bluuebunny/crossref_metadata_2025 huggingface dataset:
Examining the influence of marital status on cognitive risk in a nationally representative sample of adults in India
Authors: Zanwar Preeti Pushpalata , KJ Vinod Joseph
Published: June 2023

Background

Influence of marital status on cognitive risk remains understudied in India with 17.7% of the global population.

Methods

To examine the influence of marital status (categorized as married, never married, widowed and other which included partnered, separated or divorced) on cognitive risk and to what extent marital status is a protective factor for cognitive decline. For this observational study design, we merged nationally representative harmonized Longitudinal Aging Study of India (LASI) and the harmonized Diagnostic Assessment of Dementia (LASI‐DAD) for 4096 adults 45 years and older and their spouses regardless of age from 2017 to 2019. We accounted for multistage, stratified, area probability cluster design of the complex survey using appropriate weights. The primary outcome was cognitive impairment based on cognition score without number series based on word recall, cognition tests and Jorm IQ code < 3.9 or > 3.9 or higher. The cognitive impairment was constructed as a 0/1 dummy variable coded 0 if the respondent was at low‐risk (mid‐tertile) or very low‐risk (top‐tertile) and coded 1 if the respondent was high‐risk (bottom‐tertile). We assessed proportion at risk for cognitive impairment by marital status and used chi‐square test to test significance at p<0.05 level. We ran logistic regression model on weighted population to examine the odds ratio of cognitive risk by marital status.

Results

Our weighted population was 4,716 adults, 64.0% were married, 0.93% were never married, 33.3% were widowed, and 1.8% were other. Those married had the lowest proportion of cognitive risk (43.0%) while never married had the highest proportion of cognitive risk (71.0%), followed by widowed (59.6%) and other (55.0%). In logistic regression, in comparison to married adults, cognitive risk was three times more likely for never married adults, AOR 3.17 [95% CI, 1.55‐6.48], and nearly two times more likely for widowed, AOR 1.58 [95% CI, 1.33‐1.88].

Conclusion

Marital status likely functions as a social determinant of cognitive decline in the Indian context. These findings are relevant to U.S. and other countries as the harmonized LASI, is a sister study of the harmonized U.S. Health and Retirement Study and data can be leveraged using cross‐country comparisons.
Virtual reality can improve autobiographical memory in people with dementia: pilot test in healthy people
Authors: Torres‐Castro Sara , Álvarez‐Cisneros Teresa , López‐Ortega Mariana , Rabaneda‐Bueno Rubén , Segura Blanca A. , Robledo Luis Miguel Gutierrez
Published: June 2023

Background

We have developed a reminiscence program for people living with dementia to improve their autobiographical memory and reduce neuropsychiatric symptoms. In this paper, the objective is to present findings from a pilot’s virtual reality experience with elderly people without dementia.

Method

4 people over 60 years of age from a non‐governmental organization in Mexico City that carry out active and healthy aging activities were invited to participate, the inclusion criteria: people without dementia or other mental health problems and who accepted participate voluntarily. A focus group was held to find out their perceptions about the use of virtual reality as a therapeutic tool. Afterwards, the virtual reality glasses were placed on each of the participants, with a duration of 10 minutes. The content of the video was related to images of childhood in a context of the 40’s and 50’s. At the end, the participants met again and commented on their experience. The conduct of the focus groups and the feedback was in charge of a psychologist, and accompanied by a staff of 2 engineers and three co‐investigators, for the care of the participants.

Result

None of the 4 participants had used virtual reality, one of them had only heard her grandchildren talk about it. They thought that technology can help in everyday life, but they were unaware that virtual reality could serve as a therapeutic tool to support people living with dementia. After using the virtual reality glasses, one of the participants remembered a brother who had died at the age of 5 years and that it was something she had never talked about, she imagined that it was really her brother and some tears flowed. Another participant commented that she had remembered her family when she was a child. In general, they commented that the experience was pleasant and they would like to continue using virtual reality.

Conclusion

In this first approach in older people without dementia, the acceptance of the use of technology in a therapeutic environment and accompanied by mental health professionals to provide support and feedback about the content is shown.
ADAMTS4 as an enzyme cleaving at APP669 site
Authors: Kaneko Naoki , Yokoyama Miyabishara , Korenaga Akihito , Sekiya Sadanori , Iwamoto Shinichi , Matsuzaki Masaya , Tanaka Koichi , Tomita Taisuke , Ikemura Kentaro , Opoku Gabriel , Hirohata Satoshi
Published: June 2023

Background

We have previously identified APP669‐711 (a.k.a. Aβ(‐3)‐40) in human plasma using immunoprecipitation combined with matrix‐assisted laser desorption ionization time‐of‐flight mass spectrometry (IP‐MALDI‐MS) (Kaneko et al., Proc Jpn Acad Ser B Phys Biol Sci. 2014). Our assay has revealed that the composite biomarker, which is a combination of APP669‐711/Aβ1‐42 ratio and Aβ1‐40/ Aβ1‐42 ratio in human plasma, correlates with amyloid PET status (Nakamura et al., Nature 2018). Our previous research using cultured cells has suggested that A Disintegrin and Metalloproteinase with a Thrombospondin type 1 motif, type 4 (ADAMTS4) is involved in APP669‐711 production. Here, we present further evidence on the involvement of ADAMTS4 in the APP669 site‐cleavage.

