bluuebunny/crossref_metadata_2025 huggingface dataset:
Multimodal imaging correlates of the protective APOE2 allele
Authors: Groot Colin
Published: December 2020

Background

The protective effect of APOEε2 against Alzheimer’s disease (AD) is relatively well‐established, but the mechanisms conferring this effect are incompletely known.

Method

Studies have tried to assess these mechanisms through studying the physiological functions of the APOE protein, the most promising being clearance and degradation of amyloid.

Results

It has been consistently observed in post‐mortem studies that APOEε2‐carriers have decreased amyloid‐pathology and a large meta‐analytic investigation assessing amyloid‐status on PET or CSF across APOE genotypes also revealed that amyloid‐positivity, and age‐related increases in amyloid‐positivity, were lowest in APOEε2‐carriers. Some post‐mortem studies have also reported a protective effect of APOEε2 on tau pathology, but these results could not be replicated in all examinations. Recently, efforts have been undertaken to assess the effect of APOEε2 on amyloid and tau pathology using in‐vivo PET imaging. These studies indicate that APOEε2‐carriers have decreased cortical amyloid load while no effects were observed on cortical tau, nor on hypometabolism (FGD‐PET) or hippocampal and entorhinal gray matter (MRI). This suggests that the protective effect of APOEε2 might be selective for amyloid. However, amyloid‐independent effects on cognitive decline have been reported and it is postulated that the APOEε2 allele increases synaptic density and protects against neuroinflammation. More in‐vivo imaging studies are needed to elucidate these amyloid‐independent protective effects of APOEε2, and with recent developments in novel imaging methodologies this might soon be possible. For instance, UCB‐J PET imaging might be implemented to assess synaptic density in APOEε2‐carriers, and TSPO‐PET might be used to detect neuroinflammatory markers.

Conclusion

Studying the protective mechanisms of APOEε2 using neuroimaging studies are essential as they might inform future disease‐modifying treatments, such as using gene‐editing techniques to convert APOEε4 to APOEε2, and delivering APOEε2 into APOEε4 carriers through the use of adeno‐associated viruses. Paradoxically, it has been shown that APOEε2, while protective against AD, has a detrimental effect on markers of cerebrovascular disease and subjects who do develop AD despite being an APOEε2‐carrier display a distinct phenotype with increased small vessel disease and non‐amnestic cognitive impairments. These factors need to be considered in any future neuroimaging examinations into the protective effects of APOEε2.
Out of the shadows: Addressing resident‐to‐resident aggression in long‐term care
Authors: Malvern Riley
Published: December 2020

Background

Resident‐to‐resident aggression is a behaviour concern in long‐term care (LTC). Incidents of resident‐to‐resident aggression can have serious consequences and may result in poorer quality of life for residents, increased staff turnover, harmful psychological and physical effects, or death. Many people shy away from talking about resident‐to‐resident aggression because it can be a sensitive topic. This silence can result in missed opportunities to reduce the risk. Discussing it openly is an important step in working towards solutions.

Method

Recognizing resident‐to‐resident aggression as an urgent public health issue, the Alzheimer Society of Canada (ASC) has embarked on a multiyear project to understand the underlying needs that can trigger this behaviour, and what LTC staff need to address it. The outcome for the first phase of this project was the creation of an information booklet for LTC staff. To create the booklet an environmental scan was conducted that examined existing literature and tools on resident‐to‐resident aggression, subject‐matter experts were consulted, and focus groups were conducted with staff and families at a Canadian LTC home.

Result

The information booklet that has been developed addresses three main topic areas. First, it provides an overview of the issue of resident‐to‐resident aggression and outlines the potentially harmful consequences this can have on residents, families, staff and management if not dealt with appropriately and openly. Second, it outlines the importance of talking openly about resident‐to‐resident aggression as a first step in addressing this issue. Finally, the resource provides practical, person‐centred strategies for reducing incidents of resident‐to‐resident aggression; including structural and environmental approaches. In particular, it includes practical tips and strategies for how to respond to incidents when they do occur and how to reduce the risk of them happening again in the future.

