bluuebunny/crossref_metadata_2025 huggingface dataset:
Peroxisome Proliferator‐Activated Receptor γ is involved in the neuroprotection exerted by 2‐hydroxydocosahexaenoic acid against Alzheimer’s disease
Authors: Parets Sebastià , Miralles Marc , Fiol de‐Roque Maria A , Trujillo‐Estrada Laura , Cabot Joan , Péter Mária , Balogh Gábor , Fernández‐García Paula , Lladó Victoria , Busquets Xavier , Gutierrez Antonia , Escriba Pablo V. , Torres Manuel
Published: December 2021

Background

DHA‐H (2‐hydroxy‐docosahexaenoic acid) is a promising therapeutic approach for Alzheimer’s Disease (AD). DHA‐H gives rise to dose‐dependent increased levels of HPA (Heneicosapentaenoic acid) in blood plasma and brain whereas DHA‐H remains virtually absent from the brain of DHA‐H‐treated mice. Oral administration of DHA‐H to a transgenic model of AD (5xFAD mice) induces a significative cognitive recovery. However, the molecular mechanism underlying this neuroprotective effect remains largely unresolved.

Method

Screening of potential receptors for DHA‐H and HPA was performed using computational tools. PPARG (Peroxisome Proliferator‐Activated Receptor γ) activity was determined by cell‐based assays. Levels of proteins involved in amyloid production as well as synaptic markers were determined by WB and/or ELISA. β‐ and γ‐secretase activities were measured in cell‐free assays. Neuronal density was determined by immunohistochemistry. Brain levels of DHA‐H and HPA were determined by Electrospray Ionization – Mass Spectrometry (ESI‐MS).

Result

Both DHA‐H and HPA are activators of PPARG. We have analyzed the effect of DHA‐H treatment on the amyloidogenic route in the 5xFAD mice and this effect was related with PPARG activity. We observed a modulation of protein levels and enzymatic activities involved in β‐amyloid production as well as a prevention of synaptic and neuron degeneration in DHA‐H‐treated mice as compared with untreated controls. These changes were related with improved cognitive scores in these mice.

Conclusion

All these results together indicate that DHA‐H administration must prevent neuronal degeneration and cognitive decline in AD mice through its immediate metabolite HPA and without apparent involvement of PPARG.
Medication utilization among vascular dementia population
Authors: Razavian Narges , Dodson John , Masurkar Arjun V , Wisniewski Thomas , Horwitz Leora , Aphinyanaphongs Yindalon
Published: December 2021

Background

It is estimated that up to 40% of Alzheimer’s Disease and Related Dementias cases can be prevented or delayed by addressing modifiable factors including those that influence vascular risk (hypertension, obesity, smoking, physical activity, diabetes). Prevention may be particularly important in the vascular dementia subtypes. Despite the supporting evidence, the rates of medical therapy to reduce vascular risk are not well described.

Method

We assessed the utilization of statins, aspirin, and blood pressure (BP) medications in adults age ≥65 years cared for at NYU Langone Health, as recorded in the electronic health record. We included two cohorts: cohort 1 included patients who were diagnosed with vascular dementia (VaD) at NYU Langone Barlow Center for Memory Evaluation between January 1, 2015 and June 24, 2019. Cohort 2 extended the inclusion to seniors with VD diagnosis by any NYU Langone physician. Definitions for vascular dementia, the covariates assessed, and medications that we included in each category are shown in Tables 1‐3.

Result

We included 419 and 3745 patients in cohort 1 and cohort 2, respectively. Table 4 shows the characteristics and medication adherence in cohorts 1 and 2. In cohort 1, the prescription rates for statins, aspirin, and BP medications were 66%, 66%, 70%. In cohort 2, the rates for statin, aspirin, and BP medications were 56%, 46%, and 65%, respectively. The differences between prescription rates in cohort 1 and 2 for the three medication groups were statistically significant (p<0.05).

Conclusion

Our analysis of the utilization of cardiovascular medications among patients with vascular dementia illuminates potential gaps both among patients who receive care at specialty clinics, as well as the overall population with vascular dementia. The rates of medication utilization are higher for patients under the care of cognitive neurologists. Electronic health records can help identify large cohorts of patients who may benefit from improved access to preventative measures including cardiovascular medications.
Early onset dementia: Clinical utility of cerebrospinal fluid amyloidβ and tau measures in diagnosing mild cognitive impairment
Authors: Hosseini Akram A. , Brown Thomas , Mannino Luca , Gran Bruno , Junaid Kehinde , Mukaetova‐Ladinska Elizabeta
Published: December 2021

Background

The differentiation of a preclinical or prodromal Alzheimer’s disease (AD) is challenging particularly in patients with Early Onset Alzheimer’s or Related Dementias (EOARD). The first clinical symptoms of AD during the prodromal phase are mild cognitive impairment (MCI), with some younger adults presenting with depression or anxiety. We report a local practice on utilising diagnostic lumbar puncture to investigate the cause of MCI for the diagnosis of EOARD at a tertiary neurocognitive referral centre.

