bluuebunny/crossref_metadata_2025 huggingface dataset:
Higher allostatic load is associated with poorer structural integrity in the limbic network in cognitively unimpaired elderly
Authors: Palix Cassandre , Chocat Anne , Ferment Victor , Coulbaut Laurent , Felisatti Francesca , Haudry Sacha , Gonneaud Julie , Collette Fabienne , Mézenge Florence , Landeau Brigitte , De la Sayette Vincent , Vivien Denis , Chetelat Gael , Poisnel Géraldine
Published: December 2022

Background

Allostatic load (AL) is a cumulative measure of dysregulations across multiple physiological systems of the body occurring over time. AL was originally developed to explain how chronic stress damages physiologic systems and accelerates aging. Studies exploring the relationship between AL and brain health in older adults using a multimodal approach are limited. Our objective was to provide a comprehensive overview of the brain substrates of AL in cognitively unimpaired elderly using complementary multimodal neuroimaging techniques.

Method

Baseline data of 111 cognitively unimpaired older adults (mean age, 68.9years) from the Age‐Well study (NCT02977819) were included. They underwent multimodal neuroimaging (T1‐weighted and diffusion MRI, FDG‐PET and amyloid‐PET). A global measure of brain integrity was obtained for each modality by extracting the averaged signal across the whole gray matter (GM) or white matter (WM) for diffusion. AL was computed based on 19 markers of health. First, we examined the relationships between AL and sex or age. Second, we performed multiple regression and voxel‐wise analyses to predict AL from each neuroimaging modality and to highlight the brain regions involved. Finally, we conducted forward stepwise multiple regressions including the 19 AL‐components to determine the prognostic components of each of these associations; correcting for age, sex and education.

Result

AL was associated with sex (men>women) but not with age. Higher AL was associated with lower global GM volume and WM mean diffusivity. Adjusting for alcohol consumption, smoking habits, treatments or comorbidities, these associations remained unchanged. Association with lower GM volume was found in the parahippocampus, hypothalamus, anterior insula and prefrontal gyrus and with WM diffusivity in the corona radiata and corpus callosum. Stepwise regressions revealed that these associations with GM volume and WM diffusivity were mainly explained by the body mass index (BMI) and waist‐hip‐ratio (WHR), respectively.

Conclusion

Higher AL is associated with poorer structural integrity in regions of the limbic network, which is implicated in memory, emotion and stress processes and known to be particularly vulnerable to Alzheimer’s disease. Our results further suggest that maintenance of a healthy weight (by monitoring BMI and WHR) might help to prevent AL increase, thus promoting brain health.
Interaction between APOE4 and lifestyle on neuroimaging biomarkers and cognition in cognitively unimpaired older adults
Authors: Felisatti Francesca , Chauveau Léa , de Flores Robin , Marchant Natalie L , Collette Fabienne , Demnitz‐King Harriet , Whitfield Tim , Requier Florence , Palix Cassandre , Haudry Sacha , Delarue Marion , la Sayette Vincent De , Vivien Denis , Poisnel Géraldine , Chetelat Gael , Gonneaud Julie
Published: December 2022

Background

APOE4 is the main genetic risk factor for Alzheimer’s disease (AD). Recent findings suggest that lifestyle factors could modulate the association between APOE4 and cognitive impairment and/or dementia risk. However, a comprehensive assessment of the interactions between lifestyle and APOE4 status on neuroimaging and cognitive markers of aging and AD is still missing. Our objective is to assess this question in cognitively normal elderly.

Method

Baseline data of 134 cognitively unimpaired older adults (mean age: 69) from the Age‐Well study were analysed. They underwent lifestyle questionnaires (physical and cognitive activity, and diet), neuropsychological assessment (global cognition, memory, attention and executive functions) and multimodal neuroimaging (structural MRI, FDG‐ and Florbetapir‐PET). Interactions between lifestyle and APOE4 status on neuroimaging and cognition were assessed for each lifestyle factor separately.

Result

There was an interaction between APOE4 status and cognitive activity on neuroimaging measures (p‐values<.04), such that higher cognitive engagement was associated with lower grey matter volume in the parahippocampal cortex and lower brain perfusion in the entorhinal and perirhinal cortices in APOE4 carriers only (Figure 1A). However, greater cognitive engagement was associated with increased cognitive performance (global cognition, executive function and attention, all p‐values<.005), and this irrespective of APOE4 status (i.e., no cognitive activity x APOE4 status interaction; Figure 1B). For diet, interactions were evidenced (p‐values <.04) such that higher adherence to the Mediterranean diet was associated with i) higher brain glucose metabolism in the medial temporal lobe (Figure 2A) and ii) higher performance on attention tests (Figure 2B) in APOE4 carriers only. No interactions were found for physical activity.

Conclusion

Our results indicate that APOE4 carriers with higher cognitive activity had lower brain outcomes but preserved cognition, suggesting that enriched cognitive engagement promotes cognitive resilience in this population. On the other hand, APOE4 carriers with higher adherence to the Mediterranean diet had greater cerebral metabolism and greater attention capacities. Overall, this suggests that distinct lifestyle factors differentially help APOE4 carriers to resist or cope with brain alteration and postpone cognitive decline. ClinicalTrials.gov Identifier: NCT02977819.
Phonemic restoration in Alzheimer’s disease and semantic dementia
Authors: Jiang Jessica , Johnson Jeremy , Requena‐Komuro Mai‐Carmen , Benhamou Elia , Sivasathiaseelan Harri , Volkmer Anna , Crutch Sebastian J , Hardy Chris JD , Warren Jason D
Published: December 2022

Background

In daily life, spoken messages are often interrupted by extraneous sounds. However, we generally perceive such messages as continuous: our brains automatically and efficiently ‘repair’ interrupted speech signals by phonemic restoration, a fundamental physiological process whereby speech sounds that are obscured by noise are ‘filled‐in’ perceptually to reconstitute the underlying signal. As a dynamic, integrative process, phonemic restoration is potentially affected by neurodegenerative pathologies but this has not been clarified.

