bluuebunny/crossref_metadata_2025 huggingface dataset:
Assessing the cumulative impact of vascular burden on structural changes in the brain during ageing
Authors: Konwar Srijan , De Marco Matteo , Venneri Annalena
Published: February 2022

Background

Alzheimer’s disease (AD) is the most common cause of dementia. Yet more recent findings from epidemiological and neuropathological studies have revealed the presence of vascular pathology in AD. There is overwhelming evidence from pathological examinations that indicates the presence of ‘mixed cases’ at autopsy. The study aim was to examine whether overall vascular burden measured by the Framingham General Cardiovascular Risk Score (FGCRS) is associated with brain structural changes.

Method

In the first analysis a Voxel Based Morphometry (VBM) multiple regression model was used with group status (60 controls, 74 Mild Cognitive Impairment and 51 AD) and Framingham vascular risk scores as predictors while accounting for age, total intracranial volume, years of education. In the second model a 2x2x2 factorial design with different group comparisons was used with group, APOE ε4 carrier status and Vascular Burden (low vs high load) to understand the interactions across the factors.

Result

The VBM regression model implicated regions that included the thalamus, subcallosal gyrus, precentral and postcentral gyrus, cerebellum, occipital gyri, inferior frontal gyrus, insula and the cuneus.

The factorial analysis revealed two different set of interaction effects. There was a APOE x Vascular Burden interaction effect between controls and MCI. The regions implicated in this analysis included the cerebellum, right inferior occipital gyrus, right thalamus, left brainstem, left fusiform gyrus, left precentral and postcentral gyrus and left Insula. There also was a Group x APOE Status x Vascular Burden interaction effect that involved the left brainstem and left parahippocampal gyrus during the transition from MCI and AD.

Conclusion

The voxel‐based regression model and the first factorial analysis implicated areas that comprises both cerebellar and subcortical regions that have been previously implicated in dementia with vascular pathology. The areas implicated by vascular pathology have been shown to affect primarily gait, movement and visuospatial abilities. But given that the brainstem and its nuclei are also involved, future studies should look at examining the role of vascular pathology and how it affects the neuromodulatory systems of the brainstem and whether these projections have any effect on the efficient functioning of large‐scale brain networks.
Neuroticism moderates the association between beliefs about medications and reported adverse medication effects in mild cognitive impairment
Authors: Kelly Dana A , Davis Jennifer D , Daiello Lori A , Burke Erin M , Fernandez Tiana , Tremont Geoffrey , Ott Brian R , Margolis Seth A
Published: February 2022

Background

Adverse medication effects may negatively affect quality of life (QoL), treatment adherence, and tolerability/enrollment in investigational drug studies. No research has investigated whether negative beliefs about medications and personality influence adverse effect reporting in people with Mild Cognitive Impairment (MCI), where disease modifying therapies are needed. We examined associations among medication beliefs, neuroticism, and perceived adverse medication effects in people with MCI.

Method

Participants (N=50, age: 72±7 years, 54% female) with MCI completed the Beliefs about Medicines Questionnaire (BMQ: Harm and Necessity‐Concerns [N‐C] subscales), NEO Five‐Factor Inventory‐3 (Neuroticism), and Generic Assessment of Side Effects (GASE: adverse effect count and intensity). Correlations and ordinary least squares (OLS) regression assessed interrelationships. The moderating effect of neuroticism on the association between medication beliefs and adverse effect reporting was modeled at mean±1 standard deviations of neuroticism.

Result

Participants took an average 6±3 medications/day; 20% took anti‐dementia medications. The number of reported adverse effects per participant ranged from 0‐15 (X̅=4). On average, adverse effect intensity was rated as mild; however, 26% endorsed moderate‐to‐severe intensity. On average, participants did not believe medications were generally harmful. Yet, 30% indicated that concerns about their specific medications outweighed perceived necessity of treatment. Neuroticism was normally distributed. Higher neuroticism and stronger harm/concern beliefs correlated with adverse effect intensity (Neuroticism: r=0.378, p=0.007; Harm: r=0.315, p=0.026; N‐C: r=‐0.406, p=0.003). OLS regression models including neuroticism and Harm or N‐C beliefs (run separately) each accounted for 32% of the variance in adverse effect intensity. There was an interaction between medication beliefs and neuroticism (p’s≤0.04); stronger harm beliefs and concerns outweighing necessity beliefs corresponded to greater adverse effect intensity at average and above average neuroticism (Harm: β=0.90, p=0.01; N‐C: β=‐0.33, p=0.003 and Harm: β=1.76, p=0.001; N‐C: β=‐0.58, p=0.001, respectively) but not at low‐average levels. Neither model was associated with raw adverse effect count.

Conclusion

Individuals with MCI who are more stress‐reactive (neurotic) and maintain negative beliefs about medications tend to endorse more intense adverse effects. Supportive approaches aimed at helping stress‐reactive patients manage negative beliefs, reactions, and expectations about medications may enhance QoL, improve treatment adherence, and impact willingness to participate in clinical trials.
Continued white matter fibre degeneration over 3 years after ischemic stroke
Authors: Egorova Natalia , Dhollander Thijs , Khan Will , Khlif Mohamed Salah , Brodtmann Amy
Published: February 2022

Background

We aimed to chart white matter integrity over 3 years after stroke, to examine if post‐stroke loss of white matter continues to be accelerated compared to control participants.

