bluuebunny/crossref_metadata_2025 huggingface dataset:
Electrophysiological effects of mitochondria‐derived extracellular vesicles: implications for memory dysfunction in neurodegenerative disorders
Authors: D'Acunzo Pasquale , Argyrousi Elentina K , Ungania Jonathan M. , Kim Yohan , DeRosa Steven , Pawlik Monika , Goulbourne Chris N. , Arancio Ottavio , Levy Efrat
Published: December 2023

Background

Mitovesicles are a newly identified subtype of small extracellular vesicles (EVs) of mitochondrial origin. We recently developed a method to separate mitovesicles from other EVs after their isolation from the extracellular space of murine and human brain tissues. This method permits the study of the roles of mitovesicles in physiology and disease.

Given their origin, we hypothesized that mitochondrial dysfunction, a hallmark of both Alzheimer’s disease (AD) and Down syndrome (DS), could induce alterations in mitovesicles, thus perturbing brain homeostasis and contributing to propagation of pathology. Therefore, we studied mitovesicle components and functionality after their isolation from the brain of a mouse model of DS (hereafter Ts2) as compared to diploid (2N) controls, as well as from frontal cortices of individuals with DS as compared to their age‐matched 2N controls.

Method

Brain mitovesicles were isolated and analyzed by Western blotting, electron microscopy, nanotrack analysis, and monoamine neurotransmitter degradation assay as recently described (D’Acunzo, et al., 2022, PMID: 35962195). Coronal hippocampal slices from wild‐type mice were perfused with different subtypes of brain EVs, pretreated or not with clorgiline and pargyline (1 μM each), irreversible inhibitors of the monoamine oxidases type A and B (MAO‐A and MAO‐B), respectively. Long‐term potentiation (LTP) was induced at the level of the Schaeffer collateral fibers through a theta‐burst stimulation (Fà, et al., 2014, PMID: 24643165).

Result

Mitovesicle number is higher in brains of DS individuals and of Ts2 mice and contain a higher MAO‐B protein amount and enzymatic activity as compared to diploid controls, suggesting a potential mitovesicle‐dependent impairment of neuroamine homeostasis in DS. In agreement with that, Ts2 (but not 2N) mitovesicles stimulated a decreased LTP in recipient hippocampal slices as compared to vehicle control (Fig. 1; mtVs: mitovesicles). This biological activity was abolished when MAO‐B (but not MAO‐A) was blocked. The other EV subtypes of both genotypes, microvesicles and exosomes, did not trigger an effect on LTP. DS changes were found to be sex independent.

Conclusion

Pathogenic mitovesicles are previously undescribed active players of the brain extracellular milieu by regulating LTP via MAO‐B, and potentially contribute to memory formation deficiencies typically found in AD and DS.
Evolution of language abilities over the course of the disease in a large cohort of patients with lvPPA: More than a repetition impairment
Authors: Lavoie Monica , Tastevin Maud , Sablonnière Justine De La , Poulin Elizabeth , Carrier‐Auclair Julie , Laforce Robert
Published: December 2023

Background

Initial language impairment in lvPPA causes naming and repetition difficulties along with phonological errors (Gorno‐Tempini et al., 2011). Little is known about the evolution of other language capacities with disease progression. This study aimed at exploring the full range of language impairments throughout the course of the disease, from onset to death.

Method

We performed a retrospective chart review on a large cohort of deceased lvPPA patients (n = 38; 18 M, 19 F; Mean age at onset = 69 years old). Presence or absence of impairment in various language abilities was determined via consensus by three experienced raters at 5 time points from onset to death.

Result

All 38 patients developed anomia, repetition impairment and writing difficulties throughout disease course (Figure 1). The overall prevalence of reading difficulties was also high (Figure 1), with impairment appearing more than two years post‐onset in most cases (Figure 2). Comprehension deficits were highly prevalent, appearing mostly in the first two years post onset (Figure 2). More than 75% of patients showed grammar difficulties (Figure 1), mainly in later stages of the disease (Figure 2). Semantic deficits also appeared later (Figure 2). Finally, apraxia of speech was quite infrequent (Figure 1).

Conclusion

In addition to known language deficits in lvPPA (i.e., naming, repetition, reading and writing, see Brambati et al., 2009; Faria et al., 2013; Gorno‐Tempini et al., 2011; Sepelyak et al., 2011), our results suggest early impairments in comprehension as well as late grammar difficulties. To our knowledge, this is the first study which addresses the full range of language impairments in lvPPA over the entire course of the disease. We believe this is highly relevant for patients/families to better prepare for the future, as well as therapists to design more focused interventions.
The risk of sleep‐related cognitive impairment increases in middle‐age to older adulthood
Authors: Kim Hyun , Cohen Daniel E. , Levine Alina , Tucker Aren , Devanand Davangere P. , Lee Seonjoo , Goldberg Terry E.
Published: December 2023

Background

The association between sleep quality and cognition is widely established but the role of aging in this relationship has been unclear due to inconsistent findings with heterogeneous methods and a lack of studies in wide age ranges. The current study examined how age impacts the sleep‐cognition relationship using a large‐scale dataset with adults from young adulthood to older adulthood. Furthermore, we tested non‐linear effect of age to investigate the presence of age ranges in which the association between sleep and cognition is modified.

