bluuebunny/crossref_metadata_2025 huggingface dataset:
Prevalence of Dementia and Mild Cognitive Impairment in the United States: Findings from the Health and Retirement Study (HRS) Harmonized Cognitive Assessment Protocol (HCAP) Project
Authors: Manly Jennifer J , Jones Richard N , Langa Kenneth M , Ryan Lindsay H , Levine Deborah A , McCammon Ryan , Heeringa Steven G , Weir David R
Published: December 2022

Background

Nationally representative data are critical for understanding the causes, costs and consequences of dementia and MCI in the US and can better inform policies aimed at reducing their impact on patients, families, and public programs. Because research on dementia is often based on highly selected samples of older adults who are disproportionately White, college‐educated, and high‐income, the nationally representative Health and Retirement Study (HRS) has become an essential resource for US population‐level information on dementia prevalence and incidence. However, the original HRS substudy providing dementia diagnostic information was fielded more than 20 years ago. We developed the Harmonized Cognitive Assessment Protocol (HCAP) to provide national estimates of the prevalence of MCI and dementia in the US and to examine differences by age, race and ethnicity, and gender.

Method

A random sample of 3,496 HRS participants age 65+ completed a comprehensive neuropsychological test battery and a standard informant interview. Dementia and MCI were classified using an algorithm based on standard diagnostic criteria and comparing test performance to a robust normative sample. National prevalence was estimated using population weights.

Result

A total of 393 (9.8%) individuals [mean (SD) age, 82.3 (7.4); 243 women (62%) and 150 men (38%)] were classified as having dementia, and 804 (22%) individuals were classified as having MCI [mean (SD) age, 76.8 (7.8) years, 243 women (62%) and 150 men (38%)]. People with dementia and MCI were more likely to be older, had fewer years of school, and were more likely to be non‐Hispanic Black or Hispanic than non‐Hispanic White. No differences in prevalence were found between women and men.

Conclusion

Using a comprehensive, harmonized neuropsychological test battery and large substudy sample to derive national estimates, we found the prevalence of dementia and MCI among people age 65 and older was similar to that of other Western countries. Cognitive impairment is common among older adults, and shows significant patterning along racial, ethnic, and socioeconomic lines. Updated dementia prevalence estimates for the United States from 2016 show that the disproportionate burden of dementia and MCI among Black and Hispanic older adults and people with lower educational attainment persists.
Targeting the Nav1.6:GSK3β Protein:Protein Interaction Complex to Mitigate Hippocampal Hyperexcitability in Early‐Stage Alzheimer’s Disease
Authors: Baumgartner Timothy J , Dvorak Nolan M , Singh Aditya K , Laezza Fernanda , Group Laezza Research
Published: December 2022

Background

Nav1.6 is the most densely expressed sodium channel isoform in the adult brain and is a primary determinant of action potential initiation and propagation due to its subcellular localization at the axon initial segment (AIS). Importantly, it has been shown that the firing frequency and Na+ currents of Nav 1.6 channels in hippocampal neurons are specifically increased by Aβ exposure in a concentration‐dependent manner. Nav1.6 is regulated through its interactions with key auxiliary proteins, notably Glycogen Synthase Kinase 3‐β (GSK3β), which has increased expression in the hippocampus of AD patients as well as peripheral circulating lymphocytes in both MCI and AD patients. We have shown that GSK3β regulates Nav1.6 channel activity through phosphorylation of and direct binding to the Nav1.6’s intracellular C‐terminal domain (CTD). Furthermore, genetic silencing of GSK3Ββ significantly decreased both Na+ currents and intrinsic firing compared to controls specifically through Nav1.6, while GSK3Ββ over‐expression or pharmacological disinhibition produced opposing phenotypes. Multiple lines of evidence indicate that hippocampal hyperactivity is present in patients with MCI and early‐stage AD and it is observed that reduction of hippocampal hyperactivity in MCI patients improves cognition and memory performance. We hypothesize that small‐molecule modulation of the Nav1.6:GSK3β PPI interface can counteract hippocampal hyperexcitability and could be used to treat early phases of AD, preventing the onset of cognitive decline.

Method

HEK293 cells co‐transfected with WT or mutant Nav1.6 and GSK3β were utilized to interrogate the Nav1.6:GSK3β PPI and screen a series of 50 validated hit compounds using split‐luciferase complementation (LCA). Whole‐cell patch‐clamp electrophysiology was performed in heterologous cells and acute slice preparations to validate GSK3β‐mediated regulation of Nav1.6 activity and evaluate lead compound efficacy.

Result

Mutagenesis screening revealed putative interaction sites of the Nav1.6:GSK3β PPI. Counter‐screening of 50 validated hits revealed 5 compounds that inhibit Nav1.6:GSK3β complex assembly at low micromolar concentrations (Figure 1). Compound 5671063, identified from the counter‐screen, exhibits functional modulation of Nav1.6 activity in heterologous cells (Figure 2).

Conclusion

The Nav1.6:GSK3β complex is a critical mediator of neuronal activity and represents a novel target for treatment of pathological hippocampal hyperexcitability associated with cognitive decline.
Mobile Toolbox: Age‐related change on remote, smartphone‐based measures of cognition
Authors: Nowinski Cindy J. , Kaat Aaron J. , Slotkin Jerry , La Forte Erica M , Shono Yusuke , Novack Miriam , Pila Sarah , Amagai Saki , Hosseinian Zahra , Adam Hubert , Gershon Richard C.
Published: December 2022

Background

Differentiating normal from pathological cognitive change in adults is essential for both preventing and treating abnormal cognitive decline. The Mobile Toolbox (MTB) is an app‐based research platform and expandable test library enabling remote assessment of cognition using participants’ own smartphones (iOS and Android). MTB facilitates conduct of diverse types of cognitive research with a broad range of participants, including those who may be hard to reach. However, evidence for MTB test validity, including demonstration of expected age‐related changes in adulthood, is needed to support MTB use. We present findings on associations between age and MTB performance.