Method

We prepared a recombinant APP substrate, which is APP81 corresponding to APP619‐699 sequence with a V5/His tag at the C‐terminus and a FLAG tag at the N‐terminus (FLAG‐APP81‐V5/His) for in vitro cleavage assay. Recombinant human ADAMTS4 protein and the tagged APP81 were incubated either alone or together at 37°C. The incubated samples were desalted and then analyzed by MALDI‐TOF MS. In vivo evaluation of ADAMTS4, we analyzed plasma samples from Adamts4‐/‐ mice and WT mice using IP‐MALDI‐MS.

Result

In vitro cleavage assay, N‐ and C‐terminal fragments cleaved at APP669, Aβ4th, Aβ12th site were detected in the mixture of the recombinant APP81 and ADAMTS4 proteins but not in the sample of substrate or enzyme alone. Furthermore, a peptide derived from double digestion by APP669 and Aβ12th site‐cleavages (i.e., APP669‐Aβ11) was also identified by MS/MS analysis. The analysis of mouse plasma showed that murine APP669‐711 level was decreased in Adamts4‐/‐ mice compared to WT mice.

Conclusion

These results indicated that ADAMTS4 is one of the enzymes that can cleave the APP669 site directly and contribute to the generation of APP669‐711 in vivo.
Association between centrally active angiotensin‐converting enzyme inhibitors with dementia risk
Authors: Newby Danielle , Winchester Laura M , Sproviero William , Fernandes Marco , Ghose Upamanyu , Launer Lenore J. , Nevado‐Holgado Alejo J
Published: June 2023

Background

Hypertension is a well‐established risk factor for dementia and antihypertensive treatments could be important for disease prevention. Observational and animal studies suggest Angiotensin‐Converting Enzyme Inhibitors (ACEIs) are associated with reduced dementia risk whereas genetic studies show these drugs increase risk. One plausible explanation of this heterogeneity is that not all ACEIs cross the blood–brain barrier (BBB) and their association with disease risk may depend on whether or not the specific molecule crosses the blood brain barrier. We investigated the association of centrally vs non‐centrally active ACEIs with incident dementia compared using medical records from the USA (OPTUM).

Methods

This is a retrospective new‐user comparative cohort study using patients ≥50 years old with hypertension who were new users of centrally active ACEIs (captopril, fosinopril, lisinopril, perindopril, ramipril, trandolapril; n = 327,663 or non‐centrally active ACEIs (n = 30,867) (benazepril, enalapril, moexipril, quinapril). Patients were followed for up to 10 years (2006‐2018) during which 11,422 dementia cases were diagnosed. Stratified Cox proportional hazards models were used to estimate the hazard ratio (HR) of incidence all‐cause dementia and sub types over the follow up period, controlling for age, demographics such as geographic location and other comorbidities such as stroke, myocardial infarction and diabetes.

Results

In unadjusted and adjusted models, new users of centrally active ACEIs had a slightly greater risk for all cause dementia and vascular dementia but not for Alzheimer’s disease. HR for unadjusted models were 1.08 (95% CI 1.01‐1.15), 1.34 (95% CI 1.13‐1.60) and 1.00 (95% CI 0.90‐1.12) for all cause dementia, vascular dementia and Alzheimer’s disease respectively. Whereas HR for adjusted models for all cause dementia, vascular dementia and Alzheimer’s disease were 1.16 (95% CI 1.09‐1.24), 1.35 (95% CI 1.12‐1.62) and 1.10 (95% CI 0.98‐1.23) respectively.

Conclusions

Our results potentially indicate centrally active ACEIs are associated with a slightly higher risk of all‐cause dementia compared to non‐centrally active ACEIs. This work supports causal genetics studies which indicate links between ACE inhibitors in the brain with increased dementia risk. Future work will investigate whether other antihypertensive drug classes differ in risk based on blood brain barrier penetrating ability.
Retinal TDP43 pathology in Alzheimer’s disease, Parkinson’s disease and frontotemporal dementia
Authors: Dijkstra Anke A. , Morrema Tjado , de Ruyter Frederique J. Hart , Verbraak Frank D. , de Boer Johannes , Pijnenburg Yolande A.L. , Rozemuller Annemieke J.M. , Bouwman Femke H. , den Haan Jurre , Hoozemans Jeroen J.M.
Published: June 2023

Background

As an extension of the brain, the retina displays similarities with the brain in terms of anatomy and functionality. The accessibility of the retina provides a ‘window’ to the brain and a great potential for noninvasive imaging of neurodegenerative changes in patients. TAR DNA binding protein 43 (TDP‐43) is one of the main pathological hallmarks found in frontotemporal lobar degeneration (FTLD). Previously, we identified phosphorylated TDP‐43 (pTDP‐43) aggregation in the retina of FTLD cases with underlying TDP43 (FTLD‐TDP) pathology, including donors with C9orf72 and progranulin (GRN) mutations. The aim of this study is to assess the presence of pTDP‐43 in the retina across various neurodegenerative diseases and controls. This will provide insight in whether the presence of TDP43 pathology in the retina is exclusive for cases with FTLD‐TDP and potentially serve as an in‐vivo biomarker.

Method

Post‐mortem eyes were collected by the Netherlands Brain Bank from donors with Alzheimer’s disease (AD), Parkinson’s disease (PD), frontotemporal dementia (FTD) and controls (N = 80). Nasal superior‐temporal quadrants were cut in sections of 10 µm. Immunohistochemical stainings were performed for phosphorylated TDP‐43 (pTDP‐43).

