bluuebunny/crossref_metadata_2025 huggingface dataset:
The paradox of Urban AD/ADRD caregiving during COVID‐19 pandemic
Authors: Harrington Candace C , Witt Cheryl D
Published: June 2023

Background

The SARS‐CoV‐2 RNA COVID‐19‐related societal safety measures triggered unintended consequences with unknown ramifications for the under‐reported, under‐studied, and under‐represented older female family caregivers of those with Alzheimer’s disease/Alzheimer’s disease related dementias(AD/ADRD). The purpose of this qualitative study was to investigate older female caregivers' lived experiences in the context of caring for family members with AD/ADRD during COVID‐19.

Method

Researchers used the Dutch (Utrecht) method of phenomenology with interpretative description and thematic analysis, which is valuable to investigate the meaning and context of phenomena when scant research exists.

Result

Regardless of community setting, caregivers' physical limitations and hastened disease progression contributed to caregiving fatigue and consideration of placement. Urban caregivers of those with AD/ADRD reported less support (personal and community agency support) in spite of greater access to services in this sample (N = 20). All respondents saw hastened progression of their family member’s dementia they attributed to social isolation. AD/ADRD caregivers who provided full‐time caregiving for their family member depended heavily on their care recipients' financial resources (social security, retirement, savings, and pensions) for basic living expenses. The caregivers reported fear of financial insecurity should their family member be placed in long‐term care.

Conclusion

The findings from this study suggest the financial, emotional, and mental toll of caregiving during the COVID‐19 pandemic were greater in the urban sample than in the rural caregiving sample. These findings have practice, research, and policy implications for AD/ADRD caregivers and their care recipients.
Neuroprotective activity of Acanthus maderaspatensis L. against colchicine induced Alzheimer’s disease rat model
Authors: Anawal Lingaraj , Shalavadi Mallappa , V M Chandrashekhar
Published: June 2023

Background

Traditionally, the plants were used for various diseases and disorders, including neuronal disorders. The present study was designed to evaluate the neuroprotective effect of Acanthus maderaspatensis L. against colchicine induced neurobehavioral and biochemical changes in Alzheimer’s disease rat model.

Method

Neuroprotective activity was carried out by colchicine induced Alzheimer’s disease on Sprague‐Dawley rats. Test group animals administrated with ethanol extract Acanthus maderaspatensis L. at dose of 200, 400 and 600mg/kg for 28 days. The behavioral parameters were assessed using the Morris water maze test, Digital actophotometer and Plus maze were performed at Days 0, 7, 14 and 28 on intracerebroventricular administration of colchicine for assessing the cognitive and gross behavioral activities in all groups. Biochemical parameter such as lipid peroxidation, glutathione, superoxide dismutase, catalase, total thiols and acetylcholinesterase were assessed and histopathology of brain tissue were assessed on the final day of the experiment.

Result

Ethanol extract of Acanthus maderaspatensis L. shows a dose dependent neuroprotective activity by significant decrease in time latency of Morris water maze (p<0.001) plus maze (p<0.001) increase in the locomotor activity (p<0.001) in EAM treated group compared to colchicine induced control group. Biochemical parameters showed significant decreases in lipid peroxidation (p<0.001) and increased in superoxide dismutase (p<0.001) catalase (p<0.001) glutathione (p<0.001) total thiols (p<0.001) and acetylcholinesterase level (p<0.001) in the EAM treated groups as compared with colchicine induced control group.

Conclusion

In conclusion, the present study suggests that administration of ethanol extract of Acanthus maderaspatensis L. (EAM) possesses neuroprotective activity against colchicine induced cognitive impairment and associated oxidative stress in rats.
A systematic review of therapeutic strategies against amyloid‐β peptides in Alzheimer’s disease: Past, present, and future
Authors: Jeremic Danko , Jimenez‐Diaz Lydia , Navarro‐López Juan D.
Published: June 2023

Background

Largely recognized too late, Alzheimer’s disease (AD) affects around 46 million people worldwide. The etiology of AD is still puzzling the scientific community, and its drug development and clinical trials have had high failure rate. In the recent decade, numerous studies targeting amyloid‐β peptides (Aβ) and their metabolism have been tested in patients, raising additional questions regarding AD.

Method

In order to integrate recent (from 2014) findings and analyze their clinical potential, we conducted a systematic review of investigational studies, follow‐up studies and review articles, that focus on anti‐Aβ therapies. The records were required to investigate the safety, tolerability, pharmacokinetics, efficacy, or immunogenicity of anti‐amyloid treatments in human population, excluding short and interrupted studies (<10 days), and clinical trials concerning other pathologies or comorbidities.

Result

Thus far, experimental therapies directed against Aβ have not been able to significantly reduce the progress of AD and memory impairment. The majority of therapeutic strategies were focused on amyloid precursor protein processing, and active or passive immunotherapy. Fewer studies evaluated drugs affecting Aβ misfolding, aggregation or clearance. Targeting β‐ and γ‐secretase have had unwanted results, but the activators of α‐secretase and immunotherapy against Aβ oligomers are giving some promise. Recent FDA approval and EU refusal of aducanumab sparked hopes and controversies, since the latest trial data confirmed amyloid plaque removal, without clear cognitive benefits.

Conclusion

Targeting only Aβ was not able to significantly improve the cognition of patients or modify the AD progression. The research is slowly moving toward multifunctional drugs targeting factors that precede the Aβ aggregation process, i.e., pathologic positive feedback loop linking Aβ production and other factors, such as neuronal hyperexcitability, neuroinflammation, or oxidative stress. Further development of early detection biomarkers, antibodies and additional agents that would act on both amyloid and non‐amyloid targets, could be the key to slowing down this global epidemic.

Funding

This work was supported by grants BFU2017‐82494‐P and PID2020‐115823GB‐I00 funded by MCIN/AEI/ 10.13039/501100011033 and by ERDF “A way of making Europe” by the European Union; both to LJ‐D and JDN‐L. DJ held a predoctoral scholarship from Plan Propio de Investigación–ESF Programme of University of Castilla‐La Mancha.
Sex‐adjusted blood biomarkers differentiate AD from LATE
Authors: Wu Xinxing , Peng Chong , Cheng Qiang
Published: June 2023

Background

Alzheimer’s disease (AD) is a complex neurodegenerative disorder that affects cognition, memory, and behavior, while limbic‐predominant age‐related TDP‐43 encephalopathy (LATE) is a recently defined common neurodegenerative disease that mimics the clinical symptoms of AD (Table 1). At present, there are no effective diagnostic biomarkers for LATE which can mainly be confirmed by autopsy.

Method

We applied machine learning algorithms to identify informative blood biomarkers differentiating AD from LATE. To identify blood‐based biomarkers for discriminating AD from LATE based on imbalanced data, we proposed an innovative integrated feature selection‐based approach, Preprocessing, Environmental factor analysis, Feature selection, and Validation (PEFV).

Result

We focused on the association analysis of blood markers that differentiate LATE and/or AD, on ROSMAP (Figure 1), by considering the factors including medication and diet. We pre‐identified some sensitive medication and dietary factors, and then based on these factors, we performed sex‐stratified group analyses. We identified 3 small sets of blood biomarkers that distinguish AD from LATE adjusted for each case, including All, Male, and Female. In addition, we analyzed 3 scenarios for each case: pure LATE vs. LATE+AD, pure AD vs. AD+LATE, and pure AD vs. pure LATE (Tables 2‐4). While usually, a single biomarker cannot achieve high accuracy and reliability due to the complexity of both AD and LATE, the set of biomarkers we identified for each scenario was small. For example, in Male case, 8 biomarkers were needed to distinguish LATE+AD from LATE with an accuracy rate of 61%, an improvement of about 10% over using all blood test features; 3 biomarkers were needed to distinguish LATE+AD from AD with an accuracy rate of 77%, an improvement of about 23% over using all blood test features; 4 biomarkers were needed to distinguish AD from LATE with an accuracy rate of 75%, an improvement of about 22% over using all blood test features.

Conclusion

In this study, based on blood tests, we explored blood‐based biomarkers that can differentiate AD from LATE with imbalanced data by our proposed approach PEFV and used it to discover informative blood biomarkers distinguishing AD from LATE.
Assessing neuroinflammatory differences in FTLD‐Tau vs FTLD‐TDP using free water diffusion
Authors: Sumra Vishaal , Chad Jordan A , Vasilevskaya Anna , Mora‐Fisher Daniela , Anor Cassandra Jessica , Misquitta Karen , Lang Anthony E , Slow Elizabeth , Pasternak Ofer , Trataglia Maria Carmela
Published: June 2023

Background

Frontotemporal lobar degeneration (FTLD) is associated with two pathological substrates: Tau and TAR‐DNA‐binding protein 43 (TDP‐43). In‐vivo detection of the pathological substrate is still not possible in FTLD‐related syndromes but progressive supranuclear palsy (PSP) is consistently associated with FTLD‐Tau while semantic‐variant primary progressive aphasia (svPPA) and FTD‐MND (FTD‐ALS) are associated with FTLD‐TDP. In the absence of disease‐specific markers in FTLD, it is necessary to identify biomarkers that can help distinguish FTLD‐Tau and FTLD‐TDP. Recent research has implicated neuroinflammation as a common feature across FTLD subtypes (Bright et al., 2019), however further research is required to investigate neuroinflammatory differences between FTLD‐Tau and FTLD‐TDP, given that microglial burden and activation may differ in FTLD subtypes (Woollacott et al., 2020). The free water fraction (FW), a metric generated from diffusion MRI (dMRI) (Pasternak et al., 2009), is a non‐specific marker of neuroinflammation (Bergamino, Walsh and Stokes, 2021). We will investigate differences in FW diffusion between patients with presumed FTLD‐Tau versus FTLD‐TDP. We hypothesize that differences in neuroinflammation between FTLD‐Tau and FTLD‐TDP can be identified using the free water measure, which may infer neuroinflammatory differences.

Method

Free‐water maps were generated from dMRI datasets obtained from 43 subjects: 19 with presumed FTLD‐Tau (PSP, mean age = 70), 6 with presumed FTLD‐TDP (mean age = 67, 4 svPPA, 2 FTD‐ALS), and 19 healthy controls (mean age 63). Grey matter (GM) was segmented from T1‐weighted MRIs using FSL’s ‘fast’, projected onto the diffusion MRI space, where free‐water maps were averaged across the GM. The average free water estimates from FTLD‐Tau, FTLD‐TDP and control datasets were tested for group differences using student’s t‐tests and analysis of covariance (ANCOVA), with age as a covariate.

Results

ANCOVA revealed significant differences between the groups (F = 6.47, p < 0.01). Post‐hoc tests showed significantly higher free‐water in FTLD‐Tau (p<0.01) and FTLD‐TDP (p<0.01) compared to controls. There was also higher free water in FTLD‐TDP in comparison to FTLD‐Tau, approaching significance (p = 0.0503)

Conclusion

Our preliminary data shows significant differences between healthy controls and patients with FTLD‐Tau and FTLD‐TDP and a trend for increased free water in FTLD‐TDP patients vs FTLD‐Tau, which may be indicative of neuroinflammatory differences.
Preclinical Alzheimer’s Disease accurate prediction using plasma cell‐free RNA sequences
Authors: Cisterna‐García Alejandro , Chen Hsiang‐Han , Norton Joanne , Gentsch Jen , Bergmann Kristy , Wang Fengxian , Budde John P. , Cruchaga Carlos , Botía Juan A. , Ibanez Laura
Published: June 2023

Background

Cerebrospinal fluid (CSF) Alzheimer’s disease (AD) biomarkers are used to clinically diagnose AD with an accuracy of 70‐80%. However, they are invasive and expensive and need to be further studied on preclinical‐AD. Additionally, a blood‐based biomarker can be of great use. In order to obtain a blood‐based biomarker, we have sequenced plasma cell‐free RNA (cfRNA) from preclinical‐AD individuals to develop prediction models for AD using machine learning (Figure 1).

Method

Plasma samples were obtained from the Knight‐Alzheimer‐Disease‐Research‐Center [preclinical‐AD (n = 67), clinical‐AD (n = 92), and controls (n = 48)] (Table 1) and sequenced in two batches. Sequences were processed following standard pipelines and normalized using DESeq2. Preclinical‐AD (n = 47) and controls (n = 26) from one sequencing batch were used to train the predictive model, then preclinical‐AD (n = 20) and controls (n = 22) from the other batch were used as testing population. We applied a Z‐score scaling to the normalized gene counts and used Kullback–Leibler (KL) divergence to select the genes that had similar expression distribution in both sequencing experiments (Figure 2). We used different KL thresholds to select genes as predictors and then Ridge regression to find the best predictive models. After we tested the models on preclinical‐AD, they were further tested on the clinical‐AD individuals. Finally, Parkinson’s disease (n = 96), dementia with Lewy bodies (n = 17), and frontotemporal dementia (n = 16) individuals were used to test for specificity analyses of the AD prediction models (Table 2).

Result

Best predictors sizes include 40, 90, and 220 genes yielding models with 85.7%, 90.5%, and 95.2% testing accuracy respectively. Predicted AD risk consistently correlates with Aβ42 levels. The best model included genes such as MT‐ATP6, GAB2, or MAPK14, which have been associated with AD. We tested the specificity of these models for other neurodegenerative diseases, and we observed specificity for AD in comparison to PD, FTD, and DLB (Figure 3).

Conclusion

Plasma cfRNA is a promising tool to screen for preclinical AD. It has the potential to be used as a minimally invasive biomarker for AD since it has an accuracy higher or comparable to CSF biomarkers and it is AD‐specific.
Plasma neuregulin 1 as a synaptic biomarker in Alzheimer’s disease
Authors: Vrillon Agathe , Mouton‐Liger Francois , Martinet Matthieu , Cognat Emmanuel , Hourregue Claire , Dumurgier Julien , Amar Elodie Bouaziz , Brinkmalm Ann , Blennow Kaj , Zetterberg Henrik , Hugon Jacques , Paquet Claire
Published: June 2023

Background

Synaptic dysfunction is an early core feature of Alzheimer’s disease (AD), closely associated with cognitive symptoms. Neuregulin 1 (NRG1) is a growth and differentiation factor with a key role in the development and maintenance of synaptic transmission. Previous reports have shown that changes in cerebrospinal fluid (CSF) NRG1 concentration are associated with cognitive status and biomarker evidence of AD pathology. Plasma biomarkers reflecting synaptic impairment would be of great clinical interest. Our oubjective was to measure plasma NRG1 concentration in AD patients in comparison with other neurodegenerative disorders and neurological controls (NC) and to study its association with cerebrospinal fluid (CSF) core AD and synaptic biomarkers.

Method

This retrospective study enrolled 127 participants including patients with AD at mild cognitive impairment stage (AD‐MCI, n = 27) and at dementia stage (n = 35), non‐AD dementia (n = 26, Aβ‐negative), non‐AD MCI (n = 19) and neurological controls (n = 20). Plasma and CSF NRG1, as well as CSF core AD biomarkers (Aβ 42/Aβ 40 ratio, phospho‐tau and total tau), were measured using ELISA. CSF synaptic markers were measured using ELISA for GAP‐43 and neurogranin and through immunoprecipitation mass spectrometry for SNAP‐25.

Result

Plasma NRG1 concentration was higher in AD‐MCI and AD dementia patients compared with neurological controls (respectively P = 0.005 and P<0.001). Plasma NRG1 differentiated AD MCI patients from neurological controls with an area under the curve of 88.3%, and AD dementia patients from NC with an area under the curve of 87.3%. Plasma NRG1 correlated with CSF NRG1 (β = 0.372, P = 0.0056, adjusted on age and sex). Plasma NRG1 was associated with AD CSF core biomarkers in the whole cohort and in Aβ‐positive patients (β = ‐0.197‐ 0.423). Plasma NRG1 correlated with CSF GAP‐43, neurogranin and SNAP‐25 (β = 0.278‐0.355). Plasma NRG1 concentration correlated inversely with MMSE in the whole cohort and in Aβ‐positive patients (all, β = ‐0.188, P = 0.038; Aβ+: β = ‐0.255, P = 0.038).

Conclusion

Plasma NRG1 concentration is increased in AD patients and correlates with CSF core AD and synaptic biomarkers, and cognitive status. Thus, plasma NRG1 is a promising non‐invasive biomarker to monitor synaptic impairment in AD.
Testamentary Capacity Assessment Tool (TCAT): An update report
Authors: Voskou Panagiota , Douzenis Athanasios , Economou Alexandra , Papageorgiou Sokratis G.
Published: June 2023

Background

TCAT is a recently developed short instrument (15 minutes are required for its administration), with good psychometric properties, specialized for the assessment of testamentary capacity (TC) in dementia. It assesses memory, perception of financial parameters and judgment. The present study reports all studies about TCAT.

Method

Pubmed database as well as unpublished data by the authors of the TCAT have been used.

Result

As of now, there are no other specialized TC assessment instruments with measured psychometric properties in the scientific literature. Unpublished data on amnestic mild cognitive impairment (aMCI) performance using the TCAT show no difference of aMCI in comparison to healthy adults at any part of the tool. Another unpublished study has examined the correlation between the three parts of TCAT and the expert opinion regarding TC in patients with dementia. It has shown that Part C “financial parameters” demonstrates the highest correlation with the expert opinion. Validation and standardization of the TCAT in the Greek population is under way. The preliminary results show that age, and not educational level or gender, predicts the performance in TCAT. Validation and normative data of the TCAT in an Italian population of 323 healthy adults is provided in a recent published study showing that it is useful as an adjuvant instrument for TC assessment in the elderly.

Conclusion

While the TCAT is a useful tool, more studies are needed in different cultures, both in healthy adults and cognitively impaired adults, for its standardized use in forensic and clinical settings.
Predicting Alzheimer’s disease progression in healthy and MCI subjects using multi‐modal deep learning approach
Authors: Mirabnahrazam Ghazal , Ma Da , Beaulac Cédric , Lee Sieun , Popuri Karteek , Lee Hyunwoo , Cao Jiguo , Wang Lei , Galvin James E , Beg Mirza Faisal
Published: June 2023

Background

Alzheimer’s disease (AD) is a complex disorder influenced by many factors, but it is unclear how each factor contributes to disease progression. An in‐depth examination of these factors may yield an accurate estimate of time‐to‐conversion to AD for patients at various disease stages. Recent advances in deep learning have enabled researchers to predict patient’s disease onset time by exploring the influencing factors in AD progression.

Method

We used 543 subjects with 63 features from 3 data modalities from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database. The following modalities were used: 1) MRI, 2) genetic and 3) DTC (Demographic, cognitive Tests and Cerebrospinal fluid). The 21 most important features were automatically selected for the three modalities.

We used a Deep Learning‐based survival analysis model that extends the classic Cox regression model to predict the subjects' disease onset time. Here we re‐define the non‐AD‐progression as “survivor”, and AD‐progression as “non‐survivor”. The subjects were divided into two groups: progressive subjects (non‐survivor), who were either healthy or diagnosed with Mild Cognitive Impairment (MCI) at initial clinical visit and later developed AD, and non‐progressive subjects ("survivor”), who were either healthy or MCI at initial visit but did not develop AD later. We used 10 random sub‐samples, selecting 80% of the subjects for training and 20% for testing each time; 20% of training data was used for internal validation.

Result

Figure 1 shows the estimated survival rates over 10 years. Both groups had a high survival chance at the start. The progressive group’s survival chance dropped much faster and fell below 20% by the end of the period. The non‐progressive group’s survival chance remained around 50%.

Feature importance analysis is displayed in Figure 2. Eight of the top ten most important features are from the cognitive tests, demonstrating their importance in survival analysis. Amygdala and Hippocampus regions, as well as age, are also notable features.

Conclusion

Our study demonstrated that using powerful predictive models on multi‐modal data can improve prediction of time‐to‐conversion. This not only leads to a better understanding of AD, but also provides essential tools for practitioners who wish to follow their patients' disease progression.
Language, cognitive and neuroimaging determinants of Primary Progressive Aphasia in Hebrew Speakers, a case series
Authors: keret Ophir , Glik Amir , Friedmann Naama
Published: June 2023

Background

Primary progressive aphasias (PPA) are a group of neurocognitive disorders caused by neurodegenerative diseases and defined by progressive deterioration of language capabilities. PPA are traditionally classified into three predominant variants: nonfluent‐agrammatic, semantic, and logopenic. Emerging studies suggest an individual’s spoken language impacts the clinical presentation of PPA variants, potentially leading to misdiagnosis in languages underrepresented in research. We aimed at phenotyping PPA in native speakers of Hebrew, a Semitic language, with unique characteristics such as: under‐representation of vowels in the orthography, which makes it easier to detect various types of dyslexia, rich inflectional and derivational morphology, making it easier to identify morphosyntactic impairments, and, together with object case, making word order more flexible, enabling the examination of various syntactic deficits (e.g. in syntactic‐movement).

Methods

Four native Hebrew speakers diagnosed with PPA (Mesulam 2001 criteria), aged 58‐68, complaint duration prior to assessment 10‐60 months, underwent assessment in Rabin Medical Center, Israel. Each participant underwent neurological evaluation, brain magnetic resonance imaging (MRI), and multi‐domain cognitive testing. Regional brain atrophy on T1 weighted MRI was rated with validated visual atrophy scales. All participants subsequently underwent Hebrew language evaluation using Norm‐referenced tests, assessing syntax, lexical retrieval, reading (including words and nonwords sensitive to various dyslexia types), semantic and conceptual abilities tasks, and phonology.

Results

Participant’s presenting complaint was word finding difficulty (n = 3) and non‐fluent speech (n = 1). All participants exhibited deficits in the comprehension and production of syntactic movement including one participant with no other language deficits on formal testing and no brain atrophy. Three participants exhibited various dyslexias including morphological deficits,attentional dyslexia, vowel dyslexia, and surface dyslexia. As expected, poor scores on tests of lexical retrieval and syntax were observed in subjects with severe left anterior‐temporal and left fronto‐insular atrophy respectively.

Conclusion

To our knowledge, this is the first case series of PPA in native Hebrew speakers. Errors in syntactic movement and various dyslexia types were common in all subjects suggesting they may be useful in early‐stage diagnosis. Full results (language, cognitive and neuroimaging), including additional eight cases will be presented in the AAIC conference.
Evaluating the impact of facilitated discussion series in improving dementia caregiver stress, resiliency and well‐being
Authors: Bonifas Robin P , Cohen Wendy
Published: June 2023

Background

Emotional stress stemming from the complex grief associated with dementia care takes a greater toll on a family caregiver’s health than the physical effort of providing care. Finding Meaning and Hope is a 10‐week workshop for caregivers of persons with dementia, designed to promote understanding of grief and teach self‐care concepts that help mitigate stress. Each video session features Dr. Pauline Boss, author of Loving Someone Who Has Dementia: How to Find Hope While Coping with Stress and Grief, sharing self‐care strategies with real‐life caregivers, and is followed by a facilitator‐led discussion. Home practice activities help caregivers incorporate focal self‐care strategies into their daily lives. This research aimed to assess the relationship between participating in the workshops and caregiver outcomes in stress and well‐being.

Methods

108 caregivers, 85 percent age 60 and older, completed the workshops during 2019. Two standardized instruments were administered before and after workshop participation: the 12‐item Caregiver Self‐Assessment Questionnaire (American Medical Association, 2015) and the 11‐item Sense of Competence Questionnaire (Vernooij‐Dassen, 2008). Changes in scores were assessed using Analysis of Variance or Difference of Proportions.

Results

Participation in more than half the sessions had a positive impact on stress management, emotional well‐being, and coping, but fewer gains were made by caregivers with health limitations and those who began the workshops with lower emotional well‐being. The workshops can be strengthened by supporting consistent session attendance and individually tailoring self‐care strategies to caregivers’ unique needs.

Conclusion

Family caregivers’ mental and emotional health has been negatively impacted by the COVID‐19 pandemic (Czeisler et al. 2020). Strategies that foster caregivers’ ability to manage stress and bolster well‐being are vital in enabling them to continue care provision during a time when isolation may exacerbate the challenges of caregiving. Interventions like Finding Meaning and Hope offer a promising approach.
Associations of sleep disturbances with cognitive function and plasma Alzheimer’s biomarkers in Chinese rural‐dwelling older adults: A population‐based study
Authors: Tang Shi , Liu Rui , Wang Yongxiang , Dong Yi , Qin Yu , Ren Juan , Hou Tingting , Cong Lin , Du Yifeng , Qiu Chengxuan
Published: June 2023

Background

Sleep disturbances have been associated with cognitive impairment, but their associations with plasma Alzheimer’s disease (AD) biomarkers have been rarely explored. We sought to investigate the relationships of self‐reported and cardiopulmonary coupling (CPC)‐assessed sleep disturbances, cognitive function, and plasma AD biomarkers among rural‐dwelling older adults in China.

Method

This population‐based cross‐sectional study included 1987 dementia‐free individuals (age ≥60 years, 55.0% women) who participated in the CPC‐substudy as part of the baseline assessments of the MIND‐China Study; of these, 830 had data on plasma Aβ42, Aβ40, total‐tau, and neurofilament light chain (NfL) that were measured using the single molecule array (SIMOA) technology. We collected data via face‐to‐face interviews, clinical examinations, and neuropsychological test. Sleep disturbances were assessed using the Pittsburgh Sleep Quality Index (PSQI), the Epworth Sleepiness Scale (ESS), the self‐administered Berlin Questionnaire, and the ECG‐based CPC analysis. We used the neuropsychological test battery to assess memory, language, attention, and executive function. Data were analyzed using logistic and general linear regression models.

Result

Of the 1987 participants, CPC‐measured total sleep time (TST) >8 hours/night (vs. 5‐8 hours) was significantly associated with a lower composite z‐score of memory (β = ‐0.080; 95% CI = ‐0.160 ‐ ‐0.001), language (‐0.114; ‐0.186 ‐ ‐0.042), attention (‐0.104; ‐0.175 ‐ ‐0.033), and executive function (‐0.117; ‐0.193 ‐ ‐0.041). Self‐reported poor sleep quality was associated with a lower composite z‐score of attention function (β = ‐0.077; 95% CI = ‐0.143 ‐ ‐0.011). Self‐reported excessive daytime sleepiness (EDS) was associated with a lower composite z‐score of memory (β = ‐0.217; 95% CI = ‐0.350 ‐ ‐0.084), language (‐0.182; ‐0.303 ‐ ‐0.061), and attention function (‐0.162; ‐0.282 ‐ ‐0.041). In the plasma biomarker subsample, CPC‐measured TST >8 hours/night was significantly associated with lower plasma Aβ42/Aβ40 ratio (β = ‐0.522; 95% CI = ‐0.764‐ ‐0.281) and higher plasma concentrations of Aβ40 (13.419; 6.515‐20.323), total‐tau (0.216; 0.071‐0.360), and NfL (0.071; 0.002‐0.140). There was no significant association between CPC‐measured apnea hypopnea index (AHI) and plasma AD biomarkers (P>0.05).

Conclusion

Long sleep duration and self‐reported EDS were associated with poor memory, language, and attention function among older adults, in which AD pathology and neurodegeneration may be the common pathways linking sleep disturbances with cognitive impairment.
Multi‐branch convolutional neural network for Alzheimer’s Disease versus normal control classification using PET images
Authors: Sharma Rishabh , Sibille Ludovic , Fahmi Rachid
Published: June 2023

Background

Brain PET imaging techniques provide in‐vivo information about brain metabolism and the density/distribution of amyloid and tau proteins, the two hallmarks of Alzheimer’s disease (AD). Combination of such imaging biomarkers has led to improved performances of deep‐learning models designed for disease‐classification and prediction of disease‐progression. However, training such networks is often a challenge, especially when subjects have missing imaging markers at given time‐points. Such incomplete data is often excluded from the training process. We propose a “multibranch”‐convolutional‐neural‐network architecture to cope with this issue and make use of all available data for better AD vs. normal‐controls (NC) classification performance.

Method

We obtained multi‐time point ADNI FDG‐ and AV45‐PET scans corresponding to 257 NC and 222 AD subjects. N = 124 subjects had only one PET scan available at different time‐points. We designed a CNN with three training “branches”, taking as input either FGD, AV45, or a combination of the two when available (see Fig.1). In total, 1832 scans (786 singles and 523 pairs) were used as input for training. Branches are weighted differently (with 0 or 1) to control how training weights are updated. When both imaging‐biomarkers are available, each branch is fed with the appropriate input and contributes to the overall training. The overall network architecture is shown on Fig.1. For each branch, the calculated loss is multiplied by the associated weight and backpropagated through the network to update its training parameters. For comparison purposes, we independently trained a CNN with the same image pairs as above.

Result

For validation, we only used cases with both scans available to assess the performance of each branch on the same number of inputs. Classification sensitivity, specificity, accuracy, and area‐under‐the‐curve averaged over 10 folds were: (i) FDG‐branch: 93.11%, 88.88%, 91.35%, and 0.954, (ii) AV45‐branch: 96.53%, 74.87%, 90.27%, and 0.941, (iii) Multimodal‐branch: 94.43%, 86.50%, 91.56%, and 0.961, iv) Independent multi‐input CNN: 93.71%, 71.80%, 88.60%, and 0.959.

Conclusion

We designed a multibranch‐CNN to handle missing data when training a multimodal classification CNN. Better classification accuracy was achieved with the multi‐input branch compared to the independently trained multi‐modal CNN. We will test our network on other type and/or number of modalities.
Validity of CSF alpha‐synuclein to predict psychosis in prodromal Alzheimer´s disease
Authors: Monge‐Argilés José Antonio , Monge‐García Sonia , Cortés‐Gómez Mariangeles , Sánchez‐Payá José , Gasparini‐Berenguer Ruth , Sáez‐Valero Javier , García‐Ayllón María‐Salud
Published: June 2023

Background

The emergence of psychotic symptoms (PS) in Alzheimer´s disease (AD) involves a poor prognosis of the illness and may be related with different genetic, personal, environmental and caregiver factors, as well as unbalances in key neural proteins. In this last group, an alteration in the alpha‐synuclein (AS) metabolism may be included. Aim: To study the diagnostic validity of AS in CSF, to predict the emergence of PS in prodromal AD patients.

Method

Mild cognitive impairment patients (according to Petersen 2006) from the out‐patient consultation of Alicante University General Hospital (Spain) were recruited between 2010‐2018. All the patients followed NIA‐AA 2018 criteria for AD biomarkers. At inclusion, all of them had MMSE higher than 22, Neuropsychiatric Inventory lower than 10, Lawton‐Brody scale higher than 7, IQCODE lower than 80, Barthel index higher than 95 and a follow‐up higher than 2 years. All patients were treated with anticholinesterasic drugs from the diagnostic was made. The Pittsburgh sleep quality index and the Cummings criteria for psychosis (2020) were applied and the requirement of neuroleptic drugs was necessary to consider the inclusion in the psychosis group. Core AD biomarkers and AS were measured in CSF obtained in the prodromal phase of the illness. Different comparisons were made between the groups and subgroups following the time of emergence of PS.

Result

130 prodromal AD were included. 50 of them (38.4%) accomplished the psychosis criteria into the 8 years follow‐up. In every comparison made between groups and subgroups, AS was the best CSF biomarker to differentiate psychotic versus non psychotic groups. The level of AS 1257 pg/mL reached at least 80% of sensitivity to differentiate between both groups. A negative predictive value of 80% was found to differentiate between groups.

Conclusion

The measurement of AS in CSF is the most valid biomarker used in this study to predict the emergence of PS during the 8 years after the prodromal phase of AD. These results must be confirmed in a larger population but, in our knowledge, is the first time that a CSF biomarker shows a diagnostic validity to predict PS in prodromal AD.
A comprehensive literature search of digital health technology use in dementia: Digital tools to support dementia caregivers
Authors: Spreadbury John , Young Alexandra , Kipps Christopher
Published: June 2023

Background

Dementia can negatively impact the well‐being and quality of life of patients and informal caregivers. Digital self‐management tools have the potential to support those living with dementia. The aim of this review was to identify digital tools used in dementia care, investigate how they support users, and highlight pertinent clinical and psychosocial outcomes.

Method

Six databases were searched (i.e. CINAHL, EMBASE, MEDLINE, PsycINFO, Web of Science, and the Cochrane Review) using free text and equivalent database‐controlled vocabulary terms.

Result

Twenty‐six articles were identified reporting 21 digital tools focused mainly on caregivers ‐ thus caregivers form the focus of this review. The digital tools promoted self‐management and support through five main functions: Supporting psychoeducation and self‐help; improving competency and ability; sustaining and promoting well‐being; encouraging behaviour change and providing motivation; and facilitating contact and communication with healthcare professionals and other users. There was mixed‐to‐limited evidence to support a positive influence of digital tools on mental health, burden, quality of life, and caregiver perceived ability.

Conclusion

Digital health technology has the potential to support caregivers, however areas such as mental health, burden, and quality of life may be resistant to some digital interventions. It is important to understand issues around accessibility, uptake, and continued use of digital tools and their potential to be integrated within dementia care pathways and routine clinical care.
Effects of benzodiazepine receptor agonists on cognitive function in patients with chronic insomnia
Authors: Tang Shi , Li Shasha , Tang Jiyou
Published: June 2023

Background

To investigate the effects of benzodiazepine receptor agonists on cognitive function in patients with chronic insomnia.

Method

According to the history of taking hypnotic drugs, they were divided into no medication group (n = 62), benzodiazepines group (n = 57) and non‐benzodiazepines group (n = 53); all subjects The Pittsburgh Sleep Quality Scale, the Epworth Scale, and the Insomnia Severity Index were used to evaluate their sleep quality, and the Hamilton Anxiety and Depression Scale to evaluate their anxiety and depression. The conversion test, the auditory word learning test was used to evaluate the memory function, and the Stroop color word test and the connection function test were used to evaluate the executive function.

Result

Compared with no medication, the non‐benzodiazepine group and the benzodiazepine group had longer sleep time throughout the night (P<0.05), and the non‐benzodiazepine group and the benzodiazepine group. The anxiety and depression scores of the drug group were lower than those of the non‐drug group (P<0.05), and the immediate memory and delayed memory scores of the benzodiazepine group and the non‐drug group were lower than those of the non‐benzodiazepine group (P<0.05). 0.05), the dose and duration of medication in the benzodiazepine group were negatively correlated with immediate memory (P<0.05), and the duration of medication in the benzodiazepine group was negatively correlated with prolonged memory (P<0.05). Regression analysis showed that the immediate memory score of taking benzodiazepines was 2.612 times lower than that of the non‐drug group, and the delayed memory score of taking non‐benzodiazepines was 1.439 times higher Regression analysis showed that the immediate memory score of taking benzodiazepines was 2.612 times lower than that of the non‐drug group, and the delayed memory score of taking non‐benzodiazepines was 1.439 times higher than that of the non‐drug group (P<0.05). The difference is statistically significant.

Conclusion

Benzodiazepines increase the risk of impaired immediate memory function in patients with chronic insomnia, and non‐benzodiazepines can improve their delayed memory function.
Novel unsupervised comprehensive tool for monitoring vascular cognitive impairment following stroke
Authors: Gruia Dragos , Combrie Sabia , Geranmayeh Fatemeh
Published: June 2023

Background

Stroke is a leading cause of death and disability worldwide. Cognitive difficulties occur in up to 86% of acute stroke cases (Demeyere et al., 2015) and persist in a third. Despite the numerous efforts made thus far, developing effective therapeutic interventions for vascular cognitive impairment remains a large unmet need (Zotin et al., 2021). This is in part due to the heterogeneity of the disease mechanisms, and cognitive profiles exhibited by patients. To better understand the range of factors that contribute to long‐term cognitive outcomes after vascular insult, there is a growing need for in‐depth longitudinal assessments of cognitive function that are scalable and cost‐efficient. To address this gap and to capitalise on the recent growth of telemedicine technology driven by the pandemic, we developed a self‐administered unsupervised, adaptable, and in‐depth online cognitive assessment tool specifically for patients with stroke.

Method

This self‐administered web‐based tool offers an in‐depth cognitive profiling through 23 tasks spanning both domain‐general (attention and executive functioning) and domain‐specific deficits (memory, language, visual neglect, number skills, apraxia), together with neuropsychiatric questionnaires. In total, the assessment lasts one hour and is compatible with a variety of devices and operating systems. In light of these specifications, the battery has been named IC3 (Imperial College Comprehensive assessment for Cerebrovascular disease; https://ic3study.co.uk/)

Result

We present results outlining the normative ranges for the assessment in age and education matched controls and in a modest sample of patients following stroke. Furthermore, we present an overview of our validation studies which examine the battery’s specificity and sensitivity, and test‐retest reliability. We also discuss a comparison against established clinical batteries (e.g. CAT and MoCA). Finally, as the assessment has been designed to be self‐administered remotely, we also present a validation against face‐to‐face supervised delivery of the battery.

Conclusion

IC3 is the first assessment to offer in‐depth unsupervised cognitive phenotyping of patients with vascular brain insult, while also allowing scalable and cost‐efficient longitudinal monitoring. The assessment fares well against various validation methods, making it an attractive tool for understanding the mechanisms of recovery in a plethora of vascular disorders.
Subjective and objective prospective memory in mild cognitive impairment and Alzheimer’s disease
Authors: OBrien Tanner , Olmos Winter , Moreno Jasmin C , Saravia Sarah , Severson Ella , Hernandez Juan Pablo , Wright Matthew , Lent David D , Alving Loren , Woo Ellen
Published: June 2023

Background

Prospective memory (PM) involves remembering to execute an intended action in the future, and it is an important skill that predicts everyday functioning in older adults. Older adults with mild cognitive impairment (MCI) and Alzheimer’s disease (AD) exhibit difficulties in PM. This study examined subject and caregiver reports of PM ability and their associations with objective PM.

