bluuebunny/crossref_metadata_2025 huggingface dataset:
Understanding and improving the experience of care for people with dementia in hospital: Developing the dementia care pointers for service change
Authors: Thompson‐Coon Jo , Abbott Rebecca A , Lourida Ilianna , Gwernan‐Jones Ruth , Rogers Morwenna , Cheeseman Debbie , Moore Darren , Green Colin , Ball Sue , Clare Linda , Llewellyn David J , Hemsley Anthony , Burton Julia , Lawrence Sue , Rogers Martyn , Hussey Chrissy , Coxon George , Naldrett Tina
Published: December 2020

Background

Being in hospital can be particularly confusing and challenging not only for people living with dementia, but also for their carers and the staff that care for them.

Method

We undertook three systematic reviews of quantitative and qualitative evidence according to best practice guidelines. The reviews explored: 1) experience of care in hospital; 2) experience of interventions to improve care in hospital; and 3) effectiveness and cost ‐effectiveness of interventions to improve the experience of care in hospital for people living with dementia, their carers and staff. Links between the findings from the three reviews were explicitly identified through the creation of a conceptual map. The overarching messages and their implications were discussed with key stakeholders. An advisory group of dementia specialists, hospital staff, commissioners and family carers advised us throughout the project. PROSPERO registration CRD42018086013

Result

Our reviews show that the experience of care in hospital for people living with dementia is a dynamic process, being impacted by a complex range of personal, institutional and environmental factors. Despite the intent to deliver person centred care, and armed with the knowledge of how important this is, person centred care is still not happening consistently within hospitals. The effect of this is not only a poorer experience of care for people living with dementia and their carers, but also has a detrimental effect on staff emotional well‐being as a result of not being able to give the care they strive to provide. We highlight 12 institutional and environment practices and processes (Pointers for Service Change) that warrant consideration for those aiming to improve the experience of care in hospital for people living with dementia, their carers and staff.

Conclusion

Evidence suggests that although people living with dementia can have a good experience of care in hospital, this is still not happening for many. When staff cannot provide the care they would like to give, this has a negative effect on people living with dementia, their carers and the staff themselves. Further research needs to identify how best to change ward cultures, and how to maintain these changes in the long‐term.
Synaptic vesicle protein SV2A imaging with [11C]UCB‐J as a novel biomarker of neurodegeneration in Alzheimer's disease
Authors: Bendlin Barbara B , DiFilippo Alexandra H , Betthauser Tobey J , Chin Nathaniel A , Murali Dhanabalan , Vogt Nicholas M , McKinney Grace , Davenport Nancy J , Barnhart Todd E , Engle Jonathan W , Johnson Sterling C , Christian Bradley T
Published: December 2020

Background

Synaptic loss is a known feature of symptomatic Alzheimer’s disease (AD). Conversely, abundance of synapses may confer resilience to cognitive decline in the presence of AD pathology. Currently, the extent and distribution of synapse loss during the asymptomatic stages of AD is unknown. Synaptic vesicle glycoprotein 2A (SV2A) is found on synaptic vesicles and recent developments in PET imaging provide the capability of assessing SV2A in vivo. [C‐11]UCB‐J is a high‐affinity ligand for SV2A currently being tested as a biomarker of neurodegeneration in AD. In this project, we are testing the extent to which loss of synaptic density tracks with cognitive decline, as well as determining the temporal course of synaptic loss in relation to development of regional amyloid and tau pathology, particularly in the asymptomatic phase of AD.

Method

Approximately 120 participants from the Wisconsin Alzheimer’s Disease Research Center (ADRC) and Wisconsin Registry for Alzheimer’s Prevention study will be imaged in this study. Participants include cognitively unimpaired biomarker negative, unimpaired biomarker positive, mild cognitive impairment (MCI), and dementia due to AD. Amyloid (A) and tau (T) status are determined via [C‐11]PiB and [F‐18]MK6240 PET imaging, while synaptic density is determined with [C‐11]UCB‐J.

Result

Early results indicate lower synapse density in AD dementia and among A+T+ even in the asymptomatic phase of AD (Figure). However, participants with dementia show greater regional loss of synapses compared to cognitively unimpaired A+T+.

Conclusion

Ongoing analyses will test the extent to which severity of amyloid and tau accumulation are associated with synapse loss, and whether synaptic abundance is a correlate of preserved cognition in the context of lesion burden. Imaging with [C‐11]UCB‐J may provide improved prognostic precision in the context of AD.
[11C]MPC‐6827, a microtubule‐based PET imaging tracer: A potential early imaging biomarker for AD and other ADRDs
Authors: Sai Kiran Solingapuram , Damuka Naresh , Mintz Akiva , Whitlow Christopher T. , Craft Suzanne , Macauley‐Rambach Shannon
Published: December 2020

Background

Loss of microtubule (MT) network and impairment of MT function are considered to be part of the pathophysiology of several CNS disorders, including AD, Parkinson disease and other ADRS and tauopathies. A BBB penetrating MT‐based PET ligand would permit imaging a variety of CNS disorders. Our lab reported the first brain‐penetrant PET radiotracer [11C]MPC‐6827 to image MTs in vivo, in both wild and transgenic AD mice. Here, we report a pilot longitudinal [11C]MPC‐6827 PET imaging study with early, middle and late stages of Aβ and tau progression in APP/PS1 and P301S mice respectively. PET imaging in NHP brains was performed to test translational utility.

Method

Dynamic brain microPET/CT imaging was performed with [11C]MPC‐6827 in APP/PS1 mice at 3, 18 and 22 months and in P301S mice (n=4) at 5, and 10 months. Regions of interest (ROIs) were drawn in whole brain, cortex, cerebellum and hippocampus and time‐activity curves (TACs) were determined. Basic distribution volume ratios (DVRs) between high‐ and low‐uptake regions were calculated. Dynamic 2h PET/CT imaging was performed in adult male vervet monkeys (n=8).