Method

Sample included 711 individuals (ages 36.00‐89.83, 59.66 ± 14.91, 55.7% female) from the Human Connectome Project‐Aging (HCP‐A). Sleep quality was measured using the Pittsburgh Sleep Quality Index (PSQI), and cognitive outcome measures included the NIH Toolbox fluid cognition (Dimensional change Card Sort Test, List Sorting Working Memory Test, Picture Sequence Memory Test, Pattern comparison Processing Speed Test, Flanker Inhibitory Control and Attention Test) and crystallized cognition composite scores (Oral Reading Recognition Test and Picture Vocabulary Test), the Trail Making Test (TMT) A and B, and the Rey Auditory Verbal Learning Test (RAVLT). The association between sleep quality and cognitive performance was measured using linear regression models, with sex, race, use of sleep medication, and years of education as covariates. Age moderation was tested via the interaction between sleep and age on cognition, with age as linear and non‐linear (quadratic) terms.

Result

There was a significant interaction term between the PSQI and non‐linear age term (age2) on TMT‐B (p = 0.02) and NIH Toolbox crystallized cognition (p = 0.02), indicating that the association between poor sleep quality and cognitive performance was moderated by age. Further analyses indicated that there were “critical age ranges” in which the sleep‐cognition association was more salient (ages 50‐75 for TMT‐B and 66‐70 for crystallized cognition).

Conclusion

The association between sleep quality and cognitive performance may be modified by age. Individuals of the middle‐age to early older adulthood may be more vulnerable to sleep‐related cognitive impairment, indicating the clinical importance of detection and treatment of sleep disturbance in this particular age group.
Loss of Fatty Acid Degradation by Astrocytic Mitochondria as a Mechanism of Neuroinflammation and Neurodegeneration
Authors: Mi Yashi , Qi Guoyuan , Vitali Francesca , Shang Yuan , Raikes Adam C. , Wang Tian , Jin Yan , Brinton Roberta Diaz , Gu Haiwei , Yin Fei
Published: December 2023

Background

Astrocytes provide key neuronal support, and their phenotypic transformation is strongly implicated in neurodegenerative disorders including Alzheimer’s disease (AD). Metabolically, astrocytes possess modest mitochondrial oxidative phosphorylation (OxPhos) activity, yet the pathological role of astrocytic OxPhos in neurodegeneration remains to be defined.

Method

We generated the TfamAKO mice, in which the transcription factor A mitochondrial (Tfam) is deleted selectively in astrocytes. Behavioral, electrophysiological, immunostaining, transcriptomics, metabolomics, and magnetic resonance imaging analyses were employed to characterize AD‐relevant phenotypes of TfamAKO mice, which were further compared to an AD mouse model (5xFAD). Primary cell cultures and co‐cultures were used to determine the cell autonomous and non‐autonomous mechanisms by which disrupted astrocytic OxPhos induces astrocyte reactivity, neuroinflammation and neurodegeneration.

Result

Here we show that the brain critically depends on astrocytic OxPhos to degrade fatty acids (FAs) and maintain lipid homeostasis. Aberrant astrocytic OxPhos induces lipid droplet (LD) accumulation followed by neurodegeneration that recapitulates key features of AD including reactive astrogliosis, synaptic loss, microgliosis, demyelination, and cognitive impairment. Mechanistically, when FA load overwhelms astrocytic OxPhos capacity, elevated acetyl‐CoA levels induce astrocyte reactivity by enhancing STAT3 acetylation and activation. Intercellularly, lipid‐laden reactive astrocytes stimulate neuronal FA oxidation and oxidative stress, activate microglia via IL‐3 signaling, and inhibit the biosynthesis of FAs and phospholipids required for myelin replenishment. Moreover, the metabolic and transcriptional signatures of the hippocampus of TfamAKO mice highly overlap with that of 5xFAD mice.

Conclusion

We reveal a lipid‐centric, AD‐resembling mechanism by which astrocytic mitochondrial dysfunction progressively induces neuroinflammation and neurodegeneration.
Evaluating aperiodic components of the spontaneous magnetoencephalograpic activity along AD continuum
Authors: Quivira‐Lopesino Adrián , Blazquez Guillermo , Maest Fernando , Cuesta Pablo
Published: December 2023

Background

The increase in life expectancy has resulted in a greater number of people developing disorders associated with aging such as Alzheimer’s disease. Mild Cognitive Impairment (MCI) is a prodromal stage that has been commonly assessed with the aim of finding biomarkers associated with the dementia progression. Previous literature has stated that MCI patients suffer a slowness of the basal oscillatory brain electrophysiological activity when compared to healthy controls. This slowness, reported with EEG and MEG, is mainly characterized by a diminished alpha power and enhanced theta and delta power. These results have been found when assessing the periodic component of the brain oscillations (i.e. evaluating the spectral power), whereas the aperiodic component has usually been ignored. Recently, researchers from UCSD have developed a toolbox (FOOOF) able to assess the aperiodic component of the spectral power, by computing the exponent of the 1/f‐like activity. This exponent is an aperiodic component that has been related to the integration of the underlying synaptic currents. Under this hypothesis, the exponent will be lower (flatter spectra) when the excitation‐inhibition (E/I) balance would reflect a higher excitation relative to inhibition, whereas the exponent will be higher (steeper spectra) when the E/I balance would reflect a higher inhibition relative to excitation.

Method

In this study, using a preexisting eyes closed resting state MEG database, we have assessed differences in the aperiodic exponent between healthy (N = 195) and MCI‐diagnosed (N = 79) individuals. To this end, we computed at the sources’ space (using a LCMV beamformer with a 1 cm spacing grid at MNI space) the exponent of the spectral power, and then performed a set of between groups statistics (ANCOVA with age as covariate) with a cluster‐based permutations methodology.

Result

In our results we observed an increased aperiodic exponent in the precuneus cortex of the individuals with MCI when compared to healthy participants.