Method

We applied a longitudinal “fixel”‐based analysis, sensitive to fibre tract‐specific differences within a voxel, to assess axonal loss in stroke (N=71, 22 women) compared to control participants (N=36, 13 women) across the whole brain. We studied microstructural differences in fibre density and macrostructural (morphological) changes in fibre cross‐section.

Result

In stroke participants, we observed significantly lower fibre density and cross‐section from 3 months to 3 years. The changes were widespread and affected the corpus callosum, bilateral inferior fronto‐occipital fasciculus, right superior longitudinal fasciculus.

Conclusion

We conclude that ischemic stroke is associated with extensive and continued neurodegeneration that significantly affects white matter micro and macrostructure across the whole brain. These findings confirm that the deleterious effects of stroke on white matter continue several years following the event.
Herpes simplex diagnosis and treatment are not associated with incident dementia
Authors: Schmidt Mark A , Rawlings Andreea , Koppulo Padma D , Prado Yolanda K , Rosales A Gabriela , Weinmann Sheila A
Published: February 2022

Background

Although an association between dementia and certain infectious diseases, such as HIV, has been well‐established, recent publications have also concerningly hinted at the possibility of its association with a much more common infectious disease, as well: herpes simplex virus (HSV). We sought to better investigate potential associations between HSV diagnosis and treatment with incident dementia in a large, retrospective cohort.

Method

We conducted our analysis among members of Kaiser Permanente Northwest aged 50 and older between 2000‐2019. We matched individuals with an HSV diagnosis during this time frame to three individuals, each, without HSV, based on age at index date (HSV diagnosis date for cases and a reference date for controls), sex, and membership length prior to index date. Follow‐up time started at the index date and ended on the date of dementia diagnosis, membership end date, death, or end of follow‐up, whichever came first. We defined HSV and dementia diagnoses by ICD‐9/‐10 codes recorded in the electronic health record. We defined herpes simplex antiviral treatment, based on in‐network pharmacy fills. We used survival analysis to examine the associations between dementia with HSV diagnosis (yes/no, overall, by sex, age, and HSV type) and HSV medication fills (yes/no; and by tertiles of medication dispensed). We adjusted models by demographic and clinical factors.

Result

87,432 persons (21,661 with HSV) were included. The mean age was 60.9 years and 69% were female. Over a mean follow‐up of 6.1 years, 4,507 developed dementia. HSV diagnoses – overall and Type 2 – was significantly associated with lower risk of dementia (Figure). Anti‐viral medication (any versus none) was not associated with dementia, and we did not see a dose response when examining dose by tertile (Figure).

Conclusion

In contrast to the recent reports, we found a slight, but statistically‐significant association between HSV diagnosis with dementia. We did not observe a lower risk of dementia associated with anti‐herpetic treatment, also as had been previously reported. The relationship between HSV and dementia may be complex and deserves further study. However, that we did not see a positive association between HSV and dementia in our study is very encouraging.
Effects of interaction with people on behavioral and psychological symptoms of dementia in long‐term care facility residents
Authors: Arai Asuna , Khaltar Amartuvshin , Ozaki Takashi , Katsumata Yuriko
Published: February 2022

Background

Behavioral and psychological symptoms of dementia (BPSD) are a well‐known risk factor for an increased burden of care for staff in long‐term care facilities and family caregivers. Social interaction that emphasizes the importance of relationships and communication between individuals has been proposed as a suitable psychosocial intervention for BPSD. However, it remains unclear what type of social interaction could impact the longitudinal change of BPSD in residential care settings. This study investigated the effect of interaction with people including relationships with residents, and communication with family/relatives and friends at baseline on BPSD among long‐term care facility residents over 1 year.

Method

This follow‐up study was conducted among older adult residents with dementia or similar symptoms at 10 selected long‐term care facilities in Japan. Participants were assessed twice at a 1‐year interval using a questionnaire for care staff. The questionnaire included a brief questionnaire form of the Neuropsychiatric Inventory (NPI‐Q), a standardized scale to assess 12‐item BPSD. Generalized linear mixed effect models were used to examine associations between interaction with people and changes in the number and severity of BPSD symptoms over 1 year.

Result

Among 220 participants, poor relationships with other residents at baseline were associated with greater baseline BPSD. Less communication with family/relatives at baseline was associated with increased severity of BPSD over 1 year.

Conclusion

Active interaction with family and relatives may prevent progression of BPSD severity among long‐term care facility residents for at least 1 year.
Peripheral triggering receptor expressed on myeloid cells 2 expression is associated with myoinositol level at posterior cingulate cortex in Alzheimer’s disease
Authors: Fuh Jong‐Ling , Lee Wei‐Ju , Lirng Jiing‐Feng
Published: February 2022

Background

Triggering receptor expressed on myeloid cells 2 (TREM2) is up‐regulated in activated microglia related neuroinflammation in Alzheimer’s disease (AD). Most magnetic resonance spectroscopy (MRS) studies consistently demonstrated neuroinflammatory changes with elevated glial marker myoinositol (MI) or MI/total creatine (tCr) and lower levels of neuronal marker N‐acetylasparate (NAA) or NAA/tCr in patients with AD. We propose that the higher systemic TREM2 expression measured by TREM2 mRNA expression in peripheral blood might be associated with the neuroinflammatory marker in MRS.