Result

FTLD‐TDP cases showed pTDP‐43 immunopositive inclusions in the plexiform layers. Additionally, some AD cases showed sparse pTDP‐43 positive inclusions. Data of the other pathological groups will be available within a couple of months.

Conclusion

pTDP‐43 is abundantly present in the retina of FTLD‐TDP patients, while only sporadically seen in AD patients. With the advances in ocular imaging techniques, these findings provide a patient friendly retinal biomarker to diagnose FTLD‐TDP. This would be the first FTD specific biomarker, since no other pathology specific biomarkers for the various underlying pathological changes that are known to cause FTD (e.g. tau, FUS, etc), are currently available.
Kernel flow and the eye‐ brain connectome: Towards a more robust technique to identify high‐risk individuals before cognitive decline
Authors: DeBuc Delia Cabrera , Ramos Alberto R , Galor Anat , Sapahia Rishav , Hasalami Ardita , Fernandez Javier De Jesus , Habash Ranya
Published: June 2023

Background

Optical brain imaging allows an understanding of the structure and function of neurons. Researchers can help patients who suffer from nervous system diseases, such as Alzheimer’s disease and Lewy’s Body Dementia, by exploring brain structure and function. Despite the advent of new PET diagnostics to image amyloid deposits in living patients' brains, there remains a need for more readily available and affordable diagnostic testing.

Method

A time‐domain functional near‐infrared spectroscopy (TD‐fNIRS) system (Kernel Flow, Kernel Inc.) is presented. The system has been designed as a small modular device that can provide real‐time monitoring of tissue oxygenation in the brain as subjects take tests, perform cognitive tasks, and/or receive stimulation.

Result

We show the performance of the wearable TD‐fNIRS device in multiple settings and aim to use this technology to develop a protocol for identifying and tracking brain changes in aging and dementia from the preclinical stage of the disease.

Conclusion

Laboratory tests with study subjects and preliminary data recorded demonstrate the potential of the system as a clinical tool to be employed in multiple settings to not only monitor brain activity but with the potential for additional human neuroscience applications, making neuroimaging more accessible across health and science platforms.
Effects of T217 Phosphorylation on Tau Localization and Microtubule Binding
Authors: Rajbanshi Binita , Mandell James W , Bloom George S
Published: June 2023

Background

Biomarker‐based early detection of Alzheimer’s disease (AD) is necessary for developing therapies that counter AD symptom onset. Promising biomarkers include tau phosphorylated at T181, T217 or T231, levels of which can be measured in cerebrospinal fluid or plasma. Little is known about functional consequences of tau phosphorylation at these sites, though, especially for taupT217. We thus sought to identify where taupT217 is localized in the brains of human AD patients and AD model mice, and in cultured mouse neurons, and, in a more functional context, to determine if phosphorylation at T217 affects tau binding to microtubules.

Method

Brain tissue from human AD patients and AD model mice, and cultured mouse neurons were analyzed by western blotting and immunofluorescence microscopy to compare the intracellular localization of taupT217, taupT181, taupT231 (AT180 epitope) and taupS396,pS404 (PHF1 epitope). EGFP‐tau (2N4R) was expressed in CV‐1 African green monkey kidney fibroblasts as wild type (WT), T217A non‐phosphorylatable, and T217E pseudo‐phosphorylated tau versions of the fluorescent fusion protein. Fluorescence recovery after photobleaching (FRAP) microscopy was used to assay turnover rates of the EGFP‐tau fusion proteins on microtubules, a surrogate measurement of affinity.

Result

In human AD brains and AD model mice, taupT217 was abundant in the somatodendritic compartment and co‐localized with neurofibrillary tangles. In cultured neurons, taupT217 was concentrated in somatodendritic puncta that were closely associated with dendritic spines. Both in vivo and in cultured neurons taupT217 co‐localized only partially with taupT181 and taupT231. Exposure of cultured neurons to extracellular oligomers of tau, but not amyloid‐β, increased intracellular taupT217. In CV‐1 cells, EGFP‐tauT217E recovered from photobleaching faster than EGFP‐tauT217A or EGFP‐tauT217.

Conclusion

Intracellular taupT217 is enriched at locations that normally lack much tau and is increased by extracellular tau oligomers. TaupT217 is enriched near dendritic spines, suggesting a possible role for T217 phosphorylation in altering synaptic activity. The faster fluorescence recovery of EGFP‐tauT217E compared to EGFP‐tauT217A or EGFP‐tauT217 implies that T217 phosphorylation reduces tau’s affinity for microtubules.
Drosophila eye model to study the role of NAT9 in Alzheimer’s Disease related Dementia (ADRD)
Authors: Deshpande Prajakta , Snider Emily , Chimata Anuradha Venkatakrishnan , Kango‐Singh Madhuri , Singh Amit
Published: June 2023

Background

One of the hallmarks of Alzheimer’s disease (AD), an age‐related progressive form of dementia, is accumulation of the amyloid beta (Aβ42) plaque, which manifests in decline in cognitive function. The accumulation of these Aβ42 plaques trigger the hyperphosphorylation of tau, a microtubule associated protein, which results in the intracellular accumulation of neurofibrillary tangles (NFTs) due to destabilization of microtubules.