Conclusion

This result would be indicating a decreased E/I balance, hypothetically due to an increased inhibition. Further investigation will be needed to clarify the relevance and implications of these results.
Fully automatic deep‐learning based segmentation of Hippocampal subfields from standard resolution T1W MRI in Alzheimer’s Disease
Authors: Joules Richard , Wolz Robin
Published: December 2023

Background

Hippocampal subfield volumes are of interest in Alzheimer’s disease (AD) as sub‐regions are affected at different points in the disease trajectory and may provide increased sensitivity as biomarkers compared to the whole hippocampus alone. Subfield volume estimation typically requires a high‐resolution T2‐weighted MRI to ensure accurate anatomical parcellation; however, this increases scan times and may not be present in historical datasets. Automatic methods exist for subfield segmentation from mono‐modal standard resolution T1W MRI, with deep‐learning approaches providing the most promising results to date. Here we extend such work employing deep learning approaches to provide flexible hippocampal subfield segmentation of standard resolution (1mm3) T1W MRI.

Method

We trained a collection of deep‐learning segmentation models to perform binary segmentation of the CA1‐3, CA4/DG, Subiculum, and whole Hippocampus, using a publicly available dataset of 25 subjects with manually segmented region labels on T1 MRI (1mm3). Multilabel segmentations were generated from combination of segmentation outputs.

Result

Total hippocampal and subfield multi‐label segmentations were generated for all test subjects in each cross validated loop and DICE overlap with the ground truth label computed. Preliminary results, computed using a 5‐fold cross validation, report mean DICE in whole Hippocampus = 0.904(std: 0.014), CA1‐3 = 0.842(std:0.019), CA4/DG = 0.767(std:0.04), and Subiculum = 0.791(std:0.033).

Segmentation models were applied to 947 subjects with standard T1 MRI from the ADNI cohort and either a CN or MCI label. Subjects were selected with pre‐existing hippocampal subfield volumes, provided by ADNI, computed with the ASHS method using a multi‐modal T1 and hi‐res T2 MRI image. While the proposed method and ASHS employ subtly different parcellation schema we note significant correlation across similar regions between methods.

Logistic regression of ICV corrected volumes and MMSE, correcting for age and sex, reveal both ASHS and the proposed method can significantly discriminate between CN and MCI groups (Table 1), with subfields areas providing greater discrimination that of the whole hippocampus.

Conclusion

Here we present preliminary results for a flexible deep‐learning approach to segmentation of hippocampal subfields from standard resolution T1 MRI alone; indicating comparable performance for group discrimination to an established multi‐modal standard.
Mendelian randomization study using paired SNPs as instruments supports casual protective effect of overweight on Alzheimer’s disease
Authors: Duan Hongzhe , Holmes Rachel , Arbeev Konstantin , Wu Deqing , Yashin Anatoliy I , Ukraintseva Svetlana
Published: December 2023

Background

Mendelian Randomization (MR) is a powerful method of detecting causal effects in observational studies. However, choosing an appropriate SNP as an instrumental variable (IVar) is challenging because of difficulties in satisfying all assumption criteria. We proposed a novel strategy of creating IVar using paired SNPs between genes of interest, and tested this strategy in MR study examining causal relationships between being overweight and onset of Alzheimer’s disease (AD).

Method

We performed MR in the Health and Retirement Study (HRS) subsample of participants aged 75+, using the following binary variables: (1) ‘overweight’ BMI 25‐30 vs. (0) ‘normal’ BMI 18.5‐25, at ages 65‐75, as exposure; and (1) no AD vs. (0) AD onset at ages 75+, as outcome. We found significant association between ‘overweight’ BMI and lower odds of AD in logistic regression, and used MR to test causality. For IVar, we selected eight obesity‐related genes from the literature (ADIPOQ, FTO, LEP, LEPR, INSIG2, MC4R, PCSK1, PPARG), cross‐paired their SNPs, and used counts of minor alleles of the paired SNPs to create new ‘composite SNP’s. Analyses were stratified by sex and race, and non‐stratified. Initial models were estimated in SAS. Resulting summary statistics were used in R‐package MendelianRandomization. F‐value>10 criteria was applied to ensure the IVar strength. The causal effect was evaluated using weighted median, Inverse‐Variance Weighted (IVW), and maximum likelihood (ML).

Result

Being overweight at ages 65‐75 had significant causal protective effect on AD onset after age 75 in White females (logistic regression: OR = 1.99 [higher odds for ‘overweight’ individuals to be in ‘no AD’ group], p‐value = 8.26E‐5; MR: number of instrument ‘SNP’s = 13, weighted median causal estimate = 1.27, p‐value = 1.91E‐5; IVW causal estimate = 1.14, p‐value = 2.30E‐08; ML causal estimate = 1.20, p‐value = 7.67E‐7). No causal effects were detected using single SNPs in the same genes.

Conclusion

The proposed novel strategy of creating IVar for MR analysis, based on pairing SNPs between candidate genes, substantially improves the critical step of MR analysis: choosing efficient instrument SNPs. We successfully tested this new strategy in HRS data, and confirmed causal relationship between BMI and AD, specifically, significant causal protective effect of being overweight on AD onset later in life in white females.
Proteomic‐based Biological Aging Clock and MRI Markers of Cerebrovascular Disease: Atherosclerosis Risk in Community Study
Authors: Sedaghat Sanaz , Wang Shuo , Liu Jialing , Hughes Tim M. , Sabayan Behnam , Tang Weihong , Coresh Josef , Pankow James , Walker Keenan A. , Lutsey Pamela L. , Guan Weihua , Prizment Anna
Published: December 2023

Background

Biological aging state can be quantified by composite metrics called aging clocks using proteomics. Proteomic aging clocks (PACs) are accurate, easily measured, and are associated with age‐related diseases including Alzheimer’s Disease and Related Dementias. We aim to investigate whether an accelerated biological aging (a discrepancy between chronological age and PAC) is associated with subclinical cerebrovascular structural changes.

