bluuebunny/crossref_metadata_2025 huggingface dataset:
Natural history of apathy in Alzheimer’s disease
Authors: Zhu Carolyn W. , Grossman Hillel , Sano Mary
Published: December 2020

Background

Apathy is a common behavioral symptom of dementia, yet information on its impact dementia is limited. This study examines prevalence, incidence, and persistence of apathy longitudinally.

Method

Sample was drawn from the National Alzheimer's Coordinating Center Uniform Data Set (NACC‐UDS) including participants enrolled 9/2005‐5/2019 with at least one follow‐up, with baseline diagnosis of MCI or AD. Presence of apathy was defined using clinician judgment within the NACC‐UDS protocol, indicating whether the participant currently manifests meaningful change in behavior in apathy (yes=1/no=0). Incidence of apathy was defined as the proportion of participants who did not have an endorsement of apathy at baseline but had a new endorsement of apathy at that visit. Persistence of apathy was defined as the proportion of participants who had an endorsement of apathy between two consecutive visits.

Result

Sample included 9,607 participants with baseline CDR=0.5 (n=5,323), 1 (n=3,115), 2/3 (n=1169). Apathy was endorsed in 59.4% of participants at some point during follow‐up (CDR=0.5: 46.6%, CDR=1: 72.9%, CDR=2/3: 81.2%). Participants with apathy differed from those who never had apathy in: being male (49.0% vs. 44.7%), education (14.6±3.7 vs. 14.9±3.6), reporting depression in the past 2 years (42.7% vs. 26.6%), having at least one APOE e4 allele (58.7% vs. 52.9%), follow‐up years (4.1± 2.1 vs 3.8±2.2), MMSE (21.5±6.3 vs. 24.2±5.1), and FAQ (13.8±9.0 vs. 7.6±8.2) (all p<0.01). Differences in baseline age and comorbidities were statistically insignificant. Presence of apathy increased over time in participants with baseline CDR=0.5 (baseline to visit 5: 19.8% to 33.8%) and CDR=1 (43.9% to 59.9%), but fluctuated around 62.4% in CDR=2/3. Incidence of apathy fluctuated around 12.5%, 15.7% and 13.4 % for each baseline CDR group. Persistence of apathy between consecutive visits increased over time in participants with baseline CDR=0.5 (baseline to visit 5: 12.6% to 21.4%) and CDR=1 (33.2% to 44.8%), but fluctuated around 49.2% in CDR=2/3.

Conclusion

Prevalence and persistence of apathy increased over time and correlated with disease severity. Incident apathy appears to plateau after CDR=1. The increasing impact of apathy over the course of dementia has clinical relevance and should be considered in designing intervention studies.
ACI‐24 vaccine in adults with Down syndrome
Authors: Rafii Michael S , Mobley William C , Skotko Brian G. , Sabbagh Marwan N. , Burke Anna D. , Yuan Shauna , Rissman Robert A. , Chavez Ronelyn , Delpretti Saskia , Sol Olivier , Beth Greg , Gray Julian JG , dos Santos Antonio Melo , Hliva Valerie , Vukicevic Marija , Kosco‐Vilbois Marie , Pfeifer Andrea , Feldman Howard H.
Published: December 2020

Background

Individuals with Down syndrome (DS) are at increased risk for developing Alzheimer’s Disease (AD) with 100% exhibiting amyloid pathology by age 40, making approaches targeting beta‐amyloid a rational strategy for the prevention of dementia. ACI‐24 is a liposomal vaccine eliciting polyclonal anti‐Aβ antibodies in a T‐cell independent manner. In this study, the safety, tolerability and immunogenicity of ACI‐24 in adults with DS are being tested.

Methods

This is a sequential, dose‐escalating, placebo‐controlled, phase 1b study testing the safety and efficacy of ACI‐24 in two cohorts with 8 individuals each. Cohort 1 (ACI‐24 300μg or placebo) was followed by cohort 2 (ACI‐24 1000μg or placebo) each comprised of 6 active and 2 placebo‐treated participants. Each participant received 7 subcutaneous injections of ACI‐24 or placebo over 12 months, followed by a 12‐month safety follow‐up period. Participants are non‐demented DS individuals (25 to 45 yrs), able to complete study‐related procedures with a reliable study partner. Primary endpoints assess the safety and tolerability, including adverse events and other safety measures as well as the induction of anti‐Aβ antibody titers in serum. Secondary objectives explore the effect of ACI‐24 on cognition and behavior (Brief Praxis Test, Clinical Global Impression of Change, Vineland II Adaptive Behavior Scale, Neuropsychiatric Inventory and selected measures of the CANTAB), standard AD biomarkers, including Aβ and tau levels in plasma and/or CSF when available; T‐cell activation; and the effect on whole brain, ventricular and hippocampal volumes.

Results

Sixteen participants were randomized into two study cohorts: cohort 1 (n=8; mean age 34.1 yrs) and cohort 2, (n=8, mean age 31.1 yrs). The majority of participants are Caucasian. The study population also has a high prevalence of obesity (mean BMI = 39.6). The safety and tolerability have been good to date, with no reported dropouts, serious adverse events or MRI abnormalities.

