bluuebunny/crossref_metadata_2025 huggingface dataset:
Cannabidiol for neuropsychiatric symptoms in Alzheimer’s dementia
Authors: Velayudhan Latha , Dugonjic Marta , Pisani Sara , Chowdary Seemulamoodi Yellappa , Harborow Lucy , Aarsland Dag , Sagnik Bhattacharyya
Published: June 2023

Background

Behavioural and Psychological Symptoms of Dementia (BPSD) in people with Alzheimer’s disease (AD) is particularly distressing to patients and carers. There are currently no licensed medications for BPSD, and the current available treatments have limited benefits and greater risk for side effects. There is therefore a considerable unmet clinical need for interventions that are safe, well‐tolerated and effective for treating BPSD in AD. Cannabidiol (CBD), a non‐addictive substance present in cannabis shows promise for treating psychotic and anxiety symptoms in people without dementia and is generally safe and well‐tolerated in elderly. However, its efficacy, safety and tolerability need to be systematically tested in elderly with dementia. We aimed to evaluate acceptability and tolerability of CBD as treatment for BPSD in patients with AD.

Methods

We are conducting a double‐blind, parallel group, placebo‐controlled pragmatic randomized controlled feasibility trial (EudraCT Number ‐ 2019‐002106‐52) and recruiting AD patients with BPSD within Mental Health for Older Adults services, South London and Maudsley NHS trust, United Kingdom. Half of the participants receive 600 mg of CBD orally once a day over 6 weeks and the other half receive a placebo, in addition to their usual treatment for 6 weeks. Clinical data collected includes measures of cognition, Clinical Dementia Rating for staging, behaviour symptoms on Neuropsychiatric Inventory (NPI), global functioning, Quality of Life for patients and carer’s burden. Tolerability is assessed by self‐report of side‐effects, and side‐effect rating scale.

Results

Of the participants recruited and randomised so far, there have been no withdrawals or serious adverse events. The study is ongoing and due for completion at the end of April 2022, following which we will have the data to analyse and present the findings at the July 2022 conference.

Conclusions

CBD has been generally acceptable and safe for people with AD with BPSD. The final analysis and findings related to adverse events, and changes in clinical measures for the groups (CBD treatment versus placebo) including BPSD, cognition etc. will be presented at the conference.
Psychosocial factors associated with loneliness change during COVID‐19 pandemic in Italian older‐old individuals: Findings from the InveCe.Ab cohort
Authors: Rolandi Elena , Rossi Michele , Serini Miriam , Vaccaro Roberta , Colombo Mauro , Guaita Antonio
Published: June 2023

Background

Loneliness is an issue for many older adults, significantly affecting physical, cognitive and mental health. The aim of the present study was to evaluate if loneliness worsened in older‐old individuals during the COVID‐19 nationwide lockdown in Italy, compared to their pre‐pandemic status. Moreover, we explored which pre‐pandemic psychosocial factors predict loneliness change.

Method

The present investigation was conducted on 409 older adults without dementia and aged between 79 and 84 years, participating in the fourth evaluation wave of the InveCe.Ab study in 2018 (NCT01345110) and then performing a telephone survey between March and May 2020, during the first Italian nationwide lockdown. Loneliness was evaluated with the UCLA 3‐item loneliness scale both in 2018 and 2020. The following pre‐pandemic measures, collected as part of the in‐person multidimensional assessment in 2018, were considered: age, sex, education, social contact, leisure and physical activity, digital technology usage (yes/no), perceived support from family network (yes/no), personality traits (psychoticism, extraversion, neuroticism), depressive symptoms (Geriatric Depression Scale, GDS), global cognition (Mini Mental State Examination, MMSE) and baseline loneliness. To compare pre‐post pandemic loneliness, we performed the Wilcoxson signed‐rank test. Kendal tau rank correlations were calculated to preliminarily explore the associations between each psychosocial factors and loneliness change (delta). Finally, stepwise multiple linear regression based on the p‐value criteria was used to test which variables independently predicted loneliness change.

Result

Loneliness showed a significant increase during the lockdown (p<0.001). Loneliness change was associated with lower GDS (τ = ‐0.221, p<0.001), psychoticism (τ = ‐0.086, p = 0.024), neuroticism (τ = ‐0.116, p = 0.002) and higher extraversion (τ = 0.079, p = 0.035), MMSE (τ = 0.106, p = 0.006), social contacts (τ = 0.091, p = 0.015) leisure activities (τ = 0.103, p = 0.006). Multiple regression showed that only 2 psychosocial factors explained 27% of the variance (R2 = 0.27, F = 74,7, p<0.001). Specifically, baseline loneliness (β = ‐0.70, p<0.001) and perceived support from family network (β = ‐0.50, p = 0.007) predicted loneliness change.

Conclusion

Loneliness increased during the first nationwide lockdown among older‐old individuals in Italy, compared to their pre‐pandemic level. This change was most prominent among those with lower pre‐pandemic loneliness levels and it was mitigated by perceived support by family network.
Rate of cognitive decline before seizure diagnosis in individuals with dementia and seizures
Authors: keret Ophir , Beninger Felix , Allen Isabel Elaine , Goldberg Ilan , Glik Amir
Published: June 2023

Background

Seizures and epilepsy occur frequently in individuals diagnosed with dementia. While previous studies report highest incidence in advanced disease stages, emerging studies suggest subclinical seizures noted only on Magnetoencephalography or electroencephalography(EEG) occur frequently in early stages. Such recorded subclinical seizure activity is associated with a more rapid course of cognitive decline on longitudinal assessment. We thus hypothesized individuals with dementia who are diagnosed with seizures in any stage experience a rapid cognitive decline before they are diagnosed with seizures.