Conclusion

Educating LTC staff about resident‐to‐resident aggression can support them to think creatively and apply effective strategies to reduce the number of incidents. Doing so can improve quality of life for residents, staff, management and families. ASC’s next steps will involve creating practical tools for staff to help them address the issue of resident‐to‐resident aggression in their own LTC home.
Interactions between insulin, the blood‐brain barrier, and beta‐amyloid in Alzheimer's disease
Authors: Leclerc Manon , Bourassa Philippe , Vandal Milene , Caron Vicky , Virgili Jessica , Tremblay Cyntia , Emond Vincent , Bennett David A. , Calon Frederic
Published: December 2020

Background

Defects in central response to insulin is suspected to play a role in AD. However, to act on the brain, pancreas‐secreted insulin must interact first with the blood‐brain barrier (BBB). The aim of the present study was to better understand mechanisms underlying transport and cell‐signaling of insulin at the BBB, and how they are altered in AD.

Method

We used microvessel‐enriched brain samples from individual classified as Controls, MCI or AD and from 3xTg‐AD mice from different ages, exposed or not to a high fat diet. In situ cerebral perfusion was used to quantify the transport of [125I] insulin across the BBB.

Results

We first show that insulin receptors (INSR) in human and mouse brains are concentrated in blood microvessels. We observed lower concentrations of INSRα in microvessel extracts from the parietal cortex of AD patients, associated with cognitive symptoms. We also observed a shift toward a higher INSRα‐A: INSRα‐B ratio in AD, which is consistent with insulin resistance. We next looked at insulin‐activated cell‐signaling pathways within microvessels and found that activation was reduced in 3xTg‐AD mice, following a high‐fat diet. Although it is assumed that insulin crosses the BBB, we found that its transport rate remained very low and was not antagonized by INSR blockers. Finally, we provide some insights on the regulation of brain beta‐amyloid levels following the activation of BBB INSR.

Conclusion

Overall, our data support the hypothesis of brain insulin resistance in AD, but at the level of INSR localized in microvessels. This also suggests that the INSR and its downstream signaling within endothelial cells of the BBB may be a systemically accessible drug target in AD.
Alzheimer’s disease biomarker roadmap 2020: [18F]flortaucipir
Authors: Wolters Emma E. , Chiotis Konstantinos , Dodich Alessandra , Ashton Nicholas J. , Barthel Henryk , Bischof Gerard N. , Boccardi Marina , Carrillo Maria C. , Corre Julie , Démonet Jean‐François , Drzezga Alexander , Gietl Anton F. , Hansson Oskar , Johnson Keith A. , Leuzy Antoine , Lorenzi Marco , Rabinovici Gil D. , Ratib Osman , Sabri Osama , Treyer Valerie , Unschuld Paul G. , Villemagne Victor L.L. , Winblad Bengt , Frisoni Giovanni B. , Garibotto Valentina , Nordberg Agneta K. , Ossenkoppele Rik
Published: December 2020

Background

In the last decade, the research community focused on defining reliable biomarkers for the early detection of the pathological hallmarks of Alzheimer’s Disease (AD). In 2017, the Geneva AD Biomarker Roadmap Initiative adapted the framework for the systematic validation of oncological diagnostic biomarkers to AD, with the aim to accelerate their development and implementation in clinical practice. With this work we assess the maturity of [18F]flortaucipir and we define the research priorities.

Method

In a two‐day workshop (Geneva, November 2019), we convened a panel of experts in AD biomarkers. The level of maturity of [18F]flortaucipir has been assessed based on the Biomarker Roadmap (Frisoni et al., 2017). Biomarker maturity and research priorities were processed by thematic subgroups before the meeting, and presented and discussed during the workshop

Result

[18F]flortaucipir binds with high affinity to paired helical filaments of tau and has favorable kinetic properties. It accurately discriminates between AD and patients with non‐AD neurodegenerative disorders as well as healthy controls. Initial studies showed high correlations between ante mortem and post‐mortem tau pathology. Further research is needed to investigate the effects of covariates on tracer binding and its ability to detect tau pathology in the early phase of AD.