Method

We recruited subjects with mild cognitive impairment (MCI) and dementia due to AD from two teaching hospitals in Taiwan. All of the subjects underwent clinically functional assessments and a neuropsychological test battery. Quantitative estimates of TREM2 mRNA and the soluble form of TREM2 (an alternatively spliced TREM2 transcript (TREM2alt)) mRNA levels were measured. Proton magnetic resonance spectroscopy (MRS) was performed by using a 2 × 2 × 2 cm3 voxel situated in the midsagittal posterior cingulate cortex (PCC)/precuneus region. We analyzed the association between MRS and peripheral TREM2 mRNA expression.

Result

In total, 15 MCI patients and 26 AD patients were recruited. The mean age of MCI and AD patients was 72.1 ± 6.0 and 76.7 ± 7.6 years. The mean MMSE score was 25.8 ± 2.1 in MCI patients and 20.8 ± 3.4 in AD patients. The percentage of apolipoprotein (APOE) ɛ4 carrier status in MCI and AD patients was 21.4% and 38.5%. The correlation analysis showed the TREM2alt mRNA expression level was associated with MI/tCr at PCC in AD (r = ‐0.68, p < 0.001) and MCI (r = ‐0.63, p = 0.013) subjects, but TREM2 mRNA expression was not.

Conclusion

The TREM2alt mRNA expression is associated with the MI/tCr at PCC in both AD and MCI patients, which suggested the peripheral soluble TREM2 expression might reflect the central neuroinflammatory changes in AD patients.
A campaign to tackle discrimination
Authors: Mardones Solange , Emerson Leanne
Published: February 2022

Background

Dementia Australia’s strategic direction represents a year of extensive community consultation and identifies discrimination as a leading issue for people living with dementia.

An objective is to change community attitudes to dementia, creating greater community empathy so no‐one with dementia feels isolated.

Method

In 2019, Dementia Australia surveyed >5000 respondents to identify types of discrimination faced by people living with dementia. Of responding family members, friends and carers, 94% said people had not stayed connected with a relative living with dementia. Some 80% said people had deliberately avoided their friend or relative living with dementia; 81% felt people in shops, cafes and restaurants treated people living with dementia differently. Traditionally anti‐discrimination campaigns focus on elevating awareness and understanding to change behaviour. Dementia Australia tackled the behaviour directly: expanding people’s understanding of discrimination and its impact, providing practical information and tips to do better. The 'Help Keep the World Open' campaign used the social isolation created by COVID‐19 to show that once the crisis had passed, most people could resume regular social routines. However, for people with dementia, isolation can be a reality every day. The next campaign stage ‐ ‘A little support makes a lot of difference’ ‐ highlighted the capabilities of people living with dementia, given the right supports. The campaign shared tips and tools to support people living with dementia to live well. These broad‐ranging national campaigns were developed collaboratively with people with a lived experience of dementia. The high‐level objectives were to raise awareness of dementia and the lack of understanding that causes discrimination, to shift negative perceptions and show practical ways for people to support those living with dementia.

Result

Exceptional levels of engagement and reach were achieved across media. From May 18 to 23 December 2020, more than 35 million impressions reached 4.6 million Australians, with engagement rates well above industry averages across all channels.

Conclusion

Our content created increased awareness and understanding of dementia, changing misconceptions ‐ vital to improving quality of life. This campaign demonstrated that building empathy alongside knowledge by asking the community to change behaviour and attitudes is both engaging and effective.
Higher myelination of grey matter and white matter is associated with lower tau spreading and tau‐associated cortical thinning in Alzheimer’s
Authors: Rubinski Anna , Franzmeier Nicolai , Dewenter Anna , Luan Ying , Biel Davina , Ewers Michael
Published: February 2022

Background

Myelination of axons in the grey matter (GM) and axonal connections may modulate the spreading of brain pathologies such as pathologic tau. Here, we tested for the first time whether MRI‐assessed myelination in the GM and white matter (WM) is associated with tau‐PET assessed spreading of pathologic tau between connected brain regions. We hypothesized that 1) higher myelination of WM connections is associated with lower tau‐PET in the connected regions and 2) higher myelination of GM is associated with higher resilience against the effect of tau on GM.

Method

We included AV1451‐tau‐PET from 202 amyloid‐PET positive (Aβ+) asymptomatic and symptomatic individuals from ADNI. Using a neocortical 200‐ROI brain‐parcellation atlas, we obtained regional tau‐PET SUVR and cortical thickness. Resting‐state fMRI functional connectivity (FC) and DWI‐based fiber‐tracts between the 200 ROIs were assessed in 100 individuals from the human connectome project (HCP). Next, we applied the 200 GM‐ROIs and fiber‐tract streamlines to a myelin‐water‐imaging atlas in healthy individuals (Liu et al., JON, 2019) to assess the myelin water fraction (MWF) in GM‐ROIs and their WM connections. Using linear regression, we assessed the associations between MWF, FC and tau‐PET, as well as the interaction between MWF and tau‐PET on cortical thickness.