Method

Study design is a retrospective case‐control study, assessing clinical data from 24142 research subjects evaluated longitudinally from the National institute of health Alzheimer Coordination Center, years 2006‐2019. Seizures diagnosed during follow up were used as a predicting variable. Individuals with seizures on their first visit as well as individuals with unknown seizure status were excluded. Individuals with unknown APOE genotype and those without longitudinal data were also excluded. We assessed cognitive decline as an outcome using annual Mini Mental State Exam (MMSE) and Clinical Dementia Rating Sum of Boxes (CDR‐SB). We assessed the decline using a linear mixed effects models adjusting for other variables known to alter decline rate such as age at onset of symptoms, sex and ApoE4 genotype and included a random effect for time between visits within patients.

Result

We identified 205 and 4667 individuals with and without seizures respectively on follow up research visits. Patients with seizures had an younger mean age at symptom onset (65±11.3 vs 70±10.0), of similar sex (50.0% and 50.7% male) and remained longer on follow up (5±3 vs 3±2). Baseline MMSE and CDR‐SB was similar in both groups. Compared to subjects without seizures, those with seizures had a rapid annual decline in CDR‐SB (0.98, SE 0.24, 95% CI 0.51‐1.46, p<.0001) and MMSE (‐1.8, SE = .40, 95% CI ‐1.4 and ‐2.6, p<0.00001).

Conclusion

A rapid rate of decline can be observed in individuals with dementia prior to seizure diagnosis. Our study suggests undiagnosed seizures or seizures activity on EEG should be suspected in individuals who experience a rapid rate of cognitive decline.
Neuropathological features of antemortem atrophy‐based subtypes of Alzheimer’s disease
Authors: Mohanty Rosaleena , Ferreira Daniel , Frerich Simon , Muehlboeck J‐Sebastian , Grothe Michel J. , Westman Eric
Published: June 2023

Background

Pure Alzheimer’s disease (AD), characterized by combined amyloid and tau pathology, is not the most prevalent form of the disease as non‐AD pathologies (e.g., alpha‐synuclein and TDP‐43) are commonly observed postmortem. The role of AD and non‐AD pathologies is unclear in relation to disease heterogeneity. Therefore, we investigated whether antemortem MRI‐based atrophy subtypes of AD differ in postmortem neuropathological features and comorbid non‐AD pathologies.

Methods

We selected individuals from the ADNI with antemortem MRI evaluating brain atrophy within 2 years before death; antemortem diagnosis of AD dementia/mild cognitive impairment; and a postmortem‐confirmed AD neuropathologic change. Antemortem atrophy subtypes were modeled as continuous phenomena using a recent conceptual framework: typicality (spanning limbic predominant AD to hippocampal sparing AD) and severity (spanning typical AD to minimal atrophy AD). Postmortem neuropathological evaluation included AD hallmarks (amyloid‐beta, tau), non‐AD pathologies (alpha‐synuclein, TDP‐43) and concomitant pathological burden. Partial correlations assessed the associations between antemortem atrophy subtype dimensions and postmortem neuropathological outcomes.

Results

In 31 individuals (mean age = 80y, 26% females), antemortem typicality was significantly associated with neuropathological features: amyloid‐beta (rho = ‐0.39 overall), tau (rho = ‐0.38 regionally), neuritic plaque density (rho = ‐0.4 overall), alpha‐synuclein (rho = ‐0.39 regionally), TDP‐43 (rho = ‐0.49 overall), and concomitance pathological burden (rho = ‐0.59 regionally). This suggests that limbic predominant AD was associated with higher burden of these pathologies compared to hippocampal sparing AD. Antemortem severity was significantly associated with concomitant pathological burden (rho = ‐0.43 regionally), such that typical AD showed higher burden than minimal atrophy AD.

Conclusions

Based on our direct antemortem‐to‐postmortem validation, we hypothesize that: (a) typicality and severity in atrophy reflect differential aspects of susceptibility of the brain to AD and non‐AD pathologies; (b) limbic predominant AD and typical AD subtypes may share similar biological pathways, making them more vulnerable to the investigated AD and non‐AD pathologies compared to hippocampal sparing AD, which may follow a different biological pathway. Our findings provide a deeper understanding of associations of atrophy subtypes in AD with different pathologies, enhancing prevailing knowledge of biological heterogeneity in AD.
Development and evaluation of the Feasible and Sustainable Culture Change Model—an online training program designed to increase the provision of person‐centred care practice in residential care homes
Authors: Caspar Sienna
Published: June 2023

Background and Objectives

Interventions aimed at increasing the provision of relational and person‐centred care in residential care homes (RCHs) that do not address contextual and system issues most often fail. Promoting positive change in RCHs requires a multilevel, systems approach. The objective of this study was to examine the effectiveness of the online Feasible and Sustainable Culture Change Model (FASCCI) model training program on influencing both the implementation and outcomes of culture change initiatives aimed at increasing the provision of person‐centred care practices during ‘move‐in day’ for newly admitted residents.

Methods

Using principles consistent with Cooperative Participatory Action Research (CPAR), we collected qualitative and quantitative data to examine the processes and outcomes associated with using the online FASCCI training program to implement changes in ‘move‐in day’ care practice in two RCHs. Surveys—including likert scales (1 = strongly disagree‐ 5 = strongly agree) and open‐ended questions, were used to evaluate the staffs’ (n = 24) perceptions of the online training modules. Interviews with the Process Improvement Team leaders (n = 2) were conducted to examine treatment fidelity and ascertain their perceptions regarding the intervention processes. Practice change outcomes were determined based on detailed descriptions and observations of the move‐in practices pre‐intervention and comparing these to the move‐in practices following the intervention.