Conclusion

[18F]flortaucipir provide partial evidence for clinical utility. In vivo [18F]flortaucipir PET shows excellent discrimination for AD from controls and non‐AD neurodegenerative disorders and promising results for the validation with autopsy. However, completion of studies on analytical validity is a requirement to investigate clinical utility properly.
Hippocampal subfield microstructure abnormalities mediate associations between tau burden and memory performance
Authors: Nir Talia M , Salminen Lauren , Reina Julio E Villalon , Tubi Meral A , Thomopoulos Sophia I , Maiti Piyush , Braskie Meredith N , Thompson Paul M , Jahanshad Neda
Published: December 2020

Background

Alzheimer’s disease (AD) pathology in the medial temporal lobes, including tau accumulation, is associated with memory impairment. This relationship may be mediated by microstructural changes in hippocampal tissue, particularly in subregions with prominent tau deposition and neuronal loss such as the CA1 and subiculum. Multi‐shell diffusion MRI (dMRI) can be used to fit biophysical models, such as Neurite Orientation Dispersion and Density Imaging (NODDI), which estimate intracellular (ICVF) and CSF (ISOVF) volume fractions in brain microstructure; these measures may offer enhanced specificity and sensitivity to disease processes such as neuronal loss and inflammation. Here, we evaluated the relationships between hippocampal subfield PET tau accumulation (F‐AV1451), NODDI microstructure, and a composite measure of memory performance (ADNI‐Mem) in the ADNI‐3 database.

Methods

Data were available for 70 ADNI‐3 participants (age: 73.6±6.7yrs; 40F; 48 CN, 18 MCI, 4 with dementia). NODDI measures (ICVF, ISOVF) were estimated using a novel multi‐tissue approach (MT‐NODDI); a gray matter specific response function was used to improve estimates in the hippocampus. Hippocampal subfields were parcellated from T1w images using FreeSurfer, and mean dMRI‐NODDI and PET‐AV1451 measures were extracted from 11 individual subfields and 9 composite subregions (Fig 1a). For each ROI, linear regressions tested associations between (1) MT‐NODDIROI and TauROI,(2) ADNI‐Mem and TauROI, and (3) ADNI‐Mem and TauROI while adjusting for MT‐NODDIROI (Fig 1b). We used FDR (q=0.05) to adjust for multiple tests. Mediation analyses were performed for regions showing significant associations in models 1 and 2.

Results

Higher regional tau was associated with lower ADNI‐Mem (Fig 2a). Higher tau depositions were also associated with lower ICVF and higher ISOVF (Fig 2b); MT‐NODDI measures detected significant associations with tau where standard NODDI did not (Fig 3). Excluding subfields comprising the subiculum‐complex, the negative effects of tau on memory scores were mediated by lower ICVF and higher ISOVF (Fig 4).

Conclusions

Tau pathology may lead to memory deficits through a variety of mechanisms, including hippocampal microstructural changes such as neuronal loss or increased inflammatory processes (lower ICVF and increased ISOVF) in subfields downstream from the subiculum‐complex.
AmyQ: An index to accurately measure cerebral amyloid load
Authors: Pegueroles Jordi , Montal Victor , Vilaplana Eduard , Bejanin Alexandre , Santos‐Santos Miguel A , Aranha Mateus Rozalem , Carrió Ignasi , Camacho Valle , Lleó Alberto , Fortea Juan
Published: December 2020

Background

Quantification of amyloid‐β (Aβ) PET images is a surrogate marker of amyloid deposition in the brain. MRI‐independent approaches have been developed and have reported accurate quantification without the use of MRI but they still require a reference region to compute a SUVr value. The goal of this work was to design a new measure of amyloid deposition (AmyQ) that does not require the use of an MRI or a reference region and compare it to other commonly used measures (SUVR and Centiloid units) using two different samples of Flutemetamol (FMT) and Florbetaben (FBB) data.

