bluuebunny/crossref_metadata_2025 huggingface dataset:
Cognitive reserve, brain reserve, and cognitive performance in old age: A population‐based study
Authors: Li Yuanjing , Wang Xiang , Hou Tingting , Song Lin , Wang Mingqi , Zhang Jingwen , Ren Yifei , Shi Lin , Wang Yongxiang , Du Yifeng , Qiu Chengxuan
Published: December 2020

Background

The reserve theory has been proposed to account for the discrepancies between the load of brain pathologies and cognitive phenotypes in aging. We sought to explore the interplay of cognitive reserve and markers of brain reserve and brain lesions in determining cognitive performance in old age.

Methods

This population‐based cross‐sectional study included 215 people (age ≥65 years; 43.7% women; 28.4% illiterate) who were living in the rural communities of Yanggu County, Shandong Province, China. We used the Mini‐Mental State Examination to assess global cognitive function. We evaluated markers of brain reserve and brain lesions from the structural MRI scans, i.e., total intracranial volumes (ICV), deep white‐matter hyperintensity (DWMH) volumes, and cerebral microbleeds (CMBs). We used the structural equation modeling to generate a composite score of cognitive reserve capacity from multiple cognitive‐enhancing factors over the lifespan. We used the general linear regression model and the marginal effect model to disentangle the relations of cognitive reserve and brain reserve markers with MMSE score.

Results

The composite cognitive reserve score ranged from 6.80 to 16.55. Overall, a higher cognitive reserve score was associated with multiple‐adjusted β‐coefficient of 0.04 (95% CI 0.03−0.76) for MMSE score. There was a stronger relationship between cognitive reserve score and MMSE score in people with lower ICV (β=1.16; 95% CI 0.99−2.24) than in those with larger ICV (β=0.44; ‐0.01−0.89, p=0.053). Furthermore, the association of cognitive reserve score with MMSE score was statistically significant in people with severe DWMH load (β=0.84; 95% CI 0.22−1.45) and CMBs (β=1.50; 0.60−2.40), but not in those with mild DWMH load or without CMBs. Compared to people with a higher cognitive reserve score, those with lower cognitive reserve capacity showed stronger correlations of MMSE score with ICV (β=2.66; 95% CI 0.08−5.25) and presence of CMBs (β=‐0.24; ‐0.43−‐0.04).

Conclusion

Higher cognitive reserve is associated with better cognitive performance among rural‐dwelling older adults with limited education, and such association is stronger in people with lower brain reserve. In addition, lower brain reserve is associated with poorer cognitive performance, and such association is stronger among people with lower cognitive reserve capacity.
Restoration of mental and cognitive functions in AD after transcatheter intracerebral photobiomodulation therapy
Authors: Maksimovich Ivan V.
Published: December 2020

Background

The study shows long‐term results of the dynamics of dementia and mental and cognitive disorders in AD treatment with transcatheter intracerebral photobiomadulation therapy (PBMT).

Method

In the long‐term period (2‐10 years), we examined 93 patients aged 34‐80 (average age 67.5), men 32 (34.40%), women 61 (65.59%), who had previously undergone AD treatment.The examination included: determination of CDR, MMSE, cerebral CT, MRI with determination of dementia severity using the Tomography Dementia Rating scale (TDR), SG, rheoencephalography (REG), cerebral MUGA. Before treatment, patients were divided: Test Group ‐ 48 (51.61%) patients: preclinical AD stage (TDR‐0) – 4 patients, early AD stage (TDR‐1) ‐ 16, medium AD stage (TDR‐2) ‐ 21, severe AD stage (TDR‐ 3) ‐ 7 patients ‐ Transcatheter intracerebral PBMT was performed. Control Group ‐ 45 (48.39%) patients: preclinical AD stage (TDR‐0) ‐ 6 patients, early AD stage (TDR‐1) ‐ 13, medium AD stage (TDR‐2) ‐ 15, severe AD stage (TDR‐ 3) ‐ 11 patients ‐ conservative treatment (Memantine or Rivastigmine).

Result

Test Group: all 48 (100%) patients, along with improved microcirculation, showed development of neurogenesis and cerebral regenerative processes, which, depending on AD stage, was accompanied by a 10‐20% increase in cerebral temporal lobes volume. The process was accompanied by dementia decline, cognitive and mental functions restoration. Consequently, the patients were transferred to the lighter stage TDR group. The obtained positive dynamics in patients with TDR‐0 and TDR‐1 stages was observed over 10 years, in TDR‐2 ‐ 4‐5 years, in TDR‐3 ‐ 2‐2.5 years. Control Group: along with the treatment, stabilization of the condition for a period of about 2 years was detected only in patients with early AD stages (TDR‐0, TDR‐1). Further, cerebral involutive changes, dementia, cognitive and mental impairment increased. Patients with later AD stages (TDR‐2, TDR‐3) showed a steady increase in involutive changes, dementia, cognitive and mental impairment.

