bluuebunny/crossref_metadata_2025 huggingface dataset:
Long‐term results of Alzheimers’ dementia treated with transcranial pulse stimulation
Authors: Lohse‐Busch Henning
Published: December 2023

Background

The treatment of the brain with focused extracorporal shock waves (ESW) in patients with unresponsive wakefulness syndrome dates back to 2006 (1). This was followed by preliminary investigations for the treatment of Alzheimer’s dementia and Parkinson’s disease in the years up to 2014.

The introduction of a shock wave generator with a navigation system in 2016 (Neurolith, Storz Medical) was a breakthrough for the precise treatment of brain structures. This method of brain treatment was then called TPS. After a 3 month study with people living with Alzheimer’s dementia in 2019 (2), we now present patients with long‐term follow‐up over 3 years during continous monthly TPS treatment as a critical undertaking for future treatments.

Method

6 persons living with mild Alzheimer’s dementia (Mini Mental Status >18) were treated initially 6 times during 2 weeks with TPS. Subsequently, they received one TPS session monthly over 3 years. The results were assessed with the CERAD Plus score and compared with the data of the expected natural development with standard medication according to the ALSOVA study of Hallikainen.

Result

While cognitive skills improved by 12% over 12 months, outcomes returned to the baseline in the second year. A two‐week booster of 6 sessions with TPS improved outcomes again by 4.5% compared to the baseline. After 3 years, the results were at the level of the expected natural development with standard medication.

Conclusion

A symptomatic improvement of Alzheimer’s symptoms with low‐energy TPS over several years seems to be possible. It was a methodological mistake not to examine the patients more frequently neuropsychologically. It is conceivable that this would achieve a better long‐term result.

(1.) H. Lohse‐Busch, U. Reime and R. Falland, (2014) Symptomatic treatment of unresponsive wakefulness syndrome with transcranially focused extracorporeal shock waves. NeuroRehabilitation 35 (2014) 235‐244

(2.) Beisteiner R, Matt E, …… Lohse‐Busch H (2019) Transcranial pulse stimulation with ultrasound in Alzheimer’s disease—A new navigated focal brain therapy. Adv Sci (Weinh) 23;7(3):1902583.
Cerebrovascular Changes in Dementia Patients with Alzheimer’s Disease and Vascular Parkinsonism
Authors: Maksimovich Ivan V
Published: December 2023

Background

When examining patients with dementia, it is necessary to clearly differentiate the developed cerebrovascular and microcirculatory changes. We present the features of cerebral angioarchitectonics and microcirculation in Alzheimer’s disease (AD) and vascular parkinsonism (VP).

Methods

The research included 155 patients. The examination included assessment of CDR, TDR, MMSE, cerebral MRI, CT, scintigraphy (SG), rheoencephalography (REG), cerebral multi‐gated angiography (MUGA).

Patients were divided into:

• 93 people aged 34‐80 (mean age 67.5): men ‐ 32 (34.40%), women ‐ 61 (65.59%), suffering from AD. According to dementia severity, patients were subdivided: (TDR‐0) ‐ 10, (TDR‐1) ‐ 29, (TDR‐2) ‐ 36, (TDR‐3) ‐ 18 people;

• 62 people aged 52‐80 (mean age 77): men ‐ 48 (77.42%), women ‐ 14 (22.58%), suffering from VP. According to dementia severity, patients were subdivided: no dementia ‐ 30 people, dementia at level (CDR‐1) ‐ 32 people.

Results

In AD patients, changes in angioarchitectonics and microcirculation are manifested in:

• Absence of calcium salts deposits and atherosclerotic changes in intracerebral vessels;

• Increased tortuosity of distal intracranial arteries;

• Reduction of the capillary bed in the temporal and frontoparietal regions;

• Development of multiple, large arteriovenous shunts with early venous discharge of arterial blood in the same regions;

• Development of abnormal, intracerebral venous trunks;

• Development of intracerebral stagnation of venous blood.

These changes are called “Discirculatory angiopathy of Alzheimer’s type” (DAAT).

In patients with VP, changes in angioarchitectonics and microcirculation are manifested in:

• Multiple calcium salts deposits with atherosclerotic changes in intracranial vessels, mainly in the thalamus, basal ganglia, and pons;

• Local decrease in subcortical cerebral capillary blood flow in the same regions;

• Development of local subcortical small intracerebral arteriovenous shunts;

• Absence of expressed intracerebral venous blood stagnation.

Conclusions

Discirculatory angiopathy of Alzheimer’s type (DAAT), regardless of dementia severity, is an AD‐specific cerebrovascular and microcirculatory lesion of the brain, unconnected with atherosclerotic process.

In patients with VP, regardless of dementia, vascular and microcirculatory changes are atherosclerotic in nature. Capillary bed lesions, presence of arteriovenous shunts are subcortical in nature, mainly in the region of the thalamus, basal ganglia, and bridge. Marked venous stasis does not occur in this case.
From plan to impact: does a national dementia plan make a difference? Comparing post diagnostic care in England and Malaysia.
Authors: Robinson Louise
Published: December 2023

Background

In 2009, England introduced a National Dementia Strategy, followed by a Prime Minister’s National Dementia Challenge. By 2020, England led a ‘European league table’ regarding dementia policy and research, but performed less well for access to care and support. Malaysia has co‐developed a National Dementia Plan but implementation has been delayed due to Covid. This talk will compare and contrast findings from two research projects which explored post diagnostic dementia care and support in a High Income Country (HIC), England (https://research.ncl.ac.uk/pridem) and a Lower Middle Income Country (LMIC), Malaysia (https://research.ncl.ac.uk/global_health_depec/).