Method

The study was approved by the Ethic Committee (Ref:18/EM/0292). 30 participants aged 32‐68 years old at the onset of symptoms (mean 62 years; 61% female) from the Nottingham EOARD clinics (UK) were included. Clinical diagnosis was based on clinical presentation, neurocognitive profile, radiological features (MRI, FDG‐PET CT) and CSF amyloidβ1‐42/1‐40 (Aβ), total tau and Thr181‐phosphorylated tau measurements. Patients were classified into three groups according to the clinical diagnosis: a)MCI secondary to Alzheimer’s disease as defined by NIA‐AA Research Framework [n=16]. b)Subjective Cognitive impairment, stable impairment in cognitive battery with no evidence of neurodegeneration on neuroimaging or abnormal levels of Amyloidb/tau in the CSF [n=9]. c)Other neurodegenerative conditions [n=5] (Table).

Result

In patients with MCI, the CSF total tau and Thr181‐phosphorylated tau levels showed a non‐linear relationship with age, with an inverse U‐shaped curve reaching the highest level at the age of 55 years, followed by a significant decline in the following decade (Figure). In contrast, the CSF Aβ level decreased in the MCI group, independently of age, and was associated with the neuropsychological measures of memory impairment (p=0.037). In contrast, total and phosphorylated CSF tau levels did not correlate with the cognitive performance measures. Similarly, the principal component analysis confirmed that the clinical diagnosis of Alzheimer’s MCI (as per the NIA‐AA criteria) correlated with the CSF Aβ loss.

Conclusion

In Early Onset Alzheimer’s disease, the low levels of CSF Aβ appear to be more sensitive than the total and 181Thr‐phosphorylated tau measures in differentiating Alzheimer’s MCI from other forms of dementia. Further work on larger samples of EOARD in clinical practice will address the cost effectiveness due to making an earlier diagnosis.
The influence of cognitive reserve on Alzheimer's disease progression
Authors: Garba Asabe E , Grossberg George T , Enard Kimberly R , Jano Fabian J , Roberts Emma N , Marx Charlotte A , Buchanan Paula M
Published: December 2021

Background

The incidence and prevalence of Alzheimer’s disease (AD) continues to rise in the growing elderly population putting public health at increased economic, healthcare, and caregiving burdens. The effects of AD pathology on the brain are irreversible, making it hard to determine effective treatment after symptom onset. Primary prevention has been proven to reduce the risk of developing AD later in life. Past research found that cognitive reserve (CR), an individual’s ability to cope with brain changes, impacts AD risk. The buildup of CR over a life span has shown positive cognitive implications. However, the influence that CR has on the rate of AD progression remains to be explored. This study used a survey tool that accounts for all CR proxies to explore this gap.

Method

To quantify CR in the study population of 90 AD participants, the Cognitive Reserve Index questionnaire was used. The Clinical Dementia Rating scale was utilized to stage AD progression. One‐way ANOVA and Independent Samples T‐tests were used to test for differences between the mean CR scores of dementia groups. One‐way ANOVA was also used to test for differences between CR level groups and mean number of days it took to transition from one dementia stage to the next. Multivariable linear regression was utilized to determine the unit change in time associated with an increase in CR score.

Result

There was not a significant difference in mean CR score by dementia group (F = 1.96, p = 0.15). After collapsing the moderate and severe dementia groups to compare to the mild dementia group, there was a significant difference in mean CR score (mild mean (SD) = 131(15.0), moderate/severe mean (SD) = 123(20.6), p = 0.05). After controlling for physical activity, for every unit increase in CR score, the number of days for transitioning from mild to severe dementia increased by 34 days (β = 33.94, 95% CI: 8.07, 59.81, p = 0.01).

Conclusion

Higher CR was associated with slower AD progression. This indicates that consistent engagement in activities that promote CR buildup over a life span are methods for improving AD and dementia health outcomes.
Improving early recognition of Creutzfeldt‐Jakob disease mimics in clinical practice
Authors: Lazar Evelyn , Porter Amanda , Prusinski Christian C , Dunham S Richard , Lopez‐Chiriboga A Sebastian , Day Gregory S
Published: December 2021

Background

Diagnostic criteria emphasize the use of real‐time quaking‐induced conversion (RT‐QuIC) assays in cerebrospinal fluid (CSF) to identify patients with rapidly progressive dementia (RPD) due to for Creutzfeldt‐Jakob disease (CJD; CDC Diagnostic Criteria; Oct‐2018). Yet, this test is often performed in specialized centers, leading to delays in return of results. There is a need to leverage clinical features and the results of readily available tests to distinguish patients with CJD from those with other causes (‘CJD mimics’), including patients with potentially treatment‐responsive RPD.

Method

Patients with definite (pathology‐confirmed) or probable CJD (clinical features with positive RT‐QuIC) were identified through retrospective review of Mayo Clinic Enterprise (n=91) and Washington University in St. Louis records (n=14; Jan‐2014 to Dec‐2020). Demographic, clinical details and results of common investigations (e.g., neuroimaging, CSF analyses and electroencephalogram) were compared between CJD cases and ‘mimics’ who met clinical criteria for probable CJD but did not have CJD.

Result

CJD mimics were diagnosed with autoimmune encephalitis (n=8), neurosarcoidosis (n=1), FTLD/MND (n=1) and unknown dementia (n=1), comprising 11/155 (7%) patients enrolled with RPD at study sites. Median [range] ages‐at‐presentation (65.6 [21.9‐81.5] vs 62.4 [32.8‐76.4] years; p=0.09), % females (51% vs 46%; p>0.99) and symptoms/signs were similar between groups, with the exception of motor complaints (e.g., spasms, focal weakness), which were more common in mimics (11/11 vs 55/105; p<0.01). Electroencephalogram findings did not differ between groups. MRI findings compatible with CJD (i.e., restricted diffusion within deep nuclei/cortical ribbon) predominated in cases (80/105 vs 4/11; p<0.01), while elevations in CSF leukocytes (>5 cells/hpf: 6/11 vs 5/103; p<0.01) and protein >45 mg/dL (10/11 vs 43/103; p<0.01) were more common in mimics. Total‐tau levels >1150 pg/mL (76/84 vs 2/10; p<0.01) and ‘positive’ 14‐3‐3 (67/98 vs 3/10; p=0.03) were frequent in cases. Autoantibodies associated with autoimmune encephalitis were detected in 5/10 mimics but 0/87 cases (p<0.01). Immunosuppressant therapies were provided to 10 mimics and 24 cases, with response limited to mimics.