Conclusion

The recruitment of this world’s first clinical study using an anti‐Aβ vaccine (ACI‐24) in a DS population is now complete and has shown a good safety and tolerability to date. It represents a critical advance in developing potential therapies for the prevention of AD dementia in this at‐risk population.
White matter integrity and types of memory complaints in mild cognitive impairment
Authors: Ryu Seon Young , Lee Sang Bong , Lee Taek Jun , Jung Yu Jin
Published: December 2020

Background

Memory complaints are a frequent phenomenon in individuals with mild cognitive impairment (MCI). However, clinical significance for different types of memory complaints in MCI remains unclear. The aim of this study was to examine whether white matter (WM) integrity would be affected due to different aspects of memory complaints (i.e., prospective memory (PM) versus retrospective memory (RM) complaints) in individuals with MCI.

Method

The study included a total of 73 participants (mean age: 69.37 ± 7.40 years) with MCI. Memory complaints were assessed using the Prospective and Retrospective Memory Questionnaire (PRMQ) consisting of 16 items that describe everyday memory failure of both PM and RM. WM integrity was evaluated by anatomically defined regions of interest analysis using diffusion tensor imaging (DTI). The discrepancies regarding more PM or more RM complaints were assessed by the PM‐RM discrepancy scores (median = 1, range: −9–12) based on the PM and RM subscores of the PRMQ, and participants with more PM complaints (PRMQ‐PM score > PRMQ‐RM score) were compared to those with more RM complaints with regard to DTI‐derived WM fractional anisotropy (FA). The subjects with PM‐RM discrepancy scores of 0 or 1 were excluded from the group analyses.

Result

More PM complaints group (n = 34) had higher FA in the body of corpus callosum (p = 0.03), and a tendency to higher FA in the genu of corpus callosum (p = 0.08) and right entorhinal WM (p = 0.092) than more RM complaints group (n = 20).

Conclusion

RM complaints among subjective memory complaints might be associated with more alterations in WM integrity. This cross‐sectional study suggests that different types of memory complaints could affect WM microstructural alterations in individuals with MCI. To clarify our results, further investigations in larger samples are required.
Clinical phase I data of the first orally available anti‐aβ‐prionic drug PRI‐002 that reverses behavioral and cognitive deficits, and decelerates neurodegeneration in AD animal models
Authors: Willbold Dieter , Kutzsche Janine , Willuweit Antje , Windisch Manfred , Jürgens Dagmar
Published: December 2020

Background

More and more data suggest that the toxic protein assemblies of Aβ and TAU behave prion like. The drug candidate PRI‐002 has been developed to directly disassemble and destroy toxic Aβ oligomer prions. The anti‐prionic compound PRI‐002 (alias “RD2”) is BBB penetrable and has demonstrated target engagement in vitro and in vivo. Treatments in three different transgenic mouse models in three different laboratories yielded improved cognition and deceleration of neurodegeneration. Oral treatment of old‐aged transgenic AD mice with full‐blown pathology reversed cognitive and behavioral deficits to levels of healthy wild‐type littermates. We wanted to demonstrate safety and tolerability of PRI‐002 in healthy volunteers up to doses that are much higher than the expected therapeutic dose.

Method

We carried out a single (4 to 320 mg PRI‐002) and a multiple ascending dose (160 and 320 mg PRI‐002/volunteer) phase I clinical trial in 63 healthy volunteers.

Result

No drug‐related adverse events (AE) have been observed in the SAD study. The few possibly drug‐related AEs in the MAD study were equally distributed across groups. Already in the SAD, PRI‐002 plasma levels were reached (AUC0‐24 104 ng h/mL) that were measured in the highest dosed animals of the successful preclinical PoC studies.

Conclusion

Daily administered oral doses of PRI‐002 up to 320 mg/subject/day for 28 days have been proven to be safe. PoC studies in humans for anti‐prionic compounds may be based on shorter treatment durations and do not necessarily have to be life‐long.
The differential genetic architecture between posterior cortical atrophy and amnestic Alzheimer's disease
Authors: Scelsi Marzia Antonella , Napolioni Valerio , Mead Simon , Crutch Sebastian J. , Schott Jonathan M. , Greicius Michael D. , Altmann Andre ,   PCA Genetics Consortium and the National Alzheimer's Coordinating Center (NACC)
Published: December 2020

Background

Posterior cortical atrophy (PCA) is a rare early‐onset form of dementia, typically due to Alzheimer’s disease (PCA‐AD) characterised by predominant deficits of higher‐order visual functions, with relatively preserved memory, verbal fluency and insight with respect to typical, amnestic AD (tAD). A prior genetic study by Schott et al. (2016) investigated genetic risk factors for PCA‐AD in comparison to healthy controls; it also compared the magnitude of effect of known tAD risk loci in PCA. However, little is known about whether the difference between PCA‐AD and tAD is modulated by genetic factors outside the established tAD risk loci. Here we present the first large‐scale genetic study directly comparing PCA‐AD and tAD, in order to identify novel genetic variants driving the difference between these two syndromic variants.

Method

We imputed autosomal Single Nucleotide Polymorphism (SNP) data for 287 PCA‐AD cases from Schott et al. (2016) and 1,687 tAD cases from Naj et al. (2011), all unrelated Caucasians. We compared PCA to tAD cases in a genome‐wide association study (GWAS). SNP associations with diagnosis were tested through logistic regression, including sex, age‐at‐onset, and ten principal components of population structure as covariates. A sensitivity analysis was conducted omitting age‐at‐onset from the covariates, after detecting a significant difference in the mean age‐at‐onset of PCA and tAD cases (Table 1).