Result

Based on ROIs and TACs in whole brain, cortex and hippocampus, the radioactive uptake of 3 month‐old TG APP/PS1 mice was ∼30% higher compared to the uptake at 18 months, which in turn was ∼18% higher over 22 month‐old mice. Radioactive uptake of TG P301S mice at 5 months was ∼24% higher compared to 10‐month old mice. DVRs from cortex and hippocampus to cerebellum were ∼2‐fold higher in younger APP‐PS1 and P301S mice compared to their older littermates. Radioactive changes in all experiments were statistically significant, substantiating our preliminary imaging data. NHP‐PET brain analyses indicated brain penetration and high retention of the tracer.

Conclusion

[11C]MPC‐6827 demonstrated decreased radioactive uptake with increased brain Aβ and tau loads. A MT‐based PET imaging tracer could be a potential early imaging biomarker for AD and other ADRDs. PET imaging studies in monkey brains showed high BBB penetration. Binding distribution is in good agreement with the known MT‐mice distribution. Next steps are to correlate radioactive uptake with tau pathologies and in an NHP model of AD.
Head direction cells in the TgF344‐AD rat model of Alzheimer's disease
Authors: Berkowitz Laura E. , Harvey Ryan E. , Clark Benjamin J.
Published: December 2020

Background

Spatial navigation is impaired in the early stages of Alzheimer’s disease (AD) and may be a defining behavioral marker of preclinical AD. Head direction (HD) cells are cortical‐limbic neurons that discharge action potentials as a function of an animal’s spatial orientation in an environment. HD cells can maintain their orientation across repeated test sessions, in reference to salient landmarks, and are thought to play a critical role in guiding accurate spatial behavior. Thus, we tested the hypothesis that impairments in HD cell stability would be apparent in AD.

Methods

To test this hypothesis, we used the TgF344‐AD rat model of AD which exhibits progressive pathology in cortical‐limbic regions. Previously, we found that 10 month old TgF344‐AD rats make progressively fewer spatially and directionally precise movements during navigation. Thus, HD cells were characterized in the posterior cortex (retrosplenial, postsubiculum, and visual association area 2) and the anterior thalamus of 10 ‐ 13 month TgF344‐AD rats and age matched F344 controls. Rats performed a pellet chasing task within a cylinder fitted with a white cue card during recordings. In some sessions, the cue card was rotated to assess landmark control.

Results

HD cells were identified and were found to exhibit similar directional firing characteristics between TgF344‐AD and F344 groups. Further, we found that HD cells in TgF344‐AD rats demonstrated intact responses to cue manipulations. In contrast, we observed that HD cells exhibited more variability and instability in their directional orientation across repeated test sessions.

Conclusions

These results support the hypothesis that deficits in the stability of HD cells may underlie spatial impairments in AD.
Measurement of CSF α‐synuclein improves early differential diagnosis of mild cognitive impairment due to Alzheimer’s disease
Authors: Monge‐Argilés José Antonio , García‐Ayllón María‐Salud , García Victoria Monge , Rueda Francisco Navarrete , Robles Jorge Manzanares , Gasparini‐Berenguer Ruth , Leiva‐Santana Carlos , Sáez‐Valero Javier
Published: December 2020

Background

Previous studies have indicated the potential of cerebrospinal fluid (CSF) α‐synuclein (α‐syn) to be an additional biomarker for improving differential diagnosis of Alzheimer’s disease (AD). We evaluated α‐syn diagnostic performance across a well‐characterized patient cohort with long‐term follow‐up.

Method

CSF α‐syn levels were determined in 25 subjects diagnosed with stable mild cognitive impairment (stable MCI; n= 25), 27 MCI cases due to AD (MCI‐AD; n= 32), 24 MCI cases due to Lewy body disease (MCI‐LBD; n= 24) and control subjects (Ctrl; n= 18). Levels of central core AD‐CSF biomarkers Aβ1‐42, T‐tau and P‐tau 181 were measured using enzyme‐linked immunosorbant assay (Innotest, Innogenetics/Fujirebio). Determination of α‐syn levels in CSF were performed using the LEGEND MAXTM human α‐synuclein ELISA kit (BioLegend).

Result

CSF α‐syn levels discriminate between the four groups. There were higher α‐syn levels in MCI‐AD patients and lower levels in MCI‐LBD patients. The combination of P‐tau and α‐syn resulted in a specificity of 99% and a sensitivity of 97% for AD. MCI‐AD patients with early psychotic symptoms (n= 9) displayed a trend towards a decrease in P‐tau and α‐syn compared to the MCI‐AD patients without psychotic symptoms (n= 23).

Conclusion

Adding CSF α‐syn to central core AD biomarkers improves an early differential diagnosis of MCI‐AD from other forms of MCI.
Biomarker‐based definition of limbic‐predominant long‐lasting amnestic mild cognitive impairment
Authors: Tondo Giacomo , Carli Giulia , Santangelo Roberto , Mattoli Maria V , Presotto Luca , Filippi Massimo , Magnani Giuseppe , Iannaccone Sandro , Cerami Chiara , Perani Daniela
Published: December 2020

Background

Previous studies described amnestic Mild Cognitive Impairment (aMCI) subjects with slow rate of cognitive decline, benign disease course associated to FDG‐PET brain hypometabolism in the medial temporal lobe structures. Clinical and post‐mortem studies suggested the presence of both Alzheimer’s disease (AD) and non‐AD pathology. The identification of aMCI with a benign course has relevant consequences both for prognosis and treatment. The aim of this study was to define the role of in vivo biomarkers to predict prognosis in a large population of aMCI with long‐lasting disease course.