Conclusions

Autoimmune encephalitis, neurosarcoidosis and select neurodegenerative diseases may mimic CJD at presentation. Findings from brain MRI and commonly available CSF tests may facilitate early recognition of mimics, providing an opportunity for early treatment.
Empirical evidence of cognitive change: Calculating reliable change indices for digital tests of cognition in individuals living with Alzheimer’s disease
Authors: Harrison John E , Myers Jennifer Rae , Madero Erica N. , Mak‐McCully Rachel , Gray Michelle , Glenn Jordan M.
Published: December 2021

Background

The identification of individuals at risk of progressing from normal health to Mild Cognitive Impairment (MCI) and later to Alzheimer’s disease (AD) has focused recently on using evidence of progressive decline. This approach relies upon employing a reliable metric of cognitive change. One possible approach to this issue involves employing a Reliable Change Index (RCI) methodology

Method

A sample of N = 56 participants were assessed on exams from the Neurotrack assessment suite at baseline and 1‐week later. This assessment is composed of well‐known and previously validated measures of episodic memory, working memory, attention and executive function (see Table 1 for details of tests).

Results

Using the data from our study cohort we calculated a RCI for each measure using the Jacobson‐Truax method. This requires the determination of a threshold that separates those who are impaired from individuals who are not impaired. It also requires a comparison of an individual’s change from assessment time point 1 and 2 to the standard error of measurement (SEM) of the outcome. RCI and 95% confidence interval (CI) was calculated for each of the Neurotrack tests. By applying the 95% CI to a baseline score, a statistically normal range of later performance can be determined. Values falling outside the CI can be considered evidence of real change.

Conclusions

In this study, we provided individual RCI values and associated CI for each test in the Neurotrack battery. We are currently evaluating the Neurotrack assessment in a longitudinal validation study to investigate sensitivity to change over time.
Characterization of amyloid angiopathy in the retina
Authors: Campbell Melanie C.W. , Emptage Laura , Redekop Rachel , Kitor Monika , Neathway Peter A.C. , Ding Yifan , Hirsch‐Reinshagen Veronica , Hsiung Ging‐Yuek Robin , Mackenzie Ian R.
Published: December 2021

Background

Cerebral amyloid angiopathy (CAA) is a vascular brain disease with risk of severe complications, and high prevalence in those with Alzheimer’s disease (AD). Characteristic amyloid beta deposits in blood vessels in the cerebrum are challenging to diagnose. Amyloid deposits in blood vessels in human retinas have been previously reported. Here, we characterize postmortem, retinal amyloid angiopathy (RAA) in individuals with AD and/or CAA brain pathology. We propose a staging of RAA which could be extended to in vivo imaging, modified from CAA staging in the brain.

Method

Correlation of severity of brain pathology for AD and CAA was assessed for 52 individuals. Formalin fixed retinas from 6 of these individuals were whole‐mounted and stained with thioflavin S and DAPI, then imaged in polarized light and confocal microscopy with 3 florescence channels. While following blood vessels systematically, images of RAA were collected.

Result

Brain pathology due to CAA increased in severity with increasing severity of AD pathology as previously reported (Figure 1). RAA was present in all donors with evidence of brain CAA and in two donors with no evidence of brain CAA (Figure 2). Amyloid present in vessels can be imaged dye‐free in polarized light. Our proposed staging of RAA severity is modified from two used in the brain (Figures 3‐6). Stage 1): Amyloid within the vessel and not filling the lumen of the vessel: 1A) Amyloid is not circumferential; 1B) Amyloid is circumferential. Stage 2): Amyloid completely fills the lumen of the vessel. Stage 3): Amyloid both within and touching the outside of the vessel, analogous to dysphoric CAA.

Conclusion

Amyloid angiopathy in the retina (RAA) may occur concurrently with and potentially prior to brain CAA. Further, severity of RAA could be monitored through the proposed staging which in turn could allow comparison of severities of CAA and RAA. This would elucidate whether RAA severity is a good predictor of CAA severity. Our data confirm the previously reported correlation between brain CAA and AD. Further development of RAA imaging in the living eye may allow earlier and improved diagnosis of brain CAA, facilitating the development and testing of new treatments.
Effect of memantine and combination with vitamin D enrichment on body composition in APP/PS1 Alzheimer’s mice following vitamin D deprivation
Authors: Broberg Dana N , Wong Dickson , Doad Jagroop , Umoh Joseph U , Bellyou Miranda , Norley Chris JD , Holdsworth David , Montero‐Odasso Manuel , Beauchet Olivier , Annweiler Cedric , Bartha Robert
Published: December 2021

Background

Vitamin D (vitD) deficiency and changes in body composition are frequently observed in Alzheimer’s disease (AD). The combination of memantine and vitD has been shown to protect cortical axons from glutamate toxicity and beta‐amyloid in AD. Further to these central effects, vitD and memantine may act peripherally to alter metabolism. The purpose of this study was to assess changes in body composition (lean, adipose, and skeletal tissue) in an AD mouse model due to vitD deprivation and subsequent treatment with memantine and memantine combined with high dose vitD supplementation.