Conclusion

Transcatheter intracerebral PBMT is an effective AD treatment. The method allows brain revascularization, stimulates neurogenesis and tissue structures restoration. The effect is preserved for long causing dementia regression, cognitive and mental functions restoration.
Synaptic stimulation protects against pathological tau by enhancing lysosomal degradation
Authors: Akwa Yvette , Gondard Elise , Malta Chiara Di , Capetillo‐Zarate Estibaliz , Boiret Anne , Matute Carlos , Vaccari Thomas , Settembre Carmine , Lozano Andres M. , Baulieu Etienne E. , Tampellini Davide
Published: December 2020

Background

Changes in synaptic excitability and reduced brain metabolism are among the earliest alterations associated with the development of Alzheimer’s disease (AD) (Reiman et al., 2004; Sperling et al., 2009). Among different approaches for therapeutics, the stimulation of synaptic activity has been shown to be protective in models of AD, and deep brain stimulation (DBS) provides amelioration in AD patients (Sankar et al., 2015; Swaab and Bao, 2010; Tampellini, 2015). Such positive effects might reflect changes occurring at cellular levels when activity is induced, indicating that brain stimulation might promote cellular mechanisms correcting neuronal and synaptic dysfunctions. We have demonstrated that synaptic stimulation, via DBS or other methods, exerts protection in mouse models of AD and frontotemporal dementia (FTD) by enhancing autophagy, lysosomal degradation of pathologic tau, and protecting synapses (Akwa et al., 2018; Mann et al., 2018). Ongoing investigations are revealing the involvement of TFEB and its downstream genes in the enhancement of lysosomal activity upon stimulation.

Method

Synaptic activity was induced by electrode implantation in the entorhinal cortex of 3xTg mice (Mann et al., 2018). Cultured neurons were prepared from E15 PS19 mouse embryos (Akwa et al., 2018) and stimulated at 14 days in vitro (Ehlers, 2003). RT‐qPCR was performed as described (Napolitano et al., 2018). Confocal immunofluorescence, Western blot and statistical analyses were performed as described (Akwa et al., 2018).

Result

DBS was able to reduce levels of hyperphosphorylated and oligomeric (but not total) tau restoring levels of synaptic proteins back to wild‐type in 3xTg mice. Pathological tau clearance required lysosmal activity, which was enhanced by synaptic stimulation. Trascription factor EB (TFEB) (Sardiello et al., 2009) plays a pivotal role in regulating lysosomal biogenesis and autophagy, and is involved in activity‐driven tau degradation. Indeed, our recent RT‐qPCR data analyses revealed increase expressions of TFEB downstream genes, including ATP6‐V1H and ATP6‐V0D1, in neurons during synaptic stimulation.

Conclusion

The enhancement of lysosomal degradation by the involvement TFEB and related genes demonstrated positive effects of DBS/synaptic stimulation at cellular and molecular level against pathological tau.
Impaired lung function as a risk factor for accelerated brain ageing
Authors: Frenzel Stefan , Bülow Robin , Ewert Ralf , Habes Mohamad , Stubbe Beate , Voelzke Henry , Katharina Wittfeld , Seshadri Sudha , Grabe Hans J.
Published: December 2020

Background

Poor pulmonary health is increasingly recognized as an important risk factor for accelerated brain ageing and the development of dementia. We report on associations of spirometry with MRI‐based volumetry of the brain in the large community‐based Study of Health in Pomerania Trend (SHIP‐Trend).

Method

N=1651 participants of SHIP‐Trend underwent both spirometry and MRI scans of the head. Measurements of forced expiratory volume during first second (FEV1), forced vital capacity (FVC) and relative FEV1 were standardized with respect to age, sex, and body height using the GLI 2012 reference equations. T1‐weighted MRI scans were processed with FreeSurfer 5.3 and total brain volumes (TBV), total gray matter volumes (TGM), total hippocampal volumes (HV) were determined. In addition, we considered the total volume of white matter hyperintensities (WMHV) estimated from T2‐FLAIR images and a recently proposed MRI‐based Alzheimer’s disease index (FSAD). Linear regressions of MRI parameters on standardized FEV1, FVC, and relative FEV1, respectively, were performed. Age, sex, intracranial volume, height, smoking status, and presence of diabetes were added as covariates to each model. Effect sizes were assessed by Cohen’s f2. Analyses were performed using data from young‐aged (≤ 60y), old‐aged (>60y), and all participants, respectively.

Result

FEV1, FVC, and relative FEV1 were significantly positively associated with greater TBV, TGM, and HV in the whole sample. WMHV was significantly negatively associated with FVC and positively associated with relative FEV1. The FSAD index was significantly negatively associated with FEV1, and FVC. Associations with FEV1 and FVC were consistently stronger in old‐aged compared to young‐aged participants. For TBV, HV, WMHV, and FSAD, effect sizes were f2≈0.01. For TGM, effect sizes were f2≈0.05, significantly larger than those of diabetes. No significant associations with relative FEV1 were found in the group of old‐aged participants.

Conclusion

Our results suggest that impaired lung function is a risk factor for atrophy of brain tissue. In old‐aged individuals, this seems to be specifically related to restrictive spirometry patterns (i.e. reductions in FEV1 and FVC but not relative FEV1) but not obstructive ones (i.e. reductions in relative FEV1). This work was supported by the Cognitively Healthy Nonagenarians in the Cross‐Cohort Collaboration Consortium (CCC) grant AG059421.
Chronic exposure to mild therapeutic hypothermia prevents cognitive deterioration and neurodegeneration in a rat model of AD‐like pathology
Authors: Millon Maria Beatriz Bistue , Avila Ramiro , Bruno Martin Alejandro
Published: December 2020

Background

Mechanisms of epigenetic regulation modulate gene expression without alterations in the genomic sequence and play important roles in brain development1, synaptic plasticity and memory2. Epigenetic regulation of gene transcription would be an appropriate mechanism for cells to flexibly adapt to the environmental changes. In this context, lysine specific demethylase 1 (LSD1) is an important enzyme that modifies gene transcription3. Recently, it was reported that LSD1 is essential for the regulation of neuronal gene transcriptional programs involved in synaptic plasticity and cognition2–4. Despite, the well‐known function of LSD1 in early development1,4–6, there is some controversy about the specific role of LSD1 in aging. Upon cold exposure LSD1 regulates Brown adipose tissue function and mediates beige adipogenesis to increase thermogenic capacity and prevent changes in body temperature by inducing non‐shivering thermogenesis7. However, the role of repeat cold exposures on brain LSD1 function has never been studied. We investigated whether chronic repeat cold exposures could modulate the hippocampal expression of LSD1 and its potential impact on neurodegeneration and cognitive functions, using non‐transgenic (non‐tg) and transgenic (tg) AD‐like rat model.