Method

The PriDem programme in England initially mapped post diagnostic dementia services via an e‐survey to commissioners (n = 82) and then used qualitative approaches (1‐1 interviews, focus groups; in‐depth case studies) to explore services in depth (n = 61 commissioners/service managers; 68 health/social care providers and 48 service users (17 people with dementia, 31 carers). In Malaysia, DePEC interview sampling was restricted due to COVID (n = 20 professionals; 11 healthcare; 4 traditional medicine; 5 support services).

Result

Analysis revealed similar issues in both countries namely: i) considerable geographical inequalities in services, especially between rural and urban areas, with most support focused on the early period after diagnosis; ii) limited confidence and capacity of primary/community care services and iii) fragile, fragmented care due to funding limitations. In England, follow up interviews one year post Covid revealed further widening of these inequalities.

Conclusion

This research has shown that the development of a national dementia plan is only the first step and that translation of rhetoric into reality, i.e. better quality care and improved patient experience, is a major challenge. In order to close the gap between policy and service provision, national dementia plans must incorporate formal implementation and evaluation programmes to successfully move from ‘plan to impact’.
In vivo nanotracer for the detection of brain thrombi in an AD mouse model.
Authors: Ceron Carlos , Casquero‐Veiga Marta , Fernandez‐Barahona Irene , Muñoz‐Hernando Maria , Fernandez‐Nueda Irene , Fuster Valentin , Moro Maria Angeles , Herranz Fernando , Cortes‐Canteli Marta
Published: December 2023

Background

Alzheimer’s disease (AD) is the most common cause of dementia (1). It is a multifactorial degenerative disease pathologically characterized by intracellular neurofibrillary tangles and extracellular deposition of amyloid. An early haemostatic dysregulation is also present and contributes to an increment in clot formation, leading to hypoperfusion, blood brain barrier disruption and neuronal loss (2). The detection of this prothrombotic state is of the upmost importance in diagnostic approaches to identify AD patients who would benefit from anticoagulation.

Aim

Using the in vivo nanotracer Thrombo‐tag (3) for the detection of brain thrombi in an AD mouse model by fast pre‐targeted positron emission tomography (PET) imaging.

Method

AD animals and their wild‐type (WT) littermates were intravenously injected with the antiplatelet antibody against CD41 conjugated with transcyclooctene (TCO‐antiCD41). Twenty‐four hours later, [68Ga]core‐doped iron oxide nanoparticles (NP) functionalized with tetrazine (TZ) were intravenously administered. TCO and TZ produce a rapid in vivo reaction by means of bioorthogonal chemistry, allowing to non‐invasively evaluate platelets’ levels by PET. Two hours after [68Ga]NP‐TZ injection, a static PET study of each mouse was acquired with a scanner for small animals (nanoScan® PET/CT, Mediso, USA). Finally, biodistribution assays of different organs after the PET study were performed. All PET images were analyze by regions of interest (ROI) and voxel‐wise analyses.

Result

Thrombo‐tag has proven to be an effective and efficient method for neuroimaging in vivo. This PET probe allows us to accurately identify the presence and accumulation of platelets within the brain of animal models of Alzheimer’s disease. Additionally, Thrombo‐tag enables us to determine the distribution of platelets’ accumulations within various regions of the brain in comparison to WT controls.

Conclusion

Thrombo‐tag provides a neuroimaging biomarker that could allow us to diagnose the prothrombotic state towards the personalization of anticoagulation treatment in AD patients.

Funding: Carlos is the recipient of a Predoctoral Fellowship from the Fundación Española de Trombosis y Hemostasia.

Bibliography: 1. Alzheimers Dement, 17, 327‐406, (2021), doi.org/10.1002/alz.12328

2. Cortes‐Canteli & Iadecola, Journal of the American College of Cardiology, 75, 942‐951, (2020)

3. Adrover, Pellico et al., Nanoscale, 12, 22978‐22987, (2020)
Exploring dementia care pathways in seven LMICs with the help of case vignettes – identifying opportunities for strengthening pre‐ and post diagnostic support
Authors: Lorenz‐Dant Klara , Comas‐Herrera Adelina ,   the STRiDE team
Published: December 2023

Background

There is a scarcity of information about the care pathways of people living with dementia under different circumstances in Low and Middle Income Countries (LMICs) countries. This knowledge is important to effectively improve system responses and processes for people living with dementia and their families.

Method

During a workshop with researchers from a range of LMICs, we identified key variables likely influencing people’s access to and routes through health and long‐term care system. Based on these, we developed five case vignettes exploring these key characteristics together with the research teams in the seven STRiDE (‘Strenghtening Responses to dementia in DEveloping countries’) project countries. The multidisciplinary STRiDE country teams then narratively described the likely care pathways and validated the results with relevant stakeholders.

Result

Using the same five vignettes across Brazil, India, Indonesia, Jamaica, Kenya, Mexico and South Africa enabled us to analyse the dementia care system. The vignettes highlighted the role of infrastructure on accessibility regarding diagnosis, help and support. While health service entry points varied by health care system design and type of health insurance, we found that traditional healers and alternative medicine, often in parallel, also played a role in most countries. Where people rely on public services, awareness of dementia among entry level healthcare workers seems important.

Following diagnosis, health services were the main ongoing support provided across countries. Availability of other types of supporting therapies or social interventions varied. Non‐governmental organisations or faith‐based support seemed to be especially important in rural areas. Across all countries, families and especially women provide the bulk of care and support. Residential care has been described as stigmatised in several countries. Issues around availability, affordability and quality of care in residential care were also raised.