Method

1,120 English‐speaking participants, ages 18–90, were recruited by a market research company as part of a larger study. Participants completed MTB remote measures of executive function, episodic and working memory, processing speed, and language on their smartphones. Measure order was fixed ((Vocabulary, Memory for Sequences, Spelling, Picture Sequence Memory (PSM), Flanker, Face Name (FNAME) Learning, Dimensional Change Card Sort (DCCS), Number Match, Face Name Memory)); individual tests could be taken anytime within a 14‐day period. Spearman correlation coefficients were calculated to evaluate relationships between age and test scores.

Result

Our participant sample was 57% female, 13% Hispanic, 72% white; mean age = 45 (sd = 21). Education distribution was: < high school (2%); high school (34%); some college (34%), college (20%), graduate degree (11%). Measures of executive function (DCCS and Flanker: r = ‐0.50; ‐0.57) and processing speed (r = ‐0.56) showed decreased performance with age (all p < 0.001). Episodic memory scores also decreased with age, but correlations were weaker (PSM and FNAME: ‐0.2, ‐0.35; p.<.001). Performance on language tests did not significantly decrease with age.

Conclusion

Most MTB measures correlated with age in the expected directions. Fluid cognition (e.g., executive function and processing speed) and memory typically decrease with age, and this decrease was reflected in MTB test performance. In contrast, crystallized abilities (e.g., spelling and vocabulary), which are typically preserved as we age, did not decrease in our sample. Initial results suggest MTB can be used to identify abnormal cognitive decline and support its use in cognitive aging research.
Chimeric Phagocytic Receptors (CPR) to target Alzheimer’s disease pathology
Authors: Levites Yona , Ran Yong , Erquizi Aya , Iturbe Andrea , Dillon Kristy , Ryu Danny , Moore Brenda D , Golde Todd E
Published: December 2022

Background

Based on the premise that protein aggregation and accumulation in AD and many other neurodegenerative disorders is a key, causal, pathologic event, therapeutic strategies need to focus on i) prevention of aggregate formation ii) enhancement of clearance of the aggregate or iii) neutralization of “toxic” signaling by the aggregate. Enhancing clearance of the target protein via phagocytic mechanisms is the most direct way to test the hypothesis that enhancing clearance will be beneficial. We cloned two novel chimeric phagocytic receptors (CPRs), fused to a previously characterized anti‐Abeta scFv. The present work aims to explore whether astrocyte expressed CPRs targeting Aβ enhance phagocyte clearance and alter the target pathology, when delivered into the brain of the Alzheimer’s disease mouse model, CRND8, as a prevention paradigm, before the pathology develops, or after amyloid aggregation already occurred.

Method

Anti‐Abeta recombinant scFvs fused to two most promising CPRs were packaged in AAV under astrocytic GFAP promoter and delivered into the brains of newborn CRND8 mice (prevention paradigm) as well as older mice with preexisting pathology (treatment paradigm). Amyloid burden and Aβ levels in the soluble, SDS soluble and SDS‐insoluble, Formic Acid soluble fractions, as well as the state of astrocytosis and astrogliosis were compared between various cohorts. Backbone of the CPR without the scFv as well as pAAV‐EGFP served as controls.

Result

Initially we evaluated expression, amyloid burden and GFAP and IBA staining in mice that were injected with 2 CPRs, pAAV‐MRC1‐GFAP‐scFv9, pAAV‐FCRG‐GFAP‐scFv9, as well as pAAV‐MRC1‐BB (backbone control) and pAAV‐EGFP control. Amyloid staining revealed a significant clearance of amyloid staining in the area around the injection site, which overlapped with the expression of CPR. Additionally, expression of CPRs resulted in increased astrocytes and microglia burden.

Conclusion

These results suggest a significant amyloid alteration by chosen CPRs. Future studies will optimize brain delivery as well as determine therapeutic potential of CPRs following transplantation of the CPR expressing microglia/monocytes into the brain mice with preexisting pathology.
Challenges and opportunities in designing dementia‐friendly communities with local governments
Authors: Karamacoska Diana , Salunke Pranal , Shatnawi Eman , Caballero Gabriela , Steiner Genevieve Z. , Dadich Ann , DiGiacomo Michelle , Morrison Nicky , Alliance Canterbury‐Bankstown Dementia
Published: December 2022

Background

Communities that do not accommodate the needs and preferences of people with dementia can exacerbate disability and isolation. Although dementia‐friendly communities (DFCs) were established to foster understanding and acceptance of dementia, the built environment remains underexplored. We identified the challenges and opportunities for fostering dementia‐enabling environments among community planners.

Method

This study is set in South‐West Sydney, Australia, where a DFC is being established. The policies of seven local governments were analysed for actions that aligned with Dementia Australia’s 41 DFC recommendations: 13 for social, 14 for outdoor, and 14 for indoor environments. An online workshop was then held with 30 community planners to raise awareness for dementia‐enabling environments. Participants were surveyed about their dementia beliefs and attitudes. Facilitated discussions identified challenges and opportunities for designing DFCs. Qualitative and quantitative data across all sources were triangulated.