Method

We employed the Gal4/UAS system in Drosophila melanogaster to misexpress human Aβ42 within the developing fly retina, exhibiting AD‐like neuropathology. Accumulation of Aβ42 plaque(s) triggers the aberrant activation of signaling pathways like the JNK pathway resulting in neuronal cell death by unknown mechanism(s). Using candidate based forward genetic screening, we identified N‐acetyltransferase 9 (NAT9) as one of the genetic modifiers of GMR>Aβ42 reduced eye phenotype. Previously NAT9 has been shown to stabilize microtubules by acetylation of tubulins, thereby inhibiting JNK signaling. This study aims to understand the role of NAT9 in Aβ42‐mediated neurodegeneration.

Result

The gain‐of‐function of NAT9 rescues Aβ42‐mediated neurodegeneration whereas loss‐of‐function of NAT9 enhances Aβ42‐mediated neurodegeneration. We have also found that the gain‐of‐function of human NAT9 also suppresses Aβ42‐mediated neurodegeneration suggesting the functional conservation. Interestingly, mutated NAT9 in the acetyl‐ CoA binding site shows similar phenotype as gain‐of‐function of NAT9 suggesting its function is independent of acetylation activity. Moreover, the eye antennal imaginal discs of loss‐of‐function of NAT9 in GMR>Aβ42 background shows the activation of JNK pathway by increased pJNK levels.

Conclusion

Our data suggests that NAT9 downregulates JNK signaling pathway which can ameliorate Aβ42‐mediated neurodegeneration.
Radiomics deep learning application to differentiate mild cognitive impairment patients (MCI) from healthy control (HC)
Authors: Cheung Eva YW
Published: June 2023

Background

This study aimed to build a radiomics based model using structural MRI to differentiate patients with mild cognitive impairment (MCI) from healthy control (HC).

Methods

202 healthy controls and 136 MCI patients were downloaded from a publicly available database, the ADNI database. The MPRAGE T1W MRI were re‐oriented, segmented and normalized to the whole brain mask template using DPARSF software. 107 radiomics features were extracted within the whole brain using 3D slicer software with pyradiomics extension. Both the MCI and HC groups were divided into a training group and a validation group. To minimize the chance of overfitting, out‐of‐bag predictions were performed. A random forest model was built using training set, and validated by the validation set by R software.

Results

The receiver operating characteristics (ROC) curve showed that the average class accuracy achieved 95.7% and overall accuracy was 96.2%. The area under the curve (AUC) was 0.868.

Conclusion

The radiomics deep learning model can accurately differentiate MCI from HC. The application can be fully automatic and it is practical in applying for MCI screening.
Correlates of neuroimaging biomarkers in a middle‐age racially diverse cohort: Updates from the association between cardiovascular risk and preclinical Alzheimer’s Disease pathology (ASCEND) study
Authors: Misiura Maria , Munkombwe Chinkuli , Verble Danielle D , Likos Kelly D. S. , Igwe Kay C. , Zetterberg Henrik , Kumar Veena , Brickman Adam M. , Hu William T. , Dotson Vonetta M , Wharton Whitney
Published: June 2023

Background

Black individuals (BIs) are at an increased risk of Alzheimer’s disease (AD) than white individuals (WIs), which is partially explained by increased prevalence of vascular risk, in conjunction with structural inequities including healthcare. Studies suggest that neuroimaging and CSF AD biomarkers may differ across race. We previously identified disparate relationships between brain activity within the frontal and parietal lobes and CSF AD biomarkers. We include analysis of structural and functional neuroimaging in a racially diverse, middle‐aged cohort with an AD family history. We aimed to identify relevant neuroimaging correlates of vascular health and AD, and how relationships may vary according to race.

Methods

We analyzed data from 76 individuals (29 BIs, 47 WIs). Neuroimaging measures included functional connectivity from functional resting state magnetic resonance imaging (rs‐fMRI) between fronto‐striatal regions (putamen, middle frontal gyrus, superior frontal gyrus), regions of the default mode network (hippocampus, parrahippocampal gyrus (PHG), ventromedial prefrontal cortex, inferior parietal lobule, temporal pole), structural neuroimaging (hippocampal volumes), and regional white matter hyperintensity volumes (frontal, temporal, parietal, occipital, cerebellar volumes). AD biomarkers included CSF phospho‐tau, total tau, & AB42. We included a race X CSF biomarker interaction term in our linear models.

Results

We identified a race X tau and race X AB42 interaction term for connectivity measures between the middle frontal and superior frontal gyri and the putamen such that as biomarker burden increased, connectivity between these regions decreased within BIs. PHG to temporal pole connectivity also exhibited these same relationships to CSF tau and AB42. Hippocampal volumes did not exhibit relationships to AD biomarkers. We identified a significant race X CSF Ab42 interaction term such that increased AD CSF biomarker burden was related to increased WMH volume in the temporal and parietal lobe.