Conclusion

Exploring care pathways of people with different social profiles is important to show the responsiveness of health and long‐term care systems to people’s needs and to enable that bottlenecks to care and support can be addressed through interventions and policy. Comparing the vignettes across the seven STRiDE countries highlights similarities but also differences.
CSF proteomics in autosomal dominant Alzheimer’s disease highlights parallels with sporadic disease
Authors: van der Ende Emma L. , in ’t Veld Sjors G.J.G. , Hanskamp Iris , Van der lee Sven J , Dijkstra Janna I.R. , van Swieten John C. , Irwin David J. , Chen‐Plotkin Alice , Hu William T. , Lemstra Afina W. , Pijnenburg Yolande A.L. , van der Flier Wiesje M. , del Campo Marta , Teunissen Charlotte E. , Vermunt Lisa
Published: December 2023

Background

Autosomal dominant Alzheimer’s disease (ADAD) offers a unique opportunity to study pathophysiological changes in a relatively young population with few comorbidities. A comprehensive investigation of proteome changes occurring in ADAD could provide valuable insights into AD‐related biological mechanisms and uncover novel biomarkers and therapeutic targets. Furthermore, ADAD might serve as a model for sporadic AD, but in‐depth proteome comparisons are lacking. We aimed to identify dysregulated CSF proteins in ADAD and determine the degree of overlap with sporadic AD.

Method

Using proximity extension‐based immunoassays (PEA) by Olink, we measured 1472 proteins in CSF of APP or PSEN1 mutation carriers (n = 22) and age‐ and sex‐matched controls (n = 20) from the Amsterdam Dementia Cohort. We compared protein abundance between groups using two‐sided t‐tests and identified enriched biological pathways. Using the same protein panels in paired plasma samples, we investigated correlations between CSF proteins and their plasma counterparts. Finally, we compared our results with recently published PEA data from an international cohort of sporadic AD (n = 230) and non‐AD dementias (n = 301). All analyses were false discovery rate‐corrected.

Result

We detected 66 differentially abundant CSF proteins (65 increased, one decreased) in ADAD compared to controls (q<0.05). The most strongly upregulated proteins (fold change >1.8) were related to immunity (CHIT1, ITGB2, SMOC2), cytoskeletal structure (MAPT, NEFL) and tissue remodeling (TMSB10, MMP‐10). Significant CSF‐plasma correlations were found for the upregulated proteins SMOC2 and LILR1B. 36 of the 66 differentially expressed proteins had been previously measured in the sporadic dementias cohort, 34 of which (94%) were also significantly upregulated in sporadic AD, with a strong correlation between the fold changes of these proteins in both cohorts (rs = 0.730, p<0.001). 29 of these 36 proteins (81%) were also upregulated among non‐AD patients with suspected AD co‐pathology.

Conclusion

This CSF proteomics study demonstrates substantial biochemical similarities between ADAD and sporadic AD, suggesting involvement of the same biological processes. Besides known AD‐related proteins, we identified several relatively novel proteins, such as TMSB10, MMP‐10 and SMOC2, which have potential as novel biomarkers. With shared pathophysiological CSF changes, ADAD study findings might be translatable to sporadic AD, which could greatly expedite therapy development.
Machine‐learning derived MRI‐based atrophy biomarker predicts long‐term cognitive decline in stroke or transient ischemic attack
Authors: yuan CAI , Lam Bonnie Y.K. , Fan Xiang , Liu Wanting , Shi Lin , Au Lisa Wing Chi , Ko Ho , Mok Vincent Chung Tong
Published: December 2023

Background

Alzheimer’s disease‐resemblance atrophy index (AD‐RAI) is a machine‐learning derived MRI‐based brain atrophy biomarker that is valid in predicting cognitive decline in subjects with AD. We investigated the performance of AD‐RAI in predicting long‐term cognitive decline in subjects with stroke or transient ischemic attack (TIA).

Method

We recruited consecutive dementia‐free stroke/TIA subjects who had brain MRI at baseline (i.e., within 3‐6 months after the index event) and cognitive data at both baseline and 3 years. We defined cognitive decline as an increase in clinical dementia rating scale from 0 to 0.5 or above or from 0.5 to 1 or above at 3 years when compared with baseline. We investigated the association between AD‐RAI, traditional brain atrophy biomarkers (hippocampus volume [HV], hippocampal fraction [HF], total brain volume [TBV], TBV/intracranial volume [ICV] ratio, ventricular‐brain‐ratio, presence of medial temporal lobe atrophy [MTLA]), and cerebral small vessel disease biomarkers (white matter hyperintensity [WMH]) volume, WMHV/ICV ratio presence of confluent WMH, presence of >/ = 3 lacunes) with cognitive decline.

Result

Of 231 participants (mean age 66.0 ± 10.9, 124 [53.7] male), 55(23.8) had cognitive decline at 3 years. Among all the imaging biomarkers, AD‐RAI and HV were associated with cognitive decline in univariate regression. Such a relationship was still significant with AD‐RAI after adjusted for age, gender, and education (aOR [95%CI] 3.900 [1.221‐12.458]). Among all imaging biomarkers, only AD‐RAI was associated with slope of Montreal cognitive assessment (MoCA) after adjusted to age, gender, education (β(SE) −0.742[0.242], p = 0.002).