Method

We selected 80 aMCI (Cohort1) using the following criteria: observational time of disease duration ≥4 years; available baseline and follow‐up clinical and neuropsychological evaluations; baseline CSF analysis measuring amyloid‐β42, total‐tau and phosphorylated‐tau; FDG‐PET assessed for individual brain hypometabolism by a validated SPM procedure on a voxel‐by‐voxel basis, showing a selective medial temporal involvement, thus a non‐AD brain pattern. In addition, we selected 42 aMCI due to AD with similar baseline clinical features and biomarker measurements, and both CSF positive for amyloidopathy and FDG‐PET showing the typical AD temporo‐parietal brain hypometabolism (Cohort2).

Result

Cohort1 had mean disease duration of 8.45±3.37 years, range 4‐19 years, no decline in MMSE in most subjects, only 7% conversion to AD dementia at the clinical follow‐up. In Cohort2, 81% of aMCI converted to AD. The FDG‐PET single subject analysis predicted progression in Cohort2, or stability in Cohort1 with high accuracy (AUC=0.88), sensitivity (0.85) and specificity (0.90). Within Cohort1, the CSF biomarkers showed great variability; none of the CSF biomarkers was able to predict stability or conversion. According to the AT(N) classification, in Cohort1, 54% of subjects showed an AD profile and 46% a non‐AD profile. These two groups did not show any difference in cognitive and neuropsychological features at follow‐up, showing comparable stability.

Conclusion

The specific brain hypometabolism pattern in Cohort1 is associated with clinical stability and slow rate of memory deficit progression. Nor CSF biomarkers, neither the AT(N) classification, can predict prognosis in this population. These findings underline the key role of FDG‐PET brain metabolism as a fundamental biomarker in the diagnostic and prognostic challenge of aMCI.
Digital Trail Making Test‐Black and White: For android and iOS
Authors: Simfukwe Chanda , Baek Min Jae , Kim SangYun , An Seong Soo
Published: December 2020

Background

The pen‐paper version Trail Making Test‐Black and White (TMT‐B&W) method was developed previously, the collection of pen‐paper based results and its analyses may increase time‐consumption and create workloads for administrators/subjects while performing the trial test and afterward. To increase the efficiency of the data, collections, and analyses, the touch‐screen based digital Trail Making Test‐Black and White (dTMT‐B&W) based on Android tablets/iPad was developed to enhance the pen‐paper based TMT‐B&W.

Method

The dTMT‐B&W was developed using a Massachusetts Institute of Technology (MIT) and Thunkable X application inventor software, a visual online programming environment with the Android/iOS development tools, which are used to build fully functional apps for Android/iOS smartphones and tablets. The dTMT‐B&W is designed with self‐administration and additional features that help in easy data collection and analysis within much less time. The dTMT‐B&W was designed to run on a 10.5 inch Samsung Galaxy Tab A and 12.9 inches iPad Pro touchscreen tablets. The dTMT‐B&W, designed to be consistent with the pen‐paper based TMT‐B&W as possible, uses black and white circles with numbers arranged in sequential order consisting of two parts: Part‐A and Part‐B, where the subject is instructed to push buttons in black and white circles to connect them as quickly as possible while maintaining the accuracy and time. Paper‐based TMT‐B&W, a subject has to connect randomly distributed black & white circles with numbers distributed on a sheet of paper in ascending order in two parts as quickly as possible without lifting the pen or pencil from the paper sheet.

Result

The dTMT‐B&W was successfully developed as an Android/iOS application with some well‐improved features that were embedded into the design to look as similar to the original pen‐paper TMT‐B&W test as possible in order to establish equal convergent validity.

Conclusion

The dTMT‐B&W can measure the same aspects of cognition as the pen‐paper based TMT‐B&W more easily. Furthermore, dTMT‐B&W’s additional features and data may be able to help administer other cognitive methods not obtained by the pen‐paper TMT‐B&W.
Whole exome sequencing analysis identifies genes and pathways in sporadic early‐onset Alzheimer’s disease
Authors: Bagaria Jaya , An Seong Soo , Nho Kwangsik , Bagyinszky Eva , Kim SangYun
Published: December 2020

Background

Sporadic early‐onset Alzheimer’s disease (EOAD) patients (onset age < 65 years) do not harbor a known causative variant and have a heritability estimated to be 92‐100% (Barber et al. 2016). Here we performed whole exome sequencing (WES) to identify functional exonic variants in sporadic EOAD.

Method

DNA was extracted and sequenced from blood samples of 109 Korean patients with EOAD or Mild Cognitive Impairment (MCI) younger than 65 years of age. Short‐read sequences from WES were mapped to the NCBI reference human genome (build 37) using BWA and GATK. All the variants were annotated with ANNOVAR. PolyPhen‐2 and SIFT were used to predict potential impact on protein structure or function of missense variants. After quality control procedures for samples and variants, we performed a case‐control association using PLINK on 109 Korean patients and 405 East Asia population from the 1000 Genomes Project.

Result

The genetic association analysis in a case‐control study design identified several sporadic EOAD susceptibility genes with missense variants with minor allele frequency (MAF) greater than 1%. A common exonic variant in LILRB2 had a significant p‐value of 1.036 × 10e ‐11 with MAF 0.11 compared with MAF = 0.395 in East Asian and MAF = 0.160 in cognitively normal Korean population (source: KRGDB genome browser). A common exonic variant in HLA‐DQB2 was also identified with a p‐value of 2.252 × 10e ‐08 with MAF 0.197 compared with MAF = 0.413 in East Asian and MAF = 0.34 in KRGDB. A common exonic variant in LIPC showed a marginal significance with a p‐value of 4.537 × 10e ‐05 with MAF = 0.0688 compared to MAF = 0.208 in East Asian and MAF = 0.12 in KRGDB. Other common exonic variants were found in TNR, ITGAX (p‐values < 5.00xe ‐056. The protein‐protein interaction network analysis using STRING showed that LILRB2 has a direct interaction with ADAM10 and ITGAX, HLA‐DQB2 has a direct interaction with ITGAX that has a direct interaction with ADAM10, and LIPC has interactions with APP, SORL1 and CLU, which are known AD risk genes.