Method

Participants included older healthy controls (n = 58), persons with MCI (n = 65), and individuals with AD (n = 18). The Prospective‐Retrospective Memory Questionnaire was used to assess self‐ and caregiver‐reports of participants’ PM skills. Objective abilities were measured using tests of “simple” and “complex” PM. Simple PM was defined as remembering to perform a single action in the future. Complex PM was defined as selecting the correct action based on the context.

Result

Regression analyses revealed that caregiver‐reported PM predicted complex PM only in healthy controls. In contrast, self‐reported PM did not predict objective PM in any group.

Conclusion

The results showed that self‐reports of PM are not good indicators of objective PM. While caregiver reports may be more accurate in relation to PM in healthy older adults, they do not align as well with objective PM for those with cognitive impairment. Overall, this research indicates that objective measures should be used to evaluate this important skill that contributes to everyday functioning.
A longitudinal 18F‐FDG PET study in asymptomatic stage of genetic Creutzfeldt–Jakob disease
Authors: Chu Min , Chen Zhongyun , Xie Kexin , Liu Li , Cui Yue , Chen Kewei , Wu Liyong
Published: June 2023

Background

Pathogenic prion protein may start to deposit in some brain regions and cause functional alterations in the asymptomatic stages in Creutzfeldt–Jakob disease patients. However, the disease trajectory of Creutzfeldt–Jakob disease in the asymptomatic stage and when and where the degenerative process begins are still not clear.

Methods

At baseline, we enrolled five asymptomatic mutation carriers, six affected genetic Creutzfeldt–Jakob diseasepatients, and 23 healthy controls from whom 18F fluorodeoxyglucose‐positron emission tomography, clinical, and neuropsychological measures were acquired. Only five asymptomatic mutation carriers had completed longitudinal follow‐up. We set three‐time points to identify the changing trajectory in asymptomatic carriers group including baseline, 2‐year and 4‐year follow‐up.

Results

At baseline, the cerebral glucose metabolic rate, measured as the standardized uptake value rate ratio, clinical and neuropsychological scales in all 5 asymptomatic cases were normal. In the 4‐years follow‐up, hypometabolic brain regions in asymptomatic genetic Creutzfeldt–Jakob disease group were found in the insula, frontal, parietal, and temporal lobes (false discovery rate corrected p<0.01). The standardized uptake value rate ratio changing trajectories of all asymptomatic cases were within the range between the healthy controls and affected patients. Notably, the metabolism values of one asymptomatic individual whose baseline age was older than the expected age of onset showed a rapid decline and approached the mean value of genetic Creutzfeldt–Jakob disease condition at the last follow‐up.

Conclusion

Our study illustrates that neurodegenerative process associated with genetic Creutzfeldt–Jakob disease may involve the insula, frontal, temporal, and parietal lobes before clinical presentation of the disease, and the decline will accelerate when close to the expected age of onset. Although there are no effective means to cure this fatal disease, the time interval before clinical disease onset may aid important trials or therapies intended to slow or halt the disease process.
Associations between cerebrospinal fluid biomarkers and brain regions of relevance for very early Alzheimer’s disease processes
Authors: Seidu Nazib M. , Kern Silke , Sacuiu Simona , Sterner Therese Rydberg , Blennow Kaj , Zetterberg Henrik , Lindberg Olof , Ferreira Daniel , Westman Eric , Zettergren Anna , Skoog Ingmar
Published: June 2023

Background

The relation between cerebrospinal fluid (CSF) biomarkers of Alzheimer’s disease (AD) and neurodegeneration and brain regions of relevance for very early pathological processes in AD is poorly understood. This study aims to investigate cross‐sectional associations between the CSF biomarkers amyloid‐β1‐42 (Aβ42), total‐tau (T‐tau), phosphorylated‐tau (P‐tau), neurogranin (Ng) and neurofilament light (NfL) protein and normalized intracranial volumes of the hippocampus, amygdala, entorhinal cortex and basal forebrain observed on structural magnetic resonance imaging (MRI) in cognitively healthy 70‐year olds from the general population.

Method

The analyses included 226 cognitively normal individuals (clinical dementia rating of zero), examined during 2014‐2016 as part of the population‐based Gothenburg H70 Birth Cohort Studies in Sweden. The study participants had undergone lumbar puncture examination to extract CSF samples for biomarker measurements (pg/mL), MRI scan (volumes in mm³), and apolipoprotein E (APOE) genotyping. Linear regressions, adjusted for sex, were used to examine potential associations.

Result

Elevated CSF T‐tau, P‐tau, and Ng concentrations were associated with smaller volumes of the hippocampus, amygdala, and entorhinal cortex among individuals with amyloid pathology (p = 8×10−8 – 0.04) and among APOE ε4 carriers (p = 8×10−5 – 0.04). In addition, elevated CSF T‐tau, P‐tau, and Ng concentrations were associated with larger basal forebrain among individuals without pathological Aβ42 (p = 0.001 – 0.01) and among APOE ε4 non‐carriers (p = 0.004 – 0.02).

Conclusion

The results of our study suggest that among cognitively normal adults who have amyloid pathology or genetic susceptibility to AD, there are associations between axonal degeneration, tangle pathology, and synapse loss and decreased volumes of AD vulnerable brain regions. The associations between elevated CSF biomarkers and larger basal forebrain in cognitively normal individuals were unexpected, but could possibly be explained by compensatory mechanisms or an inflammatory response (generating neuronal or glial swelling) as a very early reaction to the presence of increased levels of tau and Ng. Our findings highlight the clinical pathophysiological relevance of CSF biomarkers of AD and neurodegeneration and how they relate to AD specific brain regions seen on structural MRI in 70‐year‐olds that may be at risk to develop dementia.