Conclusion

AD‐RAI predicted long term cognitive decline in subjects with stroke/TIA.
Associations of white matter hyperintensities with cerebrovascular architecture in Alzheimer’s disease and related dementias
Authors: Housni Ikrame , Singh Manpreet , Dadar Mahsa , Detcheverry Flavie , Anastassiadis Chloe , Filali‐Mouhim Ali , Masellis Mario , Ismail Zahinoor , Duchesne Simon , Tartaglia Carmela , Smith Eric E. , Narayanan Sridar , Badhwar AmanPreet
Published: December 2023

Background

MRI‐detected white matter hyperintensities (WMHs), a marker of cerebrovascular‐pathology, are common in Alzheimer’s disease (AD) and related dementias (ADRDs). In stroke, WMH‐volume was found to correlate most with stroke risk‐factors in the anterior cerebral arterial‐territory. Since the relationship between WMHs and arterial‐territories remains unexplored in the ADRDs, we systematically investigated WMHs’ spatial distribution (1) in 8 ADRDs relative to cognitively unimpaired (CU), and (2) across arterial‐territories per ADRD.

Methods

The extensive CCNA‐COMPASS‐ND cohort (N = 927) allowed us to investigate 9 clinical categories: CU, subjective (SCI) and mild (MCI) cognitive impairment, vascular MCI (V‐MCI), AD, vascular AD (V‐AD), Lewy‐body dementia (LBD), fronto‐temporal dementia (FTD), and Parkinson’s disease (PD) (Fig.1A). FLAIR and T1w MRI‐scans were used to segment WMHs (Dadar et al.,2017). Following registration to standard space, an arterial‐territory atlas (Schirmer et al.,2019) was used to calculate WMH‐volumes in 10 regions (Fig.1B).
Statistical analyses
were run on whole‐brain‐WMH‐volume and regional‐WMH‐ratios (region‐size‐normalized‐WMH‐volume/whole‐brain‐WMH‐volume). Data‐analyses used a series of linear models accounting for clinical category, age, and sex – followed by pairwise group‐comparisons corrected for multiple comparisons.

Results

1)
Relative to CU: Whole‐brain‐WMH‐volumes were higher for V‐MCI, V‐AD, and FTD. WMH‐ratios were higher in MCA and LMCA for 2 ADRDs (SCI;V‐MCI) and lower in PCA, LPCA, and RPCA for SCI. WMH‐ratios were higher in ACA or LACA and
lower in PCA, LPCA, or RPCA for 4 ADRDs (V‐MCI;V‐AD;FTD;PD) (Fig.1C).

Sex‐analyses:
Men’s WMH‐volumes were higher in whole‐brain (CU;V‐MCI;FTD), while their WMH‐ratios were higherin LMCA (CU), but lower in ACA (SCI;MCI), LACA (MCI), and RACA (SCI).

2) MCA contained higher WMH‐ratios than ACA and PCA in all clinical categories. Relative to PCA, ACA’s WMH‐ratio was higher in 2 ADRDs (V‐MCI;V‐AD) and lower in 4 (CU;MCI;AD;PD). Pairwise‐group comparisons between all left/right arterial‐territories demonstrated consistent results (Fig.2).

Asymmetry‐analyses:
The right arterial side had higher WMH‐ratios in ACA (CU;V‐MCI), MCA (CU;SCI;MCI;V‐MCI;AD;V‐AD;PD), and PCA (MCI;AD).

Conclusion

We identified arterial‐territories of increased susceptibility to WMH‐formation per ADRD. The two most prevalent ADRDs (AD;V‐AD) were found to accumulate WMHs in a territory‐specific manner – higher WMH‐ratios in ACA for V‐AD and PCA for AD. Overall, the arterial‐territory‐specific WMH‐signatures identified may improve ADRD‐diagnosis accuracy.
Creating an alliance for diversity in brain health for central Ohio community
Authors: Wright Kathy D , Moss Karen O , Wilson‐Lawson Kim S , Myers Pamela J , Rouse Missy , Harris Camren J , Weeks Amy E , Hill Carl V.
Published: December 2023

Background

Black, Indigenous, and other people of color are at greater risk of developing Alzheimer’s disease and related dementias (ADRD). These individuals are less likely than non‐Hispanic whites to have access to ADRD‐ related resources, thus promoting health disparities.

Method

In 2022, the Alliance for Diversity in Brain Health for the Central Ohio Community (ADHOC) was created to fill this gap. Through grass roots efforts from the College of Nursing, the African American Alzheimer’s and Wellness Association teamed up with the Central Ohio Alzheimer’s Association. With leadership support from the National Alzheimer’s Association, we identified strengths, opportunities for collaboration, and long and short‐term goals to meet the needs of the Central Ohio ADRD community. Monthly meetings were held with a core group of four members to establish a community‐driven agenda for education, support, and research.

Result

To date, ADHOC results included a) grant‐funded, inaugural Annual Brain Health Fair with 14 local partnering agencies, b) five ADRD education presentations in five minoritized communities, and c) six research collaborations.

Conclusion

Our alliance provides a template that can scaled for use in communities globally to build bridges and promote health equity in ADRD communities through education, support and research.
Integrative multi‐omics for normal brain aging and Alzheimer’s Disease in Drosophila
Authors: Burns Madeline P , Li Hongjie
Published: December 2023

Background

Normal brain aging and Alzheimer’s Disease (AD) are both characterized by neurodegeneration and share many similarities. However, the mechanisms underlying both their similarities and differences remain largely unknown. Cell‐cell interactions mediate nearly all aspects of an organism’s physiology via cell‐surface proteins; as such, ∼70% of pharmaceutical drugs target cell‐surface proteins. Glial cells play many important roles in cell‐cell communication, plasticity, and immune function; thus, glial cell‐surface proteins present ideal novel biomarkers and drug targets. However, it remains difficult to profile glial cell‐surface proteins from intact brains, or to fully characterize gene expression changes during the progression of age‐related neurodegeneration.