Method

Male APP/PS1 mice were randomized into four groups. Controls (n=14) received a standard diet throughout. The other three groups started a vitD deficient diet at month 6. At month 9, the VitD‐ group (n=14) remained on this diet, while the Mem&VitD‐ group (n=14) had memantine added, and the Mem&VitD+ group (n=14) had both memantine and 10 IU/g vitD added to their diet. Serum 25(OH)D3 levels were measured at months 6, 9, 12 and 15. Micro‐computed tomography scans were acquired at month 15 and segmented based on signal‐intensity to measure lean, adipose, and skeletal tissue mass and volume.

Result

Serum 25(OH)D3 measurements confirmed that mice on vitD‐deficient diets had lower levels (89% decrease), and mice on the vitD‐enriched diet (Mem&VitD+) had higher levels (129% increase), of 25(OH)D3 relative to mice on the standard diet. No differences were observed in adipose or lean tissue mass and volume between the four groups, however, there was a significant increase in skeletal tissue mass (9.3% increase, p<0.05) and volume (9.2% increase, p<0.05), and bone mineral content (8.7% increase, p<0.01) in the Mem&VitD‐ group relative to controls.

Conclusion

While vitD deprivation did not affect body composition in APP/PS1 mice at 15 months, memantine increased absolute skeletal tissue in mice that were vitD‐deficient. However, memantine did not have this effect in mice that were vitD‐enriched. We conclude that combination treatment of memantine and vitD enrichment had no negative effects on body composition in the APP/PS1 mouse model. Future work should clarify whether vitD status impacts the effects of memantine on bone physiology in people with AD.
Effect of vitamin D deprivation and subsequent treatment with memantine and vitamin D enrichment on gait in APP/PS1 Alzheimer’s mice
Authors: Broberg Dana N , Wong Dickson , Bellyou Miranda , Montero‐Odasso Manuel , Beauchet Olivier , Annweiler Cedric , Bartha Robert
Published: December 2021

Background

Altered gait is a common complication of Alzheimer’s disease (AD) that leads to decreased mobility and quality of life. Additionally, many individuals with AD are vitamin D (vitD) deficient. Combined treatment with memantine and vitD has been shown to protect cortical axons from glutamate toxicity and beta‐amyloid in AD. Therefore, this treatment may mitigate changes in gait associated with AD. The purpose of this study was to assess for the first time in an AD mouse model whether gait is affected by vitD deprivation and whether subsequent treatment with memantine or memantine combined with high dose vitD reverses these effects.

Method

Male APP/PS1 mice were randomized into four groups. Controls (n=14) received a standard diet throughout. The other three groups started a vitD deficient diet at month 6. The VitD‐ group (n=14) stayed on this diet, while the remaining two groups began treatment at month 9 with either memantine alone (Mem&VitD‐) or both memantine and 10 IU/g vitD (Mem&VitD+). Serum 25(OH)D3 levels and spatiotemporal parameters of gait (stride length, swing time, swing speed, and front and hind stride widths measured by CatWalk) were assessed at months 6, 9, 12 and 15.

Result

Mice on vitD‐deficient diets had 7× lower levels of serum 25(OH)D3, and mice on the vitD‐enriched diet (Mem&VitD+) had over 2× higher levels of serum 25(OH)D3, relative to controls. VitD deprivation did not significantly affect stride length, swing time, swing speed, or front stride width, however, it led to a 12% increase in hind stride width by month 15 (Figure 1, VitD‐ vs. Control, p<0.001). Therefore, we examined hind stride width at month 15 in the memantine treatment groups and found that combination treatment with vitD prevented this increase (Figure 2, Mem&VitD+ vs. VitD‐, p<0.05), while memantine alone did not (Mem&VitD‐ vs. VitD‐, p=0.28).

Conclusion

VitD deprivation led to impaired postural control (hind stride width) in APP/PS1 mice by month 15. Memantine in combination with vitD enrichment, but not memantine alone, was able to prevent this impairment. Therefore, future work should investigate the potential for memantine combined with vitD supplementation to improve gait in people with AD.
Predictors of generalized anxiety during the COVID‐19 pandemic in older African Americans in Detroit
Authors: Hanna Sophie , Bass Dwana , DiCerbo Loraine M. , Shair Sarah , Giordani Bruno , Kavcic Voyko
Published: December 2021

Background

The COVID‐19 pandemic is a health emergency that has forced a change in the daily life of individuals across all nations, races and socioeconomic groups for over a year. Such a crisis has required social isolation, the closing of businesses, schools and many recreational activities. This abrupt change has had negative effects on mental health, especially in the most vulnerable populations.

Method

For this study, 164 community‐dwelling older African Americans (mean age = 75.6, range = 65‐94) were recruited from the Wayne State Institute of Gerontology Healthier Black Elders Center and general Detroit area. Responses were gathered over the phone between July 28, 2020 to January 14, 2021. Generalized anxiety was measured by the GAD‐7. Responses to COVID‐19 were measured by: positive emotions (eg., gratitude, happiness), negative emotion (eg., anger, fear), unmet needs (eg., food, medical care), and personal issues (eg., economic problems, reduced privacy).