Results

Staff members indicated they strongly agreed that the online training modules were “useful both personally and professionally” (M = 5.0) and that they “were able to use the skills they learned in their care practice” (M = 4.7). Analysis of data from qualitative interviews demonstrated that use of the online FASCCI model training program resulted in improved team building, communication, and collaborative decision‐making. Multiple changes to care practices occurred, including but not limited to, the creation and implementation of a “Move In Ambassador”, creating an effective process for ‘personal device labelling’ (i.e., walkers), and creating and distributing “Isolation Bags’—bags with personalized, creative activities for the residents to engage with during 2‐week isolation periods (due to the pandemic) at move‐in.

Conclusions

This study offers evidence that the online FASCCI model training program provides a promising approach for improving the provision of relationship‐centred move‐in practices in LTC homes.
Risk knowledge and risk perception of MCI patients and their caregivers in predictive diagnosis of AD: Findings from the PreDADQoL study
Authors: Rostamzadeh Ayda , Schwegler Carolin , Rosende‐Roca Maitee , Canabate Pilar , Moreno Mariola , Ortega Gemma , Schmitz‐Luhn Björn , Boada Mercè , Woopen Christiane , Jessen Frank
Published: June 2023

Background

Individuals with mild cognitive impairment (MCI) and their caregivers face complex probabilistic information when seeking diagnostic work‐up of early detection of Alzheimer’s disease (AD). When counseling about biomarker‐based AD detection and communicating dementia risk, clinicians need to consider the magnitude of cognitive impairment and the numeracy skills of their patients, in order to enable an informed decision‐making. The transnational PreDADQoL project used a mixed‐methods approach to provide data on this topic and was conducted in Germany and Spain.

Method

A total of 76 MCI patients and caregivers were recruited and followed‐up over 3 months after a standardized counseling session about predictive AD diagnosis and cerebrospinal fluid (CSF)‐biomarker‐based dementia risk prediction. MCI patients consenting to biomarker testing were scheduled for a disclosure session together with their caregiver, where the individual biomarker profile together with the dementia risk was communicated. Risk communication was facilitated by graphical displays and take‐home material. Questionnaires on numeracy skills such expectations towards the predictive testing were applied. Moreover, a questionnaire and an open question on the risk perception regarding the MCI patient’s risk to develop Alzheimer’s dementia within 5 years were assessed.

Result

On average MCI patients answered 58% of items testing numeracy scale correctly, and caregivers 66%. After counseling on biomarker‐based AD detection and dementia risk prediction a substantial number of patients (25%) and caregivers (40%) expected a precise detection of a disease from the biomarker testing and not a risk prediction. MCI patients perceived their risk of developing Alzheimer’s dementia to be equal or lower as compared to a healthy person. The caregivers‘ risk perception correlated significantly with the communicated risk, however, in MCI patients no correlation between communicated risk and risk perception was detected.

Conclusion

The disclosure of dementia risk did not have a major impact on the MCI patients‘ risk perception, whereas the caregivers‘ risk perception correlated significantly with the communicated risk. This study depicts that clinicians should be aware that not all the contents of the counseling and disclosure information may be understood by patients. Furthermore, competing preexisting attitudes, expectations and knowledge of the individuals need to be acknowledged by clinicians when communicating dementia risk.
Clinical profile of primary progressive Aphasia in Peru: Case series from a Neurological care center
Authors: Castro‐Suarez Sheila , Guevara‐Silva Erik Alberto , Caparo‐Zamalloa Cesar , Meza‐Vega Maria , Cornejo‐Olivas Mario
Published: June 2023

Background

Primary Progressive Aphasia (PPA) is one of the clinical syndromes of frontotemporal dementia (1). The frequency of PPA syndromes is low (16%) in this Latin America, with just one published report in Peruvian population (2). We aim to describe clinical features of PPA patients followed up at a Neurological healthcare center in Peru.

Method

Retrospective review of clinical records of patients diagnosed with probable PPA (based on 2011 diagnostic criteria) during the 2010‐2020 period. Local IRB approval was obtained for this study.

Result

We included 11 cases that fulfilled the selection criteria. Nine cases (75%) were categorized as nfvPPA, and 3 (25%) svPPA. There was slightly female predominance (58%). The average of education was 10.8±4.8 years. Six cases (54.5%) declared place of birth from northern Peru. We found 4.2±1.8 years of diagnostic delay for PPA. The mean age at onset for nfvPPA and svPPA groups was 63 ±12.4, and 52(52‐64) respectively. The first symptom identified in the nfvPPA group was effortful, halting speech 7 (77.8%), while svPPA was impaired confrontation naming 3 (100%). nfvPPA group showed agrammatism in language production and effortful speech in 8 patients (88.9%) and impaired in comprehension of syntactically complex sentences and spared single ‐word comprehension 3(33.3%). Parkinsonism was present in 6 patients (66.7%) and only one patient reported coexistence of amyotrophic lateral sclerosis. Depression was present in most of the 50% of cases. svPPA group also presented impaired in single word‐ comprehension, in object knowledge, and spared repetition 3(100%), 3 (100%) and 2(66.8%) respectively. Less than 50% of PPA cases were in speech therapy.