Method

McGill‐R‐Thy1‐APP‐tg rats exhibited accumulation of intraneuronal Aβ peptide, display cognitive deficits and reproduce an AD‐like amyloid pathology. Thus,17 months tg and non‐tg rats were expose under therapeutic hypothermia for 2 hours at 4°C daily during 1 month.

Result

Our results demonstrated how progressive intraneuronal Aβ accumulation correlates with upregulation of LSD1 at early stages (prior plaques formation) of the AD‐like amyloid pathology, which impact on the alteration of cognitive functions. We showed that chronic mild therapeutic hypothermia modulates hippocampal LSD1 levels, improving synaptic plasticity and preventing cognitive dysfunction.

Conclusion

Taken together our work suggests that modulating brain LSD1 levels through repeat cold exposures constitute a novel non‐pharmacological therapeutic strategy to prevent neurodegeneration and preserve cognitive functions. (1) Toffolo E, et al. J Neurochem. 2014; (2) Wang J, et al. Nat Neurosci. 2016; (3) Lim CS, Nam HJ, et al. Sci Rep. 201 7; (4) Rusconi F, et al. Trends Neurosci. 2017; (5) Maes T, et al. Epigenomics. 2015; (6) Ciceri F, et al. Curr Pharm Des. 2017; (7) Marcher AB, et al. Cell Rep. 2015.
Perspectives on dementia and family caregiving among the Oneida Nation of Wisconsin
Authors: Lambrou Nickolas H , Wyman Mary F , Miller Debra A , Thomas Lauren , Strong Lois , Summers Marlene , Lassila Patricia , Petri Florence , Miller Donald , Wheelock Sunshine , Williams Betty , Gleason Carey E , Edwards Dorothy Farrar
Published: December 2020

Background

Recent research indicates that prevalence of dementia amongst American Indian/Alaska Natives (AI/AN) is > 40% higher compared to Asian Americans and ∼18% higher than Whites. Yet, little is known about how AI/AN people conceptualize dementia, caregiving, and dementia care services. This study aimed to deepen understanding and highlight how the Oneida Nation of Wisconsin experiences and makes meaning of dementia, the family caregiver role, and home and community‐based service use.

Method

Tenets of Community‐Based Participatory Research (CBPR) guided study design, recruitment, data collection and analysis. The study team conducted semi‐structured interviews with 22 Oneida Nation of Wisconsin participants. Audio recorded interviews were transcribed to text and coded thematically within and across participant narratives. A mixed‐methods approach was used to identify themes and to quantify participants’ awareness of community dementia services.

Result

Participants were a community sample of 22 Oneida Nation people in Northeastern Wisconsin. Mean participant age was 70.5 years; 16 participants identified as female and 6 as male. Of the entire sample, 77.3% of participants knew someone in the Oneida community with dementia, and 63.6% of participants identified as a caregiver (past or present) for a loved one with dementia, 82% were aware of monthly memory cafes, 43% were familiar with services provided by the dementia care specialist, and 75% were aware of the caregiver support group. Thematic analysis revealed commonalities in experiences of dementia and caregiving, including the value of family and community in caring for elders. Qualitative domains surrounding dementia diagnosis included: (1) Meaning making and stigma around “dementia” (2) The family caregiver experience, and (3) Awareness of and need for home and community based‐services.

Conclusion

Exploratory qualitative and quantitative analysis revealed the nuances of how the Oneida Nation of Wisconsin conceptualizes dementia, the family caregiving role, and community‐based dementia care services. As participants shared their lived experiences with dementia, caregiving, and care resources, themes around community and cultural values emerged. Implications for Native communities, health care practitioners, and future research directions are discussed.
Prevalence of alexithymia and its association with geriatric depression in a sample of elderly persons living in Buenos Aires, Argentina
Authors: Tartaglini María Florencia , Hermida Paula , Feldberg Carolina , Somale Maria Veronica , Caruso Diego , Stefani Dorina
Published: December 2020

Background

Alexithymia has been considered a personality trait characterized by difficulties of identifying and describing feelings, and an externally oriented thinking style. Furthermore, has been descripted as a multidimensional concept sensitive at stressful environment. Moreover, the ageing is a period characterized by physical, affective and economics loses, where alexithymia seems to be a common feature of neurological disease. Objetive: To evaluate the prevalence of Alexithymia and its possible association with geriatric depression in elderly people self‐sufficient.

Method

A simple retrospective, cross sectional, correlational study was conducted. A non‐probability, purposive sampling strategy was used. The sample was comprised of 300 older adults over sixty years old, living in Buenos Aires, Argentina. They were evaluated in individual interviews using the following measures: a socio‐demographic questionnaire (ad hoc), Latin American Consensual Toronto Alexithymia Scale LAC TAS‐20 and Geriatric Depression Scale (V‐15). Measures of central tendency and of dispersion were obtained to describe alexithymia and the Pearson’s “r” correlation coefficient was used to measure the degree of association between alexithymia and geriatric depression. An error probability minor or equal to 0.05 was established. Data were analyzed by SPSS statistical software version 21.0.