Method

1494 participants from the Atherosclerosis Risk in Communities (ARIC) Study with proteomics and 3T brain MRI data at ARIC visit 5 in 2011‐13 (mean age 76, 59% female, 25% Black) were included. Nearly 5000 plasma proteins were measured using the SomaScan assay. PAC was developed using elastic net regression model and was internally validated. Age acceleration was calculated as residuals after regressing PAC on chronological age (positive value indicates biological age is higher than the person’s chronological age). Linear and logistic regression models were used to assess the associations of age acceleration with white matter hyperintensity volume (in cm3, log2 transformed, median [IQR]: 11[6‐20]) and the presence of: subcortical (n = 281), lacunar (n = 263), and cortical infarcts (n = 150), and microbleeds (n = 355).

Result

Accelerated age (median [IQR]:‐0.04[‐1.4,1.3]; correlation with chronological age = 0) was associated with MRI markers of cerebrovascular disease after adjusting for demographic, cardiovascular risk factors, education, and kidney function. Every five years higher age acceleration was associated with larger white matter hyperintensity volume (Difference:0.34[95%CI 0.19,0.49]), higher odds of lacunar (OR:1.61[1.13,2.30]), subcortical (OR:1.63[1.15, 2.32]), and cortical infarcts (OR:1.72[1.11,2.67]). There was no association with presence of microbleeds (OR:1.25[0.91,1.73]) (Figure). Findings were consistent after excluding participants with clinical stroke and there was no difference between APOEe4+ and APOEe4‐ participants.

Conclusion

Higher accelerated age is cross‐sectionally associated with a greater prevalence of MRI markers of cerebrovascular disease. Understanding this relation has potential to help with risk stratification and personalized prevention and treatment strategies to promote brain health.
Examining longitudinal changes of disease severity scores in familial forms of frontotemporal dementia within the GENFI cohort
Authors: Foster Phoebe H , Ferry‐Bolder Eve , Peakman Georgia , Bouzigues Arabella , Greaves Caroline V , Convery Rhian S , van Swieten John C. , Jiskoot Lize C. , Seelaar Harro , Moreno Fermin , Sanchez‐Valle Raquel , Laforce Robert , Graff Caroline , Masellis Mario , Tartaglia Carmela , Rowe James B. , Borroni Barbara , Finger Elizabeth , Synofzik Matthis , Galimberti Daniela , Vandenberghe Rik , Mendonca Alexandre , Butler Christopher , Gerhard Alexander , Ducharme Simon , Ber Isabelle Le , Tiraboschi Pietro , Santana Isabel , Pasquier Florence , Levin Johannes , Otto Markus , Sorbi Sandro , Rohrer Jonathan D. , Russell Lucy L.
Published: December 2023

Background

The CDR®+NACC FTLD Sum of Boxes (SB) score is a well‐established measure of disease severity in frontotemporal dementia (FTD), however, few studies have assessed longitudinal changes in score within familial forms of FTD.

Method

343 participants from the Genetic FTD Initiative (77 mutation‐negative controls, 109 C9orf72 expansion carriers, 105 GRN mutation carriers, and 52 MAPT mutation carriers), with available scores on the CDR®+NACC FTLD‐SB and the FTD Rating Scale (FRS) at baseline and follow‐up, were examined. Using the baseline FRS percentage scores, mutation carriers were stratified into four groups: asymptomatic/very mild (100‐97%), mild (96‐80%), moderate (79‐41%), and severe (40‐0%). Linear regression models with bootstrapping were used to assess annualised change in CDR®+NACC FTLD‐SB scores across genetic groups between participants' first and follow‐up visit.

Result

C9orf72 and GRN mutation carriers in the moderate and severe groups, as well as mild GRN carriers, showed significantly greater change than controls (p < 0.050). No significant differences in change scores were observed between MAPT mutation carriers and controls. Comparisons within genetic groups revealed that both the moderate and severe GRN and C9orf72 expansion carriers showed larger annualised change relative to their asymptomatic/very mild counterparts (p < 0.001 and p = 0.037; p = 0.028 and p < 0.001, respectively). The moderate GRN and severe C9orf72 groups also demonstrated greater annualised score changes than their respective mild counterparts (p < .001; p = 0.001). For MAPT mutation carriers, no significant changes were observed. Between genetic group comparisons revealed significant change score differences between the moderate individuals, with GRN mutation carriers showing a greater change than the C9orf72 and MAPT groups (both p < 0.001), and the C9orf72 group showing a larger annualised change than the MAPT mutation carriers (p = 0.041).

Conclusion

The CDR®+NACC FTLD‐SB detects significant changes in disease severity from baseline to a first follow‐up visit in familial forms of FTD, with GRN mutation carriers showing the greatest annualised change.
Monoaminergic Disfunctions and Misfolded Proteins levels in the Alzheimer’s Disease Continuum
Authors: Orso Beatrice , Peira Enrico , Arnaldi Dario , Girtler Nicola , Brugnolo Andrea , Mattioli Pietro , Biassoni Erica , Donniaquio Andrea , Massa Federico , Uccelli Antonio , Bauckneht Matteo , Morbelli Silvia , Pardini Matteo
Published: December 2023

Background

Monoaminergic systems are pharmacologically modulable and therefore both a target for symptomatic therapies and a window for the study of disease progression. Although these mechanisms are unclear. We explore the progression and the distribution of monoaminergic deficits in the Alzheimer’s Disease (AD) continuum, along with the accumulation of misfolded pathological proteins.