Conclusion

The main clinical features of the PPA reported are mostly consistent with previous reports. In our medical records review, no cases of apraxia of speech were found. There is a significant delay of PPA diagnosis. Further studies with prospective design are required to obtain a better description. Implementing training strategies for clinicians will allow to improve the timely and accurate diagnosis of PPA in Peru.
Underlying structure of the MBI‐C in pre‐symptomatic and prodromic states of dementia: A multidimensional scaling approach
Authors: Mallo Sabela C. , Real‐Deus Eulogio , Nieto‐Vieites Ana , Felpete Alba , Lojo‐Seoane Cristina , Pérez‐Blanco Lucía , Ismail Zahinoor , Pereiro Arturo X
Published: June 2023

Background

The Mild Behavioral Impairment Checklist (MBI‐C) (Ismail et al., 2017) is a 34‐item scale that evaluates Neuropsychiatric Symptoms (NPS) in pre‐dementia states. Its underlying structure has been little studied and remains largely unknown. Factor analysis‐based approaches may have difficulty finding stable relationships between NPS collected on a checklist to account for the large heterogeneity of manifestations. Thus, our objective was to analyze the underlying structure of the MBI‐C using an alternative approach.

Method

Eighty‐two MCI and 117 SCD older adults of the CompAS were recruited in primary care health centers. Asymptomatic participants were excluded from the analyses. A weighted model of multidimensional scaling (MDS) will be used. A two‐step bidimensional weighted dichotomous MDS was performed. All items were included in the first step. Items closely associated with each dimension (1 SD above or below the mean) were selected in a second step to obtain the final model solution.

Results

The results obtained in the two analyzes were similar in terms of the good fit of the models, the type of two‐dimensional solution and the group weights. Model weights were also similar for the three diagnostic groups.

The final model was built considering the 12 most relevant items selected in the first step analysis and showed optimal fit indices (stress‐II = .59; D.A.F. = .94).

Figure 1 shows the coordinates for the 12 selected items in a bidimensional solution. Dimension I (right‐left) differentiate high and low emotional activation of NPS. Dimension II (top‐down) distinguishes between high and low behavioral activation. The combination of both generates four quadrants, indicating symptoms of resistance (Q‐I: low emotional and high behavioral activation), restlessness (Q‐II: high emotional and behavioral activation), flattening (Q‐III: low emotional and behavioral activation) and desolation (Q‐IV: high emotional and low behavioral activation) (see Figure 1).

Conclusions

The results suggest that two dimensions underlie the most discriminant NPS included in scale (i.e., emotional and behavioral activation). These two dimensions seem to differentiate between four NPS states (resistance, restlessness, flattening, and desolation), which could be the most useful NPS in the determination of risk factors for predementia patients.
Reduced beat‐to‐beat blood pressure variability is associated with cognitive decline over six years in the Malaysian Elders Longitudinal Research (MELoR) study
Authors: Asmuje Nur Fazidah , Mat Sumaiyah , Goh Choon Hian , Myint Phyo , Tan Maw Pin ,   Ageless Study
Published: June 2023

Background

Blood pressure variability (BPV) is defined as fluctuations in blood pressure (BP) from visit‐to‐visit, day‐to‐day, hour‐to‐hour and beat‐to‐beat. While published evidence on visit‐to‐visit BPV have suggested an association between BPV and cognitive decline, but published research on beat‐to‐beat BPV and cognitive decline remains limited. This prospective study, therefore, aimed to determine the relationship between beat‐to‐beat BPV and changes in cognitive performance over a six‐year period.

Method

The first and fourth wave data from Malaysian Elders Longitudinal Research (MELoR) study, which included community dwellers aged 55 years and over at recruitment, were utilized. Non‐invasive continuous beat‐to‐beat BP was recorded at baseline using the vascular unloading method (TaskforceTM,CNSystems). Systolic (SBPV) and diastolic (DBPV) BPV were calculated using standard deviation (SD), coefficient of variation (CV) and average real variability (ARV), which were then dichotomized using median cut‐offs. The Montreal Cognitive Assessment (MoCA) Blind instrument was utilized to allow for telephone‐based assessments at Wave 4 which occurred during the COVID‐19 pandemic. Cognitive decline was defined as 2 points reduction in MoCA.

Result

Data were available from492 participants, mean (SD) age = 67.8 (6.8) years. Mean MoCA‐blinds scores had increased from 17.1 (3.0) to 18.6 (2.7) from baseline to follow‐up. Cognitive decline was observed in 65 (13%). Individuals with cognitive decline had lower depression scores at baseline . Lower SD‐DBPV (mean difference, MD (95%CI) = 0.56 (0.31,0.98) and CV‐DBPV (MD (95%CI) = 0.51 (0.28,0.91) were significantly increased cognitive change after adjustment for potential co‐founders.

Conclusion

Lower BPV was associated with increased risk of cognitive decline in our population‐based study, which conflicted with available studies using primarily visit‐to‐visit and ambulatory BP measurements and involving mainly hospital‐based populations. Beat‐to‐beat BPV may be a measure of arterial stiffness which may is associated with increased risk of vasculopathy and development cognitive impairment. Future studies should determine whether interventions which lead to increased beat‐to‐beat BPV could reduce cognitive decline.
Tau‐PET imaging with 18F‐PI‐2620 reveals lateralized distribution of tau pathology in critical language regions in patients with early onset of Alzheimer’s Disease and patients with primary progressive aphasia
Authors: Mendez‐Orellana Carolina , Kramer Vasko , Bustamante Gabriel , Escobar Sebastian , Juri Carlos , Haeger Arlette , Amaral Horacio , Santibanez Rodrigo A
Published: June 2023