Method

Here we studied this phenomenon in patients with typical Alzheimer’s disease and semantic dementia, relative to healthy age‐matched controls. Participants heard isolated sounds, spoken real words and pseudowords in which noise bursts either overlaid a consonant or replaced it; a tendency to hear replaced (missing) speech sounds as present signified phonemic restoration.

Result

All groups perceived isolated noises normally and showed phonemic restoration of real words, most marked in the Alzheimer’s disease group. For pseudowords, healthy controls showed no phonemic restoration, patients with Alzheimer’s disease showed a marked suppression of phonemic restoration and patients with semantic dementia showed phonemic restoration comparable to real words.

Conclusion

Our findings provide the first evidence that phonemic restoration is preserved or even enhanced in neurodegenerative diseases, with distinct syndromic profiles that may reflect the relative integrity of bottom‐up phonological representation and top‐down lexical disambiguation mechanisms in different diseases. This work has theoretical implications for predictive coding models of language and neurodegenerative disease, and for understanding cognitive ‘repair’ processes in dementia.
Mitochondrial DNA drives AD Phenotypes in Cell Models
Authors: Troutwine Benjamin R , Weidling Ian , John Casey S. , Green Zachary D. , Kueck Paul J. , Swerdlow Russell H , Wilkins Heather M , Morris Jill K.
Published: December 2022

Background

Mitochondrial DNA (mtDNA) inheritance influences Alzheimer’s Disease (AD) risk. Adult children of mother’s afflicted with AD show decreased cognition and increased AD biomarkers (both peripheral and brain) at earlier ages than adult children with father’s afflicted with AD. These human derived data paired with prior in vitro work support a maternal inheritance association of AD risk. However, the exact mechanism linking mtDNA inheritance patterns and AD is not understood.

Methods

Cytoplasmic hybrid (cybrid) cells were derived by fusing platelet mitochondria with SH‐SY5Y cells devoid of mtDNA. Cybrid cells have the same nuclear DNA background with varying mtDNA sequences derived from human subjects. We examined mitochondrial function parameters in cybrids derived from 8 cognitively healthy (CH), 7 AD, and 5 mild cognitive impairment (MCI) subjects. Mitochondrial electron transport chain (ETC) function was measured using Seahorse XF technology. Mitochondrial membrane potential, mitochondrial superoxide, and mitochondrial calcium were measured using fluorescent assays (TMRE, MitoSox, and Rhod2AM). Mitophagy and mitochondrial biogenesis/mass were measured using adenoviral constructs (EGFP‐Cox8 and MitoTimer).

Results

Cybrids derived from AD subjects had elevated mitochondrial superoxide production when compared to CH cybrid cells. MCI cybrids did not show changes to mitochondrial superoxide production. Mitochondrial membrane potential and mitochondrial calcium were not changed in MCI or AD cybrids compared to CH. AD cybrids, but not MCI cybrids, showed reduced flux through all ETC components, including complex I, II, III, and IV. Finally, AD cybrids showed increased mitophagy levels but no change in mitochondrial biogenesis. MCI cybrids did not reflect these changes. Data do indicate AD cybrids might have increased mitochondrial mass, but further assays are needed to verify these findings.

Conclusions

Transfer of mtDNA from AD patients to cells harboring consistent nuclear DNA recapitulates mitochondrial phenotypes observed in AD. We are currently measuring AD biomarkers in these models and working to examine their correlation with clinical data from this cohort of research subjects.
A large‐scale genome‐wide association study of early‐onset Alzheimer disease
Authors: Neupane Achal , da Fonseca Eder Lucio , Kurup Jiji Thulaseedhara , Pericak‐Vance Margaret A. , Martin Eden R. , Schellenberg Gerard D. , Reitz Christiane , Beecham Gary W. , Cruchaga Carlos , Fernandez Victoria
Published: December 2022

Background

Early‐onset (≤65 years old) Alzheimer Disease (EOAD), which accounts for approximately 10% of all AD cases, is sometimes equated with dominantly inherited forms of AD (i.e., caused by known mutations in APP, PSEN1 or PSEN2). However, 90% of EOAD cases remain unexplained by these variants. This project aims to identify novel EOAD‐associated variants through a large‐scale, multi‐ethnic genome‐wide association (GWA) study.

Method

We have leveraged the Alzheimer Disease Genetics Consortium (ADGC) GWAS dataset that is aligned to GRCh38 and imputed with the TOPMed imputation server. This includes 39 studies from non‐Hispanic Whites (NHW; CA = 3,202; CO = 5,782), 17 from African American (CA = 139; CO = 253), six from Asian (CA = 133; CO = 474), and seven from Hispanic (CA = 199; CO = 59) cohorts. Only the younger (≤65yo) and older participants (>80yo) were included for analysis as cases and controls, respectively. The genetic background was confirmed using PCA. We are performing single‐variant analysis to identify variants that confer a higher risk for EOAD.