Method

We included 50 patients with Alzheimer’s Disease (AD) and 42 Healthy Controls (HC). We acquired brain [18F]FDG‐PET images as a marker of neurodegeneration and MMSE as a measure of global cognitive functioning. We performed voxel‐based analysis between AD vs. HC. Using JuSpace toolbox we explored the correlation between [18F]FDG‐PET images and PET maps of dopamine (DAT), serotonin (SERT), noradrenaline (NAT) and choline vesicular (VAChT) transporters cortical distribution. Moreover, we evaluated relative hypometabolism in the main cholinergic nucleus (Meynert nucleus). We divided in two groups the AD patients based on MMSE score (AD Dementia ‐ADD‐ <24; MCI ≥24), to explore the association between monoaminergic disfunction and pathological proteins burden, across the AD continuum.

Result

Sample characteristics are provided in Table 1. Results from voxel‐based analysis are shown in Figure 1. In the whole AD group, the distribution of relative cortical hypometabolism was associated with a significant reduction of VAChT availability (p = 0.018). This association remained significant when considering the ADD (p = 0.006), but not the MCI group. Figure 2.

β‐amyloid42 levels and β‐amyloid42/40 ratio were inversely correlated with VAChT in the ADD group (p = 0.003; p = 0.038, respectively). No correlation was observed in the MCI group. Lastly, there was no correlation between Meynert nucleus relative hypometabolism and misfolded proteins levels in all groups.

Conclusion

In the ADD phase we showed a significant damage in the cortical regions targeted by the cholinergic system. This result was not evident among the other systems studied, nor in the MCI phase. This provides an explanation of the reduction of the cholinesterase inhibitors efficiency in the dementia phase. Moreover, we showed that β‐amyloid accumulation was not associated with Meynert Nucleus degeneration, but that impacted on cholinergic function via damage accumulation in the cortical areas targeted by the cholinergic system.
Optimizing brain health after a Traumatic Brain Injury: application of dementia prevention programs regarding neuroprotective lifestyles to the field of TBI care
Authors: Bayen Eleonore , de Langavant Laurent Cleret , Cotter Eoin , Lawlor Brian , Cotter Agnès Weill‐Chounlamountry
Published: December 2023

Outcome after a Traumatic Brain Injury is multi‐determined and depends on the interaction of factors, including injury severity, pre‐injury (e.g. level of education) and post‐injury factors (e.g. access to health care resources including neuro‐cognitive rehabilitation, but also environmental factors such as family/socio‐economic support, follow‐up of comorbidity conditions, physical activity, healthy sleep and diet…). Some of these modifiable risk and neuroprotective factors have been shown to have an impact on brain health and on outcomes post‐TBI. Additionally, patients with moderate to severe TBI have an increased risk of developing dementia (Gardner, Yaffe 2014), reinforcing the need for secondary prevention post‐injury. Yet, primary‐secondary prevention regarding brain health modifiable factors remains insufficiently developped during TBI care management. We describe here the building of a hospital‐based psycho‐educational program promoting brain health in the Neuro‐Rehabilitation Center of Pitié‐Salpêtrière hospital (Paris, France): it includes raising awareness about neuroprotective lifestyles and managing modifiable risk factors that have been studied in dementia prevention (Norton, Yaffe, 2014; Livingston 2017) to the field of post‐TBI care. Indeed, detection and management of modifiable risk factors help to prevent neurodegeneration that participate to cognitive decline and clinical dementia later in life. The brain health program takes place during the out‐patient rehabilitation. It engages a transdisciplinary group of health professionals (physicians, rehabilitation professionals) that support and educate patients about easy steps towards healthy lifestyles and behavioral changes. The implementation includes 1) a medical interview about lifestyles and daily life environment (social support, physical activity, diet, sleep habits), and clinical check/follow‐up of comorbidities distinct from the TBI (cardiometabolic/vascular diseases, epilepsia, mood, addictions, sensory loss); 2) a targeted customized psychoeducation regarding modifiable risk factors. This entails recommendations regarding: cognitive stimulation, diet, physical fitness, secondary prevention of TBI, therapeutic observance for comorbidity conditions, sleep habits, the benefits of social interactions, follow‐up of mood disorders, prevention of tabacco/drug/excessive alcohol intake. Pre‐ post‐ evaluations (satisfaction, lifestyles, propensity to change behaviors and associated factors) are assessed. The TBI event stands as an opportunity to increase patients’ awareness about the importance of brain health. This program supports patients’ education regarding possible changes in patients’ daily life activities and behaviors.
Regional amyloid‐β is linked to disruptions in connected speech in amnestic mild cognitive impairment
Authors: Chou Chia‐Ju , Chang Chih‐Ting , Lee Chia‐Ying , Liu Yi‐Chien
Published: December 2023

Background

Speech changes in amnesic mild cognitive impairment (aMCI) are potential markers for the early detection of Alzheimer disease (AD). However, few studies investigate the relationship between speech and amyloid‐β burden. The focus of this study was to examine the relationship between the linguistic features and the distribution of amyloid‐β load in aMCI.