Result

Although none of the local government policies specifically mentioned dementia, up to 20/41 DFC actions were met. Most of these were in social engagement (with ≤10/13 recommendations met by each local government). Less action was taken on outdoor and indoor environments (with ≤9/14 outdoor and ≤4/14 indoor recommendations met by up to six local governments). Although beliefs and attitudes about dementia among planners were generally positive, only 48% indicated that they had a good understanding of it and nearly 80% noted they would feel anxious and depressed about a diagnosis. Key DFC challenges included a lack of awareness and conflicting priorities between government bodies. Opportunities included engaging with universities to conduct demographically relevant awareness raising, facilitate multisectoral collaboration, developing an evidence‐base, and involving service providers to engage with the dementia community.

Conclusion

This study triangulated data to identify gaps in community planning efforts, confirming that more action is required to design dementia‐friendly communities. We are now leading a multisectoral collaboration to educate community planners and the public, and are advocating for the recognition of dementia‐friendly environments in government plans. This study provides practical guidance to assist planners with DFC designs.
One Minute Early Dementia Screening Test for Indigent Countryside Indian Population: A Community Based Study
Authors: Singh Saranshi , IV Veer Bahadur Singh , Singh Saransh
Published: December 2022

Background

With the ageing of our populations there are increasing numbers of older adults with memory complaints and possible dementia. A new case of dementia in some form is diagnosed every 70 seconds according to the 2010 Alzheimer’s Disease Facts and Figures; moreover countryside population especially indigent population mostly remain undiagnosed. Hence to develop an easy to use dementia detection system has become an international priority for improving care of patients with prevalent neuropsychiatric disorders of later life.

Method

242 patients were enrolled justifying predesigned inclusion and exclusion criteria after approval from Institutional Ethics Committee. One minute dementia test was administered to them. The 1 minute dementia test is screening tool that had 4 components, testing immediate & delayed recall, orientation, and visuo‐spatial cognition. The Clock Drawing Test (CDT) component of this tool allows clinicians to administer this test among illiterate population and quickly assess numerous cognitive domains. A cutoff score of < 12 was considered abnormal. Receiver operating characteristic, partial correlation and logistic regression analyses were employed for evaluation.

Result

In this study, majority of subjects were greater than 65 years of age. Males accounted for 68% (n = 164) and females for 34% (n = 78). Mean age of the study population was 59.7 ± 13.46 years. A statistically significant decline in cognitive domain were noted in relation to patient education (p<0.001), locality predominantly rural based uneducated population (p<0.001) as well as increasing age (p<0.01) however, no statistically significant correlation (p>0.05) was observed in relation to patient’s sex. Delayed word recall was the most frequently impaired parameter (92.5%; n = 224) followed by visuo‐spatial cognition (82%; n = 198).Immediate recall (4.9%; n = 12) was minimally effected. CDT was abnormal among 69% (n = 168) patients

Conclusion

In the present study 87% (n = 210) of the patients had abnormal test. Delayed word recall was the earliest domain to get impaired followed by visuo‐spatial cognition. A cutoff score of < 12 best correlated with risk of detecting dementia. Thus, 1 minute dementia test can be a useful screening tool for detecting dementia in outdoor basis patients though larger studies are required to validate its clinical implications.
Positive Affect and Cognitive Functioning in Older African American Adults
Authors: Halter Colt M , Moll Allison C. , Kero Katherine , Hanna Sophie , DiCerbo Loraine M. , Woodard John L. , Giordani Bruno , Daugherty Ana M. , Kavcic Voyko
Published: December 2022

Background

Previous research has demonstrated a link between affect and cognitive functioning, particularly showing that negative affect is related to lower cognitive performance across several cognitive domains. However, the relationship between positive affect (PA) and cognitive functioning is not as thoroughly characterized, though some previous work suggests that PA may be related to improved memory consolidation and greater cognitive flexibility. There is little research, if any, on the relation between PA and cognition in older adults from diverse racial backgrounds, who are also at greater risk for Alzheimer’s disease. PA may be a modifiable factor and target for intervention to deter cognitive decline. Therefore, we investigated whether PA was related to cognitive functioning in a sample of community‐dwelling, older African American adults. We predicted that greater PA would be associated with greater global cognitive functioning, immediate memory recall, and delayed memory recall while controlling for age.

Method

Telephone screenings were administered to 194 older African Americans (aged 64‐94 years). Global cognitive functioning, immediate recall, and delayed recall were measured via the Telephone Interview for Cognitive Status‐Modified (TICSm). Immediate and delayed recall scores were excluded from global cognitive functioning scores to reduce conceptual overlap. PA was measured with a questionnaire of emotional functioning. We used hierarchical linear regression to determine whether PA was positively associated with cognitive functioning while controlling for age.

Result

Higher PA was predictive of greater global cognitive functioning, after accounting for the effect of age (F(2,191) = 15.70, p<.001; ΔR2 = .05, b = 0.68, SE = 0.21, p = .002). Similarly, higher PA was predictive of greater immediate recall (F(2,191) = 14.10, p<.001; ΔR2 = .03, b = 0.45, SE = 0.19, p = .019) and delayed recall (F(2,191) = 7.44, p<.001; ΔR2 = .02, b = 0.48, SE = 0.23, p = .035).

Conclusion

In support of our hypothesis, we have demonstrated that greater PA is associated with greater global cognitive functioning, immediate memory recall, and delayed memory recall among older African American adults. Past studies report some relationships between PA and cognition, though little, if any, work has been done with aging adults from diverse racial backgrounds. Understanding how PA relates to cognition in late life is crucial because it may be a modifiable protective factor and a target for intervention.
Apigenin restores memory function in stressed mice
Authors: Olayinka Juliet Nnenda , Okosun Maureen Omoazagba , Amadi Manuchim Chibuzor , Ikpen Joshua Oghenemudiakewve
Published: December 2022

Background

Stress, a known cause of neuropsychiatric disorders, is associated with cognitve dysfunction, neuroendocrine systems breakdown and altered brain oxidative status and proteins (Roozendaal, 2002; Radecki et al., 2005; Lupien et al., 2007). Apigenin (API), a natural flavonoid, with diverse biological activity, is thought to possess neuroprotective potentials (Li et al., 2015). This study investigated whether API administration abrogates chronic unpredictable mild stress (CUMS)‐induced cognitive impairment, as well as exploring its probable underlying mechanisms.

Method

Swiss male mice (n = 10) were treated with API (12.5 ‐ 25 mg/kg, intraperitoneally) 30 min before exposure to CUMS daily for 14 days, thereafter tested for memory function using the Y‐maze and novel object recognition (NOR) tests. Levels of malondialdehyde (MDA), reduced glutathione (GSH), superoxide dismutase (SOD), and corticosterone levels were assessed using enzyme‐linked immunosorbent assay. The expressions of brain derived neurotrophic factor (BDNF), phosphorylated extracellular signal‐regulated kinase (pERK), and cAMP response element‐binding protein (pCREB) were assessed using immunohistochemistry.

Result

CUMS produced cognitive impairment in mice as shown in the Y‐maze and NOR tests. CUMS significantly elevated MDA, and serum corticosterone levels, including reducing GSH and SOD levels, decreasing BDNF, pERK, and pCREB levels in the prefrontal cortex and hippocampus. However, chronic administration of API significantly prevented all these CUMS‐induced behavioral and biochemical alterations.

Conclusion

API may be a potential therapeutic agent for cognitive disturbances as seen within the stress model and its neuroprotective effect was partly mediated by restoring oxidative status, serum corticosterone levels, up‐regulating BDNF, pCREB and pERK levels.

References

Lupien SJ, Maheu F, Tu M, Fiocco A, Schramek TE. The effects of stress and stress hormones on human cognition: implications for the field of brain and cognition. Brain Cogn 2007; 65:209‐37

Roozendaal B. Stress and memory: opposing effects of glucocorticoids on memory consolidation and memory retrieval. Neurobiol Learn Mem 2002;78: 578‐95

Radecki DT, Brown LM, Martinez J, Teyler TJ. BDNF protects against stress‐induced impairments in spatial learning and memory and LTP. Hippocampus 2005;15: 246‐53.

Li R, Zhao D, Qu R, Fu Q, Ma S. The effects of apigenin on lipopolysaccharide‐induced depressive‐like behavior in mice. Neuroscience letters. 2015 May 6;594:17‐22.
Effect of Matcha green tea on cognitive functions and sleep quality in elderly adults with cognitive decline: a randomized controlled study over 12 months
Authors: Uchida Kazuhiko , Meno Kohji , Suzuki Hideaki , Korenaga Tatsumi , Ito Hitomi , Inoue Makoto , Shan Liu , Ota Miho , Shiraki Noeru , Nakamura Shin , Yomota Satoshi , Akinaga Nobuyuki , Baba Yoshitake , Tagata Chika , Araki Yoshiharu , Tsunemi Shuto , Aso Kenta , Inagaki Shun , Nakagawa Sae , Kobayashi Makoto , Asada Takashi , Arai Tetsuaki , Takihara Takanobu
Published: December 2022

Background

Nutrition is a pivotal factor in the prevention of dementia. Matcha green tea powder, which contains L‐theanine, caffeine, and epigallocatechin gallate, has the beneficial effects of each constituent on cognitive functions and mood. However, no long‐term clinical study has yet been performed to evaluate the effect of Matcha on psychological functions. Here, we performed a randomized, double‐blinded, placebo‐controlled, clinical study, conducted over 12 months, to investigate the effect of Matcha on cognitive functions and sleep quality. Furthermore, the relationship between blood and neuroimaging biomarkers and the effect of Matcha was investigated.

Methods

We recruited 939 community‐dwelling older adults aged 60–84 years and enrolled subjects with a diagnosis of subjective cognitive decline (SCD) and mild cognitive impairment (MCI). A total of 99 subjects (64 SCD, 35 MCI) were randomized, with 49 receiving Matcha (2 g/day, male 23, female 26) and 50 receiving placebo (male 20, female 30). The groups were adjusted for age, sex, and APOE4 genotype. Cognitive functions were assessed by MMSE, MoCA, ADAS‐cog, RBANS, and the CNS Vital Signs computerized neurocognitive battery. Sleep quality was measured by the Pittsburg Sleep Quality Index (PSQI). Plasma biomarkers and neuroimaging (Amyloid PET, MRI, SPECT, fNIRS) were also assessed. The change of outcome variables from the baseline to 12‐month was tested statistically using a mixed‐effects model.

Results

Compared to the placebo, the consumption of Matcha induced a significant improvement in social acuity assessed by perception of facial emotion (P = 0.034), while continuous performance showed a trend towards improvement. The PSQI differed by 0.86 between the groups, indicating an improvement in sleep quality in the Matcha group compared to the placebo group (P = 0.087). The MMSE score showed a slight increase in the Matcha group. Amyloid PET SUVR showed no change from baseline to 12‐month in either group, while the plasma Aβ42 was reduced in the Matcha group, suggesting increased clearance of peripheral Aβ42.

Conclusion

Facial emotion recognition is impaired in cognitive impairment. This long‐term intervention study suggests that Matcha consumption can improve emotion perception and attention, and sleep quality in elderly adults with cognitive decline.
Impact of Decentralized Clinical Trial Methodologies on Alzheimer’s research
Authors: Kalali Amir
Published: December 2022

Background

The Decentralized Trials and Research Alliance represents over 120 organizational members including regulatory authorities, biopharmaceutical companies, technology companies, patient advocates, clinical trial sites, and service companies. Four priority areas have been identified to accelerate the adoption of decentralized methodologies where appropriate in clinical research. Within these four priority areas, 12 initiatives were launched.

Method

The more than 120 organization members took part in a formal process to identify priority areas and initiatives that would drive these priorities. Leaders and group members were assigned to these initiatives and clear outputs. For this project we looked at the relevant initiatives that would specifically be relevant to Alzheimer’s disease clinical research and improve the conduct of these trials in areas such as recruitment, patient focus, and diversity.

Result

This presentation will discuss how these initiatives that will have an impact on improving the efficiency and success of research in Alzheimer’s disease.

Conclusion

Alzheimer’s disease research faces many challenges that include attracting enough clinical trial participants, improving access in an equitable way, including to patients not geographically near clinical trial centers. Decentralized research methodologies can assist clinical trial sponsors and clinical research sites improve on these and many other aspects of clinical research.
Comparing the accuracy of the DCTclock and Montreal Cognitive Assessment to detect cognitive impairment and cerebral amyloid status in older adults
Authors: Swaminathan Aathman , Emrani Sheina , Arthur Edmund , Strenger Jennifer , Salloway Stephen P. , Correia Stephen , Thompson Louisa I
Published: December 2022

Background

Sensitive and non‐invasive methods of screening for early‐stage Alzheimer’s disease (AD) are urgently needed. Digital assessment tools have the potential to improve the efficiency of cognitive screening for older adults in both clinical and research settings. The Linus Health DCTclock uses a digital pen to capture traditional clock drawing test performance and advanced analytics to evaluate the drawing process for indicators of cognitive difficulty.

Method

We compared the DCTclock to the Montreal Cognitive Assessment (MoCA), a standard cognitive screening test, in a sample of older adults (total N = 60) with normal cognition (n = 30) or a clinical diagnosis of mild cognitive impairment (MCI) or AD (n = 30) and investigated which measure is more accurate in predicting cerebral amyloid (Aβ) PET status in a subset of 32 participants with PET imaging data.

Result

MoCA total score was moderately correlated with DCTclock total score (r = 0.61, p < 0.01), as well as various DCTclock composite sub‐scores. ROC analysis indicated that the MoCA had superior accuracy in differentiating between cognitively impaired and unimpaired participants (AUC = 0.98) relative to the DCTclock (AUC = 0.82). ROC analysis also indicated that the MoCA had superior accuracy in differentiating elevated versus non‐elevated Aβ PET status (AUC = 0.76) relative to the DCTclock (AUC = 0.60). A composite of the MoCA and DCTclock total scores did not improve accuracy over the MoCA alone (AUC = 0.71)

Conclusion

Overall, these preliminary results suggest that the MoCA is a superior cognitive screening tool and may also be useful for detecting AD associated neuropathology.
Working Memory Performance for Semantically Related Objects Distinguishes Cognitively‐Unimpaired Mutation Carriers from Non‐Carriers in a Colombian kindred with Autosomal Dominant Alzheimer’s Disease
Authors: Fox‐Fuller Joshua T. , Baena Ana Y. , Londono Natalia , Munera Diana , Badillo‐Cabrera Alex , Martinez Eva , Noriega Daisy , Martinez Jairo E. , Aduen Paula , Vila‐Castelar Clara , Lopera Francisco , Cronin‐Golomb Alice , Quiroz Yakeel T.
Published: December 2022

Background

The identification of cognitive tests sensitive to subtle changes in the preclinical stage of Alzheimer’s disease (AD) is of upmost importance to early detection of the disease, and to optimizing AD clinical trial recruitment. We used a delayed matching‐to‐sample (DMS) paradigm to study working memory for semantic relatedness in young adult carriers and non‐carriers of an autosomal dominant AD (ADAD) mutation from the Colombian kindred.

Methods

35 cognitively‐unimpaired Presenilin1 (PSEN1) E280A mutation carriers and 26 non‐carrier family members took the “Memory for Semantically‐Related Objects” test (MESERO), a computerized DMS working memory test for semantically‐related (and unrelated objects) developed by our group. The MESERO shows an equal number of either 4 or 6 objects that are semantically‐related or unrelated and records accuracy out of 80 points total (40 semantically‐related trials; 40 unrelated trials), as well as reaction time in milliseconds. Participants also completed the Mini‐Mental State Exam (MMSE). MESERO behavioral responses between groups were evaluated with the Mann‐Whitney test; age, MMSE scores, and education were compared with independent samples t‐tests.

Results

Non‐carriers were significantly older (M = 36.7 years, SD = 6.5) and had slightly, but significantly higher MMSE scores (M = 28.8, SD = 6.5) than the carriers (age: M = 30.5, SD = 5.3; t = 3.92, p<.001; MMSE: M = 28.1, SD = 1.2; p<.001). The groups did not differ on education (∼mean of 11 years for both; t = 0.29, p = .39). On the MESERO total score, mutation carriers had significantly lower performance (mean = 70.8, SD = 6.5) relative to non‐carriers (mean = 73.5, SD = 5.7; U = 312, p = .04). The PSEN1 E280A carriers, in particular, performed worse on the semantically‐related trials (mean = 33.9, SD = 4.2) relative to non‐carriers (mean = 35.8, SD = 2.9; U = 312.5, p = .04), but not on unrelated trials (U = 357, p = .19). The carriers performed worse than non‐carriers on trials with 4‐items (mean = 35.5, SD = 4.2 vs. mean = 37.3, SD = 3.2) (U = 300.5, p = .02), but not with 6‐items in the study phase (U = 366.5, p = .19).

Conclusion

A brief computerized working memory task for semantically‐related objects was able to distinguish cognitively unimpaired mutation carriers from non‐carriers from a Colombian kindred with autosomal dominant Alzheimer’s disease, approximately 14 years before the median age of mild cognitive impairment onset in this cohort. Working memory for semantic relatedness warrants further study as a potential marker of preclinical AD.
Geo‐Cultural Influence on Change in CDR and MMSE Scores
Authors: Appleman Erica R. , Machizawa Sayaka , Chen Zinan , Kamat Rujvi
Published: December 2022

Background

Alzheimer’s disease (AD) clinical trials are increasingly global. Most measures used were validated and standardized with North American, White, English‐speaking populations with limited consideration of cultural nuance. Prior research suggests that both the Clinical Dementia Rating (CDR) and Mini Mental State Examination (MMSE) are not free from cultural and linguistic influence. It is important to understand how geo‐cultural factors influence longitudinal change in scores on these measures, which is often used as the primary endpoint for study efficacy. In this study, we examined whether change in CDR and MMSE scores over one‐year follow‐up varied across geo‐cultural regions.

Method

This study included electronic CDR (eCDR) and electronic MMSE (eMMSE) data from four multi‐national AD clinical trials of subjects with prodromal to mild AD. Data were collected at screening and one‐year follow‐up from seven geo‐cultural regions: East Asia (n = 138); Eastern Europe (n = 170); Western Europe (n = 484); North America (n = 496); South America (n = 55); Middle East/Africa (n = 26); and Oceania (n = 26).

Result

The Kruskal–Wallis test found statistically significant variance in CDR‐Sum of Box (CDR‐SB) scores across geo‐cultural regions (p <0.0001). Results of the Dunn’s test indicated mean change in CDR‐SB scores for South America was significantly lower than those for North America, Eastern Europe, Western Europe, and Mideast/Africa. Additionally, mean change in CDR‐SB scores for East Asia was significantly lower than those for Western and Eastern Europe. Change in MMSE total scores did not vary across geo‐cultural regions.

Conclusion

Our study found average change in CDR‐SB but not MMSE total scores differed significantly across geo‐cultural regions. CDR‐SB scores were relatively more stable in South America compared to most other regions, and in East Asia compared to Western/Eastern Europe. The CDR may be more susceptible to cultural factors due to its reliance on subjective information from caregivers, in contrast with the MMSE, a standardized, objective measure. Different social norms and expectations for aging, functional independence, and trial participation in these regions may have contributed to the variance. Future studies should examine if specific CDR or MMSE items are more contextually dependent on the local culture.
Lifetime clinical benefits of lecanemab in early Alzheimer’s disease using simulation modeling
Authors: Monfared Amir Abbas Tahami , Tafazzoli Ali , Ye Weicheng , Chavan Ameya , Zhang Quanwu
Published: December 2022

Background

Alzheimer’s disease (AD) is a progressive, neurodegenerative disease and imposes a substantial societal burden. Treatment strategies that slow disease progression may improve health outcomes and reduce burden. Lecanemab is a humanized IgG1 monoclonal antibody that preferentially targets soluble aggregated Aβ species. In the phase 2b BAN2401‐G000‐201 trial, lecanemab reduced clinical decline as measured by key global and cognitive scales at 18 months.

Methods

A validated disease simulation model was used to assess lifetime health outcomes of lecanemab for patient with early AD (MCI due to AD and mild AD dementia) based on BAN2401‐G000‐201 trial data and published literature. The model captures the pathophysiology and management of AD, with the aim of evaluating the effects of disease modification on disease progression and translating them into meaningful health outcomes.

Results

Lecanemab treatment was projected to delay disease progression, resulting in an increase in patient’s expected time in the early AD stages while reducing the time in more severe states. A 26% slowing of clinical decline on CDR‐SB in patients treated with lecanemab corresponded to a 7%, 13%, and 10% reduction in the proportion of patients progressing to mild, moderate, and severe AD dementia, respectively, over a lifetime horizon compared to the standard of care (SoC). Similarly, the estimated mean time to advance to mild, moderate, and severe AD dementia extended for lecanemab treatment by 2.51, 3.13, and 2.34 years, respectively. Scenario analyses indicated the potential lifetime impact of lecanemab was greater at earlier, younger onset AD. The incremental mean times for transition to mild and moderate AD dementia were 3.29 and 3.38 years, respectively, in younger adults (baseline mean age 65 vs. 71.5 years) with MCI due to AD only. Compared with SoC, lecanemab treatment improved patient’s quality of life over lifetime with additional 0.75 quality‐adjusted life‐years per patient (4.97 vs. 4.22).

Conclusions

The findings suggest that lecanemab treatment in early AD may have large health impacts by slowing disease progression to more severe stages of AD and reducing patient, caregiver, and public health burden. Predicted long‐term health outcomes provide a foundation for healthcare decision‐makers to understand the potential clinical and socioeconomic value of lecanemab.
Understanding person‐centered dementia care from the perspectives of frontline staff: Challenges, opportunities, and implications for countries with limited long‐term care resources
Authors: Wang Jing
Published: December 2022

Background

Semi‐skilled or unskilled nursing care aides primarily provide direct care to residents in long‐term care (LTC) facilities in China and many other countries around the world. There has been a significantly increased commitment from nurses and other formally trained professionals to provide person‐centered care (PCC) for people with dementia (PwD). However, it is still unclear how nursing care aides who provide direct care to older residents with dementia understand and adopt PCC in their daily work. It is of utmost importance to understand person‐centered dementia care from the perspectives of care aides, and to identify implications to facilitate and sustain their efforts in providing quality care for older residents with dementia.

Methods

We adopted a descriptive qualitative approach and interviewed 40 care aides from 5 nursing homes in China. The interview methods followed the consolidated criteria for a qualitative research report.

Findings

We found that the seemingly beneficial mental models used by care aides in their work can hinder them from playing a more adaptive role in tailoring their care to the needs of older residents. Infantilizing older residents with dementia and labeling them using mother wit can prevent meaningful, equal, and person‐centered conversations between both parties. Care aides do not have regular formal interactions and sense making with nurses and other professionals in nursing homes.

Discussion and Conclusions

Increasing interactions and communication between care aides and health care professionals in nursing homes can lead to insight for changing the approach to in‐service training to achieve better acceptance by care aides. The current study derives implications for operationalizing and embedding the principles of PCC in daily care.
BACE inhibitor treatment at different stages of amyloid deposition
Authors: Jucker Mathias
Published: December 2022

Background

We are interested in the link between Aβ deposition and neurodegeneration

Method

We analyzed the trajectories of Aβ deposition, Aβ seeding activity, and neurodegeneration in APP trangenic mice, and probed the linkage by impeding Aβ production at different amyloid stages using BACE1 inhibition. To extend the findings to humans, we studied key comparative trajectories of Aβ deposition and neurodegeneration markers in cases of familial AD.

Result

Outcome of BACE1 inhibition was dependent on the amyloid stage

Conclusion

We found a temporal uncoupling between Aβ deposition and neurodegeneration
API ADAD Colombia Trial initial findings: a randomized, double‐blind, placebo‐controlled, parallel‐ group study in cognitively unimpaired PSEN1 E280A mutation carriers evaluating efficacy and safety of crenezumab
Authors: Sink Kaycee M. , Doody Rachelle S. , Ríos‐Romenets Silvia , Tariot Pierre N. , Reiman Eric M. , Langbaum Jessica B.
Published: December 2022

The Alzheimer’s Prevention Initiative (API) ADAD Colombia trial enrolled 252 cognitively unimpaired 30‐ 60‐year‐old Presenilin 1 (PSEN1) E280A mutation carriers and non‐carriers; carriers were randomized 1:1 to crenezumab or placebo, non‐carriers received placebo only. Crenezumab is an anti‐amyloid monoclonal antibody that binds beta‐amyloid (Aβ) oligomers that is hypothesized to prevent the buildup of pathogenic Aβ plaques and modify Alzheimer’s disease (AD) progression with a low risk of amyloid related imaging abnormalities. The presentation will begin with a summary of the partnership between the Neurosciences Group of Antioquia and ADAD kindreds, including those who volunteered for the trial. Next will be a brief summary of the trial design and baseline participant characteristics, including the distribution of Aβ‐positive and ‐negative individuals, followed by the results for the co‐primary endpoints, change in cognitive function (using the API ADAD Cognitive Composite Test Battery) or episodic memory function (using the Free and Cued Selective Reminding Test); secondary efficacy results including time to clinical progression to MCI or dementia due to AD, time to Clinical Dementia Rating (CDR) score >0, and increase in CDR Sum of Boxes; other outcomes including FAST, NPI, MMSE, CERAD word recall and RBANS results; and safety and tolerability. Last will be a presentation of results for changes in Aβ, FDG and tau PET; volumetric brain MRI; CSF biomarkers; a preview of pending plasma biomarker data; and a brief summary of the historical context and strategic aims of API and the trial. There will be an interactive question and answer session.
Efficacy, Safety and Tolerability of Brexpiprazole for the Treatment of Agitation in Alzheimer’s Dementia: A 12‐Week, Randomized, Double‐Blind, Placebo‐Controlled Trial
Authors: Grossberg George T , Lee Daniel , Slomkowski Mary , Hefting Nanco , Chen Dalei , Larsen Klaus Groes , Kohegyi Eva , Hobart Mary , Cummings Jeffrey L
Published: December 2022

Background

Agitation is a prevalent clinical manifestation of Alzheimer’s dementia, and is one of the most stressful aspects of care in patients affected by the disease. However, currently, there are no FDA‐approved pharmacological treatments for agitation in this patient population. Following two prior clinical trials of brexpiprazole in this patient population, the aim of this study was to confirm the efficacy, safety and tolerability of brexpiprazole in patients with agitation in Alzheimer’s dementia.

Methods

This was a 12‐week, multicenter, randomized, double‐blind, placebo‐controlled, parallel‐arm study (NCT03548584). Eligible patients were aged 55–90 years, in a care facility or community‐based setting, had a diagnosis of probable Alzheimer’s disease, and met criteria for agitation as defined by the International Psychogeriatric Association (IPA). Patients were randomized 2:1 to brexpiprazole or placebo; within the brexpiprazole arm, patients were further randomized 1:2 to fixed‐dose 2 mg/day or 3 mg/day. Stable background medications for the treatment of Alzheimer’s disease were permitted. The primary endpoint was change from baseline to Week 12 in Cohen–Mansfield Agitation Inventory (CMAI) Total score. The key secondary endpoint was change from baseline to Week 12 in Clinical Global Impression − Severity of illness (CGI‐S) score, as related to agitation. Safety was also assessed.

Results

A total of 345 patients were randomized to brexpiprazole or placebo. On the primary endpoint, the mean change from baseline to Week 12 in CMAI Total score was statistically significantly greater in the brexpiprazole group (2 mg/day or 3 mg/day) versus the placebo group (p = 0.0026). Statistically significant separation between the brexpiprazole and placebo groups was also observed on the key secondary endpoint of change from baseline to Week 12 in CGI‐S score (p = 0.0055). Aside from headache (6.6%), no other treatment‐emergent adverse events occurred with an incidence ≥5% in the brexpiprazole group.

Conclusion

In this Phase 3 study of patients with agitation in Alzheimer’s dementia, treatment with brexpiprazole was associated with a statistically significantly greater reduction in agitation, and improvement in clinical global impression of agitation, compared with placebo, supporting the findings of two prior clinical trials. Brexpiprazole was generally well tolerated, and no new safety signals were observed.
The effects of glyphosate exposure on gene transcription and immune function of the silkworm, Bombyx mori
Authors: Feng Piao , Wang Yuanfei , Zou Hongbin , Zhu Qingyu , Ren Yuying , Shu Qilong , Su Wujie , Liu Wei , Hu Yufang , Li Bing
Published: December 2022

Glyphosate is a widely used herbicide and crop desiccant. However, whether its extensive use has any effect on the species diversity of nontarget organisms is still unclear. In this study, we used the silkworm, Bombyx mori, as the research subject, and performed RNA sequencing to analyze the transcriptional profile of silkworm midgut after exposure to glyphosate at 2975.20 mg/L (a concentration commonly used at mulberry fields). A total of 125 significantly differentially expressed genes (DEGs) were detected in the midgut of glyphosate‐exposed silkworm (q < 0.05), of which 53 were upregulated and 72 were downregulated. Gene ontology enrichment analysis showed that the DEGs were mainly enriched in biological process, cellular component, and molecular function. Kyoto encyclopedia of genes and genomes analysis showed that the differential genes were mainly related to oxidative stress, nutrient metabolism, and immune defense pathways, including oxidative stress‐related Cat and Jafrac1, nutrient metabolism‐related Fatp and Scpx, and immune‐related CYP6AN2, UGT40B4, CTL11, serpin‐2, and so forth. Experimental verification showed that glyphosate exposure led to a 4.35‐fold increase in the mortality of silkworm after Beauveria bassiana infection, which might be caused by the decreased PO (phenoloxidase) activity and impaired immunity. These results provide evidence for the potential effects of residue glyphosate on the physiological functions of silkworm, and also provide a reference for the biosafety evaluation of glyphosate.
100 Jahre Versuchsanstalt für Stahl, Holz und Steine Karlsruhe
Authors: Ruff Daniel , Sandhaas Carmen , Ummenhofer Thomas , Dietsch Philipp
Published: December 2022

Die Berufung von Prof. Dr.‐Ing. Ernst Gaber an die Technische Hochschule Karlsruhe im Jahr 1921 markierte den Startschuss des Prüfraums Gaber, aus dem später die Versuchsanstalt für Stahl, Holz und Steine hervorging. Heute ist die Versuchsanstalt Teil des Karlsruher Instituts für Technologie (KIT) und besteht aus den Abteilungen Holzbau und Baukonstruktion sowie Stahl‐ und Leichtbau. Der folgende Beitrag blickt auf die Geschichte dieser Einrichtung zurück.
Sustainability frontiers of strategic risk management and firm survival: The Altman score effectiveness. A bibliometric analysis
Authors: Campobasso Francesco , Boscia Vittorio
Published: December 2022

The financial networking of companies operating in the globalized market raises the imperative of assessing the risk of insolvency. Business survival is an extremely trending topic in the literature and the managerial context. Risk management requires new perspectives on sustainability. The aim of this work is to verify that Altman's score still maintains its supremacy as the best tool used to investigate the financial insolvency of enterprises. The novelty of the work is the implementation of a bibliometric analysis conducted on Scopus and Web of Science, using analytical software (Bibliometrix R, VOSviewer), identifying future paths of analysis and evaluations of the impact of Altman's methods. Results reveal an exceptional growth in the number of publications on this topic over the last two decades, testifying to its topicality in the academic debate. In light of rising climate change and environmental risks, findings suggested how the Altman score may preserve its function in getting deeper to prevent business bankruptcy. By providing practical evidence, Altman's models encompass a variety of fields, including finance, accounting, economics, management, and all of them addresses the area of sustainability.
Podocyte infolding glomerulopathy after 25 years of clinical remission of lupus nephritis in a patient with systemic lupus erythematosus: A case report and review of literature
Authors: Hijazi Mohamad , Aboursheid Tarek , Al Termanini Mohammad , Khanjar Izzat A. M.
Published: December 2022

Podocyte infolding glomerulopathy (PIG) is a rare pathological finding that has gained more recognition recently. Most of the reported cases have been associated with connective tissue diseases especially systemic lupus erythematosus (SLE). Here we report the first case of Infolding Glomerulopathy associated with SLE in the Middle East.