Result

Eleven independent genome‐wide significant loci were identified (Figure 1). APOE ε4 almost reached genome‐wide significance (p = 5.11 × 10−8). GWAS‐significant SNPs mapped to the following genes: MORN1, CNTNAP5, SPPL3, MARK3. The sensitivity analysis increased statistical power, with APOE ε4 and 6 additional loci reaching significance.

Conclusion

We present the first GWAS of PCA vs tAD and identify five genes. In keeping with previous findings we confirm that APOE ε4 has a weaker effect in PCA than tAD, also showing that CNTNAP5 increases risk not only vs controls (Schott et al. 2016) but also over tAD. Of the new genes identified, SPPL3 is a presenilin‐like protein, and MARK3 is involved in the phosphorylation of tau proteins MAP2 and MAP4. These findings suggest that differential genetic factors may influence the development of AD, but also its phenotypic expression.
Assessing the generalizability of findings from the Alzheimer’s Disease Neuroimaging Initiative to the Atherosclerosis Risk in Communities study cohort
Authors: Power Melinda C , Bennett Erin , Glymour M Maria , Gianattasio Kan Z , Couper David , Mosley Thomas H , Gottesman Rebecca F , Griswold Michael E , Wei Jingkai , Mehrotra Megha , Stuart Elizabeth A
Published: December 2020

Background

The Alzheimer’s Disease Neuroimaging Initiative (ADNI) collects and shares high quality imaging, biomarker, genetic, and clinical data. Whether findings from ADNI generalize broadly is unclear, given its highly‐selected, predominantly white and well‐educated participants. We compared associations estimated in ADNI to those estimated in the Atherosclerosis Risk in Communities (ARIC) study, which initially recruited participants randomly from four US communities, to examine the potential generalizability of ADNI findings.

Method

We identified common risk factor, cognitive, and imaging variables at the ADNI screening/baseline visits and ARIC Visit 5. Data were pooled to estimate associations between risk factors and cognitive or imaging data, and between cognitive and imaging data, using adjusted linear and logistic regression models. Models included a term for cohort and its interaction with the variable of interest, allowing for cohort‐specific estimates and statistical evaluation of cohort differences. We repeated analyses on data subsets defined by race and cognition. Sensitivity analyses accounted for cohort differences in the impact of confounders by including cohort by covariate interactions.

Result

The proportion of estimated associations that differed significantly by cohort (interaction p‐value<.05) in primary analyses was 42% (range 25‐42% across subset and sensitivity analyses). Many differences were substantively meaningful (e.g. OR for APOE‐4 on amyloid positivity in ARIC: OR=2.75; in ADNI: OR=8.44; OR for any functional limitations on MMSE score < 25: OR = 5.05 (2.87 ‐ 8.90) in ADNI, OR = 1.34 (0.99 ‐ 1.81) in ARIC).

Conclusion

The proportion of associations that differed significantly between ADNI and ARIC was substantially higher than would be expected by chance. Differences may stem from inherent differences in the populations from which participants were recruited. This has implications for the generalizability of highly selected samples, including deeply phenotyped samples typically used for biomarker research.
Amyloid angiopathy may contribute to white‐matter hyperintensities in Alzheimer’s disease
Authors: Xia Ying , Fazlollahi Amir , Yates Paul A. , Yassi Nawaf , Desmond Patricia M. , Salvado Olivier , Villemagne Victor L.L. , Rowe Christopher C. , Fripp Jurgen , Masters Colin L. , Raniga Parnesh
Published: December 2020

Background

Cerebral amyloid angiopathy (CAA) is characterised by the accumulation of amyloid‐b (Aβ) in cerebral vessels and is often coexistent with Alzheimer’s disease (AD). However, the overlap between CAA and AD and the contribution of CAA pathology to cerebrovascular lesions are not well understood. We hypothesize that in subjects with high Aβ load, the presence of imaging markers of CAA would be associated with greater white matter hyperintensities (WMH) burden.

Method

Data used in the preparation of this article was obtained from the Australian Imaging Biomarkers and Lifestyle flagship study of ageing (AIBL). See www.aibl.csiro.au. We analysed MRI (SWI and FLAIR) and 11C‐PiB‐PET data from 98 cognitively normal (CN), 34 mild‐cognitive impairment (MCI) and 38 AD participants. Subjects were classified as being Aβ+ if their Aβ load was above 20 centiloid.

SWI images were manually read for lobar microbleeds (LMB) and superficial siderosis. Subjects were classified as probable‐CAA (PCAA, 2 or more LMB or siderosis), possible‐CAA (SCAA, single LMB or siderosis) or non‐CAA (NCAA) based on the modified Boston criteria. Subjects classified as SCAA (n = 24) were excluded from further analysis since literature shows this group to be heterogenous and having low incidence of CAA pathology. WMH were automatically quantified on FLAIR. Group comparisons of WMH load were made using Kruskal Wallis rank test. A GLM was performed comparing WMH (log10 transformed) and CAA/ Aβ+ classification with age, intracranial volume, gender, APOE‐ε4 genotype and use of anti‐platelet or anticoagulant medication modelled as covariates.

Result

Significantly higher WMH volume was observed in PCAA (n = 17) than NCAA (n = 129) (p‐value = 0.021, d = 0.36). When amyloid status was considered, PCAA/Aβ+ (n = 15) subjects had a significantly higher WMH load than NCAA/Aβ+ (n = 57) subjects (p‐value = 0.012, d = 0.57) and NCAA/Aβ‐ (n = 72) subjects (p‐value = 0.0006, d = 0.76) (Figure 1). PCAA/Aβ‐ (n = 2) were removed from further analysis. GLM results showed a significant association of WMH with PCAA/Aβ+ as compared to NCAA/Aβ+ (p‐value = 0.02, beta = 0.322 [0.056,0.588]).