Conclusion

Whole‐exome sequencing analysis identified exonic variants associated with sporadic EOAD. Studying these genes and their pathways might lead us to a better understanding of the genetic architecture of sporadic EOAD.
Four years’ experience in an early‐onset dementia clinic in Barcelona
Authors: Contador José , Tort‐Merino Adrià , Balasa Mircea , Falgàs Neus , Olives Jaume , Castellví Magdalena , Juncà Jordi , Borrego‐Écija Sergi , Bosch Beatriz , Fernández‐Villullas Guadalupe , Ramos‐Campoy Oscar , Antonell Anna , Sanchez‐Valle Raquel , Lladó Albert
Published: December 2020

Background

Early‐onset dementia (EOD; <65 years) raises both diagnostic and social/health care challenges. Services for dementia are often designed for the elderly and might have difficulties supplying EOD needs. Clinical and epidemiological data are needed for care planning.

Method

We aim to describe the demographic and the clinical characteristics of all the new referrals to our EOD clinic during the last 4 years (2016‐2019). Clinical charts were reviewed retrospectively. Both, sporadic and genetic cases were included in the analysis. We evaluate the type of symptoms, type and frequency of ancillary tests requested and final diagnosis.

Results

We evaluated 477 new early‐onset patients [mean age at consultation (MAC) 54.6 years (SD=±9.6), 56% female] during this period. The aim of the first visit was genetic counseling in 17.8% [MAC 48.3(±13.3), 55.3% female] and evaluation of sporadic cases in 82.2% [MAC 56(±8), 56.1% female] [Figures 1 & 2]. Among sporadic cases, memory complains were the main symptom (67.1%), followed by behavioral (13%) and language disturbance (11.2%). Complete neuropsychological evaluation was performed in 61.2%, CSF biomarkers in 30.9%, PET‐FDG in 22.4%, PET‐amyloid in 12.5% and genetic testing in 10.5%. Subjective Cognitive Decline (SCD) was diagnosed in 51.8% of these sporadic cases [MAC 54.2(±8), 63.5% female, Mean MMSE 27(±4)], while an abnormal cognition was found in the 48.2% [MAC 58(±7.5), 48.1% female, Mean MMSE 23(±6)]. Regarding EOD causes, 54% was due to neurodegenerative dementias [MAC 60(±5.5), 47.1% females, MMSE 22(±6)] and 46% to non‐neurodegenerative [MAC 55.5(±8.8), 49.4% female, Mean MMSE 25(±5)]. EOD mean time to diagnosis was 3.1 years (±3.75) with no differences between groups (p=0,207). In neurodegenerative dementias, AD constitutes 51% [MAC 61.6(±4), 51.9% female, Mean MMSE 20(±6)] and Frontotemporal lobular degeneration (FTLD) 34.3% [MAC 58.5(±5.3), 45,7% female, Mean MMSE 24(±5)].

Conclusion

SCD is a frequent diagnosis among new referrals to EOD clinics. AD is the most frequent neurodegenerative EOD, followed by FTLD. Non‐neurodegenerative causes of EOD are frequent and heterogeneous. Long delay until diagnosis suggests that new care policies are needed to identify EOD in early stages.
Operationalization of the ATN classification scheme in preclinical AD: Findings from EPAD V500.0 data release
Authors: Ingala Silvia , de Boer Casper , Masselink Larissa A , Vergari Ilaria , Lorenzini Luigi , Blennow Kaj , Chetelat Gael , Perri Carol Di , Ewers Michael , Fox Nick C. , Gispert Juan Domingo , Molinuevo Jose Luis , Terrera Graciela Muniz , Mutsaerts Henri J.M.M. , Ritchie Craig W. , Schmidt Mark E. , Vermunt Lisa , Waldman Adam , Wink Alle Meije , Wolz Robin , Wottschel Viktor , Scheltens Philip , Visser Pieter Jelle , Barkhof Frederik ,   EPAD Consortium
Published: December 2020

Background

The goal of this study is to assess neuropsychological and radiological characteristics according to the ATN scheme in the EPAD Longitudinal Cohort Study (EPAD‐LCS) after establishing data‐driven cut‐offs for classification.

Method

ATN cut‐off values were determined in a deeply phenotyped cohort of 500 nondemented elderly individuals. Amyloid and p‐tau in the cerebrospinal fluid were quantified with Roche Elecsys assays. Hippocampal volume was calculated using LEAP pipeline. The intersection poin of two‐component Gaussian mixture models was used to establish cut‐off values for CSF amyloid ß42 (A) and p‐tau (T). Age‐adjusted w‐scores were used to establish a cut‐off value for neurodegeneration (N). Only subjects classified as healthy controls (A‐T‐N‐) or in the Alzheimer spectrum (A+T‐N‐, A+T+N, A+T+N+) were included. Multinomial regression was performed to test whether significant differences among the ATN groups could be detected with the EPAD Neuropsychological Examination (ENE) after correcting for age, sex, years of education, and site of data collection.