Method

To investigate, we're fully characterizing how glial cells and their cell‐surface proteins differentially contribute to the progression of normal brain aging and AD, integrating state‐of‐the‐art in‐situ cell‐surface proteomics and high‐resolution single‐cell transcriptomics. Our study will be the first to apply in‐situ cell‐surface proteomics to glial cells in Drosophila, and the first to exhaustively profile and integrate the glial cell‐surface proteomes and single‐cell transcriptomes of both aging‐ and AD‐model flies. This will allow us to capture the “full picture” of how dysregulation of glial cell‐surface proteins differentially contributes to normal brain aging and AD, as changes in gene expression at the protein and mRNA levels often show considerable discrepancies.

Result

In total, our glial cell‐surface proteomics identified 872 proteins predicted to be involved in normal brain aging, and strong replicate correlations were observed. A Gene Ontology analysis revealed that most up‐regulated genes were associated with cell localization and transport, while most down‐regulated genes were associated with neural development, circuit organization, and neuroplasticity. We selected 48 candidate genes for further screening, based on which were the most up‐ and down‐regulated. Referencing our transcriptomic data, we found that 9/48 candidate genes identified by our cell‐surface proteomics also showed significant increases/decreases in expression levels, and selected 24 additional candidate genes for further screening.

Conclusion

Currently, we are in the process of conducting several GOF/LOF genetic screens to investigate the effects of each candidate gene on lifespan. Based on preliminary data from our lifespan screens, we have identified 5 top candidate genes for further investigation.
Higher systolic and diastolic blood pressures in recently postmenopausal women are associated with greater WMH more than a decade later in the KEEPS Continuation
Authors: Kara Firat , Tosakulwong Nirubol , Lesnick Timothy G. , Fought Angela J. , Schwarz Christopher G. , Senjem Matthew L. , Fields Julie A. , Min Paul H , Lowe Val J. , Jack Clifford R. , Bailey Kent R. , James Taryn T. , Lobo Rogerio A. , Manson JoAnn E. , Pal Lubna , Hammers Dustin B. , Malek‐Ahmadi Michael H. , Cedars Marcelle I. , Naftolin Frederick N. , Miller Virginia M. , Harman Sherman M. , Dowling Maritza N. , Gleason Carey E. , Kantarci Kejal
Published: December 2023

Background

Higher blood pressure (BP) is associated with greater white matter hyperintensity (WMH) volume, but research is limited in recently menopausal and postmenopausal women. Postmenopausal women have a greater burden of WMH than men and premenopausal women, but whether hormone therapy (HT) modifies the association between systolic and diastolic BP (SBP, DBP) and WMH is unknown. We investigated the association of SBP and DBP in recently postmenopausal women who participated in an HT trial with WMH volumes measured 14 years later and explored whether HT modified the results.

Method

Women with good cardiovascular (CV) health, who were previously enrolled in a randomized placebo‐controlled HT trial, the Kronos Early Estrogen Prevention Study (KEEPS), participated in the current observational KEEPS continuation (n = 212; median age = 67; range 58‐72). SBP and DBP were measured at KEEPS baseline (median age = 54 years; range 44‐59) and continuation. Antihypertensive users were excluded (baseline, n = 34; continuation, n = 61). Approximately 10 years after the end of KEEPS HT versus placebo 4‐year interventions, automated WMH volumes were measured from 3D‐FLAIR MRI. Associations of KEEPS baseline and continuation SBP and DBP with log WMH volume at KEEPS continuation were tested using linear regression analyses adjusting for covariates in model 1 (age, total intracranial volume, study site) and model 2 (model 1 plus cardiovascular risk factors (CVRF)).

Result

Higher KEEPS baseline SBP and DBP were associated with greater WMH volume measured 14 years later, and after adjusting for CVRF (p≤0.01). Similarly, in KEEPS continuation, higher SBP and DBP were associated with greater WMH volume measured concurrently and after adjusting for CVRF (p<0.001). We did not find statistically significant evidence that HT versus placebo modified these associations. Topographically, higher SBP and DBP were associated with greater periventricular WMH in the frontal and parietal lobes after adjusting for age (Figure).

Conclusion

Higher SBP and DBP in recently menopausal women with good CV health were associated with greater WMH volumes more than a decade later after adjusting for CVRF, independent of randomization to HT. Our results show the importance of blood pressure control in recently menopausal women, that may reduce the white matter injury later in life.
Awe Walks Improve Quality of Life, Attention, Orientation, Mood & Social Behaviour in Dementia
Authors: Sheth Akshata , Bennett Cathlyn
Published: December 2023

Background

Research has consistently shown decreased quality of life (QoL) in people with dementia, with predictors of QoL ranging from education to emotional status. This study investigated the impact of Awe Walks as an intervention targeting emotional status for the first time in dementia. Awe—a positive emotion elicited when in the presence of vast things not immediately understood—promotes social connection and fosters well‐being by encouraging a “small self”.

Method

Participants with dementia between the ages of 60 and 85 took biweekly 15‐min outdoor walks for 4 weeks; a total of 53 participants were matched and randomly assigned either to an awe walk group, which oriented them to experience awe during their walks, or to a waitlist control group. Pre‐ and post‐intervention measures of QoL, cognitive functioning, behavioural pathology relevant to daily functioning, and clinical global impression were completed.