Conclusion

Our findings suggest that CAA may contribute to WMH burden in subjects with high Aβ load. Further studies are required to validate our observations and characterise the contributions of CAA compared to small vessel disease associated with traditional risk factors towards the phenotype of AD.
A pilot randomized controlled trial on iSupport in India: Results on the use of the online program and its effectiveness
Authors: Baruah Upasana , Varghese Mathew , Loganathan Santosh , Mehta Kala , Gallagher‐Thompson Dolores , Zandi Diana , Dua Tarun , Pot Anne Margriet
Published: December 2020

Background

The World Health Organization’s online program ‘iSupport’ for family caregivers of people with dementia was adapted and pilot‐tested in India. Although there are promising outcomes of Internet‐based interventions in Western countries, there has hardly been any research on the use and effectiveness of such interventions in developing countries.

Methods

Caregivers were recruited from multiple sources including physician referrals, advertisement and word‐of‐mouth. 338 caregivers were assessed for eligibility of which 187 were excluded in the trial. 151 caregivers were randomized to either the intervention group (iSupport; n=74) or the comparison group (web‐based education only; n=77). Of these, 29 caregivers in the iSupport group and 26 in the control condition completed the 3‐month follow‐up assessment. Linear regression analysis was carried out to analyze the data.

Results

Of the 151 randomized caregivers, 81 (54%) were male and 144 (95%) had a Bachelor’s degree or higher. In terms of caregiver relationship, the majority (60%) were adult children, followed by spouses (21%). No significant differences could be shown in the intervention and control conditions at 3‐month follow‐up on the primary outcomes depressive symptoms and feelings of burden. However, we did find a significant improvement in caregivers’ person‐centred attitude towards persons with dementia in the iSupport group.

Conclusion

Although no significant differences were found on the primary outcome measures, the significant improvement on person‐centredness of caregivers in the iSupport group is encouraging, since the number of participants and hence the power to find changes, was small. The difficulty in recruiting and retaining participants require closer attention and indicates need for further adaptations of the online iSupport programme. From this pilot study important lessons have been learned that will be discussed during the presentation and will guide further development of caregiver support in India.
Preparing the ground for the adaptation of iSupport in Switzerland
Authors: Fiordelli Maddalena , Albanese Emiliano
Published: December 2020

Background

In 2013, Switzerland developed a national dementia strategy, which entails the implementation of interventions for caregivers of people with dementia. iSupport, an online knowledge and skills training program purposely developed by the WHO holds the promise to respond to the complex and largely unmet needs of caregivers. There is evidence that online interventions can contribute to improve quality of care and caregivers’ wellbeing, but evidence to inform the implementation and scalability of iSupport is still extremely limited, We planned to seek funds, collaborate with local authorities, institutions, and stakeholders (including people with dementia and their informal caregivers) to locally adapt, pilot, test, and scale iSupport in selected Swiss cantons, and to pave the way to a formal monitoring of its implementation and effectiveness.

Method

We combined quantitative and qualitative methods in two preparatory studies: a pilot study aimed at testing the feasibility, acceptability, and accuracy of an innovative data capturing system to profile caregivers’ strain and needs, and care needs of people with dementia; a survey to assess the level of dementia knowledge, awareness and acceptance, and the willingness to participate in implementation research in a large sample of older adults.

Result

Data collection was feasible, well received, and efficient in a sample of caregivers of people with dementia (N=52). Strain was marked in all caregivers, who confirmed their interest in receiving a structured training to improve their understanding of dementia, and acquire competences and skills for care provision, and coping strategies. Of the 628 respondents to the survey, 47% considered dementia a normal part of aging, 95% considered research on support to family caregivers important or greatly important, and 45% declared their willingness to participate in a future study on this matter. Local authorities agreed (and committed) to mobilize resources and funds to support the implementation of iSupport, of its integration in existing health and social care services, and of appropriate indicators to monitor its use and impact.

Conclusion

Engaging local stakeholders, including local institutions and potential funders since the beginning of implementation research is feasible, and can contribute to address unmet needs of informal caregivers of people with dementia.
Hearing aid use and cognition in older adults: Can we delay decline or even improve cognitive function?
Authors: Sarant Julia , Harris David , Busby Peter , Maruff Paul T , Schembri Adrian , Phillips Jocelyn , Nixon Grace , Lemke Ulrike , Launer Stefan , Tomlin Dani , Dowell Richard
Published: December 2020

Background

Hearing loss is associated with accelerated cognitive decline in older adults, and has been identified as a modifiable risk factor for dementia. Although hearing aids are a successful treatment for hearing loss, it is unknown whether hearing aid use can delay the onset of cognitive decline or improve cognitive function in older adults with hearing loss. This prospective longitudinal study is investigating the effect of hearing aid use on cognitive decline and addresses many of the methodological limitations of previous studies.

Method

Patients are recruited from the University of Melbourne Academic Hearing Aids Audiology Clinic and assessed before and every 18 months after hearing aid fitting. When numbers are sufficient, results will be compared with those of a control group of approximately 400 participants of a cohort study of ageing in older adults. Assessments include cognitive function (visually presented computerised assessment battery), hearing, speech perception, quality of life, activity, diet, loneliness and isolation, anxiety, depression, medical health and genetic risk.