Conclusion

We extend previous work in rs‐fMRI of AD to a middle‐aged cohort, supporting neuroimaging and CSF biomarker relationships may differ by race. Front‐striatal connectivity may be a clinically relevant biomarker in mid‐life studies of AD, sensitive to CSF AD biomarker levels. Results support previous consensus that functional and WM measures are more sensitive to early AD pathology and extends this knowledge to BIs.
Association between default‐mode network and medial temporal lobe functional connectivity and episodic memory in late middle‐aged and older patients with obstructive sleep apnea
Authors: Martinez Guillermo E. , Daneault Véronique , Martineau‐Dussault Marie‐Ève , André Claire , Baril Andree‐Ann , Gagnon Katia , Montplaisir Jacques , Carrier Julie , Gosselin Nadia
Published: June 2023

Background

Obstructive sleep apnea (OSA) is associated with risk of cognitive decline in older adults. Our group previously observed that more severe OSA was associated with lower functional connectivity between the hippocampus and multiple regions of the default‐mode network (DMN) and the limbic system. However, whether these lower functional connectivity is associated with memory impairment is unknown. Here, we tested the hypothesis that lower functional connectivity previously associated with OSA severity could be related to worse episodic memory performance in late middle‐aged and older adults.

Method

We included 37 participants with moderate‐to‐severe OSA (apnea‐hypopnea index [AHI] : 33±18 events/h, 7 females, 67.2±7 years old, 15.2±3.4 years of education, 15 with mild cognitive impairment [MCI]) and 59 control participants (AHI: 5.8±3.7 events/h, 18 females, 65±6.9 years old, 15.5±3.3 years of education, 25 MCI) matched for age, sex, education and cognitive diagnosis. They underwent a neuropsychological assessment, a full‐night of polysomnography and a resting‐state functional magnetic resonance imaging. A composite score for episodic memory performance was calculated with the Rey Auditory Verbal Learning Test (trials 1 to 5, immediate and delayed recalls) and the Brief Visuospatial Memory Test‐revised (total and delayed recalls). CONN toolbox was used to perform multiple regression analyses between resting‐state functional connectivity and memory performance for each group separately. All analyses were controlled for age, sex and education, and corrected for false‐discovery rate.

Result

In OSA participants, lower functional connectivity between the medial prefrontal cortex and the hippocampus was associated with better episodic memory performance (ps<0.05), while a trend was observed in the control group (p = 0.05). Lower functional connectivity between the lateral parietal cortex and the parahippocampus was also associated with better episodic memory performance in the OSA participants (p = 0.03).

Conclusion

Contrary to our hypothesis, the lower resting‐state functional connectivity observed in OSA participants was associated with better episodic memory performance. This pattern of functional connectivity between the DMN and the limbic system negatively associated with episodic memory performance was previously reported in healthy older adults and patients with preclinical Alzheimer’s disease. Whether these functional connectivity patterns predict further cognitive decline in untreated OSA patients needs to be investigated.
Plasma metabolomics indexes time to clinical dementia in autosomal dominant Alzheimer’s disease mutation carriers
Authors: Gross Thomas J , Cheema Amrita K , Fiandaca Massimo S , Federoff Howard J , Ringman John M , Mapstone Mark
Published: June 2023

Background

Metabolic dysregulation has been implicated in the pathobiology of Alzheimer’s disease (AD), including familial autosomal dominant AD (ADAD). Recent metabolic neuroimaging of preclinical ADAD mutation carriers has suggested that levels of the reactive glial marker myo‐inositol increase with proximity to expected age at dementia onset. It remains unclear, however, if similar metabolic change related to anticipated phenoconversion can be observed at network‐scale in the peripheral plasma metabolome of ADAD mutation carriers.

Method

We collected peripheral blood plasma from ADAD mutation carriers with and without objective cognitive decline (ncarrier = 55) who participated in a longitudinal kindred study. We used untargeted liquid chromatography‐ mass spectrometry (LC‐MS) metabolomics to infer putative metabolic pathway and protein disruptions associated with impending dementia diagnosis at whole‐genome scale. Spearman 𝝆 correlation coefficients were determined for each identified mass feature in relation to clinical, family‐wise estimated years to diagnosis prior to the submission of these summary statistics to metabolomic modeling.

Result

A total of 91 LC‐MS mass features were significantly correlated with estimated years to dementia onset, nominal p’s < .05. Pathway‐based, genome‐scale metabolomic modeling analysis revealed a de novo plasma metabolomic activity network composed of interconnected lipid and small, polar metabolite hubs. These same correlations were also submitted to gene‐inferring, whole‐genome metabolomic modeling using PIUmet. Intriguingly, mRNA expression of prioritized genes was not limited to the brain and involved multiple peripheral tissues. In the CNS itself, however, genes prioritized by PIUMet metabolomic modeling frequently demonstrated expression in glia.

Conclusion

Consistent with prior metabolic findings in ADAD mutation carriers, network alterations to the peripheral plasma metabolome correspond with increasing proximity to expected age of dementia onset. Because neuroinflammation has been previously described as an immunometabolic process in pathological aging, emerging metabolic network disintegrity in ADAD may index reactive glial pathobiology previously suggested by prior metabolic investigations of this population. These perturbed networks inferred from participant blood plasma suggest targetable CNS‐peripheral metabolic dyshomeostases which otherwise precipitate pathobiological “failures of compensation” and concomitant cognitive decline in carriers of Mendelian ADAD mutations.
Decreased/increased beta/alpha functional connectivity in pathological and healthy aging. A dual pattern of brain dynamics revealed by magnetoencephalography
Authors: Chino Brenda N , Cuesta Pablo , Pacios Javier , Torres Lucia , Doval Sandra , Dolado Alberto Marcos , Fernández Ricardo Bruña , Maestú Fernando
Published: June 2023

Background

Alzheimer’s Disease (AD) is a progressive neurodegenerative disorder that develops unnoticed during several years prior to the onset of clinical symptomatology. The deterioration of delayed recall is one of the most significant predictive factors to define the progression of Mild Cognitive Impairment (MCI) to AD, and it has a strong relationship with medial temporal dysfunction. Identifying a reliable measurement of brain health and cognitive function is essential to mitigate the side effects of cognitive decline by promoting early intervention. The purpose of this study was to explore, in MCI patients and ‐healthy participants, how memory loss modifies the functional integrity of resting‐state brain activity, as measured with MEG.