Result

We found that higher MWF (i.e. higher myelin) in GM‐ROIs was associated with lower tau‐PET in corresponding ROIs (Figure 1, β=‐0.38, p<0.001). Using spatial regression, we found that for connections with lower MWF, the association between higher FC and higher tau‐PET was stronger (interaction MWF x FC on tau‐PET, Figure 2), suggesting that lower WM myelination facilitates the spreading of tau along connected regions. Lastly, the association between tau‐PET and cortical thinning in GM‐ROIs was attenuated at higher MWF in the corresponding GM‐ROIs (Figure 3, β=0.025, p<0.001), suggesting that higher GM myelination is associated with higher resilience against the effect of tau‐PET on GM atrophy.

Conclusion

Higher myelination of the GM and WM is associated with lower regional susceptibility to pathologic tau and higher resilience against effects of tau on GM integrity.
Translation and adaptation of the ABE BPSD score (ABS) for behavioral and psychological symptoms in dementia in elderly Filipinos
Authors: Evangelista Jojo Rafanan , Ampil Encarnita Raya , Abe Koji , Marasigan Simeon S
Published: February 2022

Background

Dementia is not a disease in is itself but a collection of related to cognitive decline. Aside from cognitive decline, behavioral and psychological symptoms of dementia (BPSD), which multifactorial in origin and is often brought about by maladaptation to the environment and struggles with the activities of daily living. Several tool have been made to screen BPSD, one of which is the Abe BPSD Score.

Method

Two bilingual persons independently translated the scale to the Filipino language. The translated version underwent evaluation by a team of experts composed of 5 neurologists, 5 experts in dementia and 5 psychiatrists. The items were further refined and revised, accordingly, by these specialists. The revised questionnaire was used for the face validity with 30 cognitively intact adults. The final Filipino version of the questionnaire was back translated by another independent native speaker of the Filipino language. The final Filipino version and the version translated to English were compared.

Result

All items had a CVR or >0.49 for the evaluation of content validity ratio (see table 1) and clarity of > 79% (see table 3) so that all items were retained and deemed appropriate. Regarding relevance, item 1 needed to be revised. There was a significant change of the ranking of the symptoms as compared to the English version of the Abe’s BPSD Score, thus the order of the symptoms were revised.

Conclusion

The Filipino version of the Abe score for BPSD, ABS‐P, is a simple and easily understandable scoring system for assessing the presence and extent of BPSD. The translated and adapted Filipino version is practical for use in daily clinical practice since it has short administration time. A validation study can subsequently be carried out with the ABS‐P.
Impact of COVID‐19 pandemic in an early‐onset dementia clinic in Barcelona
Authors: Contador José , Guillén Nuria , Tort‐Merino Adrià , Balasa Mircea , Martínez Neus Falgàs , Olives Jaume , Castellví Magdalena , Juncà‐Parella Jordi , Borrego‐Écija Sergi , Bosch‐Capdevila Beatriz , Fernández‐Villullas Guadalupe , Ramos‐Campoy Oscar , Antonell Anna , Sanchez‐Valle Raquel , Lladó Albert
Published: February 2022

Background

The ongoing COVID‐19 pandemic and related care policies have affected dementia patients. The characteristics of early‐onset dementia (EOD, <65 years) patients in 2020 may provide insights on how to rearrange the provision of care.

Method

We retrospectively reviewed, from 2016 to 2020, the demographic and clinical data of the new referrals at our EOD clinic (Hospital Clínic Barcelona). We used Fisher’s Exact test and Mann–Whitney U test in R4.0.2 (http://www.R‐project.org/) to analyze differences between 2020 and the period 2016‐2019.

Result

In 2020, we did not visit any new referral from 15th march to 31th may. We evaluated 104 patients in 2020 and 392 patients in 2016‐2019 (mean=98(SD=11.8) patients/year). No differences were found in age at onset (AAO), sex, diagnostic delay and MMSE score (Table1). Significant differences were found in the diagnoses obtained in each period (p<0.000005, Figure1A). In 2020, 19.2% of the patients were diagnosed with neurodegenerative diseases (ND), 48.1% with non‐neurodegenerative diseases (NND) and 32.7% with subjective cognitive decline (SCD). On contrast, in 2016‐2019, 26% of the patients were diagnosed with ND, 22.2% with NND and 51.8% with SCD. Compared to 2016‐2019, ND, but not SCD or NND, presented longer diagnostic delay in 2020 (p<0.0005, Figure1B). ND, NND and SCD did not show differences between periods in AAO, sex or MMSE.

We did not find differences in the type of ND in each period (Figure1A). Compared to 2016‐2019, Frontotemporal Lobar Degeneration (FTLD) presented longer diagnostic delay in 2020 (p<0.005, Figure1B) while ND subgroups did not show differences in AAO, sex or MMSE. Cognitive disturbances in recovered COVID‐19 patients accounted for 16% of NND in 2020 [N=8, AAO 50.63(12), 63% female, MMSE 26.8(2.3)].