Methods

We selected 198 subjects from the AIBL dataset (aibl.csiro.au) and 215 from the ADNI dataset (http://adni.loni.usc.edu/) in the Alzheimer’s Disease continuum with available amyloid PET and a T1‐weighted MRI. FMT and FBB PET images were first coregistred to its corresponding MRI and then normalized to the MNI space. Using the combination of the two first components of principal component analysis (PCA) we created a PET adaptive template (Figure1). Betas for the PCA components were optimized by maximizing the similarity between the MRI‐based spatially normalized PET images and the generated adaptive template. The AmyQ was determined using the beta of the second component (β2). Correlation analysis was used to evaluate the relationship between the AmyQ with the SUVr for each tracer, and with Centiloid units of both tracers. Finally, ROC curves were used to assess the power of the AmyQ to discriminate between positive and negative PET scans using global SUVr as the gold standard.

Results

For both tracers, the AmyQ presented high relationship with both the global SUVr (Figure2A and B; rFMT=0.88 and rFBB=0.85) and centiloid (Figure2C). The ROC curve using AmyQ to discriminate PET‐positivity (as determined by the global SUVr) showed an AUC of 0.96 and 0.92 for FMT and FBB respectively.

Conclusions

AmyQ may serve as a new index of global amyloid load, computed without MRI and independent of a reference region and tracer, which could prove highly useful for inter‐tracer studies. Additional studies are needed to confirm the relevance and potential clinical application of this new brain amyloid measure.
Dementia diagnosis affects pharmacological management of diabetes mellitus: A matched analysis of ∼20,000 patients from the Swedish registries
Authors: Secnik Juraj , Xu Hong , Schwertner Emilia , Hammar Niklas , Alvarsson Michael , Winblad Bengt , Eriksdotter Maria , Garcia‐Ptacek Sara , Religa Dorota
Published: December 2020

Background

Currently, there is no evidence‐based approach to treatment of diabetes mellitus (DM) when dementia is present. To reflect current clinical practice, we aimed to determine the differences in antidiabetic drug usage among DM patients with and without dementia.

Method

In this open‐cohort study we used five national Swedish registers to extract patients with DM & dementia and compared them to patients with DM who were dementia‐free. Overall, 10,470 DM & dementia patients registered to the Swedish Dementia Registry (until October 2018) were propensity‐score matched to 10,470 DM & dementia‐free controls originating from the Total Population Register. Information on comorbidities, antidiabetic and other medication and mortality originated from the Patient Register, Prescribed Drug Register and Cause of Death Register, respectively. Matching characteristics included index date (date of dementia diagnosis), age, sex, comorbidity score, education, DM type (excluding type 1 DM), DM duration and cardiovascular, psychotropic and dementia medication. Competing‐risk regression models (death as competing risk) were used to evaluate whether dementia status may alter the probability of antidiabetic drug usage defined using the date of first dispensation after dementia diagnosis (or index date) in patients without history of usage. Medications of interest were insulin, metformin, sulfonylurea derivates (SU), thiazolidinediones and more modern medication like dipeptidyl‐peptidase‐4 inhibitors (DPP‐4i), glucagon‐like peptid‐1 agonists (GLP‐1a) and sodium‐glucose cotransporter‐2 inhibitors (SGLT‐2i). We also assessed the likelihood of treatment with other antidiabetic drugs in addition to metformin as a proxy for treatment intensification.

Result

The dementia and DM group was significantly more likely to be treated with insulin (sHR 1.31 [95% CI 1.21‐1.43]) and less likely to receive DPP‐4i (0.79 [0.72‐0.88]), GLP‐1a (0.50 [0.40‐0.63]) and SGLT‐2i (0.42 [0.34‐0.52]). Dementia patients were also more likely to receive further medication in addition to metformin (1.08 [1.01‐1.15]).