Result

Out of the initial sample of 500 study participants, n=38 did not fulfil EPAD inclusion criteria, n=34 did not have CSF or MRI biomarkers, and n=49 were not either healthy controls or in the Alzheimer spectrum and were thus excluded. Cut‐offs were 1025 pg/mL for CSF amyloid ß1,42 (A), 24 pg/mL for CSF p‐tau (T), and age‐adjusted hippocampal volume w‐score below ‐2 standard deviations for neurodegeneration (N). Out of the n=376 sample, 229 individuals were classified as healthy controls (A‐T‐N‐), 102 as showing only amyloid pathology (A+T‐N‐), 45 showing amyloid and tau pathologies (A+T+N‐), and 3 A+T+N+ were eliminated [Table 1]. The ENE battery distinguished healthy controls (A‐T‐N‐) from individuals with preclinical AD (A+T+N‐), and individuals with Alzheimer pathological changes (A+T‐N‐) from individuals with preclinical AD (A+T+N‐).

Conclusion

We proposed a data‐driven framework of cut‐offs for classifying preclinical AD patients in the ATN scheme. The ENE battery scores were in line with the expected cognitive decline in the AD spectrum and increasing vascular burden was shown with progression along the AD spectrum. Potential applications include the selection of patients for secondary prevention trials, preclinical disease modelling and monitoring responses to disease‐modifying therapies.
A phase 1B multiple ascending dose study of the safety, tolerability, pharmacokinetics, and pharmacodynamics of a medium chain triglyceride supplement in Alzheimer’s disease
Authors: Nygaard Haakon B , Kent Brianne A , Stager Sam , Slack Penelope , DeMarco Mari L , Castellano Christian‐Alexandre , Rauscher Alexander , Cunnane Stephen , Feldman Howard H
Published: December 2020

Background

Impaired brain glucose metabolism is a prominent and early feature across neurodegenerative disorders, including Alzheimer’s disease (AD). Elevating brain ketones to bypass this metabolic failure is an emerging therapeutic strategy, with promising results in AD and Mild Cognitive Impairment (MCI). The Medium Chain Triglyceride Intervention in AD (MINT‐AD) is a randomized, placebo‐controlled Phase 1b trial investigating the pharmacokinetics and pharmacodynamics of a ketogenic supplement in Alzheimer’s disease (AD). It also explores outcome measures to support the development of larger ketogenic trials for this disorder.

Method

Patients (n=32) with a clinical diagnosis of with mild‐moderate AD (MMSE 16‐26) were randomized at 4:1 to twice daily medium chain triglyceride drink (MCT – 60% C8, 40% C10) prepared as a 12% emulsion in lactose‐free milk, or placebo. A total of four dose groups were recruited, with doses ranging from 5 grams twice daily up to 25 grams twice daily, for a total of 18 days (including 8‐day drug titration). Primary outcome measures were safety, tolerability and pharmacodynamics effects of MCT supplementation on plasma ketones, and the pharmacokinetics of the MCT supplement. Exploratory outcome measures included N‐acetyl aspartate and glutamine/glutamate MR spectroscopy, functional resting brain connectivity, brain blood flow (arterial spin labeling), continuous actigraphy, ambulatory sleep EEG, and cognitive measures.

Result

A total of 30 participants (94%) completed the study, with 2 subjects discontinuing early. MCT supplement up to 25 grams twice daily was safe and well tolerated in patients with mild‐moderate AD. Peak plasma ketones was seen around 4 hours post MCT ingestion. Exploratory cognitive and imaging measures are currently being analyzed and will be presented.

Conclusion

Ketogenic MCT supplementation is safe and well tolerated in AD, with reasonably predictable pharmacokinetic and ketogenic properties. These data exploring a larger dose range should inform dose selection in future trials with MCT supplementation.
Improved brain energetics and cognition after a 6‐month ketogenic intervention in mild cognitive impairment: Final results of the Benefic Trial
Authors: Cunnane Stephen , Fortier Melanie , Castellano Christian‐Alexandre , Pierre Valerie St. , Morin Marie‐Christine , Langlois Francis , Cuenoud Bernard , Delannoy Carla , Bocti Christian , Fulop Tamas
Published: December 2020

Background

Ketones can partially substitute for glucose as a brain fuel and may be beneficial for cognition in older people. The objective of the randomized, placebo‐controlled Benefic Trial (NCT02551419) was to assess whether counteracting the brain energy (glucose) deficit with a ketogenic medium chain triglyceride (kMCT) supplement could improve cognitive performance in mild cognitive impairment (MCI).

Methods

A cognitive battery was used to screen for MCI and cognitive outcomes after the intervention. Cognitive outcomes pre‐ and post‐intervention were obtained for the active arm (15 g kMCT twice/day in a lactose‐free skim milk emulsion; n=39 completers) and placebo arm (non‐ketogenic vegetable oil of equivalent energy value and formulation as for the kMCT; n=44 completers). Brain ketone and glucose PET were done before and at the end of the 6‐month intervention on a sub‐group of both arms (n=19/group).

Results

Several cognitive domains improved post‐intervention in the kMCT group (p≤0.01; ANCOVA; age and education as covariates). Specifically, Trial 1 of the Free and Cued Recall Test showed a +1 word improvement on kMCT (+0.5 Δ Z‐score), correct answers on the Verbal Fluency Test increased by 2 words on kMCT (+0.3 Δ Z‐score) but decreased by 1 word on placebo (‐0.1 Δ Z‐score), correct answers on the Boston Naming Test increased by 1.1 on kMCT only, time taken on the Stroop Colour Naming Test decreased by 1 sec on the kMCT (p=0.09), and errors on the Trail Making Test decreased by 0.9 on kMCT but increased by 0.8 on placebo (p=0.02). Brain ketone uptake increased in the kMCT arm only and directly as the increase in plasma ketones (r = 0.87, p<0.01). Average drop‐out rate on both arms was 31% and, in completers, protocol adherence was 89% over six months.