Method

This study recruited 25 aMCI patients (52% female, aged 70‐85 years) and 25 healthy elders (44% female, aged 68‐80 years) from the memory clinic of Cardinal Tian Hospital in Taiwan. All participants received [18F] florbetaben PET and standardized cognitive tests. Amyloid‐β load using a standardized uptake value ratio (SUVr) was estimated from 5 cortical regions (parietal, frontal, cingulate, temporal, and occipital). Spontaneous speech was recorded using the picture description task (three Taiwanese culture‐related pictures) and transcribed verbatim. Linguistic features were extracted, including lexical richness (total words, unique words, type‐token‐ratio, lexical density, and frequency), syntactic complexity (mean length of utterance/sentence, ratio of verbs/pronouns/passive sentence), and speech fluency (ratio of long pauses/ fillers).

Result

Eighteen subjects with high amyloid burden (SUVr > 1.21) progressed (defined as CDR‐SB change≧1) within 1 year. We performed linear regression analyses between linguistic features (dependent variables, separate models) and amyloid‐β load in brain regions. Analyses were adjusted for age and education. The data revealed that a high amyloid‐β burden in the frontal region was associated with fewer unique words, less lexical density, and an increased proportion of long pauses and fillers. Reduced passive sentence, short mean length of utterance and lower scores on episodic memory tests related to increased amyloid‐β burden in the parietal region.

Conclusion

Lexical richness and speech fluency was associated with amyloid‐β burden in the frontal region, indicating that voluntary lexical retrieval may require the additional recruitment of frontal lobe. Less syntactic complexity related to increased amyloid‐β burden in the parietal region. In conclusion, regional amyloid‐β is linked to subtle spontaneous speech deficits in aMCI.
Reduction in tau‐pathology induced with two novel tau aggregation inhibitors in Alzheimer mice
Authors: Drapich Patrycja , Zadrozny Maciej , Mironczuk Sandra , Gasiorowska Anna , Melis Valeria , Riedel Gernot , Harrington Charles R , Niewiadomska Grazyna , Niewiadomski Wiktor
Published: December 2023

Background

Alzheimer’s Disease (AD) is a common neurodegenerative disorder for which tau pathology is implicated. Abnormal forms of tau, which trigger neuronal dysfunction, can offer a therapeutic target. The main purpose of this study was to determine the effect of two new tau aggregation inhibitors here termed A and B, synthesised by TauRx Therapeutics Ltd., on tau pathology in a transgenic mouse model of AD.

Method

The research was conducted using the Line 1 (L1) transgenic mouse model with mild Alzheimer’s disease‐like tauopathy and the control wild‐type NMRI mice. L1 mice express a fragment of 945 amino acids fragment (296‐390) of the longest human tau CNS isoform (2N4R; htau40).

Experiments were carried out on 20‐25 weeks old animals. Compounds A and B were administered orally at daily dose 1.5 and 7.5 mg/kg for six weeks. Level of tau pathology was examined immunohistochemically using mAb7/51. Images of stained brain sections were collected and analysed using ImageJ software. Tau staining was assessed using the relative optical intensity (ROI) in three areas of interest (AoI): dorsal CA1 and CA3 subfields of hippocampus and primary motor cortex. Three measures were applied: (i) overall mean ROI of all pixels within AoI; (ii) specific mean ROI calculated only for pixels within AoI, whose ROI was below a threshold, which was set manually, and (iii) %Area – ratio of number of all pixels in AoI with ROI below manually set threshold relative to the number of all pixels in AoI.

Result

Tau labelling was significantly enhanced in overall and specific mean ROI between NMRI and L1 mice (both untreated and treated) in all structures scrutinised. Drug efficacy was strongest in cortex where a clear reduction of tau immunolabelling was revealed, followed by CA3 subfield of the hippocampus. No efficacy was obtained for CA1 independent of analysis method. The analysis of % Area affected by tau was particularly sensitive for drug efficacy in both CA3 and cortex, but there was yet again no effect in CA1.

Conclusion

Two new tau aggregation inhibitors A and B both reduced the level of pathological tau deposits in L1 mice.
Use of Chair Exercises in Increasing Heart Rate during Pilot Testing of mPACT app
Authors: Smith Lenora W , O'Brien Charles
Published: December 2023

Background

The mPACT app is a mobile application that integrates physical activity (through chair exercises) and cognitive training in one application. The aim of this study was to explore the exercise dose required to obtain target heart rates in older adults using chair exercises.

Method

The mPACT app was designed for our target population with the use of chair exercises to prevent injury and to allow older adults to complete physical activity even though they may have limitations. Chair exercises provide a less strenuous method for physical activity while still allowing for an increase in heart rate, which results in more oxygenation to the brain. The various exercises were videos that were looped to be 40 seconds, 60 seconds, and 90 seconds long, resulting in 30 minutes of physical activity. FitBit(R) inspire watches were used to monitor heart rate through the dashboard on the FitBit(R) website.

Result

Although the greatest increases in heart rate were seen during the final series of 90‐second exercises, this was likely a result of the marching and T‐pose exercises in sequences. The average heart rate displayed by the FitBit app, however, make the data inconclusive.