Background

Language disorders are frequent in patients in advanced and early stages of dementia (Goth & Strøm, 2018) together with the deterioration of other cognitive domains (e.g., memory) (Taler & Phillips, 2008). The first complaint in people with dementia often is language impairment, even preceding other cognitive declines (Ferris & Farlow, 2013). Logopenic variant primary progressive aphasia (lvPPA) and non‐fluent/agrammatic variant PPA (nf/avPPA) are rare neurodegenerative disorders being language impairment the main feature (Gono‐Tempini, 2011). Both β‐amyloid (Aβ) and tau appear to occur in Alzheimer disease (AD). Moreover, Aβ and tau aggregates also represent the underlying pathology in lvPPA (Montembeault et al. 2018) while nf/avPPA resembles a pure tau‐pathology. The purpose of this study is to explore the distribution of tau‐pathology in critical language regions in patients with early‐onset AD (EOAD) and patients diagnosed with primary progressive aphasia (PPA).

Method

Eight participants (55‐77y): 4 with EOAD, 3 with lvPPA (these first seven patients additionally had a positive 18F‐Florbetaben Amyloid PET), 1 with nf/avPPA, and 14 healthy controls (HC) (age range 54‐76y) underwent dynamic PET scans with 18F‐PI‐2620 to examine the distribution of tau‐pathology in the following cortical language regions: inferior frontal gyrus (IFG), superior temporal gyrus (STG), supramarginal and angular gyrus (PL). Group differences in language regions were examined using standardized uptake value ratios (SUVRs) normalized to the inferior gray matter of the cerebellum.

Result

Compared to HC, 3/4 patients with EOAD showed elevated levels of 18F‐PI‐2620 binding, mainly in the right IFG and IPL and left STG, while 3/4 patients with PPA (2 lvPPA and 1 nf/avPPA) showed left lateralized elevated uptake of 18F‐PI‐2620 in all language regions. All PPA patients showed increased binding of 18F‐PI‐2620 predominantly in the left parietal regions.

Conclusion

Our preliminary results reveal a lateralized distribution pattern of 18F‐PI‐2620 in language regions in patients with EOAD and particularly in those with PPA. These findings suggest that 18F‐PI‐2620 PET imaging is a promising tool to visualize tau aggregations in patients with EOAD and PPA. However, further studies are needed to confirm these preliminary results.
Relationships between cerebral tau and glucose metabolism in cognitively normal older adults
Authors: Crook Harry , Debatisse Justine , Nowell Joseph , Edison Paul
Published: June 2023

Background

Alzheimer’s disease (AD) is characterised by the accumulation of amyloid‐β and tau in the brain and subsequent neurodegeneration. The relationship between tau accumulation and glucose metabolism has been elucidated in AD, however the relationship between the two in the early stages of the AD trajectory remains elusive. Here, we examine this relationship using fluorodeoxyglucose (FDG) and flortaucipir (FTP) positron emission tomography (PET) in a cohort of cognitively normal older adults.

Method

72 cognitively normal participants (mean±SD age 78.7±6.3 years old) were recruited through the Harvard Ageing Brain Study and had available FDG‐PET, FTP‐PET, and structural MRI scans. Region of interest analysis was utilised to determine the regional uptake of each PET tracer. 40 participants were split into high‐tau and low‐tau groups based on the highest 20 and lowest 20 FTP uptake values from the medial temporal lobe excluding the hippocampus (MTL (no hippocampus)). FDG uptake was compared between high‐tau and low‐tau groups, while correlations between FDG and FTP uptake were examined.

Result

Glucose metabolism was significantly higher in the low‐tau group than the high‐tau group in the whole brain (p = 0.023), frontal lobe (p = 0.028), temporal lobe (p = 0.014), parietal lobe (p = 0.027), MTL (p = 0.01), MTL (no hippocampus) (p = 0.002), anterior cingulate cortex (p = 0.045), and posterior cingulate cortex (p = 0.023). Significant negative correlations were found between FTP uptake in the MTL (no hippocampus) and FDG uptake in the whole brain (r = ‐0.317,p = 0.046), temporal lobe (r = ‐0.383,p = 0.015), parietal lobe (r = ‐0.316,p = 0.047), MTL (r = ‐0.437, p = 0.005), MTL (no hippocampus) (r = ‐0.444,p = 0.004), anterior cingulate (r = ‐0.320,p = 0.044), and posterior cingulate (r = ‐0.361,p = 0.022). FTP uptake in the temporal lobe negatively correlated with FDG in the temporal lobe (r = ‐0.326, p = 0.04) and MTL (no hippocampus) (r = ‐0.337,p = 0.034).

Conclusion

High tau levels in the MTL was associated with hypometabolism in cognitively normal older adults, suggesting that tau accumulation may cause decreased glucose metabolism without inducing cognitive deficits. Furthermore, negative correlations between FDG and FTP uptake highlight the link between tau accumulation and neurodegeneration before the onset of cognitive decline. The association between tau accumulation and reduced glucose metabolism in cognitively normal participants supports the need for research and intervention to be aimed at the preclinical stages of AD.
Prevalence and clinical associations of atrophy subtypes using clinical routine image analysis software in MCI patients from a memory clinic population
Authors: Schwarz Adam J. , Cavedo Enrica , Gordon Elizabeth , Samper‐Gonzales Jorge , Longo Clarisse ,   the MEMENTO Study Group
Published: June 2023

Background

Three patterns of brain atrophy have been consistently identified in cases of Alzheimer’s dementia [1]: a limbic‐predominant (LP) phenotype, with atrophy of the hippocampus but relatively spared neocortex; a hippocampal sparing (HS) phenotype, with atrophy in the cortex (especially lateral temporal and parietal lobes) but sparing of the hippocampus; and a typical/diffuse (TD) phenotype that presents with atrophy in both. A recent study extended this concept to a less severely affected memory clinic population (the MEMENTO Study). Here, we assessed atrophy subtypes in that same population using an approach based on the output of QyScore® an FDA‐approved and CE‐marked image analysis software.