Method

118 MCI (aged from 58 to 87) and 261 healthy (aged from 41 to 82) participants were recruited from the Hospital Universitario San Carlos (Madrid, Spain). They all underwent an extensive neuropsychological evaluation, MRI, and MEG recordings.

Results

Delayed recall (DR). The correlation analysis between functional connectivity (FC) and DR score showed a negative correlation, (rho = ‐0.208, p <0.001), between beta‐band FC and LTM performance in the occipital region, so that participants with higher FC showed lower memory performance. Furthermore, the correlation between LTM and beta FC‐st remained significant when looking at the MCI (rho = ‐0.236, p < 0.01) and healthy groups separately (rho = ‐0.207, p< 0.001). Short Term Memory (STM). The STM was found to be associated, (rho = 0.175, p < 0.001), with increased occipital alpha‐band FC, indicating that those participants with the higher FC, the higher the memory performance. Interestingly, a separate analysis of both groups revealed that this correlation was present only in the healthy group (rho = 0.141, p <0.02).

Conclusion

A dual pattern of a respective decreased/increased beta/alpha FC in the occipital brain region appeared to be associated with memory performance in healthy and pathological aging.
Progressive electrophysiological changes in a mouse prion model of terminal neurodegenerative disease
Authors: Bowden Jessica Elisabeth Kathleen , Riddell John S , Phillips Keith G , Tobin Andrew B , Bradley Sophie J
Published: June 2023

Background

Intracerebral injection of prion brain homogenate into mice recapitulates several features of Alzheimer’s disease, including memory deficits, progressive neuronal loss and terminal disease. Pharmacological interventions can preserve species‐specific behaviour and extend survival, but whether treatment can modulate cognition‐related brain activity is unclear. The purpose of this study is to define electrophysiological changes in the murine prion model, and inform future studies of the effects of interventions on neural activity.

Method

Mice inoculated with either Rocky Mountain Laboratories prion (n = 5) or control brain homogenate (n = 3) underwent surgery to implant seven skull screw recording electrodes (Figure 1). From 4 weeks post‐inoculation, weekly recordings were made by attaching a wireless transmitter to the implant. Prion mice were humanely killed 9‐12 weeks post‐inoculation once they exhibited clinical signs of disease. Brains were retained for histological analysis.

Decibel power spectra were generated from recordings using a 2.5 s sliding window with 50% overlap. Theta peak frequency and area under the curve measures were extracted (Figure 2). Effects of prion and week post‐inoculation on these features were determined using mixed effects analyses.

Result

Prion mice exhibited a progressive reduction in peak theta frequency, which differed from control mice at 8‐ and 9‐weeks post‐inoculation. The mean ± 95% confidence interval for control mice at 8 weeks post‐inoculation was 8.9±0.4 Hz, compared to 7.0±0.7 Hz for prion mice (Figure 2). The extent of slowing at 9 weeks post‐inoculation correlated with survival outcomes: clinical signs occurred 10‐25 days earlier in mice with a peak theta frequency <6.5 Hz. Delta power showed a week by inoculation interaction, declining in control mice up to 6 weeks post‐inoculation and increasing in the latter weeks of prion infection.

Conclusion

We have shown that slowing of electrical activity, a common feature of progressive neurodegenerative diseases, occurs in the murine prion model and correlates with survival. This further validates using the prion model to investigate interventions aimed at treating Alzheimer’s disease and related dementias. Elevated delta power is associated with neurodegenerative disease and muscarinic receptor antagonism, further demonstrating the suitability of the prion model to test pro‐muscarinic interventions in neurodegenerative disease.
Lesion‐network mapping for post‐stroke cognitive impairment
Authors: Lim Jae‐Sung , Lee Jae‐Joong , Kim Geon Ha , Woo Choong‐Wan , Bae Hee‐Joon
Published: June 2023

Background

To overcome difficulty obtaining functional neuroimaging data directly from acute stroke patients, researchers have developed a new mapping approach called the “indirect lesion‐network mapping.” This mapping approach uses a priori network information obtained from normative samples to account for brain areas functionally connected to patients’ local lesions. This new method has successfully mapped some peculiar stroke symptoms, such as aphasia and post‐stroke pain. However, it remains unclear whether this method can produce sensible mapping results for the post‐stroke cognitive impairment of community samples.

Method

A total of 1,431 patients were enrolled from two university hospitals. They underwent a comprehensive neuropsychological test within one year post‐stroke. We used the Verbal Learning Test to examine memory performance and the trail‐making test‐A and digit symbol coding task to assess the speed of processing. We classified the patients into two groups— cognitively‐impaired (CI) (< ‐2.0 standard deviation) and cognitively‐unimpaired (CU) (> ‐1.0 SD)—based on the task performance. We calculated the lesion‐affected networks based on patients’ stroke lesions combined with the normative functional network data from the Human Connectome Project‐Aging cohort, n = 687. Then, we obtained and compared the lesion network maps for patients with versus without cognitive impairment.