Conclusions

In MCI, a kMCT supplement had a clinically meaningful effect on some cognitive outcomes directly related to risk of progression toward Alzheimer’s disease, and significantly improved brain energy supply. It is feasible for an MCI population to consume a kMCT supplement daily for six months. Acknowledgements: Financial support was provided by the Alzheimer Association USA, FRQS, Université de Sherbrooke and Nestlé Health Science.
Bridging the gap: Engaging people with lived experience and health care providers on research review panels
Authors: Sivananthan Saskia
Published: December 2020

Background

The Alzheimer Society of Canada’s prevailing theme is “nothing for us, without us”. This value is embedded in all aspects of their work. Since 2015, people with lived experience of dementia have been engaged in the organization’s annual grant competition, sharing their perspectives of grant applications on peer review panels. In 2019, the Alzheimer Society of Canada introduced a relevancy review panel to supplement the peer review process. This interdisciplinary panel included organizational staff with direct contact with people with lived experience as well as citizen reviewers. Collectively, they reviewed and scored research proposals for clarity and relevance to their experience, contributing to recommendations about which proposals should receive funding.

Method

In 2019, the Alzheimer Society of Canada recruited seven people with lived experience of dementia and five staff from across the country to become more deeply engaged in decision‐making for the society’s annual grant‐awarding competition. Participants attended an inaugural training workshop to learn more about the organization’s research program and its funding priorities while helping to co‐develop the training to address further need. The workshop was evaluated and feedback used to inform the planning and delivery of future engagement sessions. Participants were subsequently allocated to either the Peer Review Panel or Relevancy Review Panel. Their involvement on these panels will be evaluated in Spring 2020 and results used to inform future panel participation.

Result

All the participants agreed that the training workshop achieved its objectives. The workshop provided an opportunity for people with lived experience and staff to engage directly with each other while co‐designing the scoring criteria and guidelines of the panel. It also created a new opportunity to meaningfully engage people with lived experience in the research process while balancing the expertise required to assess proposals. Participants’ involvement on the research panels will be evaluated in Spring 2020.

Conclusion

People with lived experience of dementia are important partners in the research process. Their practical involvement in scoring research proposals for importance and relevance will ensure that research more closely meets their needs while developing a new role for their meaningful engagement.
TopMed‐imputed genome‐wide association study of Alzheimer’s disease in more than 100,000 European samples from the EADB project
Authors: Bellenguez Céline ,   EADB
Published: December 2020

Background

Genome‐wide association studies (GWAS), and more recently the next‐generation sequencing strategy, improved greatly our knowledge of the genetics of Alzheimer’s disease (AD), with more than 40 risk genes/loci now identified. As part of the genetic component of AD remains unknown, we conducted a complementary GWAS study with increased sample size and improved imputation quality of low frequency variants thanks to the new TopMed imputation panel.

Method

The GWAS was performed in the European Alzheimer DNA Biobank (EADB) dataset. It combines genome‐wide genotyping data from several studies and from more than 18,000 AD cases and 21,000 controls never included in previous AD discovery GWAS, for a total of more than 35,000 AD cases and 65,000 controls of European ancestry. Imputation was performed with the TopMed reference panel for the majority of the samples or with the Haplotype Reference Consortium panel. Variants with imputation quality below 0.3 were excluded. Logistic regressions were performed in each study with adjustment on principal components and results were combined across studies with a fixed‐effect inverse variance meta‐analysis.

Result

Preliminary association results were available for 27,752,571 variants following quality control, including 8,633,349 common variants (minor allele frequency (MAF) above 1%), and 1,324,211 low frequency variants (MAF range between 0.5% and 1%). We identified 57 loci with at least suggestive evidence (P < 1 × 10−6) of association, including 31 known AD loci. Among the 26 new loci, 10 loci reached genome‐wide significance (P < 5 × 10−8) and 9 loci had a rare lead variant (MAF below 1%).

Conclusion

Preliminary results of the EADB project allowed to identify several new associated loci for AD, including several good candidate genes linked to the APP metabolism. Additional insights on the genetics of AD are expected from ongoing analyses, including gene‐based tests of rare variants, fine‐mapping, functional annotations and pathway analyses.
Novel genetic effects on amyloid and tau protein levels in cerebrospinal fluid
Authors: Jansen Iris E. , Van Der Lee Sven J. , Bellenguez Céline , Grenier‐Boley Benjamin , de Rojas Itziar , Zettergren Anna , Kleineidam Luca ,   EADB
Published: December 2020

Background

Assuming measurable biological properties to be more strongly related to the underlying Alzheimer’s disease (AD) pathogenesis than the diagnostic classification, we studied the genetics of AD‐relevant protein levels in cerebrospinal fluid (CSF). Initiated by the European Alzheimer’s disease DNA biobank (EADB), we established the largest collaborative effort on CSF amyloid beta and tau, and aimed to improve the current understanding on the genetic etiology of AD, including the identification of novel genetic risk factors.

Method

A collection of 10 European dementia cohorts was explored to study the genetic effects on CSF amyloid beta (n = 6529 individuals), tau (n = 6455 individuals) and phosphorylated tau (n = 5865). Most of the genetic data was generated with Illumina Global Screening Array, and imputed with TOPMed reference genome. The protein level data was log transformed and normalized. Per variant linear regressions were performed within cohorts using PLINK v2.0, followed by meta‐analysis. We corrected for population structure (principal components), gender, age and biomarker assay type (if applicable within a cohort).

Results

Besides APOE (p = 3.16 × 10−251), no other loci reached genome‐wide significance for amyloid beta protein levels. For tau protein levels, we discovered 5 loci, including the known AD loci APOE (p = 1.61 × 10−61) and HLA‐DRB1 (p = 4.67 × 10−8). We additionally confirm the GMNC locus (p = 1.23 × 10−12) that previously was associated with CSF tau by an independent consortium. Two novel loci are seen on chromosome 9 (p = 5.76 × 10−8) and chromosome 16 (p = 3.67 × 10−8). These tau findings are strengthened by the identification of these same 5 loci for phosphorylated tau which has been measured by a different protein level assay. Both novel loci have shown associations with brain ventricular volume in previous large‐scale studies performed by other consortia, such as CHARGE and ADNI.