Conclusions

In comparison to dementia‐free controls, dementia patients were less likely to receive modern antidiabetic drugs, with simultaneous higher likelihood of being prescribed insulin.
Premature neuronal differentiation in familial Alzheimer’s disease human stem cells in vitro and in postmortem brain tissue
Authors: Arber Charles , Lovejoy Christopher E.J. , Willumsen Nanet , Alatza Argyro , Casey Jackie M. , Lines Georgie , Kerins Caoimhe , Zetterberg Henrik , Hardy John , Ryan Natalie S. , Fox Nick C. , Lashley Tammaryn , Wray Selina
Published: December 2020

Background

Familial Alzheimer’s disease (fAD) is caused by mutations inPSEN1, PSEN2and APP. PSEN1forms the catalytic core of g‐secretase, a membrane protease which cleaves numerous substrates including APP and Notch. We have previously shown that our panel of fAD patient‐derived iPSCs show altered APP processing and Abgeneration. Here we investigated whether mutations led to altered Notch cleavage in neural precursors. We hypothesised that reduced Notch cleavage in fAD lines would promote premature differentiation during iPSC neuronal differentiation and during adult hippocampal neurogenesis.

Methods

We generated 2D cortical neurons and 3D cerebral organoids from a panel of 14 donor‐derived iPSC lines (5 controls, 2 APPmutation lines and 7 PSEN1mutation lines). Neurogenesis was quantified via the proportion of neural precursors versus the number of post‐mitotic neurons at timepoints of neural commitment. In addition, we quantified newly generated neurons in the post‐mortem hippocampus of 3 control brains and 7 brains derived from fAD mutation carriers.

Results

We describe a small, yet reproducible premature differentiation phenotype in lines containing mutations in PSEN1during in vitro neurogenesis. This is, at least in part, due to reduced Notch signalling; which drives terminal differentiation. These findings are corroborated in independent orthogonal iPSC systems, namely 2D neurogenesis and 3D organoid differentiation. Using immunohistochemistry against b‐III‐tubulin, we describe robust, quantifiable neurogenesis in post‐mortem tissue. Results are suggestive of mutation‐specific effects and also a premature ageing phenotype in fAD tissue.

Conclusion

These findings reveal insights into the functional outcomes of fAD mutations. Mutations in PSEN1, but not APP, alter Notch signalling in neural precursors, which in turn drives premature terminal differentiation. Premature differentiation and mutation‐specific differences both necessitate careful consideration for drug design and patient stratification.
The North Carolina Registry for Brain Health: An actionable strategy to include under‐represented groups in Alzheimer’s disease research
Authors: Welsh‐Bohmer Kathleen A , Plassman Brenda L , Kaufer Daniel , Byfield Grace , Price Stephen Russ , Ries Michelle G , Zolotor Adam J , McCart Michelle , Pulliam Amy , Silbersack Johanna , Byrd Goldie S
Published: December 2020

Background

The North Carolina Institute of Medicine (NC IOM), in response to a legislative mandate, convened a Task Force on Alzheimer’s Disease and Related Dementias (2015/2016) to develop an actionable strategic plan to address the state’s rising rate of Alzheimer’s disease and related dementias and to promote brain health. A recurring state appropriation supports the North Carolina (NC) Registry for Brain Health (Registry), an outcome of the task force plan.

Methods

The NC Registry for Brain Health aims to increase public awareness of dementia services, brain health research, and opportunities to participate in clinical investigations. A focus is on under‐served communities traditionally not included in research. The Registry includes investigators from collaborating institutions across the state, including Duke University, East Carolina University, North Carolina A&T State University, the University of North Carolina at Chapel Hill, and Wake Forest School of Medicine. Governance is provided by investigators from each of the collaborating institutions with input from NC IOM, NC DHHS and stakeholders throughout the state.