Result

Of the participants, 12 reported having COVID‐19, with 48% reporting a close family member having the virus, 26% had a death in the family and 67% endorse feelings of isolation. Average anxiety on the GAD‐7 was 6.2 (SD = 5.4, range = 0‐21). Of the 163 participants that completed the scale, 46% reported no anxiety, 28% reported mild anxiety, 17% reported moderate anxiety, and 9 % reported severe anxiety. In a stepwise regression, the following factors were found to predict GAD scores: negative emotions (51% explained variance), positive emotions (3% explained variance) and daily stressors brought on by COVID‐19 (1% explained variance). Further analyses were completed to evaluate additional models to assess the interrelationships between predictors and significant COVID‐related milestones.

Conclusion

This current study among older African Americans living in an urban area highlights daily‐life risk factors for anxiety during the time of COVID‐19. Negative emotions as primary predictors are factors which can be specifically addressed with current psychosocial services. More research is needed in order to fully understand the scope and correlates of anxiety predictors during these challenging times.
Modeling cognitive processes with shuffled‐ and fixed‐order multi‐trial wordlist memory tests
Authors: Bock Jason R. , Lee Michael D. , Westfall Holly A. , Hara Junko , Fortier Dennis , Mangrola Tushar , Shankle William R.
Published: December 2021

Background

Many commonly‐used multi‐trial wordlist memory (WLM) tests present list words in a shuffled order across learning trials, while others maintain a fixed order across trials. The ADAS‐Cog employs shuffling across trials in only one sequence for all assessed subjects. Therefore, to examine the impact of presentation order shuffling on the cognitive processes of learning and memory with a hierarchical Bayesian cognitive processing (HBCP) model, we assessed healthy subjects with a computerized version of the ADAS‐Cog WLM test that randomized wordlist presentation order on each of the three learning trials for each subject (randomized group). We then applied the model with resulting modifications to Alzheimer's Disease Neuroimaging Initiative (ADNI) subjects assessed with the ADAS‐Cog (shuffled group). Finally, we compared results to cognitive processes of patients of a cognitive disorders clinic assessed with the fixed‐order MCI Screen (MCIS; fixed group).

Method

Randomized group (n = 89), shuffled group (n = 2,235), and fixed group (n = 3,635) subjects completed respective assessments for university course credit, according to ADNI protocol, or as part of clinical assessment, respectively. The HBCP model uses item response data to estimate cognitive processes of encoding, storage, and retrieval for each wordlist item for each subject (Figure 1), through the probabilities of transferring item episodic memory from one storage state to another on a given trial.

Result

Analysis of randomized group data enabled development of a model extension accounting for observed presentation order. Examination of posterior distributions shows high recall and no serial position curve in the healthy randomized group (Figure 2). Applied to the shuffled group, there is greater interpretability and descriptive adequacy (Figure 3) than there is without the model extension (Figure 4), as can be seen in comparison to fixed group posterior distributions (Figure 5).

Conclusion

These findings reveal the impact of presentation order shuffling and demonstrate our model's ability to mitigate it. Shuffling results in loss of information fidelity and the inability to estimate cognitive processing parameters in terms of serial position curves. The greater precision and range of measurement for fixed order presentation tests remains an important consideration for clinical trial design.
Race and sex differences in lifespan glycemic status and midlife cognitive function: The Bogalusa Heart Study
Authors: Newton Robert L , Gwizdala Kathryn L , Bazzano Lydia , Carmichael Owen T
Published: December 2021

Background

The association between early‐life glycemic control (during adolescence and young‐adulthood) and both cognition and risk of AD is not well understood. Furthermore, African Americans (AA) are underrepresented in aging research and disproportionally at higher risk for diseases related to glycemic control (Chow et al., 2012). This study assessed race and sex differences in the association between early‐life glycemic control and midlife cognitive function in a biracial, semi‐rural, Deep Southern population‐based epidemiological cohort.

Method

The Bogalusa Heart Study has followed participants from childhood to adulthood since 1973. Glycemic control measures including fasting insulin and glucose, and HOMA‐IR, were collected at roughly biannual visits from 1973 to today and cognitive measures were collected between 2013‐2016. Cognitive measures (n = 1295) included memory, executive function (EF), and global cognition. Glycemic control variables were averaged within specific age epochs (<20 (adolescent), 21‐40 (early adulthood) and >40 (adulthood). Linear regression models had metabolic measures as predictors and cognitive measures as outcomes. Models were run within age and race specific subgroups including sex, race, and education as covariates.

Result

Among women, greater levels of each glycemic predictor within adolescent and early‐adulthood epochs were associated with poorer memory and EF (Average Est. ‐0.018, p ≤ 0.037), and greater fasting glucose within the adolescent epoch was associated with poorer global cognition (Average Est. ‐0.061, p = 0.021). Greater HOMA‐IR and insulin levels within the adolescent epoch were associated with greater memory among men (Average Est. 0.040, p ≤ 0.020). Among AA, greater fasting glucose was associated with lesser EF performance within each epoch (Average Est. ‐0.006, p ≤ 0.037). Greater HOMA‐IR and insulin levels within early‐adulthood and >40 epochs were associated with greater memory for AA, and greater EF among whites (Average Est. 0.013, p ≤ 0.040 (AA), 0.029, p ≤ 0.025 (white)).