Result

The mean age was 71.71 year old (+ 7.34 years) and 76,2% of the participants were women. The prevalence of Alexithymia was 53.1%, and the mean of total score was 45.41 (sd 17.55). The subscales scores were: DIF 14.55 (sd + 7.3), DDF 11.40 (sd + 6.0), EOT 19.45 (sd + 7.3). Furthermore, a moderate positive correlation was found between the alexithymia and geriatric depression (“r”: .369, p: .000).

Conclusion

Detecting alexithymia could be relevant for preserving the wellbeing of elderly people and diagnose diagnosticate affective disorders and neurological diseases.
Therapeutic potential of niacin in Alzheimer's disease
Authors: Moutinho Miguel , Tsai Andy P. , Puntambekar Shweta S , Patel Jheel , Lin Peter B. , Jadhav Vaishnavi , Williams Roxanne Y , Shekhar Anantha , Landreth Gary E.
Published: December 2020

Background

Dietary intake of niacin reduces the risk of Alzheimer's disease (AD) and protects against age‐related cognitive decline. Niacin is a ligand for the niacin receptor HCAR2, which, in the brain, is selectively expressed by microglia. HCAR2 activation has been shown to be neuroprotective in stroke and demyelination models. Therefore, we hypothesized that niacin administration could have beneficial effects in AD pathology.

Method

5 month‐old 5xFAD mice, an animal model of AD, were treated with a FDA‐approved formulation of niacin (Niaspan®) daily, by oral gavage for 30 days with 100 mg niacin/kg. After treatment, the animals were sacrificed and the brains were collected for immunohistochemistry and biochemical analysis. Gene expression and Aβ uptake efficiency were analyzed in primary cultures of microglia incubated with 1.25 nM of Niaspan®.

Result

Our results indicate there is an induction of HCAR2 expression in the AD brain, prominently in activated microglia. Niaspan® treatment significantly reduced Aβ burden and number of compact plaques in 5xFAD brain. Accordingly, Niaspan® induced phagocytic genes and Aβ uptake in primary cultures of microglia. Importantly, Niaspan® exerted a neuroprotective effect evidenced by reduced neuronal loss in the subiculum and cortical layer 5 of Niaspan®‐treated mice, accompanied by a rescue of working memory deficits.

Conclusion

These preliminary data suggest that Niaspan® treatment has neuroprotective effects in AD, even after the onset of severe amyloid pathology, through an induction of Aβ cleareance by microglia. Niaspan® is a FDA‐approved drug, thus there is a translational potential of this strategy into clinical practice, supporting further study of this therapeutic approach.
Plasma‐free amino acid (PFAA) profile is a potential blood‐based biomarker for detection of mild cognitive impairment (MCI)
Authors: Yano Yuki , Sato Wataru , Kasuga Kensaku , Tokutake Takayoshi , Kitamura Hitomi , Kanda Mayuka , Arashida Naoko , Nagao Kenji , Morikawa Fumiyoshi , Toru Shuta , Nishimura Chika , Miyazawa Nobuhiko , Kuroha Yasuko , Kitamura Akihiko , Kaneko Eiji , Yamakado Minoru , Ikeuchi Takeshi
Published: December 2020

Background

Primary prevention of cognitive decline is important while development of disease modifying drugs for early Alzheimer's Disease (AD) is progressing rapidly. As a screening tool for early detection of cognitive decline, blood‐based biomarkers prior to invasive testing such as cerebral spinal fluid examination and positron emission tomography scanning could be beneficial. In our small‐scale pilot study, plasma‐free amino acid (PFAA) profiles of AD patients and mild cognitive impairment (MCI) due to AD were shown to be significantly different from those of cognitively healthy elderly. In order to examine the clinical significance of PFAAs as a novel biomarker, we started an MCI cohort study that enrolls hundreds of MCI subjects to determine practical biomarkers for MCI screening among generally healthy subjects, and to distinguish stable MCI and AD‐converted MCI. The results of interim baseline analysis regarding MCI screening will be presented here.

Method

MCI subjects from 6 medical sites in Japan (MCI, n=117) and age‐gender‐matched community dwellers in 3 different cities in Japan (healthy control, n=117) were included in the current analysis. At baseline visit, plasma samples were collected under fasting condition. The concentrations of PFAAs and plasma amines were analyzed with LC/MS or LC/MS/MS and serum biochemistry tests were done. Observation of the clinical status of MCI subjects for 3 years after the blood collection is ongoing.

Result

Several PFAAs including essential amino acids of MCI subjects were significantly lower than those of healthy control. There were no significant differences in plasma amine concentrations between MCI and control group. In addition, several serum biochemistry parameters including serum albumin of MCI subjects were significantly lower. These differences were independent of age and gender.

Conclusion

Both PFAAs including essential amino acids and serum biochemistry including albumin were shown to be potential biomarkers for MCI screening. The validation of this results will be conducted in another subset in this MCI cohort study. For further investigation, we will conduct multivariable analysis and create the robust algorithm for MCI screening. Also, observation of the clinical status of MCI subjects will continue to distinguish stable MCI and AD‐converted MCI.
The evidence for the effects of physical exercise training on cognitive function for those with mild cognitive impairment
Authors: Cox Kay L , Lautenschlager Nicola T
Published: December 2020

Background

The evidence supporting the view that physical activity (PA) and exercise training in particular aerobic or resistance training improves cognition for those with mild cognitive impairment (MCI) is accumulating. ‘PA’ usually refers to any bodily movement whereas ‘exercise’ refers to planned and/or structured activity which may be aerobic exercise, resistance training or a combination (multimodal) or mind‐body exercise. Systematic reviews and meta‐analyses report inconsistent results, highlighting methodological issues including variations in study design; the type duration and frequency of the exercise utilised; the cognitive outcome and the heterogeneity of the target group. In order to minimise the effects of these issues, in utilising the treatment framework, we limited our summary to focus on the effects of aerobic training and resistance training separately on cognition in participants 60 years and over with MCI.