Result

At baseline, multiple linear regression for 98 participants (62‐82 years), controlling for age, gender, cardiovascular conditions, education, and working/retired, with mean better ear PTA 31dB showed hearing loss and age predicted significantly poorer executive function, while tertiary education predicted significantly better executive function and visual learning. At 18‐month follow up, results for a subset of participants showed significant improvements in speech perception, listening disability and quality of life. Group mean scores across the cognitive assessment battery showed no significant decline and executive function was significantly improved. There was either clinically significant improvement or stability for executive function for over 97% of the subset, and for females for working memory, visual learning and visual attention, despite significantly greater hearing loss over this period.

Conclusion

Despite a small initial sample size, hearing loss, age and education significantly predicted baseline cognitive function. At 18‐month follow up, the majority of participants had either remained stable or demonstrated a meaningful clinical improvement in cognitive function, with significant group mean improvements for executive function and working memory. Treatment of hearing loss with hearing aids may delay cognitive decline. These are initial results, and further follow up is required.
Minocycline treatment effects on cognition, sleep, breathing and body temperature in a model for sporadic Alzheimer's disease
Authors: Vicente Mariane Cristine , Carrettiero Daniel , Almeida Maria Camila , Bícego Kênia Cardoso , Paneghini Julia de Lima , Batalhão Luciane Helena Gargaglioni
Published: December 2020

Background

Chronic inflammation plays an important role in the cascade of molecular events in the brain of patients with Alzheimer's disease (AD). Preclinical studies have shown that minocycline has a potent anti‐inflammatory effect exerted by its neuroprotective action in various neurodegenerative diseases, such as AD. Thus, we tested the hypothesis that minocycline treatment could reverse / minimize the cognitive and respiratory and sleep deficits of our sporadic AD model.

Method

We used as an animal model for sporadic Alzheimer’s disease (AD) induced by icv injection of streptozotocin (STZ) (2 mg/kg). After five consecutive days of daily dosing with minocycline (30 mg / kg, i.p) the animals were submitted to the experiments. We evaluated memory and learning by Barnes' maze (n = 12), ventilatory parameters during sleep and wakefulness by the whole body plethysmography method and sleep time by electroencephalography method. We evaluate body temperature also during all experiments.

Result

The minocycline treatment improved learning and memory of the STZ‐AD model (n = 12, p < 0.05). But it did not decrease the sensitivity of STZ‐AD model to CO2 ventilatory response during wakefulness Placebo (VE mean ± standard deviation: STZ‐AD = 2477.5 ± 514.8 mL. Kg−1. min−1 vs VE Placebo‐Vehicle = 2005.1 ± 364.2 mL. Kg−1. min−1) vs Minocycline (VE Minocycline‐STZ‐AD = 2535.0 ± 246.7 vs VE Minocycline‐Vehicle = 1936.0 ± 226.4 mL. Kg−1. min−1) (P >0.05 test Two‐Way ANOVA). Similarly, minocycline treatment had no effect on reversal of wakefulness increase in STZ‐AD model (% Time spent in awake state mean ± standard deviation: Placebo‐STZ = 66.4 ± 17.7 vs Placebo‐Vehicle = 53.0 ± 9.9 % ) (Minocycline‐STZ = 66.6 ± 8.2 vs Minocycline‐Vehicle = 44.8 ± 11.7 %). No difference was observed in the body temperature of the animals during the experiments, but the hypoxia promoted a regulated fall in body temperature.

Conclusion

In summary, our data suggest that minocycline is a promising drug to minimize cognitive dysfunctions in the AD model without changing the respiratory and sleep‐wake cycle parameters.
Assessment of magnetic resonance spectroscopy variability across metabolites and field strengths
Authors: Bracoud Luc , Port John D , Scott David , Conklin Chris , Suhy Joyce , Glaus Charles , Jacobsen Leslie
Published: December 2020

Background

Magnetic Resonance Spectroscopy (MRS) is a non‐invasive technique assessing the concentration of various metabolites within the brain, both cross‐sectionally to characterize disease type and severity, and longitudinally to assess disease progression and potential treatment efficacy in the context of disease‐modifying interventions. In such context, the involvement of multiple imaging facilities inevitably introduces variability, whose amount must be known to inform on comparability between sites and sensitivity to change. Our objective is to study variability in the concentration of various brain metabolites using a dedicated MRS phantom and assess impact of field strength.

Methods

30 sites are being considered to participate in an on‐going clinical trial in metachromatic leukodystrophy. Site qualification mandates the scanning of a dedicated MRS phantom. 30 of these HD‐polyethylene spheres were simultaneously manufactured and filled with the same mixture of chemicals mimicking main metabolite concentrations. To date, 14 sites provided data (5 1.5T scanners and 9 3T). All sites implemented a standardized single‐voxel MRS sequence. MRS voxel was placed within the phantom and acquisition repeated 3 times. Spectra were centrally analyzed using LCModel v6.3 and quality controlled by Bioclinica. Repeat acquisitions were requested for parameter deviations, voxel positioning and/or shimming issues. Results only include passing datasets. Coefficient of Variation (CV) was calculated for NAA/Cr, Cho/Cr, mI/Cr, Glx/Cr and Lac/Cr ratios for each site and overall. LCModel quality metrics (FHWM and S/N) were also extracted to assess spectra quality. Comparison between field strengths was carried out using t‐tests.

