologist / geriatrician / psychiatrist, with global screening purposes; 2) first‐level centers, deputed to biological diagnosis; and 3) second‐level centers, requiring the presence of on‐site facilities for the biological diagnosis and of at least one neurologist with expertise also in rarer neurodegenerative syndromes. Finally, specific characteristics of a center deputed to prescribe anti‐Aβ mAbs were discussed, highlighting the need for clinical and neuroradiological management protocols.ConclusionThe number of potentially treatable patients in Italy will be tens of thousands. To successfully face such a breakthrough, a quick reorganization of Italian CDCDs will be required, together with the allocation of the necessary resources.Funding: Unrestricted grants from Biogen.
A 10‐minute Digitally Administered and Scored Neuropsychological Protocol Assessing Executive Control and Episodic Memory
Authors: Libon David J , Swenson Rodney , Jannati Ali , Bates David , Tobyne Sean , Pascual‐Leone Alvaro , Gomes‐Osman Joyce Rios 
Published: December 2023

AbstractBackgroundDigital assessment technology provides rapid and reliable assessment of neurocognitive abilities associated with Alzheimer’s Disease and Related Dementia (ADRD) and Mild Cognitive Impairment (MCI). Dysexecutive and amnestic impairment typify many ADRD and MCI disorders. Here, we evaluate a 10‐minute digitally administered protocol assessing these neurocognitive constructs.Method229 community dwelling participants were assessed (age = 68.32+9.85; education = 15.01+2.58, MMSE = 26.84+2.78; 144 females). Executive abilities were assessed with three trials of 5‐digits backward digit span test (BDST) and the ‘animal’ fluency test. Episodic memory was assessed with a 6‐word Philadelphia (repeatable) Verbal Learning Test (PrVLT) consisting of 2 immediate free recall (IFR) trials, delayed free recall (DFR), and delayed recognition. Traditional pencil and paper testing was not used. Data were obtained with an iPad processed using automatic speech recognition.ResultA K‐means cluster analysis (k = 3) classified participants with possible dementia (pDem = 31), MCI (n = 96), and cognitively normal (CN, n = 100; Table 1). Groups differed from each other on all three P(r)VLT parameters (p = 0.001). CN participants outperformed other groups on executive measures (p = 0.001). All between‐group analyses yielded large effect sizes (η2 = 0.277–0.642). Logistic regression analysis using P(r)VLT‐DFR, P(r)VLT‐recognition, BDST, and ‘animal’ fluency parameters classify MCI and pDem participants into their respective groups compared to CN participants (p = 0.003). For the pDem group, within‐group t‐tests found rapid forgetting (PrVLT‐DFT<PrVLT‐IFR trial 2, p = 0.013; PrVLT‐recognition<PrVLT‐DFR (p = 0.013). Additional, within‐group pDem group comparisons found no differences between P(r)VLT‐recognition and either executive tests. Within group comparisons for the MCI group found P(r)VLT delayed recognition improved compared to P(r)VLT delayed free recall (p<0.001), and worse performance on both executive measures compared to P(r)VLT‐ recognition (p = .001). All of these comparisons are consistent with a mild dysexecutive syndrome.ConclusionThe protocol described above is efficient, reliable, removes any inter‐rater reliability issues, and is able to operationally‐define dysexecutive and amnestic cognitive impairment ‐ key neurocognitive constructs related to ADRD and MCI. This 10‐minute digitally administered and automatically scored neuropsychological protocol assessing executive abilities and episodic memory could easily be deployed in clinical trials and in primary‐ and specialty‐care settings to screen for emergent cases of MCI and ADRD by efficient assessment of episodic memory and executive abilities.
Prevention of Alzheimer’s by a Multimodal Lifestyle Protocol – Working‐mechanisms for Memory Gains: Mouse‐PAW
Authors: Alanko Vilma , Eroli Francesca , Solomon Alina , Hartmann Tobias , Kivipelto Miia , Nilsson Per , Maioli Silvia , Matton Anna 
Published: December 2023