Method

Several databases were searched to identify systematic reviews or meta‐analyses of RCT’s conducted in the last 5 years evaluating the effects of aerobic or resistance exercise on cognition. Reviews relevant to each regime were summarised to identify the ingredients and dosing parameters.

Results

Five systematic reviews and meta‐analyses reported positive effects of aerobic exercise on global cognition with small to medium effect sizes and one with weak significant benefits on memory. Session duration ranged between 20‐60 minutes, frequency between 2‐5 times/week and intensity between 60‐80% of maximum heart rate. The evidence for resistance training is more limited with 4 recent reviews. Evidence for global cognition with small to moderate effects was strongest with limited effects for executive function. Higher intensity and more frequent sessions appear to be more effective but have low adherence rates. Formats are progressive using one’s own body weight, free weights, dumbbells, resistance bands, weight machines or a combination, supervised with sessions of 60‐75 minutes in duration 2‐3 times/week.

Conclusion

The evidence for an effect of aerobic training on cognition is growing and the evidence for resistance training is promising. Refinement of the treatment specifications for optimal cognitive outcomes requires further investigations of interventions with clearly defined mode, frequency, duration and intensity of exercise and crucial reports of adherence to the treatment.
AAV mediated gene therapy as local treatment modality directed against amyloid beta oligomers in the brain using a high affinity, high specificity antibody
Authors: Blits Bas , Gouwenberg Yvonne , Gebuis Titia , van der Loo Rolinka , van Kesteren Ronald E. , Smit August B. , Preusting Hans , Scheefhals Guus
Published: December 2020

Background

Alzheimer’s disease (AD) is characterized by formation of amyloid beta (AB) plaques in the brain. Intermediate aggregates such as oligomers are considered to be the most toxic. Using AAV gene therapy, we express an antibody specifically directed against these AB oligomers. Local expression in the brain avoids the challenge of inefficient blood brain barrier transfer, and AAV vector administration would be needed only once for a long‐lasting effect. In this project, we are designing and characterizing AAV‐5 based vectors for the development of a gene therapeutic immunotherapy for AD.

Method

AAV‐5 vectors were chosen as safe and effective delivery system for antibody expression and secretion in the brain. To test whether the generated recombinant AAV is functional, primary hippocampal neurons were infected and analyzed for transgene expression. Oligomer‐binding functionality of the expressed antibody was analyzed using ELISA. Moreover, AAV vectors were administered in vivo, either directly into the hippocampus or intracerebroventricular of wild type mice.

Result

Recombinant AAV‐5 particles were able to infect and transduce primary hippocampal neurons. Western blot analysis revealed presence of antibody both in cell homogenate and secreted in medium. Functionality of the antibody was demonstrated by binding AB oligomers in an ELISA. In vivo, both routes of administration resulted in transduction patterns that could well be used to target an AD diseased brain.

Conclusion

Recombinant AAV‐5 vector encoding for the antibody is tested positive in vitro and in vivo, suggesting that the antibody can be expressed and secreted in the brain to target AB oligomers at the site where it is needed. Future studies should reveal whether native AB oligomers are also recognized and efficiently neutralized in an appropriate mouse model of AD resulting in enhanced cognitive performance.
Subtypes of Alzheimer’s disease and the ATN biomarker scheme
Authors: Cedres Nira , Ekman Urban , Ferreira Daniel , Westman Eric
Published: December 2020

Background

Understanding the association between two popular classification schemes: AD subtypes (based on patterns of brain atrophy) and the ATN (based on dichotomous categories of amyloid‐beta deposition (A), tauopathy (T) and neurodegeneration (N)) might increase our current understanding of the neurobiological heterogeneity within AD. We aimed to evaluate the association between the AD subtypes based on brain atrophy patterns and the ATN scheme, in the context of other relevant disease measures such as a marker of small vessel disease (white matter changes, WMC) and the source of the patients: ADNI vs. a memory clinic (KIDS).

Methods

AD patients from two large cohorts were investigated: Alzheimer’s Disease Neuroimaging Initiative (ADNI) and Karolinska Imaging Dementia Study (KIDS). The ATN categories were entirely based on cerebrospinal fluid (CSF) biomarkers, and the subtypes on atrophy patterns were based on visual ratings from magnetic resonance imaging. Clustering analysis was used to further investigate associations with demographic and clinical factors.

Results

The clustering analysis showed different distributions of ATN profiles and brain atrophy patterns in ADNI as compared with KIDS. Typical AD was the most frequent AD subtype in both cohorts, while limbic‐predominant and minimal atrophy AD were more frequent in KIDS than in ADNI. The A+T+N‐ profile was more frequent in ADNI, while A+T‐N+ and A+T‐N‐ profiles were more frequent in KIDS. The distribution of AD subtypes was associated with age in ADNI while in KIDS, it was also associated with MMSE as a measure of global cognition.