Conclusion

The novel loci identified for CSF tau protein levels suggest an overlap in genetic etiology for tau and brain ventricular volume, thereby strengthening the theory that neurodegeneration and tau pathology are highly correlated in dementia patients.
Data‐driven biomarker approaches to disentangle mixed pathologies in AD
Authors: Tosun Duygu
Published: December 2020

Background

Biomarker data related to AD are being collected at an ultra‐scale and are likely to unlock numerous opportunities for AD treatment. While most persons with AD dementia are confirmed to have a pathologic diagnosis of AD, additional vascular and non‐AD degenerative pathologies (e.g., Lewy bodies, TDP‐43, and hippocampal sclerosis) are found in most cases. Each of these pathologies has been previously shown to lower the threshold for cognitive impairment. Due to lack of good biomarkers for non‐AD degenerative pathologies, and overlapping cognitive phenotypes, there are few guidelines for diagnosis of multiple versus single etiology dementias.

Method

We used innovative harmonized structural MR image processing and artificial intelligence (AI) methods to model and subtype the vast and complex imaging data in relation to comorbid pathologies. We cost‐efficiently harnessed the available wealth of autopsy validated neuropathological confirmations from landmark neuroimaging studies (e.g., ADNI, NACC, ROS, MAP) and combine with efficient, scalable, and publicly available tools, powered by ‘cognitive systems’ including AI. Since prevalence of each pathology is not mutually exclusive of existence of other pathologies, we developed multi‐class deep learning models for simultaneous prediction of presence of these pathologies.

Result

When combined with age, sex, MMSE, and Apoe 4 information, within clinically normal participants (independent validation), structural‐MRI based prediction accuracy was 86%/87%/93% for AD degenerative pathologies of amyloid, tau, and neurodegeneration, respectively, with expected 4%‐6% increase in performance in MCI and AD validation cohorts. Within the clinically diverse autopsy cohort, structural‐MRI was predictive of non‐AD pathological confirmations of comorbid TDP‐43 with an AUC of 0.83‐0.85 and comorbid neocortical diffused Lewy bodies with an AUC of 0.76‐0.79.

Conclusion

There is an urgent need for biomarkers to identify patient’s neuropathology profile in vivo to inform public health planning, clinical trial enrichment, and development of effective early interventions. Our recent work aims to associate comorbid pathological confirmations across various autopsy studies with in vivo brain metrics, genomics, and plasma biomarkers for deeper understanding of pathologic basis of heterogenous trajectories of cognitive decline in aging. Focusing on routinely collected structural MRI data maximizes translational impact both in clinical practice as well as in clinical trials on AD.
Pattern of degeneration of sleep‐wake nuclei correlates with objective sleep measurements in progressive supranuclear palsy: A quantitative clinicopathological study
Authors: Oh Jun Yeop , Walsh Christine M. , Mladinov Mihovil , Petersen Catherine , Ruoff Leslie , Robbins Claire M. , Eser Rana A. , Li Song , Lew Caroline , Varbel Jonathan , Heuer Hilary W. , Boxer Adam L. , Seeley William W. , Miller Bruce L. , Neylan Thomas , Grinberg Lea Tenenholz
Published: December 2020

Background

Individuals with progressive supranuclear palsy (PSP), a form of 4‐repeat tauopathy, show an extreme sleep phenotype featuring a short sleep duration. This is likely due to tau‐associated lesions in the subcortical sleep‐wake network. Nevertheless, it is unknown how the pathological lesions in the brainstem and hypothalamus relate to sleep phenotypes in PSP because detailed clinicopathological studies focusing on sleep are lacking. To elucidate this mechanism, here we correlate objective sleep‐wake measurements with quantitative pathological findings in the key sleep‐wake network in PSP for the first time.

Method

Participants with a diagnosis of probable PSP based on the Litvan criteria were recruited at the Memory and Aging Center, UCSF from 2013 to 2019. Twenty participants (68% male; mean age: 70.95 ± 5.3) were asked to complete overnight polysomnography (PSG) and multiple sleep latency tests (MSLT) the subsequent day. Measures of interest on the PSG and MSLT are indicated in Figure 1. Of these individuals, 13 have undergone an autopsy, neurotransmitter and tau immunohistochemistry staining, and neuronal quantification using unbiased stereology in the following nuclei: noradrenergic Locus Coeruleus (LC), orexinergic lateral hypothalamic area (LHA), and histaminergic tuberomammillary nuclei (TMN).

Result

Sleep parameters and pathological parameters (nuclei neuronal number, neurotransmitter expression, and tau burden), show significant and variable correlations (Figure 1).

Conclusion

Neuronal loss and tau burden in the key neuromodulatory systems may explain clinical sleep signatures in PSP. For instance, shorter MSLT correlated with fewer histaminergic neurons which suggest that impaired histaminergic wake‐promoting system may lead to a higher tendency to fall asleep. Altogether, our preliminary data highlights the importance of clinicopathological study combining objective sleep measurements with unbiased postmortem evaluation in clarifying the contribution of subcortical tau pathology to sleep‐wake disturbances in tauopathies.
Differential dynamics of Aβ and tau oligomer synaptic binding may suggest diverse therapeutic targets for early vs. late Alzheimer's disease
Authors: Marcatti Michela , Krishnan Balaji , Kayed Rakez , Taglialatela Giulio
Published: December 2020

Background

At the basis of the Alzheimer’s Disease (AD) cognitive decline there is the targeting of synapses by small Ab and tau oligomers, which results in synaptic dysfunction and later disruption that underscore disease progression. Recent failures of Aβ‐directed therapeutics in multi‐center clinical trials suggest that Ab may not be playing a critical role in later disease stages, when clinical features of AD become manifest; rather, tau, which occurs later in the AD brain, may be the primary synaptotoxic element at that advanced stage. While attention is being currently given to the development of tau‐directed therapies for clinical AD, the mechanisms by which tau becomes the prevalent driver of synaptic dysfunction at later disease stages is still unknown.