Conclusion

Our chair exercises in general can reach target heart rate, but the exact sequence and whether one causes a drop in heart rate is inconclusive due to more sedentary adults having small rest periods during each sequence. Using heart monitors to obtain more accurate data rather than FitBits(R) would be beneficial. Further research is needed for sequencing of specific chair exercises in order to adequate show the amount of exercise needed for the mPACT app.
Development and characterization of a robust in vitro disease cell line to study tauopathies
Authors: Ritsma Laila , Bsibsi Malika , Buti Ludovico , Stevenhagen Fleur , Sancerni Sara Compte , de Kraa Esther , Popalzij Abeera , Iovino Mariangela , Oosterveen Tony , Turner Amanda , Fisher David F , Vlaming Marijn
Published: December 2023

Background

Tauopathies, such as frontotemporal dementia (FTD) and Alzheimer’s dimentia (AD), are neurodegenerative diseases characterized by the pathological aggregation of paired helical filaments (PHFs) or neurofibrillary tangles (NFTs) within neurons and glia, leading to cell death1. PHFs and NFTs are formed by aggregation of hyperphosphorylated tau1. Mutations in the microtubule‐associated protein tau (MAPT) gene result in tauopathies. Moreover, FTD is a common clinical syndrome of 4 repeat (4R) tauopathies, as defined by aggregation of tau protein isoforms with four microtubule binding domains2. Here, we aimed to develop and characterize a physiologically relevant and robust in vitro FTD model, to aid the future development of FTD disease therapeutics.

Method

Using CRISPR‐Cas9 gene editing technology, familial mutations MAPT P301S and N279K underlying AD/FTD3 were engineered into an iPSC line that carries the opti‐oxTM technology and can rapidly be reprogrammed into glutamatergic neurons4. By means of immunocytochemistry we characterized b‐amyloid oligomer treated neurons, and neurons with the MAPT mutations to assess tau hyperphosphorylation.

Result

The CRISPR‐edited MAPT neurons can mature and show a healthy morphology. b‐amyloid oligomers (dose dependently) induce tau hyperphosphorylation in wild type glutamatergic neurons. Total tau expression is reduced in MAPT P301S homozygous and N279K heterozygous cells when compared to wild type cells. The MAPT P301S cells also show hyperphosphorylation for p‐tau 217, p‐tau202/205, and p‐tau404, and the N279K cells show hyperphosphorylation for p‐tau202/205, and p‐tau404.

Conclusion

The elevated p‐tau to total tau ratio measured by the immunocytochemistry assay indicates the potential of at least two cell lines as possible disease models to aid future research into developing AD/FTD disease therapeutics.

References:

1. Silva MC, eLife, 2019

2. Seward ME, et al, 2013. Journal Cell Sci 126(5):1278‐1286

3. Hutton M, et al, 1998, Nature 393:702‐705

4. PawlowskiM, et al, 2017. Stem cell reports 8(4), 803‐812
Cap‐Independent Translation as a Physiological Process Linking Amyloid and Tau Pathology in Alzheimer’s Disease
Authors: Murphy Michael Paul , Kohler Katharina , Webb Robin
Published: December 2023

Background

Neurodegenerative diseases are complex entities that are driven by multiple pathophysiological processes. Alzheimer’s disease (AD) is no exception, with both a multifaceted etiology, and varied pathologies that interact in overlapping ways. Although AD is the most common form of dementia found in the elderly, it is typically encountered with multiple age‐related co‐morbidities that are indicative of other disease processes that likely contribute to the overall neurologic disease state, such as cerebrovascular pathology. A well known connection exists between type 2 diabetes (T2D), or metabolic dysfunction in general, and risk of dementia later in life. Our data indicate that a significant contributing factor that connects these processes may be the increased utilization of cap‐independent translation (CIT), an alternative form of eukaryotic protein manufacture that is more active during various forms of physiologic stress.

Method

Through an investigation of AD cases and controls, multiple cell lines (N2A, CHO, HEK293T, H4), rat primary neurons, cell free transcription / translation assays, and mouse models, we demonstrate that changes in CIT may drive both amyloid and tau pathology.

Result

We found that increased BACE1 protein in AD cases, as well as in vitro, was directly connected to an increase in an mRNA binding protein (ZNF9) responsible for controlling cap‐independent translation. Up and down regulation of ZNF9 produced corresponding changes in BACE1 protein (but not BACE1 mRNA), as well as BIN1, a key driver in the development of tau pathology. Cell free in vitro transcription / translation assays, mRNA binding in vitro and in vivo (both gel shift and RNA immunoprecipitation), and fluorescent reporter assays using a variety of constructs confirmed that ZNF9 is controlling CIT and likely not acting via typical cap‐dependent translation, or by affecting transcription. Additional studies in cell lines, as well as in a mouse model of metabolic dysfunction and amyloid pathology, demonstrated that this process can be driven by metabolic stress.

Conclusion

In addition to any direct connection between the development of amyloid‐beta and tau neuropathologies, these data indicate that these two primary pathologic hallmarks of AD could share an upstream connection through a basic, yet underappreciated, biological process.
Rapid review: How rare are rare dementias?
Authors: Hayes Oliver S , Baou Celine El , Brotherhood Emilie V , Crutch Sebastian J , Camic Paul
Published: December 2023

Background

Compared to global prevalence data for common forms of dementia (Alzheimer’s disease, vascular dementia, and mixed Alzheimer’s and vascular dementia), our understanding of the prevalence of atypical, inherited, and young onset forms of dementia is poor. Furthermore, estimates are biased towards figures from a subset of countries and regions. Estimates of the relative prevalence of atypical, inherited and young onset forms of dementia (colloquially referred to as ‘rare dementias’) within overall dementia prevalence should improve awareness and diagnosis rates, and enhance the access of individuals with these conditions to tailored support and interventions.

Method

Rapid review methods will be applied to a systematic review of the relative prevalence of rare forms of dementia as a proportion of overall dementia prevalence. The English language databases of CENTRAL, MEDLINE, Embase and PsycINFO will be searched for systematic reviews and primary studies relating to relevant conditions, with dementia types and search terms being determined by a consensus process involving UK and international clinicians and academics. Major national and international formal epidemiological studies, regional epidemiological studies, multi‐service data, individual clinic and service data referencing the prevalence, incidence, and risk data of at least one rare form of dementia will be included. Key grey literature from organisations and charities such as Alzheimer’s Society, Alzheimer’s Association and the WHO will also be included if available data sources provide valuable insight, and their methodologies are transparent and verifiable.

Result

We will report estimates of relative prevalence of atypical, inherited, and young onset forms of dementia, both individually and collectively.

Conclusion

The application of the present rapid review method allows for timely appraisal of evidence useful in understanding global prevalence of rare forms of dementia. Review findings will also be discussed in terms of a working definition of the convenience label ‘rare dementia’, and consideration of constraints including: (1) the paucity of information on rare forms of dementia, (2) publication bias and biases associated with organisational reports, (3) overlaps and confusions between syndrome‐ and disease‐level descriptions, and (4) the variable precision with which certain diagnostic labels can be applied at more advanced disease stages.
Histone deacetylase 4‐dependent regulation of cortical synaptic plasticity and the higher cognitive function during adulthood
Authors: Chung Seungsoo , Jeong Ji‐Hyun , Ahn Ji‐Woong , Sung Hansol , Shin Sunyoung , Jeong Minhee , Kim Young‐Hwan
Published: December 2023

Background

It is known that the primary sensory cortex contributes to the higher cognitive function, such as decision‐making. Still, a detailed synaptic mechanism explaining the relationship between sensory input and perceptual decision‐making remains elucidated. Previously, we demonstrated sensory deprivation restores critical‐period‐like synaptic plasticity to the barrel cortex in unilateral infraorbital injury (IO) mice.

Method

Therefore, we explored the relationship between adult primary synaptic input and perceptual decision‐making in adult IO mice using the head‐fixed texture discrimination test and brain slice patch‐clamp technique. We also explored a molecular mechanism underlying IO‐induced reactivation of thalamocortical (TC) synaptic plasticity in the barrel cortex using immunoblotting of HDAC4 and BDNF as well as AAV/shRNA‐mediating knockdown of HDAC4.

Result

IO mice learned the spared TC input‐mediated perceptual decision‐making task more effectively than sham‐controls. This improvement in perceptual learning was intimately correlated with spared TC synaptic efficacy. In terms of a possible molecular mechanism for the IO‐induced reactivation of TC synaptic plasticity, histone deacetylase 4 (HDAC4) and brain‐derived neurotrophic factor (BDNF) expression was significantly reduced in layers 4 and 5 of the barrel cortex from PO7 to PO9 in IO mice compared with Sham‐controls. The IO‐induced potentiation of spared TC synaptic efficacy was nearly prevented by blockage of BDNF/TrkB signaling with cyclotraxin B. In addition, HDAC4 knockdown by injecting AAV5‐U6‐mHDAC4‐shRNA‐CMV‐EGFP to the S1 barrel cortex significantly increased BDNF expression and TC synaptic efficacy in the layer4 barrel cortex. Similarly, the application of HDAC4 inhibitor to the S1 barrel cortex via an osmotic pump effectively potentiated TC synaptic efficacy without alteration of excitation/inhibition balance, similar to IO mice.

Conclusion

These results suggest that the reactivation of synaptic plasticity of primary TC input may regulate the higher cognitive function by modulating HDAC4/BDNF/TrKB signaling during adulthood.
Abnormalities of reactivity of posterior resting‐state electroencephalographic alpha rhythms during eyes opening in patients with dementia due to Alzheimer’s disease and Parkinson’s disease
Authors: Percio Claudio Del , Lizio Roberta , Lopez Susanna , Tucci Federico , Noce Giuseppe , Jakhar Dharmendra , Güntekin Bahar , Yener Görsev , Taylor John‐Paul , Babiloni Claudio
Published: December 2023

Background

Patients with dementia due to Alzheimer’s disease (ADD) and Parkinson’s disease (PDD) suffer from vigilance dysregulation. We hypothesized that such dysregulation may be reflected by altered reactivity of posterior resting‐state electroencephalographic (rsEEG) alpha rhythms during the vigilance transition from eyes‐closed to ‐open condition.

Method

A Eurasian database provided clinical, demographic, and rsEEG datasets in 73 PDD patients, 35 ADD patients, and 25 matched cognitively unimpaired (Healthy) persons. The eLORETA freeware was used to estimate cortical rsEEG sources at delta, theta, alpha, beta, and gamma frequency bands during eyes‐closed and‐open conditions.

Result

Results showed substantial (> ‐10%) reduction (reactivity) in the posterior alpha source activities from the eyes‐closed to the eyes‐open condition in 88% of the Healthy seniors, 57% of the ADD patients, and only 35% of the PDD patients (Figure 1). In these alpha‐reactive participants, there were lower reductions in the posterior alpha activities in the ADD and PDD groups than in the Healthy group. That reduction in the parietal region was lower in the PDD than in the ADD group (Figure 2).

Conclusion

These results suggest that ADD and PDD is characterized by poor reactivity of mechanisms desynchronizing posterior rsEEG alpha rhythms in response to visual inputs. This finding could be an interesting biomarker of impaired vigilance regulation in the quiet wakefulness in ADD and PDD patients. Such biomarkers may provide endpoints targets for pharmacological intervention and brain electromagnetic stimulations to improve the ADD and PDD patients’ general ability to regulate vigilance and visual primary consciousness in the activities of daily living.