Method

1642 MCI participants from the MEMENTO cohort (Age 71±9, MMSE 27.8±2.0, CDR‐SB 0.6±0.7) had 3DT1 MRI scans analyzed with QyScore®. 678 (41%) had amyloid status from CSF or PET, of which 193 (28%) were amyloid‐positive (A+). Neurodegeneration‐positive (N+) atrophy subtypes were defined on individual scans using z‐scores from parietal cortex and hippocampus volumes referenced to 1290 cognitively normal individuals. LP and HS were defined by atrophy (z←1.64) of parietal lobe or hippocampus only, and TD by atrophy in both structures (otherwise N‐).

Result

The proportion of single‐domain amnestic (aMCIsd), multi‐domain amnestic (aMCImd), single‐domain non‐amnestic (naMCIsd) and multi‐domain non‐amnestic (naMCImd) individuals was 10%, 50%, 21% and 18% respectively. N+ subtypes were more prevalent in amnestic (aMCIsd 18%, aMCImd 17%) than non‐amnestic (naMCIsd 8%, naMCImd 10%) presentations. N+ subtypes were more common in A+ participants, especially the amnestic presentations (aMCIsd 42%, aMCImd 29%). Overall, the HS subtype was the most common (8% of all cases, 16% of A+ cases), followed by LP (4%/6%) and TD (2%/3%). The LP subtype was more prevalent in amnestic presentations.

Conclusion

The relatively low prevalence of the TD subtype in this cohort is consistent with [2]. The overall prevalence of N+ subtypes in MEMENTO by this method is intermediate between those previously reported using a similar method for ADNI CN A+ and aMCI A+ cohorts [3].

[1] Ferriera et al. (2020) Neurology 94:436 [2] Planche et al. (2021) Alz & Dem 17(4):651 [3] Charil et al. (2018) AAIC
Resistance and resilience to Alzheimer’s disease pathology associated with lower severity of other neuropathologic diseases
Authors: Culhane Jessica E. , Mock Charles , Chan Kwun Chuen Gary , Chen Yen‐Chi , Kukull Walter A.
Published: June 2023

Background

Older adults with multiple types of neuropathologic disease may be at higher risk for cognitive impairment, but the impact of specific combinations of disease on cognition is unclear. Alzheimer’s disease neuropathologic change (ADNC) is the most common neuropathologic disease found in dementia cases. Cognitively normal participants without ADNC are “resistant”; those with ADNC are “resilient.” To determine if resistant and resilient participants have lower levels of non‐AD neuropathologic diseases, we compared neuropathologic features against participants with clinical Alzheimer’s dementia.

Method

We included autopsied participants from the National Alzheimer’s Coordinating Center Uniform Data Set whose last visit was within two years of death. Participants were excluded if they had rare neuropathologic diseases or were not evaluated for each neuropathologic feature. For both resilient (normal cognition, moderate or high NIA‐AA ADNC score) and resistant (85+ years old, normal cognition, no or low NIA‐AA ADNC score) individuals, we calculated the odds of having non‐AD pathologic features against a control group (moderate or high NIA‐AA ADNC score, clinical dementia), adjusting for age at death, sex, education, and presence of APOE e4 allele(s). Features included vascular pathology (number of infarcts and microinfarcts; severity of arteriosclerosis, atherosclerosis, and cerebral amyloid angiopathy), Lewy body disease (LBD) staging, and limbic‐predominant age‐related transactive response DNA‐binding protein 43 encephalopathy (LATE‐NC) staging.

Result

Of 1,190 participants who met inclusion criteria, 59 were resistant, 41 were resilient, and 1,090 were controls. Both resistant and resilient participants had lower severity of LATE‐NC (resistant aOR: 0.23, 95% CI: 0.19‐0.27; resilient aOR: 0.49, 95% CI: 0.42‐0.56) and LBD (resistant aOR: 0.71, 95% CI: 0.63‐0.80; resilient aOR 0.52, 95% CI 0.44‐0.60). Resistant individuals also had lower odds of CAA, and resilient individuals had lower odds of arteriosclerosis.

Conclusion

Resistance and resilience to ADNC is associated with lower odds of other neuropathologic disease, including Lewy bodies and LATE‐NC. This supports prior research indicating an interactive effect of multiple neuropathologic diseases on risk of dementia, and specifically that having LBD or LATE‐NC contributes to the risk of developing Alzheimer’s dementia. Understanding how to prevent LBD and LATE‐NC could lead to higher resistance and resilience to Alzheimer’s dementia.
Long‐term memory over 1‐week and markers of brain pathology in cognitively unimpaired individuals from a Colombian cohort with autosomal dominant Alzheimer’s disease
Authors: Ezama Laura , Chen Kewei , Vila‐Castelar Clara , Baena Ana Y. , Martinez Jairo E. , Aduen Paula , Munera Diana , Noriega Daisy , Langella Stephanie , Ramirez‐Gomez Liliana A. , Lopera Francisco , Quiroz Yakeel T.
Published: June 2023

Background

Long‐term forgetting (LTF) over days or weeks may be a sensitive early marker of Alzheimer’s disease (AD), useful for preclinical AD trials. We examined associations between LTF and markers of brain pathology in individuals from the world’s largest kindred with autosomal dominant AD due to the Presenilin‐1 (PSEN1) E280A mutation.