Conclusion

In 2020, albeit we were forced to stop our normal activity during 2.5 months, we visited a similar number of patients among which we observed an increase in NND, including cognitive disturbances in patients with recovered COVID‐19. On contrast, we found a reduction in SCD and, to a lesser extent, ND. ND showed a longer diagnostic delay in 2020 that mainly affected FTLD. Whether COVID‐19 pandemic entails a diagnostic delay in dementia patients must be confirmed in 2021.
Key components of person‐centered care for people with dementia: A systematic review of interventions to design a patient preference study
Authors: Mohr Wiebke , Raedke Anika , Afi Adel , Edvardsson David , Mühlichen Franka , Platen Moritz , Roes Martina , Michalowsky Bernhard , Hoffmann Wolfgang
Published: February 2022

Background

To provide Person‐Centered Care (PCC) for People with Dementia (PwD), patient’s stated preferences must be known. Data about stated care‐preferences among PwD are limited. This study aimed to identify key components of PCC for PwD by a systematic review of PCC‐interventions, to inform the construction of a decision model for PwD‐preference elicitation.

Method

A protocol was registered with PROSPERO (CRD42021225084). A search of the concepts Dementia, Person‐Centered Care, and Intervention was performed in PubMed, EMBASE, and Web of Science in Nov2020. Study selection was based on 2‐stage screening against eligibility criteria, limited to randomized controlled trials (RCT) and nonrandomized controlled study (NRS) designs. Risk of bias was assessed with version 2 of the Cochrane risk‐of‐bias tool for randomized trials (RoB2) and the Newcastle‐Ottawa Scale (NOS) for nonrandomized studies. Information about authors, interventions, and outcomes were extracted and entered into an “Effects Table”. The identified PCC‐interventions were thus synthesized into intervention categories to form key components of PCC.

Result

Searches identified 1781 records. 19 studies (15 RCT, 4 NRS) were included after screening. The quality of the studies varied between low to moderate. The individual interventions covered a wide range of non‐pharmacological, psychosocial offers, oftentimes bundled in multi‐component intervention‐sets. Nine intervention categories, i.e. key components of PCC to inform the construction of a decision model for PwD‐preference elicitation, emerged from data synthesis: sensory enhancement/relaxation, social contact, cognitive training, validation and reminiscence, physical activities, environmental adjustments, caregiver training and support, care organization and daily living assistance. Effect measures included i.a. agitation, quality of life, antipsychotic use, depression, neuropsychiatric symptoms and behavior, with mixed results concerning the effect of the PCC interventions. All studies were conducted in nursery home or hospital settings.

Conclusion

Nine intervention categories as key components of PCC to inform the construction of a decision model for PwD‐preference elicitation could be identified. As the findings were limited to nursery home and hospital settings, community‐dwelling PwD and the primary care‐setting should find greater consideration for future investigations on PCC interventions and patient preference studies.
Social network characteristics moderate associations between cortical thickness and cognitive functioning in older adults
Authors: Sharifian Neika , Zaheed Afsara B , Morris Emily P , Sol Ketlyne , Manly Jennifer J , Schupf Nicole , Mayeux Richard , Brickman Adam M , Zahodne Laura B
Published: February 2022

Background

Although prior research suggests that brain health is associated with cognitive functioning in later life, the strength of brain‐cognition associations varies. Lifestyle factors may alter these associations by either increasing or decreasing the probability of exhibiting cognitive symptoms at any given level of brain pathology. One lifestyle factor that prior clinicopathologic research has found to influence the association between greater Alzheimer’s disease pathology and lower cognitive performance is an individual’s total social network size. However, little is known about distinct social relationship types (i.e., family vs. friends).

Method

The current cross‐sectional study used data from the Washington Heights‐Inwood Columbia Aging Project (WHICAP; n = 654, 63‐96 years old, 62.40% Female) to examine whether distinct social network characteristics moderate associations between cortical thickness in regions implicated in Alzheimer’s disease and cognitive performance. Initial linear regression models examined the effects of total social network size, cortical thickness and their interaction on global cognitive functioning and individual cognitive domains (memory, language, speed/executive functioning, visuospatial function). Subsequent models tested the effects of distinct social relationship types (i.e., spouse/partner, number of children, other relatives, friends).

Result

Although there were no main effects of cortical thickness or individual social network components on cognition, there was an interaction between cortical thickness and the size of friend networks. Specifically, lower cortical thickness was associated with lower global cognition among individuals with smaller friend networks, but not individuals with larger friend networks. When broken down by individual cognitive domains, this pattern of results was most prominent for language and speed/executive functioning. Total social network size and family networks (spouse/partner, number of children or relatives) did not moderate associations between cortical thickness and cognition.

Conclusion

Results are consistent with a growing body of literature suggesting that maintaining more friendships may promote cognitive reserve in older adulthood. Longitudinal, intervention, and functional neuroimaging studies are needed to determine whether interacting with friends strengthens neural networks that can support cognitive performance in the context of poorer brain health.
New insights into the genetics of subcortical volumes across the adult lifespan
Authors: Grand Quentin Le , Satizabal Claudia L. , Seshadri Sudha , Tzourio Christophe , Mazoyer Bernard , Debette Stéphanie
Published: February 2022

Background

Subcortical brain structures play a key role in pathological processes of many age‐related neurodegenerative disorders. Mounting evidence suggests that factors already present at an early age play a crucial role in the development of common late‐life neurological diseases, including genetic factors that can influence both brain maturation and neurodegeneration.