Conclusions

The distribution of and association between AD subtypes and ATN profiles depends on the source of the patients, aligning with different demographic and clinical characteristics depending on whether the cohort is more selective (ADNI) or more naturalistic and heterogeneous (KIDS). In ADNI we found a distribution of ATN profiles that seems to mainly reflect AD staging (i.e. A+T‐N‐, A+T+N‐, and A+T+N+). In KIDS, which is a heterogeneous memory clinic cohort, the ATN distribution seem to be determined by very early disease stages, either more “pure” (i.e. A+T‐N‐) or also including comorbidities contributing to unspecific neurodegeneration in the absence of a T+ biomarker (i.e. A+T‐N+).
Impact of the disclosure of amyloid‐PET results to patients with subjective cognitive decline: the AMYPAD Diagnostic and Patient Management Study (DPMS)
Authors: Poitrine Léa , Altomare Daniele , Moro Christian , Collij Lyduine , Alves Isadora Lopes , Barkhof Frederik , Saint‐Aubert Laure , Delrieu Julien , Jessen Frank , Félez‐Sánchez Marta , Lee Lean , Walker Zuzana , Démonet Jean‐François , Nordberg Agneta K , Gismondi Rossella , Farrar Gill , Stephens Andrew W , Molinuevo Jose Luis , Frisoni Giovanni B , Wuthrich Sonia Plaza , Escher Claus , Lee Ho‐Yun , Scheltens Philip
Published: December 2020

Background

Amyloid‐PET is increasingly used for diagnostic purposes in patients with cognitive impairment due to suspected Alzheimer’s disease. However, cognitively unimpaired individuals are frequently included in research studies involving amyloid‐PET scan. Even if amyloid‐PET is not clinically recommended in these cases, these patients often want to know their amyloid status, a strong risk factor for incident dementia. Currently, evidence on the impact of the disclosure of amyloid‐PET results on patients’ psychological well‐being is scanty. The aim of this sub‐study is to assess how a positive amyloid‐PET result affects the psychological well‐being of patients with subjective cognitive decline plus (SCD+) enrolled in a prospective study on the diagnostic utility of amyloid PET (AMYPAD‐DPMS).

Method

The impact of the disclosure of amyloid‐PET results on patient’s psychological well‐being was investigated using the Impact of Event Scale–Revised (IES‐R). IES‐R is used to detect potential changes from the current time point and a previous time point preceding up to 7 days an event (the amyloid‐PET result disclosure in this case). IES‐R was administered 1‐3 days post‐disclosure, and consists of one total score (0‐88) and three sub‐scores (0‐4): avoidance (avoidance of thoughts, feelings, memories or situations), intrusions (intrusive memories, thoughts, or feelings causing distress), and hyperarousal (hypervigilance, feeling watchful and on guard, difficulty concentrating). IES‐R total score between 12‐32: symptoms of post‐traumatic stress, patient monitoring is required; ≥33: probable presence of a post‐traumatic stress disorder.

Result

So far, 36 SCD+ participants of AMYPAD‐DPMS, who received their amyloid‐PET results, have accepted to participate in this sub‐study. Amyloid‐positive patients (n=9) had higher IES‐R total score (median=10, lower‐upper quartiles=1‐14) than amyloid‐negatives (1, 0‐6), albeit at trend level (p=0.052). We also observed higher avoidance scores in amyloid‐positives compared to amyloid‐negatives (0, 0.00‐0.62 vs. 0, 0.00‐0.00, p=0.004), but no differences in the other two sub‐scores (p>0.05).

Conclusion

These preliminary data on 36 participants suggests that the disclosure of positive amyloid scan to an SCD+ patient is associated with the avoidance of thoughts and memories of the news. Future analyses will address additional outcome measures (e.g. post‐disclosure anxiety and depression) and factors associated with a milder psychological impact in amyloid‐positive patients.
Astrocyte cholesterol is essential for amyloid beta production
Authors: Kulas Joshua A. , Wang Hao , Hansen Scott B. , Ferris Heather A.
Published: December 2020

Background

Several variants of genes involved in cholesterol metabolism are risk factors for the development of Alzheimer’s disease (AD). We disrupted the master regulator of cellular cholesterol metabolism, SREBP2, and assessed the impacts of this disruption in neuron‐glia primary cell co‐cultures and in the 3xTg mouse model of AD.

Method

Glial SREBP2 ablation was induced in neuron‐glia cultures by treatment of Aldh1l1‐CREERT2xSREBP2flox mixed primary cell cultures with 4OH tamoxifen. Amyloid precursor protein (APP) trafficking to lipid raft domains was quantified by dSTORM imaging. SREBP2 was ablated in the brains of 3xTg AD mice by crossing to an SREBP2‐flox and then a GFAP‐CRE. Aged (40 week old) mouse brains were then assessed for Aβ and pTau burden by ELISA.

Result

Disruption of glial SREBP2 was sufficient to significantly alter localization of APP from α‐secretase rich disordered membrane regions to β‐ and γ‐secretase enriched lipid raft domains (Figure A). In 3xTg‐AD animals, SREBP2 ablation did not alter total levels of APP or Tau, but significantly reduced both Aβ 1‐42 peptide burden and P‐T181 Tau abundance in 40‐week hippocampus (Figure B).