Results

Phase I of the project focused on establishing the Registry infrastructure, including governance, site identification and contracting, programming of the Registry database, and website development. Two public kick off events announcing the Registry were held in June 2019. Phase II has focused on Registry enrollment to under‐served groups through an outreach strategy designed to overcome barriers of communication and trust. To date there have been over 60 outreach events across the state. Current enrollment stands at 4228 enrollees, of whom 34% are self‐identified as minority group members (30.5% African American) and 2.8% identified as Hispanic. As the Registry begins assisting research studies with recruitment, we plan to develop methods to effectively reach individuals with and without easy digital access

Conclusions

The NC Registry for Brain Health is growing rapidly and has a diverse membership representative of the state population, demonstrating that groups often under‐represented in research studies have an interest in participating in research. Interfacing with under‐served communities, through outreach events and other face to face interactions, is crucial to ensure the community has access to trusted information when making decisions about potential research participation.
iPSC‐derived engineered cerebral organoids (enCORs) as in vitro models of tauopathy
Authors: Lovejoy Christopher E.J. , Alatza Argyro , Arber Charles , Bradshaw Teisha , Lashley Tammaryn , Hardy John , Wray Selina
Published: December 2020

Background

Familial Alzheimer’s disease (fAD) is caused by mutations in PSEN1, PSEN2 and APP. PSEN1 forms the catalytic core of g‐secretase, a membrane protease which cleaves numerous substrates including APP and Notch. We have previously shown that our panel of fAD patient‐derived iPSCs show altered APP processing and Ab generation. Here we investigated whether mutations led to altered Notch cleavage in neural precursors. We hypothesised that reduced Notch cleavage in fAD lines would promote premature differentiation during iPSC neuronal differentiation and during adult hippocampal neurogenesis.

Method

We generated 2D cortical neurons and 3D cerebral organoids from a panel of 14 donor‐derived iPSC lines (5 controls, 2 APP mutation lines and 7 PSEN1 mutation lines). Neurogenesis was quantified via the proportion of neural precursors versus the number of post‐mitotic neurons at timepoints of neural commitment. In addition, we quantified newly generated neurons in the post‐mortem hippocampus of 3 control brains and 7 brains derived from fAD mutation carriers.

Result

We describe a small, yet reproducible premature differentiation phenotype in lines containing mutations in PSEN1 during in vitro neurogenesis. This is, at least in part, due to reduced Notch signalling; which drives terminal differentiation. These findings are corroborated in independent orthogonal iPSC systems, namely 2D neurogenesis and 3D organoid differentiation. We see describe robust, quantifiable neurogenesis in post‐mortem tissue using b‐III‐tubulin immunohistochemistry. Results are suggestive of mutation‐specific effects and also a premature ageing phenotype in fAD tissue.

Conclusion

These findings reveal insights into the functional outcomes of fAD mutations. Mutations in PSEN1, but not APP, alter Notch signalling in neural precursors, which in turn drives premature terminal differentiation. Premature differentiation and mutation‐specific differences both necessitate careful consideration for drug design and patient stratification.
Neuropsychological and biochemical features of cognitive resilient octogenarians and nonagenarians
Authors: Zegada Luis Fernando , Zegada Luis
Published: December 2020

Background

Alzheimer’s dementia has evolved into a biological construct based on fluid and imaging biomarkers to aid in early diagnosis. Biomarkers are expensive and not widely available. It is therefore important to define signatures of cognitive resiliency to better identify this group in the prodromal stages of dementia. Our AIM was to determine neuropsychological and biochemical characteristics of cognitively intact patients older than age 80.

Method

Single center, cross‐sectional study involving forty patients older than 80, admitted to a community hospital. Participants with diagnoses of dementia, delirium, history of falls, dependency on cognitively focused IADL, and those residing in residential care were excluded. Recruited patients were subjected to neurocognitive evaluation, with emphasis on episodic/working memory, semantic cognition, and visