bluuebunny/crossref_metadata_2025 huggingface dataset:
Absence of higher order association based mnemonic percepts in Alzheimer’s disease
Authors: Singh Aditya , Das Nirupam , Kundu Sankhanava , Saha Titli , Jayaprakash Balaji
Published: December 2023

Background

Everyday learning involves higher order associations (HOA) across new and old experiences when a response is encoded without reinforcement. However, the neural and behavioral mechanisms of HOA‐based learning during remote memory retrieval are unknown.

Method

We implement novel behavior to test the neural and behavioral mechanisms of HOA during remote memory retrieval. We train the animals in context A and sequentially test these animals for remote retrieval in same (A), similar(B), or novel (C) context, while invoking HOA‐based learning to investigate the neural correlates of HOA using hippocampal lesions, chemo genetics, and 2‐photon in vivo imaging.

Result

Cohorts of AD mice show overall differences in freezing vs. controls (1‐w ANOVA, P>F = 1.48E‐11, n = 5). Subgroups of AD (n = 12) and control (n = 14) mice during remote retrieval in BAC show overall difference (1‐w ANOVA, P>F = 4.59E‐6), with AD mice showing similar freezing in B and A (t = ‐0.70). Freezing in C is different for control mice in ABC vs. BAC order (P>F = 1.84E‐8, n = 5,14) whereas, interestingly, AD mice show similar increase in C freezing on Day3 of remote testing for ABC vs. BAC testing orders (P>F = n.s, n = 5, 12). AD (n = 3) and WT (n = 4) mice were trained with tone and tested after 70 days. Freezing before and during the tone was significantly different for WT mice (1‐t Paired‐sample‐t‐test, P<t = 0.015). Discrimination‐index indicates better discrimination ability for WT as compared to AD mice (1‐t two‐sample‐t‐test, P<t = 0.026). We further evaluate the neural correlates of such behavior in WT mice by timed‐hippocampus lesions, chemogenetic inhibition of PVcre interneurons in dorsal CA1, and longitudinal 2p‐in vivo imaging.

Conclusion

We find that PVcre neurons are necessary for HOA during remote learning in WT mice and there is a loss of specificity in HOA‐based new learning during remote memory retrieval with AD mice. Our novel findings establish a basis for early behavioral and neural markers for predicting AD diagnosis to assist with early medical interventions.
Sex differences of cerebrospinal fluid biomarkers in Alzheimer’s disease
Authors: Kanemaru Kazutomi , Kanemaru Akiko , Kurihara Masanori , Hatano Keiko , Ihara Ryoko , Higashihara Mana , Nishina Yasushi , Iwata Atsushi , Saito Yuko , Murayama Shigeo
Published: December 2023

Background

Alzheimer’s disease (AD) is more common in women than in men. Thus, to investigate the sex‐specific mechanism is important to understand the pathogenesis of AD. We examined the sex differences in levels of CSF biomarkers (tau, ptau‐181, Aβ42, HVA and 5HIAA) in AD.

Method

The subjects of this study consisted of clinically diagnosed 386 patients with AD (age 75.9±8.4 years, 237 women and 149 men). The clinical diagnosis was made based on the AD diagnostic criteria (NIA/AA, McKhann GM, et al., Alzheimers Dement 2011; 7: 263‐269). The CSF samples were obtained by lumbar puncture after informed consent was obtained. The levels of CSF tau, ptau‐181 and Aβ42 were measured by ELISA (Fujirebio, Belgium) according to the manufacturer’s protocol. The levels of CSF HVA and 5HIAA were measured by HPLC. We compared the levels of CSF biomarkers between women and men.

Result

Age, the levels of CSF tau, ptau‐181 and Aβ42 showed no sex differences. The levels of CSF HVA (ng/ml) were 32.6±19.3 in women and 25.9±14.4 in men. The levels of 5HIAA were 19.1±11.7 in women and 14.8±7.7 in men. The levels of CSF HVA and 5HIAA were significantly higher in women than those in men (t‐test, HVA: p<0.001, 5HIAA: p<0.001).

It has been reported that women have higher values of HVA and 5HIAA among normal subjects, due to higher monoamine oxidase (MAO) activity in women. The MAO‐A and MAO‐B genes are located on the X chromosome, and are controlled by XCI (X‐chromosome inactivation). However, the MAO genes may escape XCL MAO‐B has also been reported to be γ‐secretase associated protein and regulate neuronal amyloid β‐peptide levels. Thus, increased MAO‐B activity may be one of the reasons why AD is more common in women.

Conclusion

Both CSF levels of HVA and 5HIAA were significantly higher in women in AD, presumably due to increased MAO activity.
Discrimination early Alzheimer’s disease from mild cognitive impairment by using Easy Z‐score Imaging System for ECD SPECT
Authors: Pai Ya‐Tang , Pai Ming‐Chyi
Published: December 2023

Background

Prodromal AD progresses to dementia at a higher annual rate. Since cholinesterase inhibitor benefits early AD patients, discrimination between MCI due to AD and non‐MCI due to AD remains important.

Method

We conducted a retrospective study of MCI cases at National Cheng Kung University Hospital (NCKUH) from 2017 to 2019. Those who showed hypometabolism at posterior cingulate cortex, precuneus, or posterior parietal cortex on brain ECD SPECT and EZIS severity greater than 1.19 were categorized as MCI due to AD; in contrast, patients with EZIS severity lesser than 1.19 were categorized as non‐MCI due to AD. Clinical outcomes included deterioration of CASI, MMSE, SB scores and conversion from MCI to dementia.

Result

There was positive correlation between EZIS severity and deterioration of CASI, MMSE, SB according to multiple regression results, indicating EZIS severity could predict cognitive progression in three years follow‐up. There was no difference in dementia conversion rate between two groups either by chi‐square method or Kaplan‐Meier method, and EZIS severity was not a significant variable in binary logistic regression analysis for conversion. However, there was a trend toward greater dementia conversion rate in the EZIS‐favored MCI due to AD group, and in the second half period of follow‐up as seen on Kaplan‐Meier curves.

Conclusion

During three years of follow‐up, MCI patients with greater EZIS severity were significantly associated with worse cognitive assessment scores, and there was a trend toward greater dementia conversion rate based on cutoff value 1.19 of EZIS severity.
The relationship between physical activity and cognitive functioning in older adults: a cross‐sectional study from the ELSI‐Brazil data
Authors: Rabelo Wendell Lima , da Mata Fabiana A F , Barbosa Matheus Ghossain , Bertola Laiss , Lima‐Costa Maria Fernanda , Ferri Cleusa P
Published: December 2023

Background

Population aging is rapidly taking place in low‐ and middle‐income countries (LMIC) and is contributing to an increased prevalence of chronic conditions, such as dementia. Physical activity (PA) is a well‐known protective factor for cardiovascular conditions and is related to biological processes linked to cognition. Most studies linking PA with cognition come from high income countries. This study explores the relationship between PA and cognitive function in a representative sample of Brazilians aged 50 and above.

Method

This is a secondary analysis of the Brazilian Longitudinal Study of Ageing (ELSI‐Brazil) baseline data. We stratified the level of PA as low, moderate, or high according to the metabolic equivalent of task (MET) spent on different PA over a week. We also considered the level of PA recommended by the World Health Organization (WHO). The domains considered for cognitive function were memory (short‐term memory, episodic and total), and verbal fluency. Logistic regression models were conducted to estimate the relationship between PA and each of the cognitive domains.

Result

7,994 individuals with complete data were considered for the final sample. They were primarily female (52%), with a mean age of 62.9 years (SD = 9.7), did not live alone (91.5%), and had 5.6 years of schooling (SD = 4.4). Higher levels of PA were related to better cognitive performance in respect of short‐term memory (β = 0.17, CI 95% 0.08‐0.25), total memory (β = 0.14, CI 95% 0.05‐0.22) and global cognition (β = 0.10, CI 95% 0.03‐0.16). The results were in the same direction for the WHO PA recommendations variable.

Conclusion

This study shows that different levels of PA, measured in different ways, may have benefits on cognition for older people. These findings can be used to support public health interventions promoting the practice of PA. Longitudinal studies are needed to further clarify this relationship.
Insomnia and Neurocognitive Functioning in Cognitively Healthy Older Adults
Authors: Dixon Bradley J. , Halter Colt M , Woodard John L.
Published: December 2023

Background

Insomnia is the most common sleep disorder in older adults, affecting the ability to fall and stay asleep for approximately 15‐35% of aging adults (Buysse et al., 2011). Additionally, sleep fragmentation and disordered sleep are well‐established symptoms of Alzheimer’s disease (AD). Patients and their caregivers frequently find these sleep changes distressing; however, the relationship between insomnia and preclinical Alzheimer’s disease remains unclear. The purpose of the present study is to compare performance on neurocognitive measures between cognitively healthy older adults with and without clinician‐determined insomnia to assess whether insomnia acutely impacts cognitive functioning.

Method

Data were obtained from the National Alzheimer’s Coordinating Center (NACC) database. As part of ongoing data collection, NACC participants completed surveys and underwent a neuropsychological evaluation. Participants who were cognitively healthy at baseline, reported insomnia status, and were at least 65 years of age were included (N = 3,733). Clinicians determined the presence of insomnia (present/absent). A series of Welch’s t‐tests were used to compare insomnia status groups on demographic factors (age, educational attainment, and sex) as well as neurocognitive measures typically related to Alzheimer’s disease (animal and vegetable fluency, letter fluency, Trail‐Making Test, Benson Complex Figure delayed recall, Montreal Cognitive Assessment delayed recall).

Result

Preliminary analyses of sample characteristics found evidence that individuals with insomnia were older than those without insomnia (t(784.11) = 2.046, p = 0.041). As expected, clinician‐determined insomnia was more common in men than women (χ2
(1) = 29.638, p < .001). Group comparisons indicated no cross‐sectional relationship between insomnia status and neurocognitive measures (all p >.05, all d ≤ .06).

Conclusion

Disordered sleep is often seen in Alzheimer’s disease, yet the nature and timing of this relationship are unclear. We found no association between insomnia status and neurocognitive performance in a large, cross‐sectional sample of healthy older adults. It is possible that sleep disturbance is not a preclinical symptom of AD but instead may emerge closer to or following AD diagnosis. Alternatively, the nature of the disordered sleep may not be related to insomnia per se but could reflect difficulty sleeping during the night and remaining awake during the day.
RIP Kinase 1 (RIPK1) modulates disease associated microglial response during demyelination
Authors: Goodwani Sunil , Lightfoot Yaima Luzardo , Ford Bianca Gabrielle , Calderon Olivia , McReynolds Morgan , Allton Kendra , Ma Jiacheng , Botte Alexandra , Trinh Ronnie The Pong , Pearson Troy , Ding Grant S. , Acton Paul , Lewis Richard T , Ray William J
Published: December 2023

Background

RIP Kinase 1 (RIPK1) is known to regulate necroptotic cell death in response to pro‐inflammatory signaling in cells where apoptotic signaling has been compromised. Aberrant RIPK1 activation has been implicated in several neurodegenerative disorders such as Alzheimer’s disease, Multiple Sclerosis, and Amyotrophic Lateral Sclerosis.

Method

To investigate the role of RIPK1 in regulating the microglial response to demyelination, we administered a highly selective CNS penetrant RIPK1 inhibitor to C57Bl6 mice fed with cuprizone. We studied the microglial response using RNA Sequencing, single‐cell RNA Sequencing, lipidomics, and proteomics.

Result

Transcriptomic analysis of isolated microglia and brain cytokine levels revealed that rapid demyelination induced by Cuprizone diet led to a strong disease‐associated microglia (DAM) response. Of the 1957 transcripts regulated in isolated microglia (padj<0.05) by the demyelination, RIPK1 inhibition significantly attenuated the microglial transcriptomic response of 497 transcripts (padj<0.1). Single‐cell RNA Sequencing analysis revealed that RIPK1 inhibition modified demyelination‐associated microglial sub‐clusters. Furthermore, soluble TREM2, a marker of microglia activation, was reduced, as were several cytokines in the brain. Open field analysis of these mice showed that RIPK1 inhibition rescued Cuprizone‐induced motor impairment. Proteomics and lipidomics analyses demonstrated RIPK1‐dependent changes in brain lipid metabolism.

Conclusion

RIPK1 signaling promotes an inflammatory response that involves modulation of key regulatory pathways associated with demyelinating disorders.
Mannose‐labeled nanoparticle exclusive delivery of antagomirs to microglia alleviate Alzheimer’s Disease pathobiology
Authors: AMER AMAL
Published: December 2023

Background

Under normal conditions, amyloid (Aβ) is released extracellularly by neurons as a neuroprotective molecule while healthy microglia ingest and degrade Aβ to maintain a balance between production and clearance. One of the hallmarks of Alzheimer’s Disease (AD) is the presence of plaques composed of aggregated, fibrillar amyloid beta (Aβ) that usually precedes the deposition of Tau. Aggregated Aβ can be degraded within healthy microglia largely by autophagy. Most vacuoles containing Aβ acquire the autophagy marker LC3 in primary WT microglia but not in AD microglia. It is still unclear why microglia in the AD brain fail to clear Aβ. Microglia in human AD brain sections and in the 5XFAD (AD) mouse model congregate around Aβ plaques and express high levels of miR‐17 which we found targets autophagy effectors.

Method

We examined the effect of targeting microRNA miR‐17 in vitro and in vivo using designed mannose‐labeled nanoparticles for the delivery of antagomirs exclusively to microglia.

Result

Isolated primary microglia from adult AD mouse fail to degrade Aβ in comparison to wild‐type (WT) microglia. The expression of autophagy effectors Nbr1, Atg5 and Atg7, which are targets of miR‐17, are significantly reduced in AD mouse microglia (CD11b+) and not in CD11b− fraction which contains astrocytes and neuronal cells. This is the first report of significant increase of miR‐17 in the microglia of AD humans and mice. The increased expression of miR‐17 in AD microglia reduces the expression of autophagy effectors leading to defective autophagy in AD microglia. We show that reducing the expression of miR‐17 using specific antagomir (Anti‐17) in AD microglia in vitro, is sufficient to significantly improve their ability to degrade Aβ. Importantly, we successfully injected live AD mice with Anti‐17 enclosed within mannose‐labeled nanoparticles (Man‐NPs) which specifically target the mannose receptor mainly expressed on microglia. This delivery method significantly and explicitly reduced the elevated expression of miR‐17 in microglia, reduced the expression of Aβ in the brain and reduced hyperactivity behavior in live AD mice.

Conclusion

Together, we describe Man‐NPs for the delivery of antagomirs specifically to microglia. We show that targeting miR‐17 in microglia is sufficient to prevent AD pathobiology.
Signatures of abnormal deviations in excitation‐inhibition balance for amyloid positive individuals
Authors: Fortel Igor , Zhan Liang , Ajilore Olusola , Wu Yichao , Mackin Scott R , Leow Alex
Published: December 2023

Background

Dysfunctional excitation‐inhibition balance (EIB) is hypothesized to precede cognitive impairment in Alzheimer’s disease (AD); however, overlapping neuropathology (like amyloid plaques) can develop in cognitively normal (CN) and impaired (CI) individuals. We investigate EIB trajectories for individuals with significant amyloid (Aβ+).

Method

Multimodal imaging was used to construct hybrid resting‐state structural connectomes (Fortel, Igor, et al. Network Neuroscience 6.2 (2022): 420‐444.), computing whole‐brain EIB based on 105 ROIs. This cohort (N = 185, 94 Female) aged 55‐90 (μ
FEMALES = 74.9, and μ
MALES 73) was limited to Aβ+ individuals with APOE genotyping (ε3/ε3, ε3/ε4, ε4/ε4); grouped further by clinical dementia rating (CDR), with CDR > 0 indicating CI. Imaging, Aβ+ classifications, CDR, and APOE were obtained from OASIS‐3: Longitudinal Multimodal Neuroimaging: Principal Investigators: T. Benzinger, D. Marcus, J. Morris; NIH P30 AG066444, P50 AG00561, P30 NS09857781, P01 AG026276, P01 AG003991, R01 AG043434, UL1 TR000448, R01 EB009352. AV‐45 doses were provided by Avid Radiopharmaceuticals, a wholly owned subsidiary of Eli Lilly.

Result

Results presented in Figure 1 suggest whole‐brain EIB in both CN sexes with Aβ+ decreases with increasing age (APOE‐ε4 agnostic). However, sex differences are highlighted with CI; regression analyses produce a marginally significant 4‐way interaction of age, sex, cognitive status, and APOE (P = 0.085, β = ‐0.013). Partial correlation of EIB with age, controlling for sex, APOE and cognitive status is also significant (P = 0.016, r = ‐0.18). Results indicate sex‐mediated EIB differences in individuals with CI, dominated by APOE‐ε4 in women rather than amyloid.

Conclusion

We’ve demonstrated EIB deviations in cognitively impaired men and women that may be associated with AD neuropathology. Our findings are consistent with known AD sex differences and suggest novel multimodal connectomics may capture subtle disruptions in brain dynamics that traditional methods may not.

Figure. 1.

Whole‐brain excitation‐Inhibition balance (EIB) trajectories for amyloid positive (Aβ+) men and women. The cognitively normal (CN) group (rows A‐B) suggests no sex differences in EIB trajectories with age, while the cognitively impaired (CI) group (rows C‐D) begins to reveal distinct patterns of dysfunction (more significantly in women with APOE‐ε4). Note a value of 0.5 indicates perfect balance.
Neurobiological mechanisms involved in the relationship between loneliness, depression, and cognitive decline in older adults
Authors: Dabiri Sanaz , Mwendwa Denée T , Campbell Alfonso L
Published: December 2023

Background

Loneliness among older adults is one of the risk factors for developing dementia. Yet, little is known about the neurobiological and psychological conditions that link loneliness to cognitive decline. The current study had several aims: First, it sought to determine whether the relationship between loneliness and cognitive decline is sex‐specific in older adults. Second, it sought to identify neurobiological and psychological pathways that may account for the relationship between loneliness and decline across several cognitive domains. These pathways included depressive symptoms, gray matter volume, and conditional analyses of pro‐inflammatory cytokines and brain‐derived neurotrophic factor (BDNF) expression. Third, it examined loneliness as a predictor of mild cognitive impairment (MCI) and Alzheimer’s disease (AD).

Method

Longitudinal data were collected from 2130 Rush Memory and Aging Project MAP participants. Participants underwent annual cognitive and psychological assessments and neuroimaging procedures. BDNF gene expression was measured in the dorsolateral prefrontal cortex, and the final clinical diagnosis was identified upon autopsy at death. Cytokines were measured in serum. Linear mixed models and multinomial logistic regression analyses were used. All models controlled for age at baseline, education, and sex.

Result

Participants were largely women (73%), and Caucasian (93%). The average age at baseline was 80.05 (SD = 7.57) and education was 14.93 (SD = 3.34). Results showed that gray matter volume and depressive symptoms partially mediated the relationship between loneliness and cognitive decline. BDNF expression was positively related to cognitive performance, and its interaction with loneliness was related to slower cognitive decline in semantic memory and better visuospatial performance. Finally, the current study also established that loneliness was a predictor of the incidence of AD and other dementias.

Conclusion

The present findings suggest that loneliness may elicit physiological changes in our brains that lead to cognitive decline over time. Future research can explore a wide range of biological and psychological expressions of loneliness to clarify how loneliness relates to dementia.
A feasibility study to explore the use of real‐time caregiver reports for people living with dementia at home to label multi‐modal sensor data
Authors: Chu Charlene H , Abedi Ali , Dayyani Faranak , Khan Shehroz
Published: December 2023

Background

Multi‐modal sensor systems, consisting of sensors throughout the home, are able to collect data on the person living with dementia’s (PlwD’s) activities. However, caregivers may have challenges interpreting the data, leading to a lack of actionable information. It’s important to get real‐time reports from caregivers to label the sensor data to build relevant machine learning algorithms; yet, this has not been done with PlwD. The aim of this feasibility study was to explore if the use of a multi‐modal sensor system in conjunction with real‐time caregiver reports can provide valuable insights into the daily lives of PlwD.

Method

We developed the MAISON (Multimodal AI‐based Sensor platform for Older Individuals) system and deployed it into the homes of dyads (PlwD and their family caregiver) for 8‐weeks. MAISON includes: a smartphone, a smartwatch to continuously collect heart rate, step, and accelerometer data to infer walking, and running, as well as a smart mattress that can collect sleep time and quality. A digital diary was added to the MAISON system that automatically sends the caregiver 2‐3 pre‐set questions every day about their loved one. Caregivers could also report any significant occurrences throughout the day, as they see fit, through the app.

Result

Two dyads were recruited to date. Only about 15% of data was missing from the sensor system by the end of the study. Caregivers were providing their reports with high adherence. The caregivers’ reports were used to label the sensor data successfully, and upon analysis, we found that caregivers’ reports were reflected in the sensor data and the labels derived from their reports were accurate. Results indicate this study methodology is an innovative approach to utilize the family caregiver’s reports.

Conclusion

This is the first longitudinal study to demonstrate the feasibility of a multi‐modal sensor system used by caregivers and PwlD. Findings show that caregivers' reports can be useful sources of data for labeling sensor data. The conjunction of caregiver reports and sensor data will provide valuable information to build accurate machine learning models about behaviors of PlwD which is a foundational step to support dyads at home using technology.
A brain‐wide risk score of Alzheimer’s disease based on multimodal neuroimaging predicts cognition in large N>37000 population data
Authors: Zendehrouh Elaheh , Sendi Mohammad S.E. , Calhoun Vince D
Published: December 2023

Background

Alzheimer’s disease (AD) is the most frequent age‐related dementia impairing memory, thinking, and social skills. Much research has been conducted in recent years to investigate the genetic risk of AD, but little effort has been made to find a brain imaging‐based AD risk evaluation. Here, we proposed a multimodal neuroimaging‐based measure of AD risk, called brain‐wide risk score (BRS).

Method

Functional network connectivity (FNC) and voxelwise gray matter (GM) from the Open Access Series of Imaging Studies (OASIS)‐3 (N = 1302 samples) cohort was used as a reference dataset to define mild cognitive impairment (MCI) and control (CN)group to evaluate individuals in the UK Biobank (N = 37,784) dataset. We calculated the mean of FNC and GM of MCI and CN. Next, we removed the mean FNC and GM from each sample FNC and GM of the target dataset. Then, we calculated the distance between the target dataset and CN (i.e., dist_CN) and MCI (i.e., dist_MCI) of the reference dataset using Euclidian distance. Finally, we calculated Δdiff = dist_CN‐dist_MCI as a BRS of AD, where the positive values are associated with higher AD BRS. Using two BRSs estimated based on FNC and GM for target dataset, we identified four AD biotypes. Samples with two negative Δdist represent low AD risk (Biotype1), samples with two positive Δdist represent high AD risk (Biotype4), and samples with one negative and one positive Δdist represent moderate AD risk (Biotype2/3). Next, we compared cognitive scores including fluid intelligence (FI) and reaction time (RT) across four biotypes.

Result

Fig.1 shows the 2D histogram of two BRS estimated from FNC and GM. We identified 11704 participants as biotype1, 10910 as biotype2, 7804 as biotype3 and 7366 as biotype4. We also found that Biotype1, with lower AD BRS, significantly shows a higher FI score than Biotype3 and Biotype4 (Fig.2, FI panel). Additionally, Biotype 4, with the highest BRS, had the most increased RT among all four AD biotypes (Fig.2, RT panel).

Conclusion

We develop a new multimodal neuroimaging‐based BRS based which we identified four AD biotypes. We found that BRS predict cognitive scores in the identified biotypes.
Behavioral, biochemical, and neuropathological outcomes in amyloid‐bearing mice treated long‐term with a range of doses of BACE inhibitor
Authors: Watkins Elyse , Gallagher Declan , Mahesh Shreya , Reed Myles , Vassar Robert J.
Published: December 2023

Background

Small molecule BACE inhibitors, while promising for the treatment of AD, have been discontinued in clinical trials due to early and non‐progressive cognitive worsening. There is great interest in finding a dose of inhibitors that can protect from AD pathology while sparing cognitive issues. Furthermore, there is interest in determining which substrate(s) is mediating the cognitive worsening.

Method

PDAPP mice, which express human APP that lack mutations affecting BACE cleavage, were treated with five doses of BACE inhibitor in their chow. Mice were treated from 8 months to 14 months, and Morris Water Maze, Novel Object Recognition, and Rotarod were performed immediately prior to the study’s completion. Cleavage of BACE substrates, including APP, Sez6, Sez6L, APLP1, CHL1, and others were assessed by western blot, and correlated with cognitive assessments. The extent of amyloid buildup during treatment was quantified.

Result

Treatment with BACE inhibitor led to a dose dependent protection from amyloid plaque buildup. There were treatment‐dependent effects on behavior.

Conclusion

This study has implications for determining a potential safe and effective dose of BACE inhibitors in humans.
Cognitive and Exercise Training Improves Intraindividual Variability in Cognitive Performance in Older Adults: Secondary Findings of A Randomized Controlled Trial
Authors: Silva Nárlon Cássio Boa Sorte , Brinke Lisanne F Ten , Bielak Allison AM , Handy Todd C , Liu‐Ambrose Teresa
Published: December 2023

Background

Increased intraindividual variability of cognitive performance is a marker of cognitive decline. Whether computerized cognitive training (CCT) and aerobic exercise counteracts cognitive decline by reducing intraindividual variability is unknown. We investigated the effects of CCT with or without aerobic exercise on reaction time intraindividual variability in older adults.

Method

This was a secondary analysis of an 8‐week randomized controlled trial. Older adults (aged 65‐85 years) were randomized to CCT alone (n = 41), CCT with aerobic exercise (n = 41), or an active control group (n = 42). The CCT group trained using the Fit Brains® platform 3×/week for 1 hour (plus 3×/week of home‐based training). The CCT with aerobic exercise group received 15 min of walking plus 45 min of Fit Brains® 3×/week (plus 3×/week of home‐based training). The control group received sham exercise and cognitive training (3×/week for 1 hour). We extracted reaction times from the Dimensional Change Card Sort Test, Flanker Inhibitory Control and Attention Test (Flanker), and Pattern Comparison Processing Speed Test (PACPS). Intraindividual variability was measured as residual intraindividual standard deviation (residual ISD) of raw reaction time latencies. Residual ISD is an unbiased measure of variability that accounts for within and between participant source of variation that could influence reaction time latencies. We also calculated reaction time intraindividual SD (raw‐score ISD) and intraindividual coefficient of variation (ICV).

Result

Compared with the control group, residual ISD improved in a processing speed task (PACPS) following CCT alone (mean difference [95% confidence interval]: ‐0.147 [‐0.230 to ‐0.065], p<0.001) and CCT with aerobic exercise (‐0.111 [‐0.195 to ‐0.027], p<0.01). Also, for processing speed, both CCT (‐0.173 [‐0.261 to ‐0.084], p<0.001) and CCT with aerobic exercise (‐0.122 [‐0.213 to ‐0.032], p<0.01) showed greater reduction in raw‐score ISD compared with controls, while only CCT reduced ICV for this task (‐0.108 [‐0.176 to ‐0.040], p<0.001). Inhibitory attention (Flanker) improved only after CCT with aerobic exercise (congruent = ‐0.128 [‐0.250 to ‐0.006], incongruent = ‐0.121 [‐0.237 to ‐0.005], both p<0.05).

Conclusion

A CCT program promoted cognitive health via reductions in intraindividual variability of cognitive performance and combining it with aerobic exercise resulted in broader benefits.
The effect of aquaporin‐4 mis‐localization on Aβ pathology in mice
Authors: Pedersen Taylor J , Keil Samantha A , Han Warren , Wang Marie X , Iliff Jeffrey J
Published: December 2023

Background

The reduced clearance of amyloid‐beta (Aβ) is thought to contribute to the development of Alzheimer’s disease (AD) pathology, characterized by the deposition of Aβ plaques. Previous studies have shown that Aβ is cleared via the glymphatic system, a brain‐wide network of perivascular pathways that support exchange between cerebrospinal fluid and interstitial fluid within the brain. Such exchange is mediated by the water channel aquaporin‐4 (AQP4), localized at astrocytic endfeet. Research has found that the deletion or mislocalization of Aqp4 is associated with reduced Aβ clearance and, in turn, Aβ plaque formation.

Method

In this study, we evaluated how the deposition of Aβ plaques within a 5xFAD mouse model is impacted by either the mislocalization or deletion of perivascular AQP4. We utilized both the AQP4 knockout mouse and α‐syntrophin (Snta1) knockout mouse, which lacks perivascular AQP4 localization, and crossed them with a mouse model line of amyloidosis (5xFAD) to determine the effect on Aβ deposition. Mice were perfused at 18 weeks and amyloid‐beta, AQP4, and lectin were assessed by immunofluorescence. Amyloid β distribution was evaluated anterior to posterior through the brain utilizing regions of interests for entire slice, cortex, corpus callosum, hippocampus, subiculum, sub cortical structures, and amygdala when applicable.

Result

We observed that both the absence (Aqp4KO) and mislocalization (Snta1KO) of AQP4 significantly increases amyloid distribution across the brain, when compared with 5xFAD littermate controls. Further, the mislocalization of AQP4 resulted in a significant increase in the size of Aβ plaque deposition not present with AQP4 deletion.

Conclusion

s highlights that the mislocalization of perivascular AQP4 has a greater impact on increased amyloid burden than the deletion of AQP4. In suggesting that the mechanism of AQP4 mislocalization may lie upstream of amyloid or tau pathology, targeting perivascular AQP4 localization may be provide a novel pathway toward secondary, or potentially primary prevention of Alzheimer’s disease.
Association of GAB2 genotype with EEG characteristics and vascular reactivity to hyperventilation in nondemented adults during aging
Authors: Ponomareva Natalya V , Andreeva Tatiana , Protasova Maria , Kunizheva Svetlana , Kolesnikova Ekaterina P , Malina Daria , Fokin Vitaly , Illarioshkin Sergey , Rogaev Evgeny I
Published: December 2023

Background

GAB2 rs2373115 genotype increases the risk of Alzheimer’s (AD) and vascular (VD) diseases (Reiman et al., 2007; Lambert et al., 2013; Kondreddy et al., 2021). EEG reactivity to hyperventilation (HV) depends on hypocapnia‐induced cerebral vasoconstriction, which may be impaired in subjects with preclinical AD and VD. EEG differences in the carriers of GAB2 genotype in nondemented adults remain unknown. The study was aimed to determine the possible effect of GAB2 rs2373115 genotype on resting EEG and EEG reactivity to HV in non‐demented adults during aging.

Method

The enrolled cohort included 151 healthy volunteers, age range 20‐80 years, stratified by GAB2 rs2373115 genotype. Informed written consent was obtained from all participants. All subjects underwent a neurological examination and cognitive screening. The significance of the differences between the EEG in different subgroups was estimated using ANOVA in the general linear model. APOE and sex was included in the analysis as covariates.

Result

In the entire sample the presence of GAB2 C allele was associated with higher alpha2 relative power in resting EEG, with more pronounced differences in the right parietal area.

EEG reactivity to HV decreased with aging, and the decrease was more pronounced in the carriers of GAB2 C allele. Under HV the older GAB2 AC&CC carriers as compared with the older GAB2 AA carriers had lower theta power. The HV reactivity of blood pressure and heart rate was decreased in aging to a greater extend in the GAB2 C allele carriers than in the homozygous GAB2 AA individuals.

Conclusion

The results show that GAB2 genotype is associated with alpha2 relative power difference in non‐demented adults. Reduced EEG and vascular reactivity to HV in the older GAB2 C allele carriers indicates altered cerebrovascular reactivity to hypocapnia and suggests that vascular factors can mediate GAB2‐related AD susceptibility.

The study was supported by Russian Science Foundation (Project N 22‐15‐00448, Project N 19‐75‐30039 genotyping) and the National Institutes of Health, United States (grant R01AG054712 to ER statistical analysis).
Neuroprotective effect of Tropisetron in Streptozotocin induced animal model of Alzheimer’s disease
Authors: Kumari Shilpa , Deshmukh Rahul Renukadas , Sharma Rupali
Published: December 2023

Background

Alzheimer’s disease is a neurodegenerative pathology having genetic and non‐genetic forms. Non‐genetic forms of AD dominate over the genetic condition and is mainly sporadic. However, both forms affect cognitive functions. Although exact mechanisms are not fully understood, amyloid β deposition & tau tangle formation are considered central mechanisms to cause neurodegenerative changes in the AD brain. On the other hand, cognitive deterioration began way before the accumulation of amyloid or tau tangle formation. Cognitive functions, including learning and memory, have been majorly controlled/regulated by the cholinergic system. Here in the present study, we have explored the neuroprotective effect of tropisetron in streptozotocin‐induced animal model of Alzheimer’s disease. During the last two decades, the involvement of other neurotransmitter systems has been explored, and the serotonergic system has been demonstrated to play an essential role in memory and learning. The serotonergic system is the most extensive monoaminergic system in the brain, and alterations in serotonergic signals have been linked with Aβ and tau tangle formation. Moreover, serotonin acting through its receptor antagonist has been reported beneficial in various experimental AD models.

Method

In the present study animals were infused with STZ alternatively on 1st and 3rd day. From 15th day animals were treated with tropisteron with two subsequent doses (2.2.5mg/kg) and (5mg/kg). On 28th day animals were sacrificed. Further animals were tested for behavioral, biochemical and histopathological parameters.

Result

Tropisetron significantly attenuated oxidative damage and restored the reduced levels of anti‐oxidant enzymes. ICV‐STZ treatment had shown significant neuronal damage in hippocampal and cortical regions of AD brain in histopathological examination. Moreover, hippocampal neurons were observed to be irregular in morphology with dark pyknotic nuclei. This confirms the neurodegeneration in ICV‐STZ animals. Target drug tropisetron resulted in significant neuroprotection against ICV‐STZ.

Conclusion

The observed outcomes of the present study suggest the neuroprotective effect of tropisteron in STZ induced animal model of Alzheimer’s disease.It would be safe to conclude that tropisetron may improve the behavioral outcomes by attenuating oxidative burden & its neuroprotective potential as seen in our histological assessment.
Changes of the texture and volume of brain MRI in Suspected Non Alzheimer Pathology and Alzheimer’s disease
Authors: Kwon Min Jeong
Published: December 2023

Background

Suspected Non Alzheimer Pathology (SNAP) is a biomarker‐defined syndrome that encompasses a group of individuals with neurodegeneration, but no evidence of amyloid deposition. However, it is still unclear whether SNAP represents distinct pathology separate from AD. We examined the differences in the volume and texture of key regions of interest (ROIs) in brain MRI between SNAP and AD to discuss the different causes of neurodegeneration.

Method

We enrolled all participants from dementia clinics of Seoul National University Bundang Hospital. We obtained three‐dimensional structural T1‐weighted magnetic resonance images of the participants using 3.0 Tesla Achieva Scanner and compared the texture and volume of ROIs between the groups using analysis of variance with Bonferroni post hoc comparisons.

Result

The SNAP group showed comparable volumes to the AD group in all ROIs. Compared with regional volume, regional texture showed different features between SNAP and AD. The SNAP group showed different texture in precuneus, posterior cingulate cortex, superior parietal cortex and inferior parietal cortex. In these regions, the entropy which reflects the randomness of spatial distribution of gray levels was higher in the AD group compared to the SNAP group.

Conclusion

This study demonstrated that the texture change of SNAP was different from that of AD despite a similar volume change. In conclusion, our study suggests that MRI texture can be used for detection of microstructural changes in the early stage of the disease.
Dementia and Stroke Risk Associated with Brain Artery Luminal Diameters
Authors: Melgarejo Jesus D , Gurel Kursat , Compton Cassidy R. , Liu Minghua , Assuras Stephanie , Levin Bonnie , Sacco Ralph , Elkind Mitchell S.V. , Rundek Tatjana , Ikram M. Kamran , Kavousi Maryam , Ikram M. Arfan , Wright Clinton B. , Crivello Fabrice , Laurent Alexandre , Tzourio Christophe , Vernooij Meike W , Yu Zhang Zhen‐ , Bos Daniel , Gutierrez Jose
Published: December 2023

Background

It is unclear whether brain artery diameters measured on conventional T2‐weighted brain MRI images relate to dementia and stroke outcomes across distinct populations. We aimed this study to evaluate the association of T2‐weighted brain artery luminal diameters with dementia and stroke in three distinct population‐based studies.

Methods

Three longitudinal population‐based studies with 8420 adults >40 years old (Northern Manhattan Study [NOMAS] from the United States, and the Rotterdam Study [RS], from the Netherlands, and Three‐City, from France) with brain MRI scans obtained between 1999 and 2015. The median follow‐up time for clinical events ranged between 7 and 12.5 years. We tested our hypothesis in each cohort separately due to local data‐sharing regulations. The exposure variable was brain carotid and basilar artery luminal diameters measured on MRI axial T2‐weighted scans. Multivariable hazard ratios (HRs) and their 95% confidence intervals (CI) expressed the risk of dementia and stroke (primary outcomes) associated with the lowest (<5th) and highest (>95th) percentiles of the rank‐normalized brain artery diameters compared to a reference group defined as the diameters distributed between the 5th and 95th percentiles. Secondary outcomes included total and vascular mortality, and fatal and nonfatal cardiovascular and coronary end points.

Results

Among the three cohorts (mean age ranged from 65 to 73 y, ≥57% women), 335 participants developed dementia and 331 strokes. Compared with the reference group, participants with arterial diameters >95th percentile had a higher risk of dementia (HR range 1.15‐4.50) and any stroke (HR range 1.29‐2.03). For secondary outcomes, participants with arterial diameters >95th percentile had a consistent higher risk of coronary outcomes, vascular mortality and a composite of any vascular events. The results were less supportive of a higher risk of events among participants with arterial diameters <5th percentile except for vascular mortality.

Conclusions

Individuals with dilated brain arteries are at higher risk of dementia and vascular events. Our findings were consistency across distinct populations in spite of using a non‐enhanced, conventional T2‐weighted MRI sequence. Understanding the underlying physiopathology of the reported associations, particularly with dementia and stroke, might reveal novel vascular contributions to dementia
Neural correlates of episodic memory encoding and resilience to Alzheimer’s Disease in amyloid‐positive cognitively unimpaired individuals
Authors: Joseph Jane E , Warner Graham , Nowling Duncan , Bustos Nicholas , Barlis Katie L , Mintzer Jacobo , Brawman‐Mintzer Olga , Lawson Andrew , Dean Brian , Jensen Jens H. , Rodriguez‐Porcel Federico E , Turner Travis E , Benitez Andreana
Published: December 2023

Background

Episodic memory (EM) impairment is an important feature of early Alzheimer’s Disease and is related to well accepted biomarkers of AD. Monitoring healthy individuals for EM impairment may allow for early detection of risk for AD or a better understanding of resilience to cognitive decline. The present study used a functional magnetic resonance imaging (fMRI) EM task to examine whether neural substrates of EM are associated with classic features of AD.

Method

Healthy adults (n = 120, 84 females, 45‐85 years of age) completed a 5‐minute fMRI EM encoding task which presented photographs of unfamiliar faces and objects with instructions to remember the items for later recognition. Following fMRI preprocessing using FSL, first‐level statistical analysis (using Feat) included an explanatory variable that modeled Items that were correctly remembered in the recognition phase to reflect successful encoding. Group‐level voxel‐wise analysis then examined which of a number of different AD features independently moderated fMRI response during successful encoding, including amyloid deposition from PET, hippocampal volume from MRI, APOE e4 status, and performance on neuropsychological tests (Craft story recall, Multi‐Lingual Naming Test: MINT, global cognition: MOCA). Age, sex and education were included as covariates in all voxel‐wise analyses and activation maps were cluster‐corrected using Z > 3.1, p = .05.

Result

The only AD marker that significantly moderated EM successful encoding was amyloid status. Amyloid+ individuals (n = 25) recruited an area of the left antero‐lateral temporal cortex (MNI coordinates: x = ‐68, y = ‐30, z = ‐14) more strongly than Amyloid‐ individuals (n = 94). A post‐hoc exploratory analysis (controlling for age, sex and education) revealed that in Amyloid+ individuals, activation in the dorsal aspect of this temporal region was associated with better delayed memory performance (partial r = .426, p = .048) and activation in the ventral aspect of this region was associated with greater left hippocampal volume (partial r = .489, p = .021). In contrast, in Amyloid‐ individuals, activation in the dorsal aspect of this temporal region was associated with better performance on the MINT (partial r = .288, p = .006).

Conclusion

Recruitment of left lateral temporal cortex during successful encoding in Amyloid+ individuals was associated with better delayed memory recall performance and greater hippocampal volume, suggesting a potential profile of resilience to AD.
Pathogenic motor neuron disease‐linked mutations distinctly alter TDP‐43 nanoscale dynamics
Authors: Bademosi Adekunle T.
Published: December 2023

Background

The hallmark of motor neuron disease (MND) pathology is the abnormal accumulation of insoluble proteins that form inclusions in motor neurons within the spinal cord and primary motor cortex. How, why, and when these proteins begin to aggregate has not been fully elucidated. In up to 97% of all MND cases, TAR DNA‐binding protein‐43 (TDP‐43) is a key protein that is mislocalised from its native nuclear presence into cytoplasmic inclusions. Furthermore, genetic mutations in TDP‐43 are implicated in familial MND, further linking the function of this protein to this neurodegenerative disease. The precise mechanism that drives the aggregation of TDP‐43 in MND is unknown, however identifying the changes in the dynamics of the protein within the nucleus could shed light on how the different mutations contribute to its altered function in MND.

Method

We applied nanoscale single‐molecule imaging to identify the changes in the dynamics and localisation of TDP‐43 caused by well characterised pathogenic‐causing mutation. This was done by tagging the proteins with the photoconvertible fluorescent protien ‐ mEOS3.2. Single molecule imaging was subsequently carried out in cells and neurons expressing the proteins.

Result

We observe that the different pathogenic mutations uniquely influence the mobility of TDP‐43. Most of the MND‐linked mutations inhibit the movement of TDP‐43 similar to how oxidative stressors such as arsenite induce inclusions of TDP‐43 thereby immobilising the molecules. Furthermore, our data indicates that post‐translational modifications in TDP‐43 such as acetylation similarly restricts its dynamics within the nucleus.

Conclusion

Together, our data suggests that the confinement of mobility of TDP‐43 is a key step in the formation of toxic aggregates in disease.
ALLICIN PREVENTS MPTP‐INDUCED MOTOR DYSFUNCTION AND BIOCHEMICAL ABNORMALITIES IN WISTAR RATS
Authors: Attri Paras , Deshmukh Rahul Renukadas
Published: December 2023

Background

Parkinson’s disease (PD) is an age‐related progressive neurodegenerative disorder, characterized by loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) region of the brain. Dopaminergic degeneration involves the number of mechanisms such as oxidative stress and neuroinflammation. Allicin has been reported to exert various anti‐oxidative and anti‐inflammatory activities in in‐vitro and in‐vivo studies. Therefore, in the present study, we have investigated neuroprotective effect of allicin against MPTP induced Parkinson’s disease in rats.

Method

Repeated intranigral infusion of MPTP at day 1st, 4th, and 7th produced significantly loss in body weight, locomotor activity, motor coordination, antioxidant defense enzymes (reduced glutathione) and significantly increase oxidative stress markers (lipid peroxidation and nitrite level) in the striatum. MPTP treatment also increased pro‐inflammatory cytokines (TNF‐α, IL‐6, and IL‐1β) level and decreased neurotransmitter level in the striatum. Allicin (5, 10 and 20mg/kg/day i.p.) treatment from day 8th to 21st significant reversed the behavioral, antioxidant defense enzymes, oxidative stress marker and pro‐inflammatory cytokines in MPTP infused rats.

Result

Allicin (5, 10 and 20mg/kg/day i.p.) treatment from day 8th to 21st significant reversed the behavioral, antioxidant defense enzymes, oxidative stress marker and pro‐inflammatory cytokines in MPTP infused rats.

Conclusion

The consequences of particular study suggest the beneficial effects of allicin in PD.