Method

Synaptosomes were isolated from the human and mouse cortex and hippocampus and Aβ and tau binding evaluated ex vivo using a flow‐cytometry based approach employing fluorescence‐labeled preformed oligomers. Western blots were used to confirm flow‐cytometry results and electrophysiology measurements of hippocampal long‐term potentiation (LTP) used to evaluate functional outcome of oligomer synaptic impact.

Result

Here we show that the binding of tau to both human and mouse hippocampus and cortex synaptosomes competes Aβ oligomers off the synapses, thus becoming the most prevalent and toxic oligomeric form. On the other hand, Aβ oligomers are not able to compete off tau oligomers thus suggesting that the mechanism is tau specific. Surprisingly, the presence of Aβ oligomers promotes tau synaptic binding and levels of tau that would normally fail to negatively affect LTP becomes effective in the presence of Aβ oligomers.

Conclusion

These results suggest a previously unappreciated mechanism whereby as the levels of Aβ oligomers increase and tau oligomers appear during disease progression, tau oligomers becomes the prevalent toxic species at synapses. This mechanism is consistent with failure of Aβ‐targeting therapies in late AD and further support the credence of tau oligomers as the main culprit in clinically‐manifest AD. Supported by NIH/NIA grant R01AG060718
Brainstem tau protein burden is associated with cortical hyper‐excitability in healthy aging
Authors: Van Egroo Maxime
Published: December 2020

Background

Alzheimer’s disease (AD) neuropathology spreads over decades prior to cognitive symptom onset. Its first signs consist in misfolded tau protein accumulation in the brainstem, particularly in the locus coeruleus (LC). Neuronal hyper‐excitability also occurs early in the pathogenesis of AD and contributes to neuronal network dysfunction. Here, we tested whether early cortical hyper‐excitability may be related to tau aggregates in the brainstem.

Method

We probed cortical excitability over the frontal cortex using transcranial magnetic stimulation combined with electroencephalography in a sample of late middle‐aged healthy individuals (n = 65; 50‐70 years). We assessed whole‐brain tau protein burden with [18F]THK5351 positron emission tomography and we extracted radiotracer uptake values in a brainstem monoaminergic compartment including notably the LC. Diffusion‐weighted magnetic resonance imaging data were also acquired to explore cortico‐LC white matter pathways.

Result

We found that higher tau burden in the brainstem monoaminergic grey matter was specifically associated with increased cortical excitability. By contrast, tau deposits in the hippocampus and entorhinal cortex, although correlating with brainstem tau signal, were not associated with cortical excitability. Tractography analysis revealed that frontal cortical excitability was linked to the integrity of the tracts connecting the frontal cortex and a dorsal pontine tegmentum area encompassing the LC.

Conclusion

These findings reveal potential brain substrates for increased cortical excitability in preclinical and early AD, and they constitute the first human functional correlates of in vivo early tau protein accumulation in the brainstem.
Significant reduction of Alzheimer’s disease symptoms by transcranial pulse stimulation, TPS
Authors: Novak Pavel
Published: December 2020

Background

Low intensity shock waves proofed to be efficient for the treatment of non‐unions, tendon and muscular pain, wound healing, heart insufficiency, erectile dysfunction, aesthetic and finally neurological indications. The working principle is the mechanical stimulation of biological processes called mechanotransduction resulting in increased cell metabolism, release of nitric oxide (eNO) and numerous growth factors. There is also an anti‐inflammatory effect, stimulation of stem cells and the innate immune system. Alzheimer’s disease or dementia in general is multi modal disease resulting from different causes like deposition of dedicated proteins (tau, beta‐amyloid), inflammation, reduced blood supply and others.

Method

Transcranial Pulse Stimulation (shockwave pulses) was applied to patients suffering from minor Alzheimer’s disease in two centers. 35 patients were treated in this multicenter clinical pilot study. The treatment consisted of 6 sessions in 2 weeks, with 6000 pulses per session, energy flux density of 0.2 mJ/mm2 at 5Hz. It was performed with an unshaved head through the hair. The treatment is painless and very well tolerated by the patients.

Result

The patients showed a significant improvement of the Alzheimer’s disease symptoms of over 10% measured with CERAD Plus battery of tests. The improvement was maintained until 3 months follow‐up. No side effects have been observed.

Conclusion

In spite of the unique positive results, further clinical evaluations are needed. Placebo controlled, randomized trials are ongoing. The device (Neurolith) has meanwhile the CE mark clearance in Europe and there are regulatory activities in further regions. References: [1] Beisteiner R, Matt E, Fan C, Baldysiak H, Schönfeld M, Philippi Novak T, Amini A, Aslan T, Reinecke R, Lehrne J, Weber A, Reime U, Goldenstedt C, Marlinghaus E, Hallett M, Lohse‐Busch H. Transcranial Pulse Stimulation with Ultrasound in Alzheimer’s disease – A new navigated focal brain therapy. Advanced Science 2019. [2] Lohse‐Busch H. Reime U, Falland R. Symptomatic treatment of unresponsive wakefulness syndrome with transcranially focused extracorporeal shock waves. Neuro Rehabilitation 35(2014) 235‐244.