Result

Compared to degenerative deterioration in controls, individuals who participated in the Awe Walk intervention exhibited greater improvements in QoL, attention, orientation, mood, and social behaviour.

Conclusion

These results suggest cultivating awe enhances positive emotions that improve quality of life and diminishes negative emotions that hasten decline. An intervention such as this, cost‐effective and simply executed, has important implications for providing quality care to this population served by neuropsychologists.
Genome‐wide association study for Alzheimer disease in APOE ɛ4/ɛ4 carriers
Authors: Clayton Samantha , Goldstein Daniel , Wang Li‐San , Mayeux Richard , Haines Jonathan L. , Pericak‐Vance Margaret A. , Schellenberg Gerald D. , Lunetta Kathryn L. , Au Rhoda , Farrer Lindsay A. , Stein Thor D. , Jun Gyungah R
Published: December 2023

Background

The APOE ɛ4/ɛ4 genotype has the greatest risk for late‐onset Alzheimer disease (AD). However, modifying effects of other genes on AD risk in APOE ɛ4 homozygotes are not fully understood.

Methods

We conducted a genome‐wide association study (GWAS) for AD among 1,223 non‐Hispanic White APOE ɛ4/ɛ4 carriers assembled by the Alzheimer’s Disease Genetics Consortium (ADGC). Expression of genes within 50 kb of suggestively associated single nucleotide polymorphisms (SNPs, P<10−6) were compared between AD and control brains from 576 Religious Orders Study and Memory and Aging Project (ROSMAP) subjects. We conducted survival analysis between carriers and non‐carriers of AD risk alleles for the suggestive SNPs in 4,287 Framingham Heart Study (FHS) participants. We compared expression of the top‐ranked genes between ɛ2/ɛ2 (APOE2) and ɛ4/ɛ4 (APOE4) human induced pluripotent stem cells (iPSC)‐derived neurons (iNeurons) and astrocytes (iAstrocytes) in a co‐culture system (Jun et al, 2022) and separately evaluated associations of their expression levels with neuropathological traits from 208 brains from FHS participants.

Results

We identified association of AD with 11 SNPs at the suggestive level of which four near TRIB2, CTNNA2, ZNF443, and KLHL29 were genome‐wide significant (P<5×10−8). Rs75983775 near TRIB2, the most significant finding (P = 9.4×10−11), was associated with decreased risk of AD in ADGC APOE ɛ4 homozygotes (odds ratio = 0.12) and increased TRIB2 expression in ROSMAP ɛ4‐carrier brains (P = 0.02). TRIB2 expression was increased in APOE2 compared to APOE4 iAstrocytes (log2 fold change (log2FC) = 0.41, adjusted P (adjP) = 0.03) and iNeurons (log2FC = 0.31, adjP = 0.002) and elevated the Iba1 level in FHS brains (P = 0.03). Association with TENM3 SNP rs56035906 was suggestively associated with reduced AD risk in ADGC APOE ɛ4 homozygotes (odds ratio = 0.30, P = 4.3×10−7) and with lower incidence of AD among FHS ɛ4 carriers (P = 0.03). TENM3 expression was decreased in APOE2 compared to APOE4 iNeurons (log2FC = 0.59, adjP = 2.4×10−4) and associated with increasing phosphorylated tau 181 (P = 0.007) and C4a protein expression (P = 9.6×10−4) in FHS brains.

Conclusion

We identified variants that may protect against AD risk among APOE ɛ4/ɛ4 carriers, delay disease onset, modulate expression of nearby genes in iAstrocytes and iNeurons, and are associated with measures of tau and neuroinflammation in autopsied brains.
Whole Genome Deconvolution Unveils Alzheimer’s Resilient Epigenetic Signature.
Authors: Berson Eloise
Published: December 2023

Background

The pathological hallmarks of Alzheimer’s disease (AD) are amyloid beta plaques and neurofibrillary tangles that usually progressively affect characteristic brain regions as individuals advance from latent to prodromal to severe AD dementia (ADD). An uncommon exception to coupled progression of disease burden and clinical impairment are resilient individuals who harbor a high pathological load sufficient to cause ADD yet remain cognitively normal. We hypothesize that determining the biological mechanisms of such underlying resilience to AD (RAD) will provide unique insights into therapeutic opportunities.

Method

Here, we combined epigenetic sequencing data and an innovative computational algorithm to identify gene regulatory mechanisms and putative mediators distinguishing RAD from normal control and ADD at an unprecedented scale. We developed and validated a novel machine learning method, Cellformer, for deconvoluting bulk ATAC‐seq into cell type‐specific expression across the whole genome, leading to extensive regional and cellular chromatin profiling of RAD.

Result

Cellformer successfully deconvoluted in silico bulk ATAC‐seq data across cross‐validation iterations, achieving strong performances with a mean Spearman coefficient of 0.82 between deconvoluted and ground truth expressions, outperforming other approaches. Validation was performed using external single nucleus datasets and showed a significant correlation above 0.75 (P‐value<0.05) between deconvoluted cell type‐specific ATAC‐seq and single‐ATAC‐seq expressions for each cell type. Applied on 191 samples from normal control, RAD and ADD’s 3 brain regions, CellFormer predicted cell type‐specific expression of more than 41954 open chromatin regions (OCR), preserving regional and phenotypic variations. Downstream analysis of the derived RAD‐specific epigenetic features pinpointed the hippocampus, a region critical for learning and memory, as the major player in the resilience, modulating synaptic and neuronal process in a cell‐type specific manner.