Using large population‐based brain imaging datasets across the adult lifespan, we aimed to identify whether genetic loci associated with subcortical brain structures in older persons also show significant association with the same structures in early adulthood and explore underlying genes using transcriptome‐wide association studies (TWAS).

Method

We first tested variants, previously identified in genome‐wide association study (GWAS) of subcortical volumes in older adults, in young adults (i‐Share cohort, 18‐35y) individually and aggregated in genetic risk scores (GRS). We conducted a TWAS using the summary statistics from the GWAS of subcortical volumes. For the significant signals, we generated gene expression scores in i‐Share and tested them in association with subcortical volumes.

Result

We observed that GRS for smaller caudate nucleus and putamen volume in older adults were associated with smaller volumes of the same structures in young adults. Individually, ten independent loci associated with subcortical volumes in older adults also showed associations with the corresponding volume in young adults, with the strongest association between a variant near KTN1 and putamen volume. In TWAS, expression of several genes in brain tissues was significantly associated with caudate nucleus, putamen and pallidum volumes both in older and young adults, pointing to biological pathways underlying structural brain changes across the adult lifespan, with particularly strong evidence for a causal implication of MYLK2 and TUFM, in relation with caudate nucleus and putamen volume. We observed an association of genetically predicted Alzheimer’s disease with smaller volumes of most subcortical structures in older adults, but not in young adults.

Conclusion

Our findings provide novel insight into the genetic determinants of changes in subcortical brain structures across the adult lifespan. Further research is needed to decipher the underlying biological mechanisms and inform prevention strategies for common late life neurological diseases.
Alpha power is associated with hippocampal volume in Alzheimer’s disease: A combined MEG and MRI study
Authors: Pitt Jemma , Quinn Andrew J. , Kocagoncu Ece , Karadag‐Assem Melek , Lanskey Juliette , Klimovich‐Gray Anastasia , Cheng Yun‐Ju , Raymont Vanessa , Rowe James B. , Nobre Anna Christina , Woolrich Mark W.
Published: February 2022

Background

New Therapeutics in Alzheimer’s Disease (NTAD) is a multi‐centre, longitudinal study to develop reliable and sensitive biomarkers for patients in the early stage of Mild Cognitive Impairment (MCI) and Alzheimer’s Disease (AD). The hallmark of E/MEG abnormalities in AD patients is changes to the power and frequency of the alpha rhythm. Here, we explore spontaneous alpha oscillations in the NTAD cohort and how they relate to diagnostic condition (patient vs control), resting task (eyes open vs eyes closed) and hippocampal atrophy.

Method

At present, there has been MRI and E/MEG data collected on neurologically healthy controls (N=15; MMSE M=29.4±0.74) and amyloid positive MCI and AD patients (N=46; MMSE M=24.8±3.37). Resting‐state E/MEG recordings were obtained for two 5‐minute sessions; eyes opened and eyes closed. Average power and peak frequency were computed for each participant. A T1‐weighted MR scan was used to calculate hippocampal volume, whilst accounting for individual brain volume. Firstly, we compared the average power and peak frequency for patients and controls in both the eyes opened and eyes closed conditions. Secondly, we explored how alpha varies across these conditions and diagnoses and how these differences relate to hippocampal volume.

Result

We found that patients had lower peak frequency and power compared to controls. Specifically, there was a decreased power in eyes closed, and decreased frequency in eyes opened. These differences were also present in hippocampal volume as patients had significantly smaller hippocampi than controls, and this was correlated with decreased alpha peak frequency specifically in the eyes opened session (R2 = 0.172). These individual differences were further associated with MMSE scores.

Conclusion

There are individual differences between alpha frequency and power between patients and controls. Alpha decreases with increasing cognitive impairment and is related to hippocampal volume. Whilst this is specific to eyes opened or eyes closed, results suggest that progressive atrophy of the hippocampus is associated with decreased alpha frequency. This confirms the clinical benefit of E/MEG measurements in dementia research and improve our understanding of the integration between structural and electrophysiological measures of synaptic dysfunction. Ongoing data analysis will be conducted to standardise these measures for future clinical trials.
Exploring the experiences of living at risk of familial frontotemporal dementia
Authors: Greaves Caroline V , Stott Joshua , Rohrer Jonathan D
Published: February 2022

Background

Frontotemporal dementia is the second most common form of dementia in those under 65 years of age and is found to be genetic in around a third of cases. Familial FTD has an autosomal dominant pattern of inheritance meaning that the offspring of a mutation carrier has a 50% chance of carrying the mutation themselves. For those at risk of FTD, there are a number of issues that can cause distress including the high penetrance of the most common FTD‐causing genes, heterogeneity of symptoms and unpredictable age of symptom onset. Despite this, there have been no studies looking at the experiences of this group, particularly those who do not pursue predictive testing.

Method

Sixteen qualitative interviews were analysed using an inductive approach to thematic analysis. Participants were asked about their experience finding out about their risk, how they felt throughout different parts of their journey, their experience of genetic testing if this was performed, as well as the support they had or feel they would have benefited from.