Results

Average CV by site was 2.0% for NAA/Cr (2.5% at 1.5T and 1.8% at 3T), 2.4% for Cho/Cr, 3.0% for mI/Cr, 4.5% for Glx/Cr and 6.1% for Lac/Cr. CVs were generally lower at 3T (except for Lac/Cr) although difference was not significant. As expected, Signal‐to‐Noise was higher at 3T (p=0.05). Overall CV by metabolite across scanners was much higher (ranging from 4.6% for Cho/Cr up to 12.1% for Lac/Cr).

Conclusion

MRS measures of metabolite concentrations have low variability at scanner‐level, insensitive to field strength. Nevertheless, variability across sites is much higher and would require, if possible, cross‐calibration. These phantom data make such calibration possible and will improve sensitivity of subject data analyses.
Use of wearable technology to assess activity in cognitively impaired populations: Inside care homes and the community
Authors: McArdle Ríona , Buckley Christopher , Din Silvia Del , Parsons John , Lord Sue , Galna Brook , Taylor Lynne , Thomas Alan J , Kerse Ngaire , Rochester Lynn
Published: December 2020

Background

Preservation of mobility is a key mediator for maintaining functional abilities, preventing falls, and slowing cognitive decline in older adults with cognitive impairments, such as dementia. Community‐dwellers with dementia are less active than cognitively‐intact older adults, spending less time walking and taking less varied walking activities [Mc Ardle et al., 2019]. Care homes might further increase barriers to mobility for cognitively‐impaired residents due to organizational and environmental constraints [Benjamin et al., 2014]. However, there are limited objective studies characterising activity in care home residents with cognitive impairment. This study aims to investigate activity in care home residents compared to community‐dwellers with cognitive impairment.

Method

Data from the Staying UpRight study (University of Auckland, NZ) provided information about 37 care home residents with predominately mild‐moderate cognitive impairment, while the GaitDem study (University of Newcastle, UK) illustrated activity in 51 community‐dwellers with dementia. Both studies placed a tri‐axial accelerometer (Axivity, AX3) on participants’ lower backs, which continuously monitored their activity for 7 days on average. Activity measures included volume (time spent walking, steps and ambulatory bouts per day), pattern (mean bout length, proportion of short to long walking bouts) and variability (of bout length). Independent t‐tests compared activity measures between care home residents and community dwellers.

Result

Controlling for age and sex, care home residents (Age: 85±8, MOCA: 14±7, 74%female) spent less minutes walking (p<.001), took less steps (p<.001) and fewer ambulatory bouts (p<.001) compared to community‐dwellers with dementia (Age: 77±6, sMMSE: 22±4, 29%female). Their ambulatory bout lengths were also shorter (p=.032), and they spent proportionally more time in short bouts (p=.012).

Conclusion

This study provides initial evidence that care home residents with cognitive impairment are objectively less active compared to community‐dwellers. Improving mobility in care homes is an important target for maintaining functional abilities, lowering falls risk and enhancing longevity. Future work should identify modifiable factors for activity preservation when residing in care homes. This analysis was limited by the synthesis of two discrete datasets with culturally‐diverse populations at different stages of cognitive impairment. This highlights the need for a comprehensive study to investigate the complexities of activity loss in care homes.
Mental representations of daily activities throughout the course of dementia
Authors: Ross Sabrina D. , Rodriguez Francisca S.
Published: December 2020

Background

Since dementia is a result of cognitive rather than physical impairment, cognitive functioning should also be considered when estimating the care of older people. This study investigated how the loss of cognitive functioning affects mental representations of daily activities and their performance throughout the course of dementia. A mixed‐model study was conducted to investigate how the content of the mental representations differs between stages of dementia.

Method

In order to gain a better insight into how changes of mental representations of daily activities get affected throughout the disease of dementia, we conducted the script generation task of daily activities (grocery shopping, doing laundry, going to the dentists) and the Montreal Cognitive Assessment (MoCa), from 25 people (age (mean: 67.64; SD: 23.625), sex (f: 14 (56%); m: 17 (68%)), cognitive status (healthy: n=6; mild demented: n=7; severe demented: n=12)) as well as a qualitative semi‐structured interview. In this mixed‐method design, the qualitative analysis was based on the Grounded Theory.

Result

Overall, we found evidence that mental representations of daily activities loose in content and get inaccurate throughout the course of the disease, whereas not always a steady transition according to the assessed cognitive status was observed. However, mental representations on performing daily activities remained correct throughout the course of dementia, even though the ability to perform those activities decreased. We further observed a great variance in the content generated by severe demented people ranging from a complete reduction of actions to expansive script action generation. It was also shown that, in early stages of dementia, mental representations of daily activities are disrupted, which is predominantly shown in an incipient increase in sequencing errors and, in the further course of the disease, an increase in intrusions and personalizations.

Conclusion

This study outlines how dementia affects mental representations and performance of daily activities throughout dementia. It turns out that script generation is hampered by decreasing cognitive functioning, the content of the generated actions for mental representations of daily activities reflect functional impairment. Further research is needed to gain a detailed understanding in how script generation gets affected along decreasing cognitive status.
Effect of trazodone on cognitive function in people with dementia: Cohort study using UK routinely collected data
Authors: Sommerlad Andrew , Werbeloff Nomi , Perera Gayan , Smith Tanya , Costello Harry , Mueller Christoph , Kormilitzin Andrey , Broadbent Matthew , Nevado‐Holgado Alejo J , Lovestone Simon , Stewart Robert , Livingston Gill
Published: December 2020

Background

The antidepressant trazodone has been found in recent evidence from mouse neurodegenerative disease models to be neuroprotective, leading to interest in whether trazodone could be repurposed to improve cognition in people with dementia. We aimed to examine trazodone’s effect using routinely collected clinical data, by comparing cognitive decline of people with dementia taking trazodone with those taking other antidepressants.