AbstractBackgroundThe approach of changing multiple lifestyle factors simultaneously targeting different risk factors is expected to have the greatest potential in preventing or delaying the progression of dementia. Nevertheless, it is largely unidentified what are the biological working mechanism underlying the positive findings from clinical trials of multimodal lifestyle interventions.MethodWe have set up a novel protocol to study multimodal lifestyle intervention in mice. The protocol was developed to recapitulate the FINGER (NCT01041989) and MIND‐AD (NCT03249688) clinical trials. In the lifestyle Prevention of Alzheimer’s Working‐mechanisms (PAW) group, mice were given access to running wheels (voluntary exercise), Fortasyn Connect (healthy diet), and they were subjected to cognitive training in an IntelliCage (IC) environment. To separately investigate the effects of an intervention resembling vascular monitoring, a group of mice was given Atorvastatin and Enalapril mixed in the diet. Control mice were housed in normal conditions. We included 12 wild‐type female C57BL/J6 mice six‐months‐of‐age per group. The full intervention lasted for 8 weeks.ResultThe study aimed to evaluate the feasibility of this innovative housing setup that provides a lifestyle intervention for the mice. The housing setup furthermore provides diverse data for individual mice on their learning and physical activity. Definite strengths of the protocol are the minimal need for mouse handling, the possibility of group housing, and that the intervention runs fully in a homecage environment. During the intervention, the PAW group undergoes cognitive training in the form of learning the location (corner) of a bottle from which they receive water (positive reinforcement). Regardless of individual variation in learning different cognitive training paradigms, PAW mice on a group level were able to reduce the error rates (incorrect corner visits) by approximately 25% in all paradigms.ConclusionWe constructed a way of performing multimodal lifestyle intervention in mice in a homecage environment, which provides a platform for detailed mechanistic studies. Moreover, our protocol minimizes stress due to handling and provides quantitative data for both cognitive training and exercise. The future steps involve studying animal models of cognitive decline, Alzheimer’s disease and vascular/metabolic dysfunction to assess mechanisms impacted by lifestyle change.
Geo‐Cultural Influence on Quality of Life and Activities of Daily Living in Older Adults with Alzheimer’s disease
Authors: Appleman Erica R. , Machizawa Sayaka , Stenclik Jessica , Kamat Rujvi , Iacob Andrei 
Published: December 2023

AbstractBackgroundIn addition to measures of cognition, global Alzheimer’s disease (AD) clinical trials commonly include measures to assess functional status (activities of daily living; ADLs) and quality of life (QoL) reported by participants and study partners. Most common assessments were validated with North American, White, English‐speaking populations and research suggests that these are not free from cultural and linguistic influence. ADLs and QoL may exhibit regional differences due to socioeconomic and cultural factors. It is important to understand how geo‐cultural factors influence these measures, which are often used as trial efficacy endpoints. In this study, we examined the impact of geo‐cultural region on ADCS‐MCI‐ADL and QoL‐AD when considering baseline cognitive status.MethodThis study included electronic ADCS‐MCI‐ADL, QoL‐AD, and ADAS‐Cog data from two multi‐national AD clinical trials of participants with prodromal to mild AD. Data were collected from three geo‐cultural regions: Asia (n = 688); Western Europe (WE; n = 589); and North America (NA; n = 1925). Participants were stratified into five cohorts based on ADAS‐Cog13 scores.ResultQoL‐AD Study Partner and AD Participant scores varied significantly across geo‐cultural regions (Kruskal‐Wallis test; p<0.0001). Both study partner‐reported and participant reported QoL‐AD scores in Asia were lower than scores in NA and WE for all ADAS‐Cog13 cohorts (Dunn’s test; p<0.0001). QoL‐AD AD Participant scores in NA and WE did not differ. For participants with lower cognitive performance (ADAS‐Cog > 40th percentile), study partner‐reported QoL‐AD scores in NA were significantly higher than those in WE (Dunn’s test; p<0.05), but there was not significant difference on the participant‐reported QoL‐AD scores between these regions. ADCS‐MCI‐ADL scores were not significantly different across groups.ConclusionOur study found that QoL‐AD, but not ADCS‐MCI‐ADL scores differed significantly across geo‐cultural regions when considering baseline cognitive performance. Both participant and study‐partner reported QoL was lower in Asia than in WE and NA. Cross‐regional differences in QoL may also be moderated by baseline cognitive performance. Different social norms and aging expectation, healthcare resources, and trial participation may have contributed to the regional variance observed. Future studies should examine if specific constructs are more contextually dependent on the local culture.
Equating the ADAS‐Cog and MMSE to Cogstate Brief Battery scores
Authors: Barbone Jordan Mark , Khurshid Kiran , Edgar Chris J. , Maruff Paul 
Published: December 2023