Conclusion

Cellformer opens new perspectives to advance bulk analysis and understand biological mechanisms using cost effective bulk sequencing. Through this study, we showed that cell type‐resolved data nominated potential epigenetic and transcriptional mediators underlying RAD that may illuminate therapeutic opportunities to limit the cognitive impact of this highly prevalent yet stubbornly incurable disease. Cellformer will be made publicly available to advance analysis of high‐throughput bulk ATAC‐seq in future investigations.
Study on the effectiveness of acetylcholinesterase inhibitors in the treatment of primary progressive logopenic aphasia
Authors: Carrier‐Auclair Julie , Laforce Robert , Lavoie Monica
Published: December 2023

Background

For over 25 years, cholinesterase inhibitors (ChEIs) have been the main symptomatic treatment for Alzheimer’s disease (AD). Several meta‐analyses have supported their effectiveness in various neurocognitive aspects of amnestic AD. Over 86% of cases of the logopenic variant of primary progressive aphasia (lvPPA) are caused by a similar pathologic process than AD, yet no study has examined the efficacy of ChEIs in this AD variant. We aimed to explore the efficacy of ChEIs in the treatment of lvPPA by comparing their longitudinal MMSEs to that of treated amnestic AD patients.

Method

A retrospective chart review was performed on 48 patients with lvPPA and 52 patients with amnestic AD. Both groups were similar with respect to age, level of education, and onset of symptoms. Drug history and MMSE scores were collected on several time points before and after the introduction of ChEIs.

Results

Patients with lvPPA showed a similar trajectory of decline than amnestic AD patients on serial MMSEs (both WORLD and 100‐7) up to twelve months after the introduction of ChEIs (Figure 1 and 2).

Conclusion

This study provides preliminary evidence for efficacy of ChEIs in patients with lvPPA and suggests similar benefits to those seen in amnestic AD patients.
Impact of the COVID‐19 Pandemic on Patients with Dementia or Parkinson’s Disease and their Caregivers in Lima, Peru
Authors: Diaz Monica M , Beauchamp Morgan T , Aguilar Ximena R , Bailey Maisie , Coronel Danilo A Sanchez
Published: December 2023

Background

Progressive neurodegenerative diseases, such as dementia and Parkinson’s disease (PD), lead to difficulties completing activities of daily living (ADLs). In Peru, a low‐to‐middle income country, caregivers are family members who learn to provide caregiving based on the patient’s primary neurologists’ recommendations and through social media. During the COVID‐19 pandemic, Peru had one of the strictest enforced lockdowns, yet the country had one of the highest mortality rates worldwide. Little is known of the pandemic’s effect on patients with neurodegenerative conditions and their caregivers in Peru. This study aimed to examine the effect of the pandemic on patients and caregivers.

Method

We enrolled participants who were caregivers of patients with dementia or PD who receive care at a large public neurology hospital in Lima, Peru. A modified version of the Zarit Caregiver burden scale and a questionnaire on COVID‐19 symptoms, mental and physical well‐being was administered to each caregiver by phone. We performed descriptive statistics.

Result

We enrolled 44 caregivers with females comprising 80% of patients and 60% of caregivers, mean+/‐ standard deviation (SD) age of 73.2+/‐11.4 and 48.6+/‐12.1 years, respectively. More than 70% of patients had dementia and 20.5% had PD. Nearly one‐third of patients tested positive for COVID‐19 and nearly all patients were fully vaccinated with a booster. Nearly all patients (98%) adopted social isolation measures and 86% of patients maintained social connections with family by phone. Unfortunately, many patients had difficulties obtaining medications (48%), felt lonelier (52%), and had an increase in anxiety (60%), agitation (43%), hallucinations (50%), and forgetfulness (71%) compared to before the pandemic.

The majority of caregivers had only completed secondary school (34%) with nearly 40% reporting working full‐time in addition to caregiving. We found that 82% felt more overwhelmed with caregiving, 16% reported interruptions in additional caregiving support and 73% needed to dedicate more time to caregiving.

Conclusion

More studies are needed to highlight where the most difficult aspects of caregiving in low‐and‐ middle income countries to target caregiving resources and ameliorate caregiving burden worsened during the pandemic. Developing caregiver training sessions to improve patient quality of life is crucial.
A cross‐sectional study of telemedicine use during the COVID‐19 pandemic in people with Alzheimer’s disease
Authors: Patel Anisha M , Schuldt Robert , Boudreau Denise M , Win Nikki , Cobb Bryan R , McGinley Marisa
Published: December 2023

Background

People with Alzheimer’s disease (pwAD) may struggle to access medical care due to declining cognitive function. Telemedicine (TM) provides timely, remote access to AD‐related health services. During the COVID‐19 pandemic, the use of TM increased; however, it is unclear how its use and accessibility vary among commercially insured pwAD.

Method

This cross‐sectional study used US PharMetrics Plus commercial claims data (01/01/2019−12/31/2021). TM use, identified using ≥1 current procedural terminology code, was assessed in each pandemic year (2020 and 2021) in adults with ≥1 inpatient or ≥2 outpatient ICD‐10‐CM diagnosis codes for AD ≥30 days apart. Any TM use and AD‐related visits (AD diagnosis code in TM claim) were summarized, and characteristics of TM users vs nonusers among pwAD were described.

Result

Among pwAD, 48.3% (8948/18,513) in 2020 and 35.7% (7436/20,823) in 2021 used TM. Of these TM users, the mean (SD) number of TM claims was 2.8 (2.6) in 2020 and 2.7 (2.7) in 2021; approximately half had AD‐related TM visits (56.2% in 2020; 48.4% in 2021). Among pwAD, TM visits accounted for 3.0% of all healthcare claims in 2020 and 2.0% in 2021, and approximately a third of these claims were AD‐related (35.5% in 2020 and 32.9% in 2021). Most TM visits among pwAD included ≥1 interactive audio/video component (75.5% in 2020 and 77.8% in 2021) and involved an established patient visit (73.7% in 2020 and 75.3% in 2021). Of 44,303 total TM visits by pwAD in 2020 and 2021, 14.2% were provided by a neurologist. Compared with nonusers, TM users had a higher mean (SD) Charlson Comorbidity Index score (3 [2] vs 4 [2]), were less likely to be self‐insured (22.5% vs 18.1%) and were more likely to reside in western (18.5% vs 28.3%) or eastern (12.7% vs 17.1%) regions. TM use was highest in Massachusetts (83.2%) and California (78.9%).

Conclusion

Over a third of pwAD in a commercially insured population used TM during the pandemic; its use varied most notably by region and state and among those with a high comorbidity burden. Additional analyses will further inform TM access and its utility in pwAD.
Automatic classification of underlying AD vs. FTLD pathology in people with clinical Frontotemporal Dementia using digital speech markers
Authors: Cho Sunghye , Shellikeri Sanjana , Cousins Katheryn A Q , Ash Sharon , Agmon Galit , Gonzalez‐Recober Carmen , Irwin David J. , Liberman Mark Y , Grossman Murray , Nevler Naomi
Published: December 2023

Background

Recent studies show promising results using speech features to automatically distinguish patients with amnestic Alzheimer’s disease (AD) from healthy controls (HC). However these studies exclude atypical presentations of AD, which present with linguistic and/or behavioral impairments that clinically overlap with frontotemporal dementia (FTD). A clinically meaningful challenge is distinguishing underlying AD pathology from frontotemporal lobar degeneration (FTLD) pathology in people presenting with an FTD phenotype. We used digital speech features to automatically classify patients with clinical FTD with as to underlying AD or FTLD pathology.

Method

We extracted 90 lexical and 9 acoustic features from one‐minute picture descriptions produced by 179 participants using our previously validated automated pipelines (Table 1). All patients presented clinically with FTD and had AD or FTLD pathology based on either autopsy or CSF (AD: CSF pTau/Aβ42³0.1 and tTau/Aβ42³0.34). Extracted features included part‐of‐speech, unique words per 100 words, several lexical characteristics, and acoustic/durational measures. Support Vector Machine (SVM), Random Forest (RF), and Multilayer Perceptron (MLP) classifiers were trained for two tasks: 1) AD vs. FTLD pathology and 2) all patients vs. HC. Five feature sets were tested: Set 1 (baseline): demographics+MMSE, Set 2: speech only, Set 3: speech+demographics, Set 4: speech+MMSE, Set 5: speech+demographics+MMSE. Features were selected using the elastic net regression with 10‐fold validations; the best performance models were reported after hyperparameter tuning.

Result

Distinguishing AD from FTLD, the MLP model trained with speech had the highest AUC (0.88; accuracy = 83%) (Table 2). The RF model trained with speech and MMSE showed similar performance (accuracy = 84%, AUC = 0.85). Verb counts had the highest feature importance (FI) values in the MLP model trained with speech, followed by noun length. Distinguishing all patients from HC, the MLP model trained with speech only had the highest accuracy (93%; AUC = 0.93) (Table 3). The MLP model trained with speech and MMSE showed a comparable result (accuracy = 92%, AUC = 0.94). Unique adjective counts had the highest FI in the MLP model trained with speech, followed by word length.

Conclusion

Speech models outperformed baseline models and showed comparable results with speech+MMSE. Features extracted from brief speech samples are valuable in automatically distinguishing AD from FTLD pathology, and FTD from HC.
DDR1 regulates CNS collagen IV expression and vascular fibrosis in AD to improve CNS vascular integrity
Authors: Stevenson Max E , Varghese Rency , Hebron Michaeline , Liu Xiaoguang , Turner R. Scott , Moussa Charbel E‐H
Published: December 2023

Background

Blood‐brain barrier breakdown, a feature associated with AD pathology and treatments, was examined as a potential therapeutic target in both genetic mouse models of AD and clinical trial data from human patients with AD treated with nilotinib.

Methods

DDR1 knockout mice crossed with TgAPP mice were probed for levels of CNS collagen to examine the effects of DDR1 in vivo. CSF samples obtained from AD subjects treated with either nilotinib (n = 12) or placebo (n = 11) for 12 months were analyzed using whole genome RNA sequencing; significantly altered miRNA expression was examined for potential downstream effects regulating neurovascular integrity.

Results

Compared to TgAPP mice, staining of CNS sections for collagen IV in TgAPP/DDR1 knockout mice revealed decreased vascular collagen. CSF obtained from AD subjects treated with nilotinib revealed increased levels of miRNAs regulating collagen production, suggesting decreased vascular fibrosis and neuroinflammation, and improved neurovascular integrity.

Conclusion

DDR1 inhibition with nilotinib may improve neurovascular integrity in AD by reducing CNS collagen IV, vascular fibrosis, and neuroinflammation. Nilotinib should be considered as an adjunctive therapy to approved treatments ‐ including anti‐amyloid antibodies ‐ for individuals with AD.