Method

We conducted three identical naturalistic pharmaco‐epidemiological cohort studies using large secondary mental healthcare databases in North London, South London, and Oxford, covering around 2% of the UK’s population. We included all people with dementia who were recorded between 2008‐16 taking trazodone, citalopram or mirtazapine for at least 6 weeks and had cognition assessed by mini‐mental state examination (MMSE). Linear mixed models examined age, time and sex‐adjusted MMSE change in people with all‐cause dementia taking trazodone compared with those taking citalopram and mirtazapine. Sensitivity analyses examined those with non‐vascular dementia; mild dementia; and adjusted results for neuropsychiatric symptoms. Results from the three study sites were combined using random‐effects meta‐analysis.

Result

We included 2,199 people with dementia, including 406 taking trazodone, with mean 2.2 years follow‐up. There was no difference in adjusted cognitive decline in people with all‐cause or non‐vascular dementia taking trazodone, citalopram or mirtazapine in any of the three study sites. Meta‐analysed results from the three sites indicated greater mean MMSE decline in people with all‐cause dementia taking trazodone compared to those taking citalopram (0.26 points per successive MMSE measurement, 95% CI 0.03 to 0.49; p=0.03). Pooled MMSE change was not different for those taking trazodone v mirtazapine. The main limitation of our study design was the potential for confounding by indication, but results in sensitivity analyses adjusting for neuropsychiatric symptoms and analysing only those with mild dementia were consistent with the primary analysis, suggesting that confounding by indication did not explain results.

Conclusion

There was no evidence of cognitive benefit from taking trazodone compared to citalopram or mirtazapine in people with established dementia in these three separate naturalistic cohort studies or when results were combined. Despite the preclinical evidence, trazodone should not be advocated for cognition in dementia.
Mild cognitive impairment with Lewy bodies: Clinical characteristics and risk factors for progression
Authors: van de Beek Marleen , van Steenoven Inger , van der Zande Jessica J. , Barkhof Frederik , Teunissen Charlotte E. , van Der Flier Wiesje , Lemstra Evelien
Published: December 2020

Background

Little is known about the clinical presentation and prognosis of patients with mild cognitive impairment with Lewy Bodies (MCI‐LB). We aimed to describe clinical characteristics, cognitive decline and risk factors for progression to dementia in MCI‐LB and compare these to MCI due to Alzheimer’s disease (MCI‐AD).

Method

We included 194 MCI patients from the Amsterdam Dementia Cohort. MCI‐LB (n=73, 68±6yrs, 12%F, MMSE:27±2) was defined as MCI + (1)two or more core clinical features (hallucinations, parkinsonism, fluctuations, RBD), or (2)one core clinical feature and abnormal DAT‐SPECT and/or (3)probable Dementia with Lewy Bodies (DLB) at follow‐up. MCI‐AD (n=124, 68±7yrs, 48%F, MMSE:27±2) was defined as having MCI + abnormal CSF AD biomarkers. Cross‐sectional analyses included neuropsychiatric symptoms (GDS, NPI), caregiver burden (ZARIT), MRI, CSF biomarkers (tau/Ab1‐42 ratio) and APOE‐genotype. Annual follow‐up was available for 61 MCI‐LB patients and all MCI‐AD patients(3±2yrs). Linear mixed models(LMM) analyzed decline in MMSE and cognitive domains over time (memory, attention, executive and visuospatial functioning). Cox proportional‐hazards analyses identified risk factors for progression to dementia.

Result

Parkinsonism was the most frequently reported feature in MCI‐LB (70%). In MCI‐LB, 33% had a CSF AD biomarker profile and 47% were APOE‐ɛ4 carrier. MCI‐LB patients scored higher on NPI, GDS and ZARIT than MCI‐AD. There were no differences in MRI characteristics(Table 1). MCI‐LB had lower baseline attention, executive and visuospatial functioning, while MCI‐AD had lower baseline memory scores. MCI‐LB declined faster over time on attention, whereas MCI‐AD had faster decline on MMSE and memory (Table 2, Figure 1). In MCI‐DLB, 53% progressed to DLB after 3±2 years. Posterior cortical atrophy(HR=3.0[1.5–5.8]) and lower attention(HR=1.6[1.1–2.3]) predicted shorter time to DLB(Figure 2). In MCI‐AD, 69% progressed to dementia after 3±2 years and lower executive functions(HR=1.3[1.0–1.6]) and memory(HR=1.1[1.0–1.2]) predicted faster progression to AD.

Conclusion

MCI‐LB patients had more non‐cognitive symptoms, a distinct cognitive profile with prominent attentional decline and higher caregiver burden, compared to MCI‐AD. Attention impairment and posterior atrophy are potential risk factors for progression towards DLB. Our results underline the need for early diagnosis, since several of these symptoms already have impact in this disease stage and could be treated.
Validation and calibration of machine‐learning predictive models aimed to identify dementia‐related neuropsychiatric symptoms on real‐world data (RWD)
Authors: Mar Javier , Gorostiza Ania , Ibarrondo Oliver , Cernuda Carlos , Alberdi Ane , Iruin Álvaro , Tainta Mikel
Published: December 2020

Background

8% of currently under evaluation new drugs for Alzheimer’s disease are intended to treat neuropsychiatric symptoms (NPS). But, the lack of their presence in codded format in clinical records registries determines that their population impact is underestimated. Validation studies are required in order to systematically use real‐world data (RWD) as a source of epidemiological information for dementia. The objective of this study was to build and validate predictive models to identify the presence of both behavioral or psychotic and depressive symptoms in dementia‐diagnosed patients from administrative and clinical databases.