Result

Our preliminary single‐variant association analysis (using sex, PC1‐PC10 as covariates) emerging from the largest NHW cohort (CA = 3,202; CO = 5,782) have revealed nine different loci that were associated with EOAD at a suggestive P‐value<1×10−6. The strongest signal from our analysis was in the APOE region. Additionally, we identified three novel genome‐wide significant (P‐value <5×10−8) loci of interest at HLA‐DRB9 (rs9268852, P‐value = 2.9×10−9, OR = 1.22); FAM86B3P (rs73199790, P‐value = 3×10−11, OR = 1.32); and MSMB (rs2075895, P‐value = 2.83×10−16, OR = 1.26); while also confirming the previously identified loci at MS4A4A (rs7108663, P‐value = 1.13×10−10, OR = 0.80) and CR1 (rs6656401, P‐value = 2.54×10−12, OR = 1.32). We will perform qualitative associations on the other three ethnicities to confirm the transferability of these signals.

Conclusion

Our single‐variant analysis has identified three novel loci associated with EOAD. This study is the largest genetic screening for risk and protective variants in EOAD and will be instrumental to identifying novel variants and pathways implicated in unexplained EOAD. Our future analysis includes gene‐based association and pathway analyses per ethnicity to identify variants that confer a higher risk for EOAD, followed by transethnic analysis to validate the comprehensive nature of these risk factors. Additionally, we have also generated GWAS data from the Knight‐ADRC participants, which will be merged with the ADGC datasets for our future analysis.
The effect of microglial DMT1 inhibition on neuroinflammation in male and female mice
Authors: Volk Katrina M. , Harrison Fiona E. , Hasty Alyssa H.
Published: December 2022

Background

Neuroinflammation and microglial activation are critical components of Alzheimer’s Disease neuropathology as observed in patients and animal models. Microglia have multiple functions in addition to their inflammatory phenotype that can contribute to disease. Specifically, iron accumulates in AD‐associated brain regions, and we and others have shown enhanced iron load in activated microglia surrounding amyloid‐beta (Aβ) plaques. Furthermore, we and others have shown a distinct upregulation in the microglial iron importer, divalent metal transporter 1 (DMT1) in response to Aβ. Our aim is to further elucidate the role of microglial iron‐handling in age and AD‐associated inflammation.

Method

We measured DMT1 gene expression to assess changes in iron‐handling in response to age and inflammation. Microglia isolated from aged mice were treated with an inflammatory Aβ stimulus before measuring DMT1 expression and immunohistochemical markers of iron load. To determine the role of microglial DMT1 during inflammatory pathology in vivo, we targeted DMT1 expression utilizing a microglial‐specific tamoxifen‐inducible genetic mouse model in males and females. Transgenic mice were given intraperitoneal lipopolysaccharide (LPS) as a widely‐used model of neuroinflammation. We isolated microglia 24hr after LPS administration and measured DMT1 expression via qRT‐PCR for knockdown confirmation. Sickness behavior and markers of inflammatory state were also assessed.

Result

Microglia from 2‐year‐old aged mice display an augmented increase in Aβ‐induced DMT1 expression compared to young controls. Our in vivo studies also suggest a sex‐dependent increase in microglial DMT1 expression following systemic LPS. In our genetic mouse model, we obtained a 79% and 89% knockdown of microglial DMT1 gene expression in males and females, respectively. Male knockdown animals exhibited a trending decrease in Il‐1β expression in response to LPS, indicating an intimate link between pro‐inflammatory signaling and microglial iron‐handling.

Conclusion

These studies link changes in microglial iron‐handling and the neuroinflammatory response. Additional in vivo work is further being analyzed to comprehensively determine the effects of DMT1 inhibition on the neuroinflammatory response. Considering the prominence of iron‐loaded microglia and chronic neuroinflammation in late‐stage AD, early intervention aimed at a specific aspect of microglial iron‐handling could be a target to decrease inflammation and AD‐related pathology.
Carbonic anhydrase inhibitors: a novel pharmacological strategy to rescue Aβ‐induced neurovascular pathology and gliosis in vivo
Authors: Canepa Elisa , Vazquez‐Torres Rafael , Guzman‐Hernandez Roberto , Debure Ludovic , Angiulli Federica , Parodi‐Rullan Rebecca M , Lemon Nicole L , Fossati Silvia
Published: December 2022

Background

Cerebrovascular dysfunction (CVD) and neuroinflammation are associated and contribute to Alzheimer's disease (AD) progression. Most AD cases also present cerebral amyloid angiopathy (CAA), characterized by amyloid beta (Aβ) deposits at the brain vasculature, which trigger CVD and dysregulated brain clearance. In addition, CVD and altered clearance worsen vascular Aβ deposition, inducing cellular stress, neuroinflammation, metabolic waste accumulation, vascular permeability, infiltration of blood‐borne cells, and eventually leading to neurodegenerative processes and cognitive impairment. Endothelial cells (ECs) and glial cells are major players in mediating vascular fitness and brain clearance, promoting the removal of toxic material from the brain, including Aβ. Our previous findings demonstrated that Aβ elicits mitochondrial dysregulation and caspase‐mediated apoptosis in ECs and glial cells. Moreover, we showed that acetazolamide (ATZ) and methazolamide (MTZ), FDA‐approved carbonic anhydrase inhibitors (CAIs), employed in non‐AD related conditions, hinder these pathological events.

Methods

TgSwDI mice, expressing human Amyloid‐β Precursor Protein, APP, carrying the Swedish, Dutch and Iowa mutations, were employed as AD/CAA model. Tg mice, which develop, starting at 6 months, fibrillar Aβ burden, primarily in the cerebral microvasculature, and gliosis, were fed a CAI‐diet (from 8 to 16 months of age), following which we tested cognitive function, and harvested the brains for biochemical and immunohistochemical analyses.

Results

ATZ‐ and MTZ‐diet improve behavioral performances, and decrease total brain Aβ burden and caspase‐3 activation. Specifically, CAIs reduce Aβ accumulation in ECs, astrocytes and microglia, and the cell‐specific Aβ‐initiated caspase activity, promoting vascular health, glial anti‐inflammatory/pro‐healing phenotype and perivascular Aβ phagocytosis, which may underlie cerebral Aβ reduction.

Conclusions

Our results show that CAIs foster endothelial and glial proper function, improving Aβ clearance, and ultimately providing neuroprotection, and indicate CAIs as a novel pharmacological strategy to rescue Aβ‐induced neurovascular pathology and gliosis in AD/CAA pathology.
Proteomics reveals associations between inflammation and chronic depression in a prospective study of post‐stroke cognition
Authors: Zera Kristy A , Bidoki Neda , Nassar Huda , Drag Lauren , Mlynash Michael , Osborn Elizabeth , Musabbir Muhith , Kim Da Eun , Mendez Maria , Lansberg Maarten , Aghaeepour Nima , Buckwalter Marion S
Published: December 2022

Background

Depression affects approximately 40% of people with dementia, and is critical to quality of life. Here we examined the relationship between chronic depression and cognition in people with ischemic stroke and used plasma proteomics to get at potential mechanisms and identify novel therapeutic targets.

Method

We recruited subjects 5 months to 9 years after ischemia, age >40, who completed a 60 minute battery of cognitive tests. Composite scores of memory, processing speed, working memory, spatial functioning, and a global cognition score (the average of all cognitive tests) were created based on age‐normed performance. Mood was assessed with the Stroke Impact Scale (SIS3), transformed to a 100‐point scale. Linear regression models analyzed the relationship between depression and cognitive scores in 99 subjects. Plasma was analyzed by O‐link proteomics for 1011 proteins in 85 subjects. Additional regression models were constructed to estimate SIS3 using proteomics. Models were subject to bootstrapping for robustness, and cross‐validation to ensure results were reported on subjects blinded during model training. Pearson correlation identified linear associations between individual proteins and mood. We also investigated differences in proteins with subjects dichotomized into non‐depressed (SIS3>63) or depressed (SIS3≤63) groups.

Result

Mood was significantly associated with global cognitive score (R=0.368; p<0.001), visuospatial score (R=0.255; p=0.014), and processing speed (R=0.430; p<0.001), but not memory (p=0.441) or working memory (p=0.166). Proteomics alone predicted SIS3 in multivariable models. A total of 180 proteins correlated significantly with SIS3. Plasma levels of IL‐6 (p=0.0325), and TRIM5 (p=0.0011) were significantly elevated in subjects with depression, while HPGDS was significantly reduced (p<0.001). There was no difference in plasma levels of candidate proteins IL‐1ß (p= 0.0830) or TNF (p=0.5287) between depressed and non‐depressed subjects.

Conclusion

We report that depression is associated with cognitive outcomes in a population with ischemia, and that machine learning models can predict mood from comprehensive plasma proteomics. We also identified proteins of interest including HPGDS (produces Prostaglandin D) and TRIM5 (upstream of NFkB) that point to an immune association with ischemia‐triggered depression. Future studies are needed to replicate these findings, and preclinical models may help uncover mechanistic relationships that could lead to new therapies.
Plasma pTau181/Aβ42 identifies cognitive change earlier than CSF pTau181/Ab42
Authors: Fowler Christopher , Stoops Erik , Rainey‐Smith Stephanie , Vanmechelen Eugeen , Vanbrabant Jeroen , Dewit Nele , Mauroo Kimberley , Rowe Christopher , Fripp Jurgen , Li Qiao‐Xin , Bourgeat Pierrick , Collins Steven , Martins Ralph N , Masters Colin L , Maruff Paul , Doecke James D
Published: December 2022

Background

Plasma biomarkers now show an accuracy in detecting Amyloid Beta (Aβ) similar to AD biomarkers derived from cerebral spinal fluid (CSF). However, the ability of plasma AD biomarkers, alone or in combination, to predict cognitive decline has not yet been compared to that of CSF AD biomarkers.

Method

Plasma biomarker data from 233 participants’ first visit in the Australian Imaging, Biomarkers and Lifestyle study (AIBL) was submitted to linear mixed effects models (LME) to quantify the relationship with change in cognition (measured using the AIBL PACC) and in clinical disease stage (CDR SoB) in both PET Aβ‐ (Centiloid value <20CL) and Aβ+ (Centiloid value ≥20CL) participant subgroups. Separate models were used to assess CSF (Elecsys) and plasma (ADx NeuroSciences) data for Aβ42, pTau181 and the pTau181/Aβ42 ratio. Biomarker values were classified into low vs high levels based on ROC‐derived thresholds optimizing separation of PET Aβ status (low vs high at 20 CL). Changes in cognitive and clinical symptoms were then compared between the low/high plasma biomarker groups.

Result

In Aβ‐ participants, no significant interactions between binary biomarker classification and time were observed for AIBL PACC or CDR SoB, for either CSF or plasma biomarkers. In the Aβ+ participants, interactions between the binary plasma biomarker classification and change in cognition were greater in magnitude that those detected for CSF biomarker classification. For plasma, abnormally high values of both pTau181 and the pTau181/Aβ42 ratio predicted a significant increase over time in CDR SoB (Figure 1H & 1L) and a significant decrease over time in the AIBL PACC score (Figure 1F & 1J), compared the group with low values on the same biomarkers. In cognitively unimpaired Aβ‐ participants, the AIBL PACC score declined in those with abnormally high values of the pTau181 and the pTau181/Aβ42 ratio (Figure 1F & 1J).

Conclusion

Assays to measure pTau181 and Aβ42 in the plasma possess an accuracy equivalent to those derived from CSF. In particular, abnormally high levels of plasma pTau181 or the ratio of pTau181 to Aβ42 ratio provide a strong prediction of early cognitive changes, even in those with normal PET Aβ status.
Social Networks and Incident Alzheimer’s Disease: the Kuakini Honolulu‐Asia Aging Study
Authors: Kallianpur Kalpana J , Masaki Kamal H , Chen Randi , Willcox Bradley J , Allsopp Richard C , Dodge Hiroko H
Published: December 2022

Background

We assessed the longitudinal association between social networks in late life and the incidence of all‐cause dementia (DEM), Alzheimer’s disease (AD) and vascular dementia (VaD) over a 10‐year follow‐up period in a community‐based cohort of older Japanese‐American men.

Method

This prospective study analyzed data from cognitively intact participants of the Kuakini Honolulu‐Asia Aging Study (K‐HAAS). The K‐HAAS began with the Kuakini Honolulu Heart Program’s fourth examination in 1991‐1993, which served as our baseline timepoint. We followed 2,636 Japanese‐American men through the seventh exam (1999‐2000). Participants were dementia‐free at baseline and during the first 3 years of follow‐up. Social network strength was assessed by the Lubben Social Network Scale (LSNS). Weak and strong social network groups were defined by a median split of LSNS scores. Global cognitive functioning was evaluated by the Cognitive Abilities Screening Instrument (CASI), and depressive symptoms by the Center for Epidemiologic Studies Depression (CES‐D) 11‐item Scale. Dementia was diagnosed and classified by consensus of neurologists and geriatricians using standard criteria. Associations between baseline LSNS scores and the risks of DEM, AD and VaD were evaluated by multivariable Cox regression and Kaplan‐Meier estimators using age as the time scale.

Result

Study participants had a median (range) baseline age of 77 (71‐93) years. The age‐adjusted incidence of DEM was significantly higher among men who had weak (LSNS score ≤29) vs. strong (>29) social networks (12.6 vs. 8.7 per 1,000 person‐years of follow‐up; p = 0.014). Kaplan‐Meier survival curves showed that the men with strong social networks were less likely to develop DEM (p<0.0001) and AD (p = 0.0006); the probability of DEM‐free survival at almost 10 years was 93.8% for participants with strong social networks and 89.0% (11% incidence) for those with weak networks. In Cox regression models adjusting for baseline age, education, presence of at least one ApoE ɛ4 allele, prevalent stroke, depressive symptoms (CES‐D score ≥9), and CASI score, weak social networks were significantly associated with increased risk of DEM (HR = 1.52, 95%CI = 1.11‐2.08, p = 0.009) and AD (HR = 1.67, 95%CI = 1.11‐2.51, p = 0.014).

Conclusion

Strong social networks may protect against incident dementia and Alzheimer’s disease. Effective strategies should be devised to prevent the social isolation of older adults.
Characteristics of β‐secretase activity on APP‐V604M and APP‐V669L
Authors: Kim Danyeong , Shim Kyu Hwan , Bagyinszky Eva , Van Vo Giau , Kang Min Ju , Senanarong Vorapun , Limwongse Chanin , Shin Seunghwan , Jeong SoonPyo , Kim Jongsung , Park Young Ho , Youn Young Chul , Kim SangYun , An Seong Soo
Published: December 2022

Background

Several mutations near the amyloid‐beta peptide (Aβ) of Amyloid Precursor Protein (APP) were reported to as pathogenic mutations in Alzheimer's disease (AD), especially in early‐onset Alzheimer's disease (EOAD). β‐Secretase would cleave APP and release sAPPβ and CTF99. Then, γ‐secretase would cleave CTF99 sequentially in generating Aβ. Previously, APP‐V604M and APP‐V669L mutations (APP Seoul mutation) were found from patients with EOAD and their mutant cell lines were established by CRISPR/Cas9. Their pathogenicity of APP‐V604M was demonstrated the mutant cells from observing the increased both of Aβ42/40 ratio and oligomers. For APP‐V669L, the decreased ratio Aβ42/40 was noticeable from the elevation of Aβ40. Still, increased Aβ oligomers were measured. Here, their pathogenicity was supported by measuring β‐secretase activity in above mutant cells.

Method

Previously, APP‐V604M and APP‐V669L cells were generated by CRISPR/Cas9. Cells were seeded and incubated for 48 h. After washing, conditioned media was added and incubated for 48 h. Afterwards, cytosolic proteins and solubilized membrane were extracted with the commercial kit. β‐secretase activities were measured with the substrate at ex/em 355/510 nm.

Result

Differences of β‐secretase activity were observed from above mutations in comparison with control. From the cytosolic protein fractions, the increased β‐secretase activity was observed from APP‐V604M, whereas the decreased activity was monitored from APP‐V669L. Interestingly, from the solubilized membrane fractions, the higher β‐secretase activities were seen than cytosolic protein tractions. The similar activities were measured between APP‐V604M and the control, whereas the decreased β‐secretase activities were measured in APP‐V669L than the control.

Conclusion

Since APP mutations would directly affect by β‐secretase in generating Aβ, it was important to monitor the β‐secretase activity for supporting the mutant. Here, differences in β‐secretase activities were quantified in APP‐V604M and APP‐V669L mutant cells. As APP Seoul mutation was located at the β‐secretase cleavage site, it would be detrimental to β‐secretase activity. Increased activity on APP‐V604M suggested the possible alteration of structural/cleavage β‐secretase activity from outside of Aβ region. Moreover, the higher β‐secretase activity was observed in the fraction from membrane than the cytosolic fraction. Our results emphasize the importance of measuring β‐secretase activity from the membrane fraction.
Aβ1‐42‐related sodium‐calcium exchanger isoform‐3 downregulation in models of Alzheimer’s disease: Therapeutic significance of Withania somnifera roots extract
Authors: Afewerky Henok Kessete , Li Hao , Zhang Tongmei , Li Xinyan , Mahaman Yacoubou Abdoul Razak , Duan Limin , Qin Pengwei , Zheng Jiequn , Pei Lei , Lu Youming
Published: December 2022

Background

Na+‐Ca2+ exchanger isoform‐3 (NCX3) take‐parts in the aberrant Ca2+‐influx seen during neuronal excitotoxicity. However, the NCX3‐Aβ1‐42‐associated cytotoxicity and whether renovation of the aggregated Aβ1‐42‐induced NCX3 downregulation prevents or delays the onset of Alzheimer’s disease (AD) and AD‐related pathology remain unclear. Withania somnifera (W. somnifera), an indigenous traditional medicinal plant, has a long history of uses in preventing aging‐related neurological‐health impairments. However, this plant’s roots extract therapeutic value in neurodegenerative diseases, such as AD, albeit far less well studied.

Methods

Microscopic fluorescence and haemocytometer cell viability counting were performed to examine contributions of NCX3 against Aβ1‐42‐induced cytotoxicity in BHK‐cells. Authenticated W. somnifera‐dried‐roots were powdered, and the powder’s methanolic extract was used for phytochemical screening of the roots‐bioactive constituents and the 5×FAD mice gavage treatments from postnatal day 30 (P30) to P60 while maintaining their daily bodyweight records. After treatments, in vivo‐cognitional studies and then neurochemical‐examinations of the NCX3 immunoblot expression level, a sandwich ELISA and microscopy of Aβ plaque deposition, and antioxidant activity assays were performed in the AD‐associated brain regions at the mice age of 4 months.

Results

The cell‐based studies revealed positive roles of NCX3 in the resistance against Aβ1‐42 exposure toxicological damages. Phytochemical screening of the extract attested presence of antioxidants as major bioactive constituents of the roots. The mice recorded bodyweights during treatments statistical‐analysis evidenced that the extract has no potential toxicity. The cognitional studies data indicates that the treatment group mice showed significant improvements than vehicles (p<0.01). Interestingly, subsequent studies in the mice’s cortex‐ and hippocampus‐homogenates showed that the W. somnifera prevents NCX3 suppression, significantly reduces Aβ1‐42 expression, and normalizes oxidative stress. Moreover, confocal microscope immunoreactive studies indicated reduced depositions and distributions of Aβ plaques in the treatment group AD‐associated brain tissues.

Conclusion

These findings suggest the relevance of NCX3 against effects of Aβ1‐42‐associated cytotoxicity and that the W. somnifera antioxidant constituent’s bioactivity with no indications of toxicity, operating against Aβ‐induced NCX3 downregulation, may have a therapeutic role for augmenting NCX3 physiological properties in the maintenance of ionic Ca2+ homeostasis and ameliorates cognition in the 5×FAD mouse‐model, and therefore, might be valuable in AD‐pharmacological medicine.
PART is part of SNAP‐MCI
Authors: Wisse Laura EM , Xie Long , Lyu Xueying , Das Sandhitsu R. , de Flores Robin , Lane Jacqueline , Yushkevich Paul A. , Wolk David A. , Initiative Disease Neuroimaging
Published: December 2022

Background

Mild Cognitive Impairment with Suspected non‐Alzheimer’s Pathophysiology (SNAP‐MCI) represents a group of patients with Alzheimer’s disease (AD) like neurodegeneration without beta‐amyloid pathology. While this group likely has a heterogeneous etiology, tau pathology, as in Primary Age‐Related Tauopathy (PART), has been hypothesized to play a major role. We investigate tau positron emission tomography (PET) uptake in the medial temporal lobe (MTL) in SNAP‐MCI and the association of MTL Tau‐PET uptake with structural measures and delayed recall in beta‐amyloid negative (A‐) MCI patients.

Method

237 MCI patients and 301 A‐ controls with available beta‐amyloid and tau PET and magnetic resonance images (within 200 days) were included. Baseline hippocampal volume and entorhinal cortex (ERC) and Brodmann areas (BA)35 thickness were obtained using an in‐house developed pipeline and annualized atrophy rates were estimated in an unbiased fashion using follow‐up MRIs within 4.5 years. Βeta‐amyloid status (A+/‐) was determined by a standard cut‐off (Florbetapir: 1.11; Florbetaben: 1.08) and neurodegeneration status (N+/‐) by hippocampal volumes, corrected for intracranial volume, using the 90th percentile of A+ AD patients as the cut‐off. Tau‐PET standardized uptake value ratio (SUVR) in the ERC/BA35 was calculated. A composite z‐score of delayed recall at baseline and change over 2 years was obtained.

Result

SNAP‐MCI had significantly higher ERC/BA35 Tau‐PET SUVR than A‐ controls (Table 1, corrected for age) and qualitatively higher than A‐N‐ MCI (p=0.10). ERC/BA35 Tau‐PET SUVR in A‐N‐ MCI was not significantly different from A‐ controls.

In A‐ MCI patients, ERC/BA35 Tau‐PET SUVR was significantly associated with BA35 thickness and hippocampal, ERC and BA35 atrophy rates, corrected for beta‐amyloid PET SUVR (Table 2; Figure 1). MTL structural measures, but not ERC/BA35 Tau‐PET SUVR, were associated with cross‐sectional and longitudinal delayed recall measures (Table 3; Figure 2).

Conclusion

SNAP‐MCI had elevated ERC/BA35 Tau‐PET SUVR and ERC/BA35 Tau‐PET SUVR was associated with MTL structural measures in A‐ MCI patients. This indicates that tau pathology might be an important driver of neurodegeneration in the absence of beta‐amyloid pathology, supporting the notion that PART contributes to SNAP‐MCI. Additionally, MTL structure was associated with memory performance, consistent with SNAP not being a benign condition.
CSF‐plasma biomarker profiles from BioFINDER MCI patients using the same technology
Authors: Vanmechelen Eugeen , Dewit Nele , Vanbrabant Jeroen , Mauroo Kimberley , Stoops Erik , Stomrud Erik , Janelidze Shorena , Hansson Oskar
Published: December 2022

Background

Technological advancements have made it possible to translate changes in cerebrospinal fluid (CSF) into promising plasma biomarkers, such as the amyloid β ratio (Aβ42/Aβ40) and phosphorylated tau (p‐tau), but comparing CSF and plasma levels were often based on different technologies. Combining biomarkers have demonstrated a superior performance of the ratio of p‐tau over Aβ42 to discriminate Aβ‐positive (Aβ+) and Aβ‐negative (Aβ‐) groups in CSF, especially using automated immunoassay platforms, but has not yet been studied in plasma.

Method

In a subset of 155 MCI individuals of the BioFINDER‐1 study, from which 84 paired CSF‐plasma were available for analysis, Aβ42, Aβ40 and p‐tau181 were determined using ADx Simoa assays (Thijssen et al, 2021; Bayoumy et al, 2021) in both fluids using the appropriate dilution factors.

Result

The intra‐run %CV was between 1.7 and 2.6% for both Aβ markers in CSF and plasma and was higher in plasma for p‐tau181 than in CSF with respectively 10.5 and 1.7%. Both CSF Aβ42, Aβ40 and Aβ42/Aβ40 were highly correlated to CSF Aβ measurements using the MSD platform: spearman ρ of 0.845; 0.828; and 0.882 for respectively for Aβ42, Aβ40 and their ratio. In the paired CSF‐plasma analysis the strongest correlation was found for p‐tau181/Aβ42 and p‐tau181 with respectively a ρ=0.689 and 0.616 and a significantly weaker correlation for Aβ42/Aβ40 ratio (ρ=0.283). Defining an Aβ+ and an Aβ‐ subgroup by using a previously verified CSF Aβ42/Aβ40 of 0.07, all plasma biomarkers could differentiate Aβ+ and Aβ‐ individuals. The highest AUC was observed for p‐tau181/ Aβ42, 0.806, significantly (p=0.0465) higher than p‐tau181 (0.784) and the Aβ42/Aβ40 (0.688)(Fig 1).

Conclusion

Correlations in paired CSF‐plasma samples using the same technology are significant, but weak for some of them suggesting a different turnover of these analytes in these fluids. Nevertheless combining both well‐established pathological markers in plasma, p‐tau and Aβ42, may be a simple way to enhance early diagnosis based especially if automated immunoassay platforms are envisaged.
African American experience of FTD: A sub‐cohort assessment of the FTD Insights Survey
Authors: Dodge Shana G. , Vincent Lakecia , Dacks Penny A. , Wheaton Dianna K.H.
Published: December 2022

Background

While efforts are underway to better understand the prevalence, incidence, pathophysiology, and phenomenology of FTD, most research participation has been dominated by persons of European descent. Better understanding of early signs, the diagnostic journey, and the functional impacts in historically underrepresented groups may help shed light on healthcare inequities, support the development of more inclusive research study design, and lay the foundation for more targeted care and interventions.

Method

In preparation for an Externally Led Patient‐Focused Drug Development (PFDD) meeting, the Association for Frontotemporal Degeneration (AFTD) and the FTD Disorders Registry (FTDDR) collaborated to develop the FTD Insights Survey. The online survey queried aspects of the lived experience of FTD from the patient/family/carer perspective.

Result

Of the 1,796 respondents that completed the survey, twenty‐five represented the experience of African American persons diagnosed with FTD from the perspective of those diagnosed (n = 4) and care partners (n = 21). Two additional respondents reported on their experience as African American biological family members of those with FTD. Thirty‐six percent of African Americans needed to see 4 or more doctors before receiving an FTD diagnosis, compared to 18% of total respondents, and were more likely to initially receive a different diagnosis (80% vs. 45%). While patterns of the first symptoms were reported similarly across all participants, African Americans were more likely to report having initially experienced changes in thinking, spatial reasoning, or delusions/hallucinations. African Americans were also more likely to report distress related to language, sleep, and delusions/hallucinations and less likely to report no distress or distress related to cognitive symptoms. African American participants were more likely to endorse wanting a treatment to maintain independence and hold a job than overall participants.

Conclusion

The African American perspectives reported on the FTD Insights Survey represent a small sample size of individuals with greater than average levels of education (76% had an Associate’s degree or higher). The experience they report overlaps with those of other respondents, but with key differences including more difficulty in access to timely diagnosis. More information is needed on the lived experience of FTD across people of different cultural, social, economic backgrounds.
User Experience and Compliance Rates of Remote Monitoring Technologies in Alzheimer’s Disease: Preliminary Results of the RADAR‐AD Study
Authors: Muurling Marijn , Hinds Chris , Wu Yuhao , Curcic Jelena , Doherty Aiden , Conde Pauline , Owens Andrew P , de Boer Casper , Aarsland Dag , Narayan Vaibhav A , Visser Pieter Jelle ,   the RADAR‐AD consortium
Published: December 2022

Background

Unlike traditional pen‐and‐paper clinical assessments, remote monitoring technologies (RMTs) can assess participants’ function continuously and objectively during activities of daily living. Despite the potential of RMTs to assess function or assist early disease detection, there is skepticism that age or impairment may render participants unable or unwilling to comply with complex RMT protocols. The 8‐week RADAR‐AD study protocol asks Alzheimer’s disease (AD) patients in all disease stages to wear, amongst others, two activity trackers (Axivity, Fitbit), a wearable camera (Autographer), and use an active smartphone app (Mezurio), with a daily schedule totaling over 400 separate tasks and a parallel schedule for caregivers. This abstract presents preliminary compliance data and participant feedback.

Method

We included amyloid negative control participants (n=47) and amyloid positive preclinical (n=16), prodromal (n=19) and mild‐to‐moderate (n=16) AD participants (Table 1), based on MMSE and CDR scores, in 8 European countries. Metrics based on device data were calculated for participant commitment (study duration completion percentage or wear time) and compliance (task completion percentage). Patient experiences were monitored using bi‐weekly semi‐structured phone interviews.

Result

Mezurio average commitment and compliance were 90% and 85% respectively (Table 2) and were comparable across diagnostic groups. Wear time of Axivity, Fitbit and wearable camera was high (>86%), with 48% of those offered adopting the optional wearable camera (Table 2). Participant feedback was positive, with relatively few problems reported (Figure 1).

Conclusion

RADAR‐AD shows that age and impairment are not necessarily barriers to successful deployment of complex RMT study protocols. We acknowledge that our high commitment and compliance rates benefitted from an active rapport between researchers, participants and care givers, which may not be reproducible in every scenario. Nevertheless, this study shows that AD patients are able and willing to comply and engage with technology.

This work has received support from the EU/EFPIA Innovative Medicines Initiative Joint Undertaking (grant No 806999). www.imi.europa.eu. This communication reflects the views of the RADAR‐AD consortium and neither IMI nor the European Union and EFPIA are liable for any use that may be made of the information contained herein.
GCase activity and long‐term risk of dementia in Parkinson’s disease
Authors: Oftedal Linn , Dalen Ingvild , Tysnes Ole‐Bjørn , Pedersen Kenn Freddy , Alves Guido , Maple‐Grødem Jodi , Lange Johannes
Published: December 2022

Background

Clinically, patients with Parkinson disease (PD) carrying a mutation in the glucocerebrosidase (GCase) gene (GBA) are at higher risk of dementia, suggesting that GCase dysfunction may contribute to a more severe disease course, although evidence is lacking. We aimed to discover if cerebrospinal fluid (CSF) GCase activity is altered in newly diagnosed PD patients and if GCase activity at diagnosis predicts the future development of dementia.

Method

We measured CSF GCase activity in 117 PD patients from the Norwegian ParkWest study, a population‐based study of incident PD with 10 years of biannual, prospective follow up, and 50 control subjects without neurological disease. PD dementia diagnosis was set according to established clinical criteria. Parametric accelerated failure time models were applied to analyze the association of GCase activity at the time of PD diagnosis with dementia free survival.

Result

GCase activity was reduced in PD patients with (0.92±0.40 mU/mg) or without GBA mutations (1.00±0.37 mU/mg) compared to controls (1.20±0.35 mU/mg). GCase activity at the time of diagnosis was lower in PD patients who developed dementia within 10 years (n=41, 35%) than in those who remained free of dementia (p = 0.001). Further, patients in the lowest tertile of GCase activity at PD diagnosis were at 3‐fold increased risk of developing dementia in the next ten years (HR 3.10; 95% 0.72 to 4.68; P= .014; Figure), a finding that was also independent of GBA carrier status.

Conclusion

This is the first study to show both that GCase dysfunction is evident in idiopathic PD at the time of diagnosis and that low GCase activity is associated with greater risk of developing dementia over the next ten years. GCase‐targeting compounds are among the most promising strategies towards disease‐modifying treatments in PD, and evidence for the association of CSF GCase activity with disease progression, independent of GBA mutation status, will have important implications for clinical trial design and patient management.
A Role for Epigenetic Mechanisms in the Lewy Body Dementias
Authors: Imm Jennifer L , Harvey Joshua , Creese Byron , Chouliaras Leonidas , Dempster Emma , Ballard Clive G , O'Brien John T , Aarsland Dag , Mill Jonathan , Pishva Ehsan , Lunnon Katie
Published: December 2022

Background

The Lewy body diseases, Dementia with Lewy bodies (DLB), Parkinson’s disease (PD) and Parkinson’s disease dementia (PDD) are all neurodegenerative diseases classified by the accumulation of alpha‐synuclein in neurons, forming Lewy bodies (LB). We hypothesise that these LBs cause epigenetic changes within neurons and surrounding cells and that these changes can be used to distinguish the different diseases from one another.

Method

Bulk tissue from the cingulate gyrus and prefrontal cortex was analyzed on the Illumina Infinium Methylation EPIC array generating a quantitative measure of DNA methylation for over 850,000 CpG sites (n=∼100/disease group). Linear regression and pathway analyses were then used to identify loci that are significantly different or specific to each disease.

Result

Study groups have been sourced consisting of cases with PD, PDD and DLB based on LB deposition and clinical symptom staging. Age‐matched control cases have been selected that have similar levels of concomitant AD pathology to the disease groups. We have identified significant changes in methylation associated with both phenotype and neuropathology alongside the cellular pathways these changes correspond with.

Conclusion

We have collated a well powered study cohort to interrogate the epigenetic basis of neuropathological progression and clinical staging of LB disease, controlling for levels of concomitant AD pathology. We have completed DNA methylation analysis for two disease relevant brain regions and identified both phenotype neuropathology associated changes within these regions. Processing of samples for fluorescence activated nuclei sorting (FANS) and laser capture microdissection (LCM) has begun (n=15/group) to assess the cell type specificity of the methylation changes and the effect of Lewy bodies on neuronal methylation respectively.