Result

A total of 348 patients showed impairment in the memory task, while 247 patients demonstrated impairment in the speed‐of‐processing task. For both tasks, the conventional lesion‐network mapping approach produced highly similar results between the CI versus CU groups—both groups were localized to the major hubs of the large‐scale functional networks, such as mid‐cingulate and insular cortices. However, the mapping results became more sensible when we contrasted the lesion‐network maps between the CI versus CU groups. For example, the memory impairment was localized to the functional network including the left medial and anterior temporal, inferior and dorsolateral frontal cortices, whereas the speed‐of‐processing impairment was localized to the network including both occipital and anterior temporal cortices.

Conclusion

We suggest that some additional analysis steps to the conventional lesion‐network mapping, including the contrast analysis, can help improve the specificity and sensitivity of the results when targeting the stroke‐induced cognitive impairment of community samples.
Four‐year cognitive decline in mild cognitive impairment patients with distinct baseline neuroanatomical atrophy profiles: A MEMENTO and QyScore® study
Authors: Gordon Elizabeth , Cavedo Enrica , Santos Clarisse Longo dos , Samper‐González Jorge , Schwarz Adam J. ,   the MEMENTO Study Group
Published: June 2023

Background

Neuroanatomical atrophy profile is increasingly recognised as a valuable characterisation in mild cognitive impairment (MCI) individuals and may provide prognostic information about cognitive decline.

Method

1153 MCI participants from the MEMENTO memory clinic study with 48‐month longitudinal follow‐up were included (mean (sd) Age = 70.6 (8.2), 60% female, CDR‐SB = 0.63 (0.72)). QyScore® volumetric quantification was applied to baseline 3DT1 images and four recognized neuroanatomical subtypes defined based on regional atrophy with respect to an internal normative database (z←1.64) [1,2]: no/minimal atrophy [N‐] (n = 1,012), limbic predominant: LP (n = 37), hippocampal sparing: HS (n = 84) and combined hippocampal and cortical atrophy [typical/diffuse: TD] (n = 20). 145 participants were amyloid positive (A+) via CSF or PET (Age = 73.7 (5.9): 47% female: N‐ = 114, LP = 8, HS = 21 and TD = 2). All participants underwent cognitive and functional assessments at baseline and 48 months, including mini‐mental state examination (MMSE), clinical dementia rating (CDR), Free and Cued Selective Reminding Test (FCRST) and Instrumental Activities of Daily Living (IADL) scale. Linear regression analysis (correcting for age, sex and baseline performance) investigated the relationship between baseline neuroanatomical subtype and subsequent 4‐year cognitive decline. Bonferroni correction was applied.

Result

At month 48, all subtypes demonstrated significant decline across memory, orientation, and executive function. Severity of decline varied across subscales and subtype and was particularly marked in A+ LP individuals (Figure 1). IADL remained stable for the N‐ and TD subgroups. 143 participants converted to dementia [102 = N‐, 18 = LP, 15 = HS, and 8 = TD subtypes, representing 10%, 49%, 18% and 40% of the total N‐, LP, HS and TD atrophy subtypes respectively]. HS and N‐ individuals also demonstrated the least decline across all domains and did not significantly differ on any tests. LP atrophy subtype demonstrated the greatest decline across all cognitive domains as well as global CDR and IADL (p<0.001 compared with N‐ and HS subtypes). Similarly, TD phenotypes showed significant decline across multiple cognitive subscales compared with N‐ and HS subtypes (p<0.001) particularly for orientation and global CDR.

Conclusion

Early atrophy profiles in MCI populations can provide insights into the domains and severity of future patient progression over 4 years.

[1] Planche et al., (2020)

[2] Schwarz et al., (AAIC2022)
CSF sTREM2 has opposite association with brain structural damage rate at early and late stage of Alzheimer’s disease
Authors: Leng Fangda , Zhan Zhenying , Edison Paul , Sun Yunchuang , Liu Fang , Sun Yongan , wang Zhaoxia
Published: June 2023

Background

The role of neuroinflammation in the pathogenesis of Alzheimer’s disease (AD) is still controversial. Recent studies proposed that microglial response may have a stage‐dependent effect on disease progression. Considering the CSF soluble triggering receptor expressed on myeloid cells 2 (sTREM2) has emerged as a promising marker of microglial activation, we aimed to further test this hypothesis by studying the association between baseline sTREM2 with dynamic brain structural changes in different stage of AD.

Method

22 amyloid‐positive (A+) and tau‐positive (T+) AD patients and 24 A+T+ MCI patients were identified from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database. The patients had baseline measurements of CSF A‐beta, P‐Tau, sTREM2, baseline and follow‐up T1‐weighted and diffusion tensor imaging (DTI) scans, and were followed up for at least one year. Voxel‐based morphometry (VBM) analysis was performed to assess grey matter volumetric change, while fractional anisotropy (FA) and mean diffusivity (MD) were derived from DTI scans to evaluate white matter microstructural integrity. Linear mixed effect models were then applied to model the longitudinal change of grey and white matter integrity, and to analyze the influence of baseline sTREM2 on the rate of brain structural changes.

