bluuebunny/crossref_metadata_2025 huggingface dataset:
Full complement activation is associated with capillary cerebral amyloid angiopathy in Alzheimer’s disease.
Authors: Hondius David , Veerhuis Robert , Li Ka Wan , van Nifterick Anne M , Kuiperij H. Bea , Verbeek Marcel M. , Smit August B. , Rozemuller Annemieke J.M. , Hoozemans Jeroen
Published: December 2023

Background

Alzheimer’s disease is the most common form of dementia and mainly characterized by the accumulation the amyloid β (Aβ) peptide in the parenchyma and often around the blood vessels of the brain. The accumulation of Aβ in vessels walls is referred to as cerebral amyloid angiopathy (CAA). In a subset of AD cases CAA is observed in both capillaries and larger vessels which is designated as CAA type‐1. CAA type‐1 is associated with an increased neuroinflammatory response involving activated microglia and increased oxidative stress, which supposedly results in loss of blood‐brain barrier (BBB) integrity in CAA. Complement activation is an integral part of neuroinflammation associated with parenchymal Aβ deposits and CAA. However, a direct comparison of the complement activation in relation to plaque pathology and CAA type‐1 has not been made.

Method

Using immunohistochemistry we performed a semi‐quantitative analysis on the expression and localization of complement factors C1q, C3, C4 and the membrane attack complex (MAC) in post mortem cortical brain tissue derived from AD cases with severe occurrence of CAA type‐1, AD cases without CAA and non‐demented control cases. In addition, label free quantitative mass spectrometry was applied to quantify complement components in whole cortical tissue lysates.

Result

The complement factors C1q, C3 and C4 were found to be associated with CAA type‐1. No clear differences were observed in level of occurrence of C1q, C3 and C4 between AD cases with CAA type‐1, AD cases without CAA and non‐demented control cases. Interestingly, a subset of the AD cases with CAA type‐1 displayed MAC in affected vessels, whereas this was not observed in AD cases without CAA or control cases. Mass spectrometry analysis revealed an increase in C9, the primary component of MAC, in CAA type‐1 but not in AD without CAA.

Conclusion

Early complement factors are present in all AD cases while the presence of MAC is restricted to a subset of CAA type‐1 cases, indicating full‐blown complement activation in CAA type‐1 but not in AD without CAA.
Back‐translation of clinical tau‐aggregation inhibitor trials to experimental models: negative interactions of dementia therapies
Authors: Riedel Gernot , Melis Valeria , Schwab Karima , Klein Jochen , Niewiadomska Grazyna , Niewiadomski Wiktor , Wischik Claude M , Harrington Charles R
Published: December 2023

Background

Alzheimer disease (AD) has attracted considerable interest in novel therapies. Two Phase III trials by TauRx Pharmaceuticals (TRx‐005, TRx‐015) failed to attain their endpoints. A significant number of recruits, however, remained on symptomatic treatment and a post‐hoc analysis confirmed this sub‐cohort was selectively resilient against the tau aggregation inhibitor hydromethylthionine (HMT; previously termed LMT). By contrast, drug‐naïve patients were highly sensitive to the novel therapy and showed little decline over 18‐month. We here back‐translated this study to the preclinic.

Methods

Experiments used female tau transgenic Line 1 mice (L1) aged 6‐8 months previously characterised for cognitive impairments, tau pathology, and sensitivity to the tau aggregation inhibitor HMT. Here, multiple groups and doses of drugs were chronically administered (up to 11 weeks) with pre‐exposure to the acetylcholine esterase inhibitor rivastigmine followed by add‐on of HMT. Drugs were also dosed singly.

Results

(i) Tested for spatial learning in the water maze, L1 mice were significantly impaired and benefitted from exposure to HMT. By contrast, combination therapy with rivastigmine precluded some of the benefits of HMT while rivastigmine alone was non‐efficacious.

(ii) Chronic drug administration was followed by tissue harvest and histological preparation of sections through 6 brain regions (3 x cortical, 3x basal forebrain) and labelling of 6 presynaptic structural (3) and functional proteins (3. Reduced protein levels were found in cortex; they were heightened by HMT, but abnormally altered in the presence of rivastigmine (single and combination therapy).

(iii) Chronic drug administration was followed by in vivo brain dialysis from hippocampus for acetylcholine at rest and under behavioural challenge. L1 showed a lowering of cholinergic neurones in the basal forebrain, but no difference in acetylcholine levels at rest; a heightening of choline levels was observed to HMT alone at rest and challenge, but not to combinations with rivastigmine.

Conclusion

We successfully back‐translate the clinical trials on HMT into the preclinic using L1 tau transgenic mice . Data suggest not only a reduced cognitive efficacy of HMT in subjects pre‐exposed to the choline esterase inhibitor rivastigmine, but also offer mechanistic explanations for potential interactions at presynaptic function and for transmitter release.
Developing a psychoeducational programme for family caregivers of people living with late stage dementia
Authors: Waddington Claire , Zimmermann Nikki , Crutch Sebastian J , Stott Joshua , Brotherhood Emilie V , Support Rare Dementia
Published: December 2023

Background

Family caregivers often find it difficult to access information and support in the later stages of dementia. They may have difficulties attending in‐person support groups due to caring responsibilities. If caregivers are able to attend these groups, the information and support is often targeted towards the earlier stages of dementia.

Method

An eight session psychoeducational programme was developed in order to enable caregivers to access peer support and information from professionals with expertise relevant to the later stages of dementia. The programme sessions are held over Zoom and include the following topics: sensory stimulation, nutrition diet and swallowing, legal matters, care in the home and care homes, palliative care and pain management, funeral planning and brain donation. Sessions are co‐facilitated by health and social care professionals with relevant expertise, including a speech and language therapist, dietitian, solicitor and palliative care practitioner. Themes and session content have been co‐created through partnership working between facilitators and programme participants.

Result

The programme has been completed by four groups of caregivers (n = 26). All participants care for someone living with a rare or young onset form of dementia, and include those caring at home as well as caregivers of people living in a care or nursing home. Participants have reported a number of positive outcomes from attending the programme, with one participant stating: ‘Joining this late stage carers group – I was a bit worried about it… it’s absolutely one of the best things I could have done. In some respects, I wish I could have joined this earlier’. The programme is currently being evaluated using a time and cost survey to determine ongoing feasibility.

Conclusion

There is a need for accurate and timely access to information and support for family caregivers of people living with dementia in the later stages. Online psychoeducational programmes provide the opportunity for caregivers to access both peer and professional support in their own homes. The development of this programme has benefited from ongoing and iterative input from both caregivers and professionals in the dementia support field.
Sphingomyelin 14:0 – the link between obesity and neuroinflammation
Authors: Mcmanus Roisin M. , Gorki Frederike , Asmann Nils , Griep Angelika , Thiele Christoph , Latz Eicke
Published: December 2023

Background

Our laboratory has demonstrated that the consumption of a Western‐type diet (WD), triggers sterile inflammation and long‐term epigenetic reprogramming of myeloid cells, altering their immune response (Christ et al 2018). However, the precise molecular trigger mediating these changes was unknown. We have recently identified that during these WD conditions, there is an increase in circulating sphingomyelin 14:0 (S14), which was associated with atherosclerotic disease progression. As obesity, WD and atherosclerosis are all risk factors for Alzheimer’s disease (AD) and dementia, we set out to determine whether S14 was the signaling factor linking these conditions with AD development.

Method

Serum samples were obtained from obese patients for lipidomic analysis. Mice were fed a high‐fat diet mimicking WD for a period of 8 weeks, before samples were obtained for lipidomic analysis. Microglia and macrophages were prepared from wildtype, TLR4−/−, Trif−/− and MyD88−/− mice to assess whether myeloid cells recognize S14, and the molecular pathways triggered by the lipid. Cells were prepared for RNA sequencing, to determine the genes and networks induced by S14. These genes and pathways were confirmed at a protein level by western blot and flow cytometry, and at a functional level using real‐time metabolic, and phagocytic assays. Results were confirmed in human myeloid cells.

Result

Lipidomic analysis confirmed that obese patients have increased circulating levels of S14, which were associated with inflammatory markers and cardiovascular disease. In vitro, we found using RNAseq that S14 triggers an extensive increase in pro‐inflammatory genes and pathways. We confirmed that S14 binds to TLR4/MD2 triggering NFkB activation and the release of TNFα in macrophages and microglial cells. S14 also reduced metabolic function and altered phagocytic capacity in microglia.

Conclusion

We have found that S14, a lipid increased during obesity and WD conditions, is a novel TLR4 ligand that can activate macrophages and microglia triggering sterile inflammation. This pathway is conserved between murine and human cells. Critically, S14 reduced microglial phagocytosis, and rewired cellular metabolism. Together, our data shows for the first time that S14 is an immune stimulus, capable of triggering the innate immune responses and inflammation associated with dementia progression.
Long COVID‐19 symptoms in people with Dementia or Mild Cognitive Impairment
Authors: Tsapanou Angeliki , Zoi Panagiota , KALLIGEROU FAIDRA , Blekou Patra , Sakka Paraskevi
Published: December 2023

Background

Long COVID is broadly defined as signs, symptoms, and conditions that continue or develop after initial COVID‐19 or SARS‐CoV‐2 infection. What is its impact though on people with Mild Cognitive Impairment (MCI) or dementia?

Method

Self‐reported questionnaire was used for the report of the Long‐Covid 19 symptoms, regarding the duration, the exact symptoms, and the amount of the effect. People with MCI or dementia or their caregivers regarding patients’ health were recruited from the Athens Alzheimer’s Association.

Result

Our sample consisted of 56 participants. Twenty‐two (39.3%) had the diagnosis of MCI, while 34 were people with dementia. Most of the people reported symptoms of Long Covid‐19 for 3‐4 weeks. Significant were all the symptoms reported (problem in breathing, fatigue, sore throat, and psychological distress/ depression), with the majority of the people answered the questionnaire reporting fatigue as the major disturbance. This was followed by the “Psychological distress/ depression”. The symptoms affected people significantly, with almost 40% reporting “Quite enough” disturbance.

Conclusion

Long Covid‐19 is reported to be similar to other geriatric syndromes, in that the exact mechanism that leads to the symptoms is complex and not clearly understood. Therefore, the diagnosis and the management of the Long Covid‐19 symptom requires a more holistic and comprehensive approach.
Novel EEG tools to predict early cognitive impairments in Parkinson’s disease
Authors: Segura Masha Burelo , Bray Jack , Gagnon Jean‐François , Platt Bettina
Published: December 2023

Background

Parkinson’s disease (PD) is a neurodegenerative disorder mainly characterised by motor symptoms but often also associated with dementia, increasing in likelihood with duration of disease. Electroencephalography (EEG) can aid in the early diagnosis of those at risk of developing dementia. Therefore, we analysed EEG recordings across conscious states from PD patients with and without cognitive symptoms (Latreille et al in 2016, https://doi.org/10.1093/brain/aww018).

Method

Baseline data (REM sleep, NREM sleep, WAKE) from 38 PD patients (15 with and 23 without mild cognitive impairment) and 27 healthy subjects provided power spectra (qEEG), relative band power, as well as dominant frequency and its standard deviation to investigate markers for cognitive impairment. At follow‐up (an average 4.5 years after baseline), 11 patients developed dementia (PDD). Connectivity measures for left and right occipital and central electrodes were obtained as described in Crouch et al, 2018, https://doi.org/10.1038/s41598‐018‐19707‐1.

Result

qEGG analyses confirmed previous reports of enhanced theta power during REM, NREM and WAKE for patients who developed PDD. A reduction in alpha power during WAKE was observed for MCI and PDD groups when compared to controls. Alpha rhythms generally decrease with age, alongside enhanced theta power, and this outcome may contribute to the global cognitive status of patients. A reduced and less variable dominant frequency was evident for MCI and PDD patients during WAKE, indicative of reduced flexibility of the network. Finally, rPDC detected disease‐specific changes, such as enhanced cross‐hemispheric connectivity in PDD in the alpha band during NREM sleep that indicate a lack of dynamism in the network. Also noted was the diminished interhemispheric communication in delta power between both central and occipital channels in PDD during WAKE.

Conclusion

Together, we here confirm that changes of theta and alpha power are optimal discriminatory biomarkers for PD with cognitive decline (with MCI and at risk of dementia). Also, spectral and rPDC analyses indicate that dementia in PD is preceded by a loss of dynamism in EEG activity during MCI stages, both at the electrode and network level.
A retinal tauopathy with a characteristic molecular pattern points to the existence of a “Primary retinal tauopathy”
Authors: Walkiewicz Grzegorz , Ronisz Alicja , Van Ginderdeuren Rita , Lemmens Sophie , Bouwman Femke H. , Hoozemans Jeroen , Morrema Tjado , Rozemuller Annemieke J.M. , de Ruyter Frederique J. Hart , De Groef Lies , Stalmans Ingeborg , Thal Dietmar Rudolf
Published: December 2023

Background

Pathogenic processes characteristic of neurodegenerative brain diseases, such as accumulation of phosphorylated Tau protein (pTau), can also be detected in the retina. Given the advanced state of retinal imaging technology and its potential to aid in the clinical diagnosis of Alzheimer’s disease (AD), it is imperative to investigate the part the retina plays in neurodegenerative diseases of the brain, as well as the associated eye‐specific degenerative processes.

Methods

Retinas from 129 individuals who underwent eyeball resection/evisceration for severe ophthalmological conditions and from 35 post‐mortem donors with or without AD were analyzed. Paraffin‐embedded sections from cross‐sectioned retinas were stained with antibodies against different pTau species and Gallyas staining to detect neurofibrillary tangles. Retinal pTau accumulation, its distribution over the retinal layers, and molecular composition were determined neuropathologically and correlated with visual performance, age, and the presence of dementia.

Results

Retinal pTau pathology showed a consistent topographical expansion pattern that allowed distinguishing four stages: Stage 0: no pTau pathology; Stage 1: thread‐like pTau in the outer plexiform layer; Stage 2: additional cytoplasmic pTau in the inner nuclear layer; Stage 3: thread‐like pTau also in the inner plexiform layers. Antibodies against pTauS202/pT205 (AT8), pTauT231 (AT180), and anti‐MC‐1 Tau showed comparable results. Neurofibrillary tangles were not found. The stage of retinal tauopathy was correlated with age (r = 0.176, p = 0.024, n = 164), the underlying ophthalmologic diseases (p = 0.001; β = 0.292), and independently associated with vision impairment (p = 0.030; β = 0.192) in a linear regression model. Cases with a clinical diagnosis of dementia were associated with slightly higher stages of retinal tauopathy (binary logistic regression: p = 0.026; odds ratio (OR) = 1.685 [95% C.I.1.066‐2.664), although some demented cases were free of pTau pathology.

Conclusions

These results point towards the existence of a primary retinal tauopathy (PReT). It differs in its molecular composition from cerebral tauopathies by the lack of argyrophilic inclusions and the predominance of 3‐repeat Tau. However, PReT may be a prerequisite for developing AD pathology in the retina. Altogether, these findings support the presence of retinal neurodegenerative changes that may reflect changes in the brain.

Funding

SAO/FRA 2020/017
Longitudinal resting‐state EEG along the Alzheimer’s disease continuum: Sample size considerations for clinical trials.
Authors: Scheijbeler Elliz P. , de Haan Willem , Stam Cornelis J , Gouw Alida A
Published: December 2023

Background

To enable successful inclusion of resting‐state electroencephalography (EEG) outcome measures in Alzheimer’s disease (AD) clinical trials, we (retrospectively) mapped the progression of EEG markers over time in amyloid‐positive subjects.

Methods

Resting‐state 21‐channel EEG was recorded in 173 subjects positive for amyloid deposition (subjective cognitive decline, n = 16; mild cognitive impairment, n = 94; dementia due to AD, n = 63). Two or more EEG recordings were available for all subjects. We computed whole‐brain and regional relative power (i.e., theta (4‐8Hz), alpha1 (8‐10Hz), alpha2 (10‐13Hz), beta (13‐30Hz)), peak frequency, signal variability (i.e., theta Permutation Entropy) and functional connectivity values (i.e., alpha and beta corrected Amplitude Envelope Correlation, theta Phase Lag Index, weighted Symbolic Mutual Information, inverted Joint Permutation Entropy). Whole‐group linear mixed effects models were used to model the development of EEG markers over time. Group‐wise analysis was performed to investigate potential differences in change trajectories between diagnostic groups. The longitudinal relation between EEG and cognition was evaluated. Finally, we estimated the minimum sample size required to detect a stabilizing treatment effect using EEG markers, in hypothetical clinical trials of 1‐ or 2‐year duration.

Results

Whole‐group analysis revealed significant regional and global oscillatory slowing over time (i.e., increased relative theta power, decreased alpha2 and beta power), with strongest effects for temporal and parieto‐occipital regions. Signal variability showed stronger decline on a global scale. We report no significant longitudinal changes in functional connectivity strength. Disease severity at baseline influenced EEG markers’ rates of change, with fastest deterioration in MCI subjects. A decrease of the parieto‐occipital peak frequency, temporal relative alpha2 and beta power, as well as an increase in temporal relative theta power, were significantly associated with a decline in Mini Mental State Examination score. We estimate that 1‐year trials, focusing on amyloid‐positive MCI subjects, require 148 or 438 subjects per arm to detect a stabilizing treatment effect on temporal relative theta‐ or beta power, respectively.

Conclusion

Resting‐state EEG markers can facilitate early detection of target engagement in an objective, non‐invasive, low‐cost manner. Spectral measures, particularly recorded from temporal regions, present robust secondary endpoints for AD interventions.
Ageing, dementia, and the mortality experience of older Lebanese people: findings from a prospective cohort study
Authors: Chaaya Monique , Idokoko Abraham Braimah , Assaad Sarah , Asmar Khalil El
Published: December 2023

Background

Ageing is a foremost predictor of mortality and neurodegenerative disorders such as dementia, a global priority ageing‐related sequelae that significantly influence quality of life. There is limited published knowledge of the survival experience of the rapidly ageing Lebanese population. This study examined the mortality experience of older Lebanese adults and assessed the influence of ageing, dementia, and other covariates on all‐cause mortality hazard.

Methods

COLDS (Cohort of Older Lebanese Adults) is a prospective population‐based study of Lebanese participants aged ≥65 years at baseline, along with their designated informants. In this study, 476 participants consented to follow‐up out of 502 surveyed at baseline for dementia, and 344 had their mortality status assessed after 3 years. Proportionate, age‐specific and crude mortality rates were estimated while, Cox proportional regression model of mortality hazard was built, adjusted for covariates.

Results

After 3.34±0.69 person‐years, 114 deaths were observed among participants yielding an age‐adjusted death rate of 32.2% (95% CI. 31.2, 33.2). Cardiovascular diseases were the commonest (50%) reported cause of death. Dementia and age were not statistically significantly associated with mortality. Literacy, place of residence, religion, physical activity, and diabetes were significantly associated with mortality at 95% confidence level.

Conclusions

Being physically active was the most powerful protective factor against mortality among the older adults, while living in Beirut, the capital city, heightened death‐risk. These findings have extensive implications for more research, which is crucial to improving health system policies and action in support of healthy ageing.
Alzheimer’s pathology in older people with HIV in South Africa: protocol of a case‐control study examining mechanisms of inflammation and infection
Authors: Nightingale Sam
Published: December 2023

Background

Due to the success of modern antiretroviral therapy, people with HIV in South Africa are now living into older age. This provides an opportunity to study Alzheimer’s pathology in the context of chronic inflammation and infection. Here we present the protocol of a large case‐control study examining Alzheimer’s pathogenesis.

Method

250 South African people over 70 years of age will be recruited from a low‐income area of Cape Town with high HIV prevalence. Half will be living with HIV and half will be HIV‐negative and sociodemographically similar. Our primary outcome is CSF biomarkers of amyloidopathy. We have power to detect a 1.5‐fold increase in CSF amyloid positivity from 40% to 60%. Secondary analyses will compare clinical diagnoses of Alzheimer’s disease, and correlate indicators of HIV‐related neuroinflammation with degree of amyloidopathy.

Result

Protocol presentation only. Funding is from the Race Against Dementia.

Conclusion

This unique cohort will provide a valuable resource for mechanistic studies of Alzheimer’s pathogenesis.
Phase‐locked auditory stimulation in three consecutive nights to prevent cognitive decline
Authors: Zeller Céline J. , Wunderlin Marina , Nissen Christoph , Klöppel Stefan , Züst Marc Alain
Published: December 2023

Background

Over the past 10 years, disturbed sleep has been indicated as potential early, modifiable risk factor for severe cognitive decline and dementia. When we get older, sleep becomes more fragmented, we have more awakenings during the night and less deep sleep. During deep slow‐wave sleep (SWS) memory is strengthened and metabolic waste‐products like amyloid beta are cleared from the brain. Losing SWS therefore entails losing opportunities for these important functions. Leading to impairments of sleep and cognitive decline being caught in a vicious cycle. These effects are more pronounced in individuals with mild cognitive impairment (MCI) and dementia. An improvement of SWS might break this vicious cycle by recuperating the brain and ameliorating the progression of cognitive decline.

Method

We use phase‐locked auditory stimulation (PLAS) to boost slow‐wave activity in older adults with subjective cognitive decline (SCD) or MCI to prevent dementia across multiple nights of stimulation.

Result

Preliminary results show that physiological responsiveness to PLAS is associated with memory gains (F(1,10) = 6.58, p = .028, R2 = .34), replicating our previous results in healthy older individuals.

Conclusion

We show first evidence that PLAS can improve memory performance in older individuals with MCI or SCD if applied across several nights of intervention. PLAS has emerged as a promising non‐invasive tool to enhance slow‐wave sleep, potentially ameliorating cognitive decline.

Keywords:

Sleep, dementia, prevention, phase‐locked auditory stimulation, blood‐based biomarkers
Long‐read sequencing of the whole‐blood compartment reveals similar telomere lengths between Alzheimer’s disease patients and cognitively‐healthy centenarians
Authors: Salazar Alex N , Tesi Niccoló , Hulsman Marc , Holstege Henne , Knoop Lydian , Wijesekera Sanduni
Published: December 2023

Background

Telomere stability may be a potential biomarker for Alzheimer’s disease progression. Indeed, previous studies have observed significant associations with telomere length and risk for Alzheimer’s disease (AD) in both carriers and non‐carriers of APOE4. In contrast, (cognitively healthy) centenarians—an extreme control group in the spectrum of brain health—have been observed to harbour longer telomere lengths relative to younger age groups. In this study, we investigated telomere stability in the whole‐blood compartment of AD patients, centenarians, and centenarian children through single‐molecule long‐read sequencing.

Method

Long‐read HiFi sequencing of the whole‐blood compartment was performed in AD patients (n = 59, mean age = 68.5), centenarians (n = 84, mean age = 101.6), and centenarian children (n = 10, mean age = 71.0), using the Pacific Bioscience Sequel II instrument. For each sample, we identified reads with telomeric content based on alignments to the CHM13 reference genome. Per‐read telomere lengths were calculated via a high‐density clustering approach of the TTAGGG repeat sequence, keeping only reads that have a higher likelihood of harbouring complete telomeric content. The sub‐telomeric portion of each read was then used to assign chromosomal origin based on sequence similarity all chromosomes in CHM13. Whole‐blood and chromosome‐specific telomere lengths were then compared across the three sample‐groups.

Result

Centenarian children were observed to harbour the longest telomeres with a median length of 6.88 kbp, and 95% C.I. of 6.78‐7.00 kbp. This was followed by AD patients with median length of 5.82 kbp, 95% CI 5.78‐5.85 kb; and centenarians with a median length of 5.52 kbp, and 95% C.I. of 5.50‐5.55 kbp. Telomere lengths across all groups were significantly different (p < 0.001). A similar pattern was observed across each individual chromosome, with the exception of chromosome X which harboured smaller telomere lengths in AD patients and centenarians.

Centenarians harboured significantly smaller telomere lengths than their children (p < 0.001), with the exception of two centenarians that did not have significant differences.

Conclusion

Despite being aged‐match, AD patients harbour shorter telomere lengths than centenarian children, and only slightly longer telomere lengths than centenarians.
Caring through Graphic Medicine
Authors: Sethurathinam Pushpanathan S
Published: December 2023

Background

Humanity is developed with language and memory. Memory gives us personality, emotional intelligence, family relations, and community. Alzheimer’s is a type of dementia that causes problems with memory, thinking and behavior. Symptoms usually develop slowly and get worse over time, becoming severe enough to interfere with daily tasks. There is a notion that caregiving for patients is the primary responsibility of female family members.Certainly, caregiving has been associated with women, at least since it was incorporated into the emerging feminine sphere of domesticity in nineteenth‐century notions of gendered separate spheres.Physical nature of female and emotional strength are also centered on caring. All over the world women are the predominant providers of informal care for family members with chronic medical conditions or disabilities, including the elderly and adults with mental illnesses. It has been suggested that there are several societal and cultural demands on women to adopt the role of a family‐caregiver. Many theories propose that women are more likely to be exposed to caregiving stressors.This study explores how challenges of care giving Alzheimer/Dementia patients affect the caregiver especially female care givers in multiple perspectives. The activity of care giving involves economic, social and psychological impact not only on the care recipient but also the care giver, who devotes the entire period of care giving sacrificing the personal needs and ambitions.

Method

Primary data were collected from caregivers located in different parts of India.Secondary data from Govt agencies were also used for analysis. Wherever possible case studies were conducted and also personal interviews with family members. Analysis was effected through SPSS with relelevant inputs.

Result

Post Covid caregiving has become a challenging task for caregivers especially female caregivers throughout the world.As there was slowdown in economic activity, challenges commuted in terms of finance,emotions and moral support.

Conclusion

There is a need for understanding the issues involved in caregiving and appropriate steps are to be initiated for provision of adequate support from the Govt and also the social responsibility has to be properly propogated among all sections of the society.
Anesthetic Drugs as a Pharmacologic Stress Test for the Aging Brain: Towards a Real Time EEG Read‐Out
Authors: Berger Miles
Published: December 2023

Background

Roughly 65 million older adults (ie age >65 years) undergo anesthesia/surgery each year and are at risk for postoperative delirium. Further, postoperative delirium is itself associated with increased long term risk for Alzheimer’s Disease and Related Dementias (ADRD). Recent work has also shown that some patients have deeply suppressed neurophysiologic (ie EEG) patterns in response to relatively low anesthetic drug doses, and that these patients are more likely to have preoperative cognitive impairment and to develop postoperative delirium. However, to date few if any studies have examined the role of specific ADRD pathologic processes and neuroimaging abnormalities in these altered anesthetic dose‐dependent EEG response patterns in older adults.

Method

We examined relationships between intraoperative 32 channel EEG data (in cognitively normal older non‐cardiac surgery patients who received inhaled anesthetics such as isoflurane) and both 1) preoperative CSF ADRD biomarker levels and 2) preoperative structural and functional MRI imaging characteristics. CSF abeta, tau and p‐tau‐181p were measured using the Roche elecsys platform. Frontal‐parietal alpha band phase lag index and alpha power were calculated from frontal and parietal electrode regions of interest (ROIs), and normalized to inhaled anesthetic dosage.

Result

Lower anesthetic dose‐adjusted frontal‐parietal alpha band phase lag index values were associated with higher preoperative CSF p‐tau/Ab ratios (p = 0.013, N = 9‐18 per group, Fig 1A), lower cortical thickness in the left and right parahippocampal regions (Fig 1B, N = 16, p<0.001), and altered resting state fMRI connectivity between the left anterior entorhinal cortex and both the left medial prefrontal cortex and the left angular gyrus (two key default mode network regions; Fig 1C, N = 16, peak voxel p<0.01).

Conclusion

These data suggest that both molecular markers and neuroimaging features of preclinical AD neuropathology in cognitively normal older adults are associated with altered anesthetic dose‐dependent changes in neurophysiologic/EEG functional connectivity. More generally, these data demonstrate the need for additional studies to understand the extent to which intraoperative EEG data can be used to make inferences about ADRD‐related neuropathologic processes in older adults, which could provide a real‐time EEG “readout” for the stress test of anesthesia and surgery on the aging brain
Role of microglial extracellular vesicles in the propagation of early synaptic dysfunction in Alzheimer’s disease
Authors: Gabrielli Martina , Tozzi Francesca , Falcicchia Chiara , D'Arrigo Giulia , Amoretti Stefano , Joshi Pooja , Tonoli Elisa , Rutigliano Grazia , Masini Greta , Nardi Gabriele , Battocchio Elisabetta , Zenatelli Rossella , Radeghieri Annalisa , Verderio‐Edwards Elisabetta , Ratto Gianmichele , Arancio Ottavio , Prada Ilaria , Origlia Nicola , Verderio Claudia
Published: December 2023

Background

Synaptic dysfunction is an early mechanism in Alzheimer’s disease (AD) which involves progressively larger areas of the brain over time. However, how it starts and propagates is unknown. We hypothesised that large extracellular vesicles (EVs) released by microglia may be responsible for these early events in AD.

Method

Large EVs carrying Aβ peptides (Aβ‐EVs) were obtained from primary microglia exposed to Aβ42. Optical manipulation was combined with time lapse imaging to study EV‐neuron interaction. Then, EVs were stereotaxically injected into naïve mice entorhinal cortex (EC), a vulnerable region in AD, to evaluate: i) long‐term potentiation (LTP) in EC and its main target region, the dentate gyrus of the hippocampus (DG), through field potential extracellular recordings in slices; ii) possible alterations in cortico‐hippocampal network activity by chronic EEG recordings; iii) progressive memory impairment in behavioural tasks. Finally, taking advantage of high‐resolution accurate‐mass spectrometry SWATH™‐MS, we investigated the molecular differences between Aβ‐ and ctrl‐EVs (from cells not exposed to Aβ). The influence of mesenchymal stem cell (MSC) indirect co‐colture with microglia primed with Aβ on cell phenotype, EVs and functions is also being explored.

Result

Aβ‐EVs were able to move along the axonal surface more efficiently than ctrl‐EVs and predominantly in an anterograde direction, altering dendritic spine morphology in vitro. LTP was impaired in the EC 1h after Aβ‐EV (but not ctrl‐EV) local injection, while 24h later LTP was impaired also in the DG, indicating a spreading of synaptic dysfunction between connected regions. This translated into network alterations and progressive memory deficits. Interestingly, Aβ42 alone was unable to spread alterations. Aβ‐EVs limited in their motion could neither propagate impairment nor cause network abnormalities, thus implicating Aβ‐EV extracellular motion in these processes. Proteomic analysis provided insights into the molecular mechanisms underneath Aβ‐EV motion at the neuronal surface.

Conclusion

Our data provide evidence of the involvement of microglial EVs in early synaptic dysfunction in AD, through a new mechanism ‐ extracellular motion at the neuronal surface ‐ not implying EV internalization, paving the way for novel therapeutic strategies. Reference: Gabrielli et al., Brain, 2022 https://doi.org/10.1093/brain/awac083 Fundings: 2018‐AARF‐588984, Horizon2020#874721PREMSTEM
New Anti‐Hyperglycaemic Medications and the Risk of Dementia: A Nationwide Population‐Based Study
Authors: Cohen Avi , Levine Stephen Z , Vainstein Gabriel , Weinstein Galit
Published: December 2023

Background

Drug repurposing has been encouraged to accelerate the drug discovery process. The new generation of type 2 diabetes (T2D) medications have neuroprotective properties that may extend beyond their glycaemic control effects. We examined the association between exposure to newer anti‐hyperglycaemic medications and the risk of dementia in a nationwide sample of Israeli older adults with T2D.

Method

In this retrospective cohort study, we utilized electronic medical record data from “Maccabi Healthcare Services”, a large health maintenance organization in Israel. The source population was adults aged ≥55 years with a T2D diagnosis from 2000 to 2022. The exposure was defined as the use of the following new T2D medications: Dipeptidyl peptidase 4 inhibitors (DPP‐4i), Sodium‐glucose cotransporter inhibitors (SGLT2i), and Glucagon‐like peptide‐1 (GLP‐1) analogues. We compared individuals exposed to the new T2D medications (alone or in combination) to those unexposed (using other antidiabetic drugs and non‐users; i.e., lifestyle only). Exposure accounted for the use period was based on the Prescription drug purchase to Drug Use Periods method. Dementia diagnosis was based on ICD‐9 codes for any dementia or anti‐dementia drug use. Competing risk Cox model regression models with age as the underlying time scale were implemented to quantify the associations between medication exposure and dementia risk with inverse probability weights, with and without adjustment for time‐varying covariates.

Result

Of the total sample (N = 87,323), the mean age at T2D diagnosis was 64.3±6.8 years, 49.6% were women and 13,584 (15.56%) developed dementia during a mean follow‐up of 14.8±5.6 years. Of the total sample, 26,867 (30.77%) individuals purchased more than one new anti‐hyperglycaemic medication (13,081 DPP‐4i, 9,698 SGLT2i, and 12,547 GLP‐1). The group exposed to new T2D medications did not differ compared to the unexposed group (HR = 1.01, CI = 0.95‐1.06). However, analysis by specific medications showed that the group exposed to SGLT2i had a 29% reduced dementia risk compared to the unexposed group (HR = 0.71, CI = 0.58‐0.87). The associations of DPP‐4i and GLP‐1 exposure with dementia risk were null (HR = 1.00, CI = 0.90‐1.10, HR = 0.99, CI = 0.83‐1.17, respectively).

Conclusion

Evidence from our large‐scale observational study suggests that SGLT2i exposure may be associated with a reduced risk of dementia in individuals with T2D.
Correlation between heartrate and alpha Event‐Related Desynchronization during a Stroop task helps reveal cognitively healthy individuals with pathological CSF amyloid/tau
Authors: Molloy Cathleen , Choy Elizabeth Hok Yee , Al‐Ezzi Abdulhakim Abdullah A , Buennagel David P , Aguda Shelly , Nolty Anne , Spezzaferri Mitchell , Sin Caleb , Rising Shant , Fonteh Alfred N. , Minazad Yafa , Kleinman Michael T. , Kloner Robert A , Arakaki Xianghong
Published: December 2023

Background

Alzheimer’s Disease (AD) impacts brain regions associated with memory and executive function in early stages. The Stroop task is used to evaluate inhibition, a common factor for executive functioning. Alpha Event‐Related Desynchronization (ERD) from electroencephalogram (EEG) analysis evaluates brain activation during a task. Also of interest is cardiovascular function such as heart rate (HR) and blood pressure (BP) as it relates to cognitive functioning in AD progression. However, the combined analysis of functional EEG with HR and BP have not been thoroughly reported in a Cognitively Healthy (CH) cohort. To fill this gap, we studied these measurements in CH participants who underwent a Stroop task.

Method

We previously reported Stroop alpha ERD of CH participants when their cerebrospinal fluid amyloid/tau ratio were normal (≥2.71, CH‐NATs) or pathological (<2.71, CH‐PATs). Their heart rate (HRmax, HRmin, and HRmax‐HRmin) were analyzed from 5‐minute electrocardiogram (ECG) during resting or Stroop testing. Using a second cohort, including 22 CH‐NATs and 15 CH‐PATs, we analyzed alpha ERD while participants completed a Stroop task on a computer wearing a dry electroencephalogram (EEG) headset with 19 head sensors, which were correlated with HR and BP collected pre‐ and post‐task using an automatic blood pressure monitor.

Result

HRmax and HRmax‐HRmin from rest to task were significantly increased in CH‐PATs but not CH‐NATs, while HRmin significantly increased in CH‐NATs (Fig. 1). Frontal alpha ERD during incongruent trials were positively correlated with pre‐(R2 = 0.43, p = 0.008) and post‐(R2 = 0.42, p = 0.009) task HR in CH‐PATs but not CH‐NATs. Pre‐test diastolic BP correlated positively with central alpha ERD during congruent trials in CH‐NATs (R2 = 0.20, p = 0.039) but not CH‐PATs (Fig. 2).

Conclusion

These pilot results suggest 1) from resting to task, CH‐NATs presented greater HRmin, while CH‐PATs presented greater HRmax and HRmax‐HRmin; 2) HR is positively correlated with alpha ERD in CH‐PATs such that higher HR related to less brain activation (less negative alpha ERD). Higher pre‐task diastolic BP related to less brain activation in CH‐NATs. Although a larger sample is needed, these results support a potential application of non‐invasive EEG and ECG to identify those at higher risk of cognitive decline.
Developing an automated Cognitive assessment based on language; CognoSpeak‐ working with an ethnic minority group
Authors: Blackburn Daniel J , Sproson Lise , Egbuta Caleb , Bell Simon M , O'Malley Ronan , Mirheidari Bahman , Pevy Nathan , Christensen Heidi
Published: December 2023

Background

This study aimed to explore the issues around developing a new automated cognitive assessment. Current cognitive screening or stratification tools were typically developed only using white people so having a normative data set from almost exclusively white populations. In this part of the project we are co‐developing an automated cognitive assessment tool; CognoSpeak (https://cognospeak.github.io/website/) with a Somali ethnic minority group.

CognoSpeak is a fully automated cognitive assessment tool based in language an interaction. A virtual clinician asking questions and listening to responses using automatic speech recognition and Machine Learning algorithms

Methods

We recruited 2 members of the Somali community team (Israac) and undertook workshops to explore the themes of dementia and cognitive impairment. We trained the Research champions to use cognitive assessment tools and have piloted these on 20 healthy controls from the Somali community. Participants were assessed using the Montreal Cognitive Assessment (MoCA), Rowland Universal Dementia Assessment Scale (RUDAS) and the Multicultural Cognitive Examination (MCE).

Results

We have undertaken a pilot study, recruiting 14 females, and 7 males ranging from 34 years to 80 years old (with mean age of 48.8). Participants were all from a non‐English background and spoke English and identified as either Somalian or British Somalian. 76.19%(16/21 scored below MoCA = 26; MoCA. Zero scored below cut off on RUDAS (RUDAS = 22; RUDAS: all the patients scored more than 22 and zero scored below cut off of 70 on MCE and 14.29% (3/21)

We will aim to recruit 50 participants to interact with CognoSpeak and have results from the three cognitive screens described above.

Conclusion

We have trained two research champions with no prior research experience to help recruit Healthy controls to start testing CognoSpeak. Validation of novel cognitive tools needs co‐developed methodologies and culturally appropriate cognitive assessment tools. We will have further data on a larger data set, comparing different cognitive screening tools and our automated tool.
Assessment of the dietary intake among patients with Alzheimer’s disease in Kazakhstan
Authors: Kaiyrlykyzy Aiym , Zholdasbekova Gulnaz , Alzhanova Dinara , Kushugulova Almagul , Askarova Sholpan
Published: December 2023

Background

Dietary intake alterations have been studied in relation to Alzheimer’s disease and have shown that a diet that is rich in fruits, vegetables, whole grains, and low‐fat dairy products may be associated with a reduced risk of cognitive decline, including Alzheimer’s disease (AD). Traditionally, the Kazakh diet is high in protein, fats, and carbohydrates, and low in fruits and vegetables. With the increasing urbanization and globalization, the diet of Kazakhs is starting to change, and more people are starting to adopt a more Westernized diet which is higher in processed foods and sugar. However, little is known about dietary patterns in AD patients from the Central Asia region. Thus, the aim of the study was to identify dietary intake among local Alzheimer’s patients

Method

We included 106 patients with AD dementia and 100 controls and retrospectively assessed the average intake over a given time period of foods and dishes in a defined food list using the Food Frequency Questionnaire (FFQ). The FETA tool was used to analyze nutrient and food group data from the questionnaire

Result

Our results demonstrate that AD patients’ diets are characterized by lower fruit, vegetable, and fish consumption compared to the controls. Patients with AD dementia did significantly differ from controls in total daily energy intake (1696 (IQR 1152;2168) vs 2019 (IQR 1424;2515) kcal/day, p > 0.05), in protein, total carbohydrate, and fats. The daily Vitamin C, D, E, and iodine intake was lower than recommended amounts in both groups.

Conclusion

AD patients in Kazakhstan have a diet with low income of fruits and vegetables which leads to certain nutrients and vitamin deficiencies. It is advised that patients follow a balanced diet that is rich in fruits, vegetables, whole grains, and lean protein sources.
Analysis of oral microbiome diversity in Alzheimer’s disease patients from Kazakhstan
Authors: Kaiyrlykyzy Aiym , Kushugulova Almagul , Kozhakhmetov Samat , Jarmukhanov Zharkyn , Mukhanbetzhanov Nurislam , Pernebek Zhanel , Zholdasbekova Gulnaz , Alzhanova Dinara , Askarova Sholpan
Published: December 2023

Background

Recent studies have suggested that periodontal disease and alterations in the oral microbiome may be associated with cognitive decline and the development of Alzheimer’s disease (AD). Here, we report a pilot case‐control study of oral microbiota diversity in AD patients in comparison with healthy seniors from the Central Asian region.

Method

We have characterized the bacterial taxonomic composition of the oral microbiome from AD patients (n = 69) compared to the healthy group (n = 72) using 16S ribosomal RNA sequencing.

Result

Our analysis showed that the oral microbiome of AD has a higher microbial diversity. More importantly, differences across taxonomic groups are distinguished by the diversity of opportunistic flora in the AD group. We identified differences between phyla and genera in bacterial abundance, including a decrease in the Firmicutes/Bacteroidetes ratio in the microbiome of AD participants. LEfSe allowed determining an enrichment at the Genus Pseudomonas, Prevotella_9, UCG_002, Esherichia_Shigella, Mogibacterium, Ralstonia, and Bergeyella in the AD group. A significant increase in the genus Mogibacterium, which is also associated with an aggressive form of periodontitis and type 2 diabetes mellitus, was revealed. The genus Ralstonia are commensal representatives of the oral microbiome, but with a reduced immune system they exhibit pathogenic properties and are associated with a higher risk of mortality in hematological malignancies and hereditary disorders of hematopoiesis. One of the least studied Bergeyella spp, which is a representative of the oral microbiome of dogs, cats, and pigs, therefore, it is isolated on contact and is associated with the risk of preterm birth, as well as the development of endocarditis in a weakened body.

Conclusion

Our results confirm that the oral microbiome is a potential target for therapeutic intervention in AD. However, a comprehensive picture of the full composition of the oral microbiome in patients with AD requires further investigation.