Methods

A total of 14 cognitively unimpaired PSEN1 mutation carriers (mean age: 35.9 years) and 16 matched non‐carriers (mean age: 32.8 years) from the Colombia‐Boston Biomarker Study of autosomal dominant AD were included. Participants underwent amyloid (11‐C Pittsburgh compound B) and tau (Flortaucipir) PET imaging, and memory tasks (NEUROPSI word list, stories and semi‐complex figure). We examined performance on learning and delayed recall after a 20‐min, 1‐day and 7‐day interval. LTF was calculated for the three tasks as the proportion of material retained at 20 min that was recalled 7 days later. Mann‐Whitney tests were conducted to compare memory performance and LTF between PSEN1 mutation carriers and non‐carriers. Spearman’s correlations were used to examine the association between LTF and brain pathology markers of amyloid burden and regional tau (entorhinal and inferior temporal cortices). Fisher’s exact tests were used to compare correlation coefficients between groups.

Results

Learning did not differ between carriers and non‐carriers. Compared to non‐carriers, carriers had lower 20‐min recall in all three tasks (p<0.05), and lower 1‐day and 7‐day recall of word list and stories. There were no group differences in word list, stories or figure LTF. Further, no group differences were observed in the association of amyloid burden and LTF on any of the tasks. Lower word list LTF was associated with greater entorhinal burden among carriers, and the strength of this association was significantly different between carriers and non‐carriers (p = 0.046; carriers: r = 0.73, p = 0.003; non‐carriers: r = 0.43, p = 0.094).

Conclusions

Our preliminary findings show that, while rates of LTF over 7 days did not differ between PSEN1 carriers and non‐carriers, carriers had lower verbal memory recall over 1 and 7 days. Further, LTF was associated with early tau accumulation, suggesting that longer recall intervals may be more sensitive to detect subtle memory changes in cognitively unimpaired individuals at risk for AD.
Identification of SNP interactions in chromosome 19 for Alzheimer’s Disease through Capsule Network
Authors: Bae Jinhyeong , Nho Kwangsik , Saykin Andrew J. , Risacher Shannon L. , Penchev Valentin , Apostolova Liana G.
Published: June 2023

Background

Alzheimer’s disease (AD) is highly heritable. Genome‐wide association studies and whole genome sequencing have uncovered many AD‐risk variants but are still falling short from providing an explanation of the full heritability. To address this issue, we devised a novel deep learning approach that can quantify the polygenic risk score (PRS) of genetic variants and their interactive effects at the individual level.

Method

We applied a novel deep learning model to the 266,161 SNP chromosome 19 data of 313 AD and 457 cognitively unimpaired (CU) ADNI patients. Through occlusion maps, we quantified the predictive value of 70,643 possible AD‐determining SNPs and identified the top 0.05%, i.e., 35 SNPs, without imposing any additional pre‐assumptions. Epistatic effects increasing or decreasing the risk of AD were further investigated by using the co‐occlusion method. The top 35 AD‐determining SNPs were validated in an external dataset.

Result

The model achieved 68.18% in predicting AD vs. CU. The top 35 AD SNPs showed dominant impact in AD prediction as single as well as an interactive factors. 574 interactions that increased AD risk were found for AD‐predicted patients while 358 interactions predictive of cognitively unimpaired performance were found for CU‐predicted patients. Rs56131196 (APOC1) was recognized as the most significant AD‐determining SNP. It showed interactions with at least 8 other SNPs that further influenced the risk of AD. Rs2229918 (EERC1) was recognized as the most powerful SNP influencing CU diagnostic accuracy.

Conclusion

Our deep learning model provides a novel approach for assessing the genetic risk for AD at the individual chromosomal level. The results indicate that APOC1 and ERCC1 are strong genetic risk factors for the development of AD. These findings are consistent to the previous medical research. Our model’s capability in deciphering the impact of SNPs on AD development could prove critical for early presymptomatic risk assessment and personalized therapeutic strategy approaches.
Clinically relevant monitoring of long‐term night‐time behaviour and physiology from the homes of people living with dementia
Authors: Kolanko Magdalena A , Soreq Eyal , Barnaghi Payam , Lai Helen , Dijk Derk‐Jan , Sharp David J
Published: June 2023

Background

Disturbances of sleep and night‐time behaviours are amongst the most disabling symptoms of dementia. They often increase carers’ burden and the risk of institutionalization. The causes are complex and are difficult to investigate because of a lack of acceptable methods for monitoring behaviours in the home. Here we show that a passive under‐mattress can be used to track changes in night‐time behaviour and physiology, and that a range of digital biomarkers produced are informative in understanding the effects of medication changes, disease progression and intercurrent illness in patients living with dementia (PLWD).

Method

We used contactless Withings Sleep Mattress (WSM) to monitor bed‐occupancy in 4 PLWD (age 74‐93, 3males) enrolled into the CR&T MINDER cohort study. Each participant was tracked over 1000 nights between 2019 and 2021. Minute‐to‐minute timeseries were extracted from WSM to calculate bed occupancy metrics and nocturnal physiology measures (heart and breathing rates (HR/BR)). Raw measures were standardized within subjects by comparing each time point to the mean of the time points that preceded it. We then investigated the relationship between these metrics and clinical events such as infections and medication.