AbstractBackgroundThe Alzheimer’s Disease Assessment Scale‐Cognitive subscale (ADAS‐Cog) and Mini‐Mental State Examination (MMSE) are used as clinical outcome assessments (COAs) to investigate Mild Cognitive Impairment (MCI) and Alzheimer’s disease (AD). The Cogstate Brief Battery (CBB) is a digital assessment of psychomotor function, attention, visual learning, and working memory. Digital assessments may overcome limitations of traditional assessments but score conversions haven’t been undertaken.MethodData were aggregated for baseline visits from the A4, ADNI, and AXON studies. Participants included healthy/cognitively normal (HC), MCI, pre‐clinical AD, and mild AD. An equipercentile linking routine for single‐group designs, using bootstrap‐resampled standard error (SE; variability of estimated CBB scores for each COA score) and bias (mean differences of resampled results from full model) metrics, was employed to fit score distributions. Reaction time (RT; log10 ms) and accuracy (proportion correct) for each of the CBB tests and two composite accuracy (LWM) and reaction time (ATT) scores were fit to ADAS‐Cog and MMSE totals.ResultData for 8,878 participants were analyzed (HC = 4,021; PC = 773; MCI = 420; AD = 414; Unclassified/Mixed = 3,250). Scores ranged from 0‐39 (ADAS‐Cog13), 0‐27 (ADAS‐Cog11), and 9‐30 (MMSE). Estimates of CBB scores by COA scores showed expected associations between assessments. CBB composites for Accuracy and RT at MMSE > = 26 were estimated at approximately 0.7‐0.9 and 2.8‐2.6 respectively. SE in ADAS‐Cog and MMSE totals from CBB scores were larger for scores which reflect worse performance and were from smaller samples (accuracy: > 0.10; RT > 1.0). MMSE RT SE estimates were significantly smaller (all < 0.2) than ADAS‐Cog estimates. Results of both ADAS‐Cog versions were virtually identical.ConclusionTables for converting ADAS‐Cog and MMSE totals to CBB scores will be provided. Results can be reliably converted when performance is clinically better. Lack of samples in lower performance ranges presents an issue for reliable conversion. Demonstrating how traditional COAs compare to digital assessments can aid clinical interpretation and the understanding of limitations in each assessment. Using score equating tables may help establish a robust method for exploring associations and differences between assessments and scores.
Behavioral symptoms of Alzheimer’s disease and autism spectrum disorder: Insights to guide future non‐pharmacological interventions
Authors: Rhodus Elizabeth K. , Barber Justin M , Abner Erin L , Kryscio Richard J , Nelson Peter T. , Van Eldik Linda J. J. , Jicha Gregory 
Published: December 2023

AbstractBackgroundMany behavioral and psychiatric symptoms of dementia (BPSD) share similarities with those described in pediatric autism spectrum disorder (ASD), including anxiety, depression, and communication deficits. However, the possibility of late‐life onset of behaviors stereotypic of ASD in Alzheimer’s disease (AD) has been poorly explored. Findings of three studies are presented here to illustrate associations in behaviors between ASD and AD.MethodsCare partners of persons with cognitive impairment (MCI or dementia) from the University of Kentucky Alzheimer’s Disease Research Center community‐based longitudinal cohort were surveyed using the Gilliam Autism Rating Scale‐2 (GARS‐2). Analyses included t‐tests, chi‐square, analysis of variance, and linear regression models to explore frequency of ASD behaviors in this cohort, and the relationship of behaviors represented in the GARS‐2 compared to behavioral categories used in AD assessment (Neuropsychiatric Inventory‐Questionnaire; NPI‐Q). Lastly, cross‐sectional postmortem neuropathological analyses compared “Autism Possible” to “Autism Unlikely” in available cases.ResultsAnalyses included 142 GARS‐2 respondents. A substantial number of participants presented with ASD‐like behaviors, and those with high Autism Index scores had significantly younger age at onset (71.1±11.0 vs. 76.7±8.3; p = 0.034) and more severe cognitive impairment than those who scored in the “Autism Unlikely” range. ASD‐like behaviors were also significantly correlated with BPSD severity ratings (r = 0.47; p < 0.001). In neuropathological analyses, the two groups differed in the frontal and temporal regions, specific to tau pathology.ConclusionThese findings suggest that ASD‐like behaviors may emerge in AD as a result of shared neurological substrates, given that such behaviors are associated with an earlier age of onset and more severe cognitive impairment. With emerging evidence linking BPSD and ASD, additional research is needed to understand shared mechanisms, as well as development of novel treatment approaches to address behavioral symptoms of AD.