Conclusion

Disruption of astrocyte‐mediated cholesterol metabolism is sufficient to robustly reduce Aβ and pTau burden in a mouse model of AD, which likely occurs in part through reduced APP localization to lipid rafts.
Long‐term exposure to ambient air pollution and risk of dementia: Results of the prospective Three‐City Study
Authors: Mortamais Marion , Gutierrez Laure Anne , de Hoogh Kees , Benmarhnia Tarik , Helmer Catherine , Tzourio Christophe , Dartigues Jean‐François , Letellier Noemie , Jacquemin Benedicte , Berr Claudine
Published: December 2020

Background

Chronic exposure to air pollution (AP) is associated with cardiovascular morbidity and mortality. Emerging epidemiological evidence suggests a relationship between exposure to various air pollutants (fine particulate matter (PM2.5), ozone (O3), and nitrogen dioxide (NO2)) and dementia. However, most of existing studies relied on population‐based health administrative databases to obtain a dementia diagnosis. In a large French population‐based cohort (the Three‐City Study) and using state‐of‐the‐art models for AP exposure, we aimed at assessing the effects of different air pollutants on dementia risk using reliable diagnosis tools.

Methods

Participants aged ≥65 years were recruited between 1999 and 2001 and followed for 12 years. At baseline and every 2 years, dementia diagnoses were preliminary made using DSM‐IV criteria and validated by an adjudication committee. Levels of NO2, O3, Black Carbon and PM2.5 were obtained at the residential addresses of participants using land‐use regression models developed for Europe in the ELAPSE project (de Hoogh et al., Env Int 120 (2018) 81‐92). For each year of follow‐up, we estimated for each subject a 10‐year moving window of mean past exposure to each pollutant. We used a Cox Proportional Hazard model where exposure to AP was included as a time‐varying variable. Analyses were adjusted for individual (age, sex, education, APOE4 genotype, vascular risk factors, depression, respiratory diseases) and contextual (neighborhood’s deprivation index) level confounders.

Result

At baseline, the mean (SD) age of the 7956 participants was 73.2 (5.4) years‐old. Sixty‐one percent of them were women. The mean time of follow‐up was 9.2 (3.6) years. Over the follow‐up period, the mean annual PM2.5 levels ranged from 15 to 33 µg/m3 and 910 participants developed dementia. We observed a positive association between levels of PM2.5 and dementia risk [HR=1.16, 95%CI (1.02‐1.32) for a 5µg/m3 increase in PM2.5]. We did not observe any relationship between exposure to the other air pollutants and dementia risk.

Conclusion

In this large cohort with reliable diagnosis of dementia and individual estimates of AP exposure, we observed that long‐term exposure to PM2.5 was associated with higher dementia incidence. These results suggest that PM2.5 exposure might be a modifiable risk factor of dementia.
Creating a patient‐centered guide to navigating cognitive change in Parkinson’s disease
Authors: Dolhun Rachel , Amodeo Katherine , Goldman Jennifer , Ruhlin Susan , Butler Ava , Iverson Dave
Published: December 2020

Background

The Michael J. Fox Foundation for Parkinson’s Research (MJFF) regularly gathers feedback from patients and families about their experiences with Parkinson’s disease (PD). We often hear that cognitive changes are among the most feared and troublesome symptoms. Participants in Fox Insight, MJFF’s online observational study, reported cognition as their third most bothersome symptom1 and in an informal survey of 797 webinar attendees, more than 40 percent said cognitive changes always or often affect daily life, confirming known research.2 Mild cognitive impairment affects 25 percent3,4 and dementia impacts 40 percent5 of people with Parkinson’s. Yet honest, relatable, actionable information on this topic is lacking. To fill this information gap, MJFF’s on‐staff movement disorder specialist facilitated question‐driven discussion with three groups: 1. Providers — four movement and cognitive specialists; 2. Patients — 23 people with PD; 3. Care partners — two social workers and seven care partners of people with Alzheimer’s disease or Lewy body dementia. Care partners also completed a 17‐item questionnaire. Sessions focused on understanding how participants think and talk about cognitive changes as well as what patients and care partners want to know about cognitive changes and how to manage them. Patients and families want early, honest information so they can be proactive and plan. Clinicians recognize the need to mitigate fear and denial and to address cognitive changes in compassionate, reassuring and useful ways. We used these insights to create accessible, practical resources including a 35‐page guide, a webinar and a video. These materials offer information on how thinking and memory can change in Parkinson’s, tips and treatments to promote brain health and ease cognitive symptoms, strategies for talking with loved ones and providers about cognitive changes, and connections with the latest research. Demonstrating the urgent need for this information, the guide and associated materials have been downloaded over 325,000 times in less than four months and over 3,400 people attended the webinar. MJFF’s resources convey a sensitive topic in a relatable and empathic manner to decrease fear and stigma, stimulate discussion, promote research participation, and help patients and families maintain quality of life with cognitive changes.
Reliability assessment of tissue classification algorithms for multi‐center and multi‐scanner data
Authors: Dadar Mahsa , Duchesne Simon
Published: December 2020

Background

Gray and white matter volumes are important imaging markers of pathology and disease progression. Such measures are usually estimated from tissue segmentation maps produced by image processing pipelines. However, the reliability of the produced segmentations when using multi‐center and multi‐scanner data remains understudied. Here, we assess the robustness of six publicly available tissue classification pipelines across images acquired from different scanners models and sites.

Method

Data included 90 T1‐weighted images of a single individual, scanned in 73 sessions across 27 sites (Duchesne et al., 2019). An average T1‐weighted image template was created out of all scans (Fonov et al., 2009). For each algorithm, their respective segmentation masks on this template was used as a silver standard (Figure 1). Dice Kappa similarity scores between these silver standards and individual segmentations and variability in tissue volumes across segmentations were assessed for Atropos (Avants et al., 2011); BISON (Dadar and Collins, 2019); Classify_Clean (Cocosco et al., 2003); FAST5.0 (Zhang et al., 2001); FreeSurfer6.0.0 (Fischl, 2012); and SPM12 (Penny et al., 2011). We also estimated the sample size necessary to detect a significant 1% volume reduction based on the variability of the estimates from each method within and across scanner models (80% power, 2‐tailed significance).