Conclusion

Poorer early to mid‐life glycemic control is associated with poorer EF and memory for women, better memory for men and AA, poorer EF for AA, and better EF for whites. Race and sex differences in the relationship between lifespan glycemic exposures and cognition decades later are pronounced and could reflect disparities in health‐related exposures throughout the lifespan.
Using digital twins to reduce sample sizes while maintaining power and statistical accuracy
Authors: Walsh David , Schuler Alejandro M , Hall Diana , Walsh Jonathan R. , Fisher Charles K.
Published: December 2021

Background

Alzheimer’s Disease (AD) trials are challenging due to their size, length and costs. Bayesian designs can reduce the required sample sizes by using external data sources to construct prior distributions for treatment effects, so that the same effect sizes can be detected with fewer trial participants. We apply a Bayesian approach based on digital twins ‐ longitudinal, patient‐level placebo records with baseline characteristics matched to those of actual subjects in AD trials. These records are generated by a machine learning model of AD progression that we have trained on data from placebo arms of past clinical trials and from observational studies.

Method

We re‐analyzed a Phase II, double‐blind, placebo‐controlled trial of Resveratol in 119 patients with mild‐to‐moderate AD ‐ Mini‐Mental State Examination (MMSE) scores between 14‐26 ‐ using a method we call PROCOVA+. We focused on the Alzheimer's Disease Assessment Scale ‐ Cognitive (ADAS‐Cog11, primary endpoint), the Clinical Dementia Rating ‐ Sum of Boxes (CDR‐SB) and MMSE.

PROCOVA+ leverages the digital twins’ outcomes in two ways: as covariate information on the actual trial participants, and to construct prior distributions for the expected placebo outcomes for each endpoint. These prior distributions are centered on the mean outcomes of all digital twins, with dispersions that reflect how accurately digital twins match actual subjects on similar clinical trials. We determined the necessary sample sizes for PROCOVA+ to achieve the same power as the original study, while fixing a 2:1 randomization ratio between the active treatment and placebo arms. We randomly sampled that number of subjects from the original study and computed estimates and credible intervals for each endpoint.

Result

The total sample size across the two arms was reduced by 17%. The estimates of the treatment effects agreed closely with those of the original study for all three endpoints, with credible intervals which were no wider than the original confidence intervals.

Conclusion

Digital twins present an opportunity to design and analyze AD trials in a way that maintains statistical accuracy, while reducing the required sample sizes and hence the time and cost associated with recruiting and treating extra subjects.
Identification of small molecule drugs that target apolipoprotein E4‐catalyzed amyloid‐β fibrillization: A new therapeutic approach to Alzheimer’s disease
Authors: Johnson Noah R , Wang Athena Ching‐Jung , Coughlan Christina M , Sillau Stefan H , Lucero Esteban M , Viltz Lisa , Markham Neil , Allen Cody , Dhanasekaran A. Ranjitha , Chial Heidi J , Potter Huntington
Published: December 2021

Background

Carrying the ε4 allele of the apolipoprotein E (APOE) gene is the strongest risk factor for Alzheimer’s disease (AD) besides age itself. Having one copy of APOE4 triples the risk for AD, whereas being homozygous for APOE4 increases the risk by greater than 12‐fold. As one potential mechanism, apoE, and especially apoE4, acts as a catalyst to accelerate the polymerization rate of amyloid‐β (Aβ) into neurotoxic oligomers and filaments. Thus, inhibiting this catalytic process is a promising therapeutic approach to preventing AD. Repurposing a known drug to inhibit the apoE4‐Aβ interaction would have numerous benefits such as faster, less expensive testing in clinical trials, and a greater chance of making it to market.

Method

We developed an apoE4‐Aβ fibrillization assay and screened two small molecule drug repurposing libraries containing more than 3,000 compounds with a history of use in human clinical trials. The cytotoxicity and efficacy of hit compounds were evaluated in transgenic mouse and rat primary neurons. We also modeled changes in cognition using MMSE scores and clinical diagnoses of National Alzheimer’s Coordinating Center (NACC) participants using time slopes and Cox proportional hazards, respectively, and adjusted for age and sex.

Result

Our high‐throughput screen identified 31 hit compounds that inhibited apoE4‐catalyzed Aβ fibrillization in a dose‐dependent manner. Five of those hit compounds were non‐toxic, blood‐brain barrier permeable, and reduced apoE4‐induced Aβ and tau neuropathology in AD cell culture models. One hit compound was the anti‐depressant imipramine, which, when taken by AD patients, was associated with improved cognition (P=0.0490) and increased incidence of receiving an improved clinical diagnosis (P<0.0001), compared to all other anti‐depressants. Another hit compound was the anti‐psychotic olanzapine, which, when taken by AD patients who were APOE4 carriers, was associated with improved cognition (P=0.0235) and improved clinical diagnosis (P=0.0435), compared to all other anti‐psychotics.