Result

Key themes identified included: 1) Depression, uncertainty and survivor guilt – the ups and downs of living at‐risk, 2) Worries about the wider family, 3) Lack of support ‐ “You need people who really understand”, 4) Coping mechanisms ‐ Living like a gene carrier and 5) Seeing at risk status as a positive thing. Almost all participants expressed a need for tailored psychological support facilitated by “someone who understands” the unique issues they face.

Conclusion

Living at risk of familial FTD is a psychologically challenging experience, independent of the challenges presented by predictive testing. Those who choose not to undergo predictive testing may also, at times, require specific support. Future research should explore tailored support strategies to assist people in coping with these challenges.
Longitudinal changes in neuropsychiatric symptoms: Impact of discrepancy in everyday preferences between people with cognitive impairment and their care partners
Authors: Wilkins James M
Published: February 2022

Background

Neuropsychiatric symptoms (NPS) of major neurocognitive disorders are common and debilitating facets of the illness process. Yet, little is known about the impact on NPS of discrepancy in the importance of everyday preferences between persons with cognitive impairment (CI) and proxy ratings by their care partners.

Method

The sample included 48 dyads of persons with CI (Clinical Dementia Rating Scale score ≥ 0.5) and their care partners. NPS of the person with CI were measured using the Neuropsychiatric Inventory brief Questionnaire (NPI‐Q) and 15‐item Geriatric Depression Scale (GDS‐15) at baseline and follow‐up (mean 486 days). The Preferences for Everyday Living Inventory was used to assess importance of preferences for persons with CI at baseline; care partners separately completed concurrent proxy assessments at baseline. Mixed random and fixed effects longitudinal models were used to evaluate the impact of baseline discrepancy in everyday preferences assessment between persons with CI and their car partners on changes in NPS across time.

Result

Higher levels of underestimation of the importance of “social engagement” preferences in the proxy ratings of care partners relative to the self‐ratings of persons with CI were associated with a higher degree of neuropsychiatric symptoms across time as a whole as measured by the NPI‐Q but not the GDS‐15.

Conclusion

This study yields new insights into the relationship between discrepant importance ratings of “social engagement” preferences and neuropsychiatric manifestations of neurocognitive disorders, suggesting that a baseline level of discrepancy is associated with changes in neuropsychiatric symptoms over time. Resolving such discrepancies may then offer a therapeutic avenue to lessen NPS over time for persons with CI.
Dyadic interactions, physical environment, and social environment in dementia mealtime care: A systematic review of psychometric properties of instruments
Authors: Liu Wen
Published: February 2022

Background

It is critical to use validated instruments to assess dyadic interactions, social environment, and/or physical environment during mealtime care of persons living with dementia to evaluate the process and efficacy of mealtime assistance and environmental interventions. However, the quantity and psychometric quality of such instruments are unknown. This systematic review aimed to synthesize the quantity and quality of instruments that assess dyadic interactions, physical environment, and/or social environment during mealtime care for persons living with dementia.

Methods

We searched Pubmed, CINAHL, AgeLine, PsychINFO, and Cochrane Library for records published between 1980 and 2020. Records were eligible if they included any instrument that measures concepts of interest (i.e., mealtime dyadic interactions, physical and/or social dining environment). From eligible records, eligible instruments originally developed or later modified to measure concepts of interest were identified. From eligible records, eight characteristics of eligible instruments were extracted: 1) development process, 2) concept/construct being operationalized, 3) sample and setting, 4) administration method, 5) description of items, 6) scoring format/interpretation, 7) reliability, and 8) validity. A newly developed psychometric quality assessment tool was used to evaluate the psychometric quality of eligible instruments.

Results

In total, 26 eligible instruments were identified. Seventeen instruments assessed dyadic interactions, 1 assessed only physical environment, and 8 assessed physical and social environment. All instruments were observational tools and scored as having low psychometric quality. Reasons for low psychometric quality included use of small sample size compared to the number of items, limited psychometric testing, and inadequate estimates.

Conclusions

A number of instruments were developed and/or used to assess dyadic interactions, physical and/or social environment in dementia mealtime care. All instruments warrant further testing to accumulate psychometric evidence in larger diverse samples in different care settings for use in research and practice.
MIND MAPS: Molecular imaging of the mitochondrial‐endoplasmic reticulum‐synaptic axis in patients with Alzheimer's spectrum disorders
Authors: Rabiner Eugenii A.
Published: February 2022

Background

Neurodegeneration is a pathognomonic feature of a variety of CNS disorders, including ALzhemimer's diosease. A dysfucntion of the mitochondrial‐endoplasmic reticulum‐synaptic axis is found in a variety of neurodegenerative disorders and has been linked to other pathological features such as misfolded protein accumulation, neuroinflammation, dysfunction of neurotransmitter release and neuronal loss.

Method

We examined a 12 patients with Alzheimer's spectrum disorder (ASD, MMSE range 16‐29) at baseline and 12‐18 months later with three PET radioligands; [18f]BCPP‐EF, [11C]SA4503 and [11C]UCB‐J, highly specific molecular markers of the mitochondrial complex 1 (MC1), the sigma 1 receptor (s1R) and the synaptic vesicular glycoprotein 2A (SV2A). The baseline data from the patient group was compared to a group of 16 age matched healthy volunteers.

Result

We found significant differences between the patient group and healthy volunteers for all three molecular markers in multiple brain regions. In addition, changes in mitochondrial markers were seen in the cortical areas of patients over the period of 12‐18 month.