Result

Across tissue types, BISON had the lowest overall variability in Dice Kappa, followed by SPM12 (Figure 2). For GM, BISON had the highest overall Dice Kappa (0.94±0.01), followed by SPM12 (0.93±0.01) and Atropos (0.92±0.03); while Atropos had the highest overall Dice Kappa for WM (0.94±0.02), followed by BISON (0.93±0.01) and SPM12 (0.93±0.01). BISON had the lowest overall variability in its volumetric estimates (GM:57.60±0.4, WM:34.49±0.4, CSF:7.90±0.3), followed by FreeSurfer (GM: 49.80±0.7, WM: 39.52±0.8, CSF: 10.71±1.2), and SPM12 (GM:57.76±1.3, WM:33.08±1.1, CSF:9.12±0.9, Figure 3). BISON also had the smallest sample size requirement across all scanners and tissue types, followed by FreeSurfer, and SPM12 (Table 1). As expected, the necessary sample sizes decreased when using data from a specific scanner.

Conclusion

Our comparisons provide a benchmark on the reliability of currently used tissue classification techniques and the amount of variability that can be expected when using large multi‐center and multi‐scanner databases.
Degradation of amyloid beta by multi‐copper oxidases
Authors: Ran Chongzhao , Yang Jing , Ran Kathleen , Lu Ying
Published: December 2020

Background

The accumulation of amyloid beta (Aβ) species has been widely considered to be one of the possible causes of the pathology of Alzheimer’s disease (AD). Inhibiting Aβ production to prevent the accumulation and aggregation has been intensively investigated. However, the degradation of Aβ, which can also reduce the accumulation, has received much less attentions.

Method

In this study, we used FAM‐Aβ42, a fluorescent dye conjugated Aβ, to investigate the degradation of Aβ in the presence of various multi‐copper oxidases.

Result

We first discovered that ceruloplasmin (CP), the major copper‐carrying protein in the blood, could degrade Aβs. We then validated the CP‐Aβ interaction using total internal reflection fluorescence (TIRF) microscopy, fluorescence photometer and fluorescence polarization measurement. We further found that the presence of Vitamin C could enhance the degrading effect in a concentration‐dependent manner. Based on the above discovery, we hypothesized that other multi‐copper oxidases (MCO) had similar Aβ‐degrading function. Indeed, we found that other MCOs could induce Aβ cleavage. Remarkably, we revealed that ascorbate oxidase (AO) had the strongest degrading effect amony the tested MCOs. Using iPS‐induced neuron cells, we observed that AO could rescue cell apoptosis and neuron toxicity which induced by Aβ oligmers. In addition, our electrophysiological analysis with brain slides suggested that AO could prevent an Aβ induced deficit in synaptic transmission in the hippocampus.

Conclusion

To the best of our knowledge, our report is the first to demonstrate that MCOs could bind to Aβs and mediate cleavage of Aβs. Further investigations are warranted to explore the possible benefits of the Aβ‐degrading function of MCOs.
Multilayer OMICS characterization of APOE‐modulated isogenic hiPSCs elucidates cell‐type–specific mechanisms modified by APOE: A study of the IMI ADAPTED Consortium
Authors: Ried Janina S. , Curado Marco Rocha , Sáez María Eugenia , Bahnassawy Lamiaa , Lee Heyne , Reinhardt Peter , Mohler Eric G. , Madrid Laura , Socorro Alfredo Cabrera , Grezella Clara , Nicolas Armel , Rao Francesco , Ramaswamy Gayathri , Bakker Margot H.M.
Published: December 2020

Background

Alzheimer’s Disease (AD) is the most common cause of dementia in the elderly and affects over 35 million people worldwide, imposing increasing social and economic burden as the population ages. While it is widely known that the most prominent genetic risk factor for AD is the presence of the Apolipoprotein E (APOE) ε4 allele, the effects of APOE in the development of AD is still poorly understood. As part of the IMI ADAPTED consortium, we aim to clarify the role of APOE as a risk factor in the development of AD. Here we present an in‐depth analysis of the effect of the APOE genotype on the transcriptome of brain cells derived from human‐induced pluripotent stem cells (hiPSCs).

Method

Isogenic hiPSC lines were modified to carry different APOE genotypes: ε3/ε3, ε4/ε4, ε3/ε4, ε2/ε2, as well as an APOE knock‐out (KO) cell line. Lines carrying each of these genotypes were differentiated into distinct cell types. Differential gene expression (DGE) and protein expression (DPE) was calculated, followed by gene set enrichment. Clustering approaches were used to identify shared and differing gene signatures across genotypes. We further applied upstream regulator and network analysis on the individual cell‐type results and integrated these results across cell types. The results were compared with DGE and DEP results from an APOE mouse model. Finally, the identified genes and mechanisms were combined with the results of data from postmortem human brain samples of AD cases and controls.

Results

The observed transcriptional changes confirmed phenotypic observations made for the hiPSCs and refined the insight of genes identified human brain OMICS data. Several genes and pathways were identified, which showed consistent gene expression on transcriptome and proteome level. Further, shared patterns of expressions of genes across genotypes and potential mechanisms involved in this were detected.

Conclusions

In depth transcriptomics and proteomics analysis of APOE modified hiPSCs enabled to study cell type specific effects and contributed with this to the understanding of mechanisms affected by different APOE genotypes.