Method

We searched the Electronic Health Recordings (EHR) of 4,003 patients with dementia looking for mood and psychotic symptoms. First, codded diagnoses, drugs prescriptions and other clinical variables were used to identify the dementia cases in the Basque Service corporate database. Second, Random Forests algorithms were applied to build predictive models by using the training sample (N=3,003) to select the best models separately for mood and behavioral symptoms. Third, we measured calibration and discrimination in the remaining testing sample (N= 1000) separately for each model.

Result

Neuropsychiatric Symptoms (NPS) were identified in 58% of the sample. The model predicting psychotic symptoms achieved 80% of AUC when depressive model only achieved 74%. Kappa index and accuracy also showed better discrimination in the psychotic symptoms model. As displayed by the calibration plot, the models made worse predictions when the probability of the cases was lower than 25%. The most relevant variables in the psychotic symptoms model were the highest sedation level achieved followed by the use of quetiapine and risperidone and the number of different antipsychotic treatments. In the depressive symptoms model, the most relevant variable is the number of antidepressant treatments followed by the use of escitalopram, sedation level and age. Calibration was poorer when the probability was low.

Conclusion

Given the good performance, the resulting models can be applied to estimate the prevalence of NPS in population databases (RWD). Our work showed how machine learning tools can be used to predict complex clinical conditions like NPS and possess the capacity to convert RWD into smart data.
Odorant‐induced brain activation as a function of normal aging and Alzheimer’s disease
Authors: Motter Jeffrey N. , Steffener Jason , Tabert Matthias H. , Devanand Davangere P.
Published: December 2020

Background

Olfactory dysfunction consistently occurs in patients with Alzheimer’s disease (AD), beyond the mild and gradual decline in olfactory ability found in normal aging. This dysfunction begins early in the disease course, typically before clinical diagnosis, and progresses with disease severity. While odor identification and detection deficits clearly differentiate AD from controls, there remains uncertainty as to whether these are determined by olfactory threshold. The primary purpose of the current fMRI study was to examine the neural correlates of olfactory processing in healthy young and old adults and compare them with AD patients.

Method

Health young adults (n=10), healthy old adults (n=10), and AD patients (n=12) participated in psychophysical olfactory testing and an fMRI odorant detection paradigm. We analyzed the interplay between age and disease‐related psychophysical olfactory declines and odorant‐induced brain activation. This tested whether odor threshold deficits reflect disease progression and explain group differences in detection, identification and brain activity.

Result

AD patients had decreased odor detection task‐related signal in all regions of the primary olfactory cortex, with activity in the entorhinal cortex best differentiating the groups. Within the secondary olfactory regions, AD patients showed decreased activity in orbitofrontal cortex compared to healthy age matched individuals. Moderated‐mediation analyses on neuro‐psychophysical relationships found that increased brain activation in the entorhinal cortex moderated the negative effect of disease‐related threshold decline on olfactory detection.

Conclusion

Even in the face of declining olfactory thresholds, older adults compensated for this effect with increased brain activation in a primary olfactory brain region. This was the case for odor detection but not odor identification. fMRI activation induced by an olfactory identification task may eventually be useful in improving early detection of AD and may, eventually, facilitate early treatment interventions in subjects at risk for AD.
Clinical factors associated with progression to dementia in people with late‐life depression: A cohort study of patients in secondary care
Authors: Mueller Christoph , Peakman Georgia , Karunatilake Nishshanka , Seynaeve Mathieu , Perera Gayan , Aarsland Dag , Stewart Robert
Published: December 2020

Background

Depression in later life is increasingly being recognised as a prodrome for the development of dementia. We aimed to investigate which clinical factors are associated with more rapid conversion from depression to dementia.

Method

The South London and Maudsley NHS Foundation Trust (SLaM) Clinical Record Interactive Search (CRIS) was used to retrieve anonymised data on patients who were aged 65 years or older and received a diagnosis of depression in mental health services, followed by a diagnosis of dementia >3 months later. Predictors of accelerated dementia development were investigated including demographic factors, health status rated on the Health of the National Outcome scale for older people (HoNOS65+), depression recurrence, and treatments including psychotropic drugs and cognitive behavioural therapy (CBT).

Result

In 806 patients with late‐life depression who later received a diagnosis of dementia, significant predictors of shorter time to dementia diagnosis in fully adjusted models were older age, male gender, higher deprivation, and HoNOS65+ subscales measuring depressed mood and cognitive problems. A diagnosis of recurrent depressive disorder was independently associated with a longer time to dementia diagnosis. Antipsychotic drugs and CBT were significantly associated with longer times to dementia diagnosis when adjusted for demographic factors and severity of mood and cognitive difficulties, but not in fully adjusted models.

Conclusion

In older adults with depression and subsequent dementia diagnosed by mental health services, faster progression to a diagnosis of dementia was predicted by age and gender, new onset depression, and severity of depressive and cognitive symptoms.