Conclusion

We identified five novel inhibitors of the apoE4‐Aβ interaction, two of which were associated with clinical improvements when prescribed to AD patients for their normal indications. These findings validate an apoE‐centric approach to developing new AD therapeutics. This set of small molecules may be useful for preventing or reversing AD, particularly in APOE4 carriers.
The first MultiTEP‐based conjugated vaccine targeting pyroglutamated pE3‐Aβ is immunogenic and effective in a 5xFAD animal model
Authors: Zagorski Karen , King Olga , Hovakimyan Armine , Antonyan Tatevik , Petrushina Irina , Chadarevian Jean Paul , Danhash Emma , Cribbs David H. , Davtyan Hayk , Blurton‐Jones Mathew , Agadjanyan Michael G , Ghochikyan Anahit
Published: December 2021

Background

Many ongoing studies for AD immunotherapy are focused on the immunodominant N‐terminus of Aβ. This region is often truncated and post‐translationally modified in amyloid. The pyroglutamate modified variant of Aβ40/42 (pE3‐Aβ) is more neurotoxic and aggregation‐prone and is thought to play an important role in disease onset. We have previously demonstrated that our proprietary vaccine platform MultiTEP is extremely immunogenic in various mammals, including disease models of AD and aged monkeys, and can be used to generate a robust immune response towards various targets. Based on these we developed a MutiTEP‐based vaccine targeting pE3‐Aβ.

Method

A genetically engineered variant of MultiTEP was generated to enable chemoselective bioconjugation of synthetic peptides under mild aqueous conditions. The peptide‐protein stoichiometry was selected at 3:1 based on previous data. C57Bl6 and 5xFAD mice were monthly immunized with pE3‐Aβ‐MultiTEP adjuvanted vaccine, AV‐1986R. Antibody titers were tested via ELISA on plates coated with pE3‐Aβ42 and unmodified Aβ42 as control. The reduction of brain pathology in 5xFAD was assessed via biochemical assessment (MSD ELISA) as well as IHC and confocal microscopy using various commercial antibodies. The binding of immune sera to brain sections from non‐AD, MCI, and AD cases was examined.

Result

The AV‐1986R generates a robust immune response in transgenic and WT mice after two immunizations. The generated antibodies exhibit three orders of magnitude higher affinity (one to a million avg endpoint titer) to the pE3‐Aβ compared to Aβ42 and recognized Aβ plaques in brain tissue slices from both transgenic animals and AD cases. Importantly, vaccination significantly reduced AD‐like pathology in 5xFAD mice.

Conclusion

AV‐1986R is immunogenic and effective. A recent report from Elly‐Lilly about the pE3‐Aβ specific monoclonal antibody donanemab shows that treatment slows down the cognitive decline in humans. While this is promising and re‐affirms the selection of pE3‐Aβ as a therapeutic target, the regular injections of monoclonal antibodies are extremely expensive and have low patient compliance due to the frequent and invasive nature of the treatment. We suggest using active vaccine as a feasible alternative, allowing the maintenance of a constant level of therapeutic antibodies with minimal costs and infrequent vaccine injections.
The role of inflammation on the association between apathy and motoric‐cognitive outcomes
Authors: Ceide Mirnova E.
Published: December 2021

Background

Recent literature indicates that apathy is associated with poor cognitive outcomes in community dwelling older adults, including motoric cognitive risk syndrome (MCR), a predementia syndrome defined by subjective cognitive complaints and slow gait. The role of biological markers in the association between apathy and motoric‐cognitive outcomes has not been established. The objectives of this study were to 1) examine the association between inflammation and apathy and 2) to evaluate the moderating effect of inflammation on the association between apathy and motoric‐cognitive outcomes.

Method

We measured apathy in 347 community dwelling older adults enrolled in the Central Control of Mobility in Aging study using an apathy scale score derived from confirmatory factory analysis of the Geriatric Depression Scale Long Form. We conducted cross‐sectional analyses of the following: the association between IL‐6 and CRP with apathy and the moderating effect of IL‐6 on the association between apathy and MCR and slow gait, using logistic regression and linear regression models, respectively. Linear associations were reported using β‐coefficients, while logistic associations were reported using odds ratio (OR) with 95% confidence intervals (CI), adjusting for age, gender, general health status and depression scale score.

Result

logIL‐6 but not logCRP was associated with apathy, in adjusted models (β=.037, 95% CI: .002‐.072, p=.04). Apathy was not significantly associated with MCR at cross‐section (OR: 0.48, 95% CI: .08‐2.97, p=.43), but apathy was significantly associated with gait velocity (β=‐14.45, 95% CI: ‐24.89 ‐ 4.01, p=.01). IL‐6 was associated with gait velocity (β=‐4.48, 95% CI: ‐7.42 ‐ 1.53, p=.003) and moderated the association between apathy and gait velocity by a change in β of 14.5%.

Conclusion

We found that IL‐6, but not CRP was associated with apathy in a cohort of community dwelling older adults. Furthermore, IL‐6 moderated the association between apathy and gait velocity, a risk factor for dementia. Apathy was not associated with MCR at cross‐section, despite being associated with incident MCR in prior studies, suggesting that apathy is an early predictor of motoric‐cognitive decline.
Objective cognitive performance and informant‐rated dysexecutive symptoms in mild cognitive impairment and Alzheimer’s disease
Authors: Moreno Jasmin C , Wise Lisa , O'Brien Tanner , Severson Ella , Olmos Winter , Price Barbara , Alving Loren , Woo Ellen
Published: December 2021

Background

Older adults with mild cognitive impairment (MCI) and Alzheimer’s disease (AD) often exhibit memory and executive deficits on objective cognitive tests. Meanwhile, significant others often report observing symptoms of a dysexecutive nature while labeling them as “memory” difficulties. Our study examined whether objective test performances were predictive of informant‐rated executive symptoms in healthy aging, MCI, and AD.