Conclusion

Markers of disruption of the mitochondrial‐endoplasmic reticulum‐synaptic axis can be detected in ASD patients in vivo, and can be demonstrated to change over a period of 12 ‐18 months. The imaging of multiple molecular markers enhances the evaluation of neurodegeneration pathology. Ashwin V. Venkataraman, Gaia Rizzo, and the MIND MAPS Consortium
Centiloid scale evaluation for β‐amyloid PET of cognitively normal elderly and SuperAgers
Authors: de Souza Giordana Salvi , Andrade Michele Alberton , Borelli Wyllians Vendramini , de Araújo Adriel Silva , De Almeida Mantovani Dimitri Brigide , Schilling Lucas Porcello , Matushita Cristina Sebastião , da Costa Jaderson Costa , Portuguez Mirna Wetters , da Silva Ana Maria Marques
Published: February 2022

Background

The Centiloid scale (CL) represents an attempt to standardize amyloid imaging to create a measure of global cortical β‐amyloid deposition using positron emission tomography (PET). The CL approach transforms standard uptake value ratio (SUVR) into values ranging from 0 to 100. This study aims to investigate the brain amyloid load in SuperAgers (SA), healthy age‐matched controls (ACs), and healthy middle‐aged controls (MCs).

Method

Thirty cognitively healthy individuals were evaluated with a cognitive screening and the Rey Auditory‐Verbal Learning Test (A7 list). They underwent an amyloid PET image with PIB were acquired in 3D mode from 40 to 60 minutes after injection using a PET/CT scanner (Discovery 600, GE Healthcare). Image analysis was performed using the PMOD software ‐ PNEURO tool (PMOD Technologies). SUVR was transformed to CTX (Global Cortical Target region) using the whole cerebellum (WC) as reference. The equation used to convert SUVR to CL is CL=100 (SUVR‐0.987)/1.019 and fits the parameters described previously.

Result

Total sample included 10 MCs (58.7±5.52 years‐old; A7 = 10.7±3.4), 10 ACs (83.5±4.2 years‐old; A7 = 6.9±1.7) and 10 SA (83.3±2.63 years‐old; A7 = 11.4±2.01). No significant difference was observed in the group analysis between amyloid SUVR between MC, SA, and AC groups (p=0.084). However, the mean CL values were for MCs: 0.65±6.5 CL; ACs: 31.20±34.5 CL; SA: 21.2±33.7 CL. The SuperAgers group exhibited a similar amyloid‐β burden compared with AC, even though A7‐RAVLT test results were significantly different (p=0.001).

Conclusion

The CL approach was successfully implemented in various cognitive aging trajectories using the [11C]PiB PET. SuperAgers exhibited a similar amyloid‐β load to that of age‐matched healthy controls in both SUVR and CL analyses. Tau studies could help to find a better relationship between biomarker load and cognitive behavior.
Impact of polygenic risk score on normative models of hippocampal volumes
Authors: Janahi Mohammed , Aksman Leon M. , Schott Jonathan M. , Altmann Andre
Published: February 2022

Background

Normative Models are widely used across clinical applications from infant growth charts to brain volume charts. For Alzheimer’s disease (AD), reduction in hippocampal volume (HV) is an early and often presymptomatic feature. Thus, precisely measuring deviation of HV from healthy aging facilitates earlier diagnosis. Brain volumes have been reported with heritability of 40‐90%, thus, implying that normative ranges of HV are heavily influenced by genetics. Here we investigate whether genetic information can improve HV nomograms for AD.

Method

We used Gaussian Process Regression (GPR) to generate nomograms of HV from 40,000 participants in UKBB aged 45‐82. These nomograms were contrasted to a previously reported Sliding Window method (SWM; PMID: 31254939). Next, we computed a Polygenic Risk Score (PRS) for HV using a large independent GWAS (N=33,536; PMID: 28098162). Participants were stratified into high and low PRS for HV; nomograms were built for each strata separately. Next, we used subjects from the ADNI dataset labelled cognitively normal (CN) or AD (N=226 and N=122) to examine the difference between using stratified versus non‐stratified nomograms.

Result

Nomograms generated using GPR matched those generated with the SWM with an average of difference of 17 mm3 (about 0.4%). Compared to the SWM, GPR extended the age range of the nomograms by ten years in either direction (from 56‐73 y/o to 47‐83 y/o: Figure 1). Nomograms stratified by PRS showed an average shift of 28 mm3 upward/downward for high/low PRS scoring samples (Figure 1). In ADNI, using non‐stratified nomograms led to a difference of 13% in median HV percentiles between high‐PRS and low‐PRS CN participants, which was reduced to 3.3% using stratified nomograms (Figure 2); this effect was not observed for the AD group.

Conclusion

GPR‐based nomograms were similar to the SWM‐nomograms while extending the range into areas critical for the analysis of aging diseases. Including genetics through a PRS for HV shifted HV nomograms in the expected direction. The small shift in nomograms of HV did not affect the sensitivity of AD diagnosis. However, it led to better adjusted estimates within CN subjects. Thus, genetics‐adjusted HV estimates may improve biomarker‐based AD‐risk predictions (PMID: 31526625).