Result

The 4 case studies illustrate the potential of this technology for passive health monitoring in PLWD. High levels of intraindividual variability in behavioural and physiological metrics were observed. Progressive changes in bed occupancy were observed in two patients with frontotemporal dementia and Alzheimer’s disease (Cases 1&2). Intercurrent illness and medications changes influenced the measures. For example, Patient 1 showed progressive night‐time wandering with increasing time spent out of bed, which improved following the initiation of risperidone. Case 2 showed recurrent episodes of heart failure accompanied by increased nocturnal HR. Cases 3 and 4 showed urinary tract infections, which were accompanied by transient changes in bed occupancy measures.

Conclusion

Passive monitoring of night‐time behaviour and physiology is a simple and cost‐effective way to monitor the effects of medication change and medical events in PLWD. Digital biomarkers derived from these simple measures hold great promise as measures of dementia progression, to enhance dementia care by identifying at risk individuals and as novel clinical outcome measures in clinical trials.
The microglial challenge to encapsulated cell mediated drug delivery in brain tissue
Authors: Mitra Sumonto , Gera Ruchi , Sundheimer Julia , Lemee Marine , Wahlberg Lars , Linderoth Bengt , Behbahani Homira , Eriksdotter Maria
Published: June 2023

Background

Dementia disorders affect millions of people worldwide, among which Alzheimer’s disease (AD) accounts for 60% cases. Treatment of these disorders are constrained due to inefficient brain availability of peripherally administered drugs. Conversely, direct intracerebroventricular injections are counterintuitive due to unspecific side‐effects. Recently, Aducanumab has shown potential to clear amyloid plaques from AD brain, but its efficacy to revive clinical symptoms are under debate. In this regard, direct delivery of regenerative biological drugs utilizing encapsulated cell biodelivery (ECB) has gained much attention. Conversely, how the pathological microenvironment of the AD brain affects these encapsulated drug‐delivering cells are scarcely understood. The ECB approach nullifies immune reaction from host tissue by protecting drug‐delivering cells from direct physical contact with the host tissue. Thus, in this study we probe the effect of factors released from activated human microglial cells (HMC3 cell line) on ECB devices harboring nerve growth factor (NGF) releasing cells (NGC0211; modified human ARPE‐19 cells).

Method

ECB devices harboring NGC0211 cells were manufactured and maintained in DMEM/F12 culture medium containing 10% serum until used. HMC3 cells were activated using AD related molecules including 1µM amyloid beta (Aβ40 and Aβ42) peptides and 10ng/mL inflammatory cytokines (interferon‐γ, IFN‐γ; interleukin‐1β, IL‐1β; or both) for 24hrs, and a cell free microglia conditioned medium (MCM) was obtained. ECB devices were then exposed to various MCMs, and NGF release was followed for several weeks assessed by ELISA (DY256, R&D systems). Similarly, non‐encapsulated NGC0211 cells grown in multi‐well slides were exposed to MCMs and cellular proliferation (Ki67 expression) along with senescence parameters (SA‐β‐galactosidase) were evaluated.

Result

We found that factors released from activated microglia hampered NGF release from ECB devices. Simultaneously, MCMs reduced Ki67 expression and elevated SA‐β‐galactosidase activity in NGC0211 cells.

Conclusion

Activated microglia, a common feature of all neurodegenerative conditions, impair NGF release, cellular proliferation and induce senescence in NGC0211 cells. Similar impact of microglia on other types of drug‐delivering cells (stem cells or genetically modified) needs to be studied. Our study highlights one of the probable underlying causes for impaired long‐term cell mediated drug delivery in neurodegenerative diseases and helps guide improvements in the technologies.
Sex differences in the prevalence of mild behavioral impairment: A systematic review and meta‐analysis
Authors: Mudalige Dinithi M , Ebrahim Inaara , Guan Dylan X. , Goodarzi Zahra , Ismail Zahinoor
Published: June 2023

Background

Mild behavioral impairment (MBI) is an early indicator of dementia risk characterized by the later life onset of persistent changes in behaviour or personality. An under‐investigated feature of MBI is the difference in symptoms and risk based on sex. This systematic review and meta‐analysis investigates the differences in the prevalence of MBI domains based on sex.

Method

EMBASE, MEDLINE, PsycINFO and the grey literature were systematically searched for articles mentioning MBI. Participants with dementia were excluded. Abstracts and full‐text articles retrieved from the search were screened by two independent reviewers and included if sex‐specific prevalence data were reported. A standardized data extraction sheet was used for included articles, with data items for demographics, cognitive diagnosis, prevalence of females within each MBI domain, stratified by sex. There was insufficient evidence to look at gender. A random‐effects meta‐analysis was performed to combine the extracted data to identify pooled prevalence.

Result

A total of 5476 articles were retrieved from the initial search, and 3435 papers remained after deduplication. After full‐text screening, 35 papers were selected for data extraction. In normal cognition, four out of five MBI domains were more prevalent in males (decreased motivation, impulse dyscontrol, social inappropriateness and abnormal perception or thought content). In mild cognitive impairment (MCI), three out of five domains were more prevalent in males (decreased motivation, impulse dyscontrol, and abnormal perception or thought content). However, in the mixed cognitive category, four out of five domains were more prevalent in females (decreased motivation, emotional dysregulation, impulse dyscontrol and social inappropriateness (Table 1).

Conclusion

In this group of dementia‐free older adults, sex differences in prevalence of MBI domains varied by baseline cognitive status. Although the differences are not large, these findings raise interesting questions about sex‐specific trajectories of neuropsychiatric symptoms across the cognitive spectrum. This study highlights the need to explore differences in MBI by factors such as sex and gender.