Method

Participants included healthy older controls (n=71), individuals with MCI [n=98 (amnestic MCI n=52; non‐amnestic MCI n=43)], and persons with AD (n=40). Objective cognitive performances were measured using a standardized executive composite (Trail Making Test B and Stroop Color‐Word Interference) and a standardized memory composite (delayed recall scores from the California Verbal Learning Test‐II and Visual Reproduction‐II). Study partners completed the Dysexecutive Questionnaire (DEX), which assesses executive behaviors and symptoms.

Result

Multiple regression analyses revealed that objective memory performance predicted informant‐rated dysexecutive symptoms in the AD group and in the MCI group as a whole. In contrast, objective executive performance did not predict DEX scores in any of the groups. As expected, objective cognitive performance and DEX scores were not significantly associated in the control group.

Conclusion

Interestingly, we found that objective memory performance predicted informant‐rated dysexecutive symptoms in MCI and AD, while objective executive performance did not. This finding suggests that in everyday life, patient behaviors labeled as “dysexecutive” may be driven by memory deficits. For example, the DEX reviews behaviors that involve attentional difficulties and perseverative thinking, which can be assessed in both memory and executive tests. Overall, these findings underline the importance of integrating objective test performance with reports of patient symptoms in the real world.
Deregulation of CypA‐EMMPRIN pathway in chronic cerebral hypoperfusion: Implication in vascular dementia
Authors: Chai Yuek Ling , Rajeev Vismitha , Chen Christopher , Arumugam Thiruma Valavan , Lai Mitchell Kim Peng
Published: December 2021

Background

Chronic cerebral hypoperfusion (CCH) has been shown to be a key mechanism in vascular cognitive impairment and dementia, leading to various pathologies including blood brain barrier disruption, extracellular matrix dysfunction and inflammation. Cyclophilin A (CypA), an oxidative stress‐induced factor, is secreted into the extracellular space upon stimulation or during cell death and binds to the extracellular matrix metalloproteinase inducer (EMMPRIN). EMMPRIN may in turn activate matrix metalloproteinases (MMPs), leading to downstream inflammatory processes and vascular remodeling. While CypA and EMMPRIN have been studied in animal models of acute ischemic and hemorrhagic stroke [1‐4], their potential involvement in CCH as well as in the clinical setting of VaD awaits investigation.

Method

In the first part of the study, the bilateral common carotid artery stenosis (BCAS) model was utilised: microcoils were inserted in both the left and right common carotid arteries for 30 days to induce CCH in male C57BL/6J mice. Sham controls were operated in the same manner without the insertion of microcoils. At the 30‐days endpoint, the animals were euthanized; brain samples were collected and processed for CypA, EMMPRIN, MMP‐2 and MMP‐9 measurement using western blot. In the second part of the study, a cross‐sectional clinical study with 36 non‐cognitive impaired controls and 48 vascular dementia (VaD) subjects was performed. Blood samples were collected, and serum CypA, EMMPRIN, MMP‐2 and MMP‐9 levels were measured using sandwich ELISAs.

Result

Lower CypA and higher EMMPRIN levels were found in the brains of BCAS‐induced mice, and in the serum of VaD patients. While MMP‐2 was higher in BCAS‐inducted mice, MMP‐9 was higher in VaD patients. Interestingly in the clinical cohort, higher MMP‐2 was found in the presence of lacunes while MMP‐9 was higher in the presence of white matter hyperintensities, cortical infarct and lacunae, suggesting that the MMPs may be involved in differential pathways despite both being downstream of the CypA‐EMMPRIN pathway.

Conclusion

The present study demonstrated that the deregulation of CypA, EMMPRIN and MMPs may play an important role during CCH, and thus be useful clinical biomarkers and potential therapeutic targets in VaD.
Prospective memory and depression symptoms in mild cognitive impairment
Authors: Olmos Winter , Moore Jacob , Saravia Sarah , Moreno Jasmin C , Donny Chandler , Baez Abril , Hernandez Juan Pablo , Miller Christopher , Alving Loren , Woo Ellen
Published: December 2021

Background

Prospective memory involves executing an intended action in the future. This cognitive ability declines in mild cognitive impairment (MCI) and Alzheimer’s disease and affects everyday functioning. Prospective memory is usually assessed by asking participants to execute a single action in the future. We developed a complex prospective memory test that involves selecting the correct action to execute based on the context of the situation. In this study, we examined both types of prospective memory and their relationships with depression symptoms. Prospective memory involves significant cognitive effort, which could be dampened by depression symptoms.

Method

Participants included healthy controls (n= 58) and persons with amnestic MCI (n= 28) and non‐amnestic MCI (n= 36). Before testing, all participants were informed that they should request a pill after completing each of 10 neuropsychological tests that would be administered. Simple prospective memory was assessed using the total number of correct requests. They were also told that if the most recent test involved memorization, they should request one pill, and if it did not, they should request two pills. The number of correct contingency‐based requests was used to assess complex prospective memory. The Geriatric Depression Scale (GDS) was used to measure depressive symptoms.

Result

Analyses of variance revealed that the amnestic MCI group performed significantly worse in simple prospective memory compared to both the controls and the non‐amnestic MCI group. The same pattern was found for complex prospective memory. We found that GDS scores did not predict prospective memory in any group.

Conclusion

Overall, we found that older adults with objective memory deficits (amnestic MCI) had difficulties with both simple and complex prospective memory, while those with no memory impairment (controls and non‐amnestic MCI) performed better on these tests. Importantly, depressive symptoms were not associated with performance on prospective memory tests for any of the groups. These findings suggest that prospective memory tests are useful for assessing MCI and are resistant to the impact of depressive symptoms.