Result

In A+T+ AD patients, baseline CSF sTREM2 was associated with faster FA decline and MD increase in association fibers including corpus callosum, inferior longitudinal fasciculus, cingulum, inferior fronto‐occipital fasciculus, and superior longitudinal fasciculus. In A+T+ MCI patients, baseline CSF sTREM2 was associated slower grey matter volumetric loss in regions including Alzheimer’s signature cortices such as angular gyrus and precuneus, while mixed findings were found regarding white matter integrity, with a protective effect with regard to MD but a potential negative effect against FA values in association fibers.

Conclusion

The current study suggests that microglial activation at early AD stage might have a protective effect against neurodegeneration, while at late stage, it might facilitate neurodegenerative process. These observations support the hypotheses that microglial response is an active factor in the process of Alzheimer’s pathogenesis, and that it has stage‐dependent effects on disease progression. Future efforts on modulating microglial activation could be promising, given a carefully selected time window for intervention.
Impact of episodes of lucidity on people living with dementia and their caregivers: A qualitative study
Authors: Gilmore‐Bykovskyi Andrea L , Block Laura M , Benson Clark , Fehland Jess , Botsch Meghan , Mueller Kimberly D
Published: June 2023

Background

Episodes of lucidity (EL) are generally characterized by a spontaneous and unexpected return of abilities previously believed to be lost in individuals with Alzheimer’s disease and Alzheimer’s disease related dementias (AD/ADRD). Among the myriad implications of lucidity are the impact these episodes have on the person living with ADRD and their family caregivers. Family caregivers provide the majority of support for persons with AD/ADRD and frequently experience complex grief associated with identity and relationship changes over the course of the disease. Consequentially, a transient return of abilities and connection in the person with AD/ADRD may have a substantial impact on their conceptualization of consciousness in the care recipient living with AD/ADRD, approach to care, and emotional wellbeing. It is also not understood how persons living with AD/ADRD may respond to EL.

Methods

This study utilized a descriptive qualitative method employing semi‐structured interviews with family caregivers (N = 22) of persons living with AD/ADRD. Interviews elicited information about participant’s experiences with EL, interpretation of these events, and appraisal of the impact of the event on themselves and the person experiencing it. Interview data were analyzed using a modified, two‐phase thematic analysis approach.

Results

EL were commonly conceptualized by caregivers as illustrative of the ongoing presence of self and consciousness in the person living with AD/ADRD that they posit is at other times concealed due to cognitive impairment. Caregivers overwhelmingly reported that these episodes were valued moments that offered meaningful connection to their loved ones, also at times facilitating acts of saying goodbye or making hard decisions. Caregivers perceived EL as having variable impact on the person living with AD/ADRD. In some situations, EL were perceived as providing the person living with AD/ADRD greater capacity to engage. Sometimes, EL were described as being accompanied by insight regarding deficits and perceived as upsetting to the person living with AD/ADRD.

Conclusion

We found that EL can have both positive and negative impacts on caregivers and people living with AD/ADRD. Future research is needed to address ethical considerations surrounding EL and to support caregivers in how to anticipate and respond to these events.
UPS of the CNS: Longitudinal profiling of mitochondrial DNA in neuronal‐enriched packages from plasma of individuals with cognitive decline
Authors: Hall Courtney , Barber Robert , Phillips Nicole
Published: June 2023

Background

Alzheimer’s disease (AD) is a complex neurodegenerative disorder that disproportionately burdens Mexican Americans (MAs) due to a combination of population‐specific environmental exposures and genetic risk factors. In addition to AD, MAs have a higher prevalence of metabolic comorbidities such as type 2 diabetes (T2D) that have been implicated in accelerated age‐related cognitive impairment. Tissue‐specific mitochondrial dysfunction and oxidative stress are early and prominent features of both AD and T2D that propagate systemic inflammation as these diseases progress. Despite the shared pathophysiology, we do not fully understand the underlying molecular mechanisms linking cognitive decline and metabolic stress, especially in understudied minority populations. Mitochondrial dysfunction may serve as the biological basis of the AD health disparity in MAs who experience earlier onset of symptoms and have an overrepresentation of T2D compared to non‐Hispanic whites (NHWs). This project aims to study T2D‐related risk for cognitive impairment by assessing the packages that neurons secrete to communicate with cells in the periphery. These neuronal‐enriched exosomes (NEEs) can cross the blood‐brain barrier and are thus capable of mediating systemic inflammation in response to CNS‐sourced stress through their mitochondrial DNA (mtDNA) cargo. We hypothesize that plasma NEE mtDNA load will reflect cognitive status and T2D comorbidity over time.

Methods

Exosomes of neuronal origin were enriched via CD171‐based immunocapture in longitudinal plasma samples (two timepoints, 5 years apart) from 348 Texas Alzheimer’s Research and Care Consortium (TARCC) participants stratified by race/ethnicity (MA/NHW), cognitive status (AD/MCI/NC), and T2D comorbidity (+/‐). The success of NEE isolation was assessed using nanoparticle tracking analysis (NTA) and immunoblotting against CD171 and CD81 (canonical exosome surface marker). Following extraction of total DNA from NEEs, absolute mtDNA load and deletion ratio were estimated using a real‐time qPCR assay targeting sites within the minor (D‐loop) and major (ND4) arcs.

Results

Herein, we demonstrate the ability to isolate NEEs from plasma and quantify their mtDNA cargo. Resultant values were analyzed for longitudinal differences and correlation with disease status based on various neuropsychological measures.

Conclusion

As the first effort to assess mtDNA in NEEs, this project provides novel insight into how T2D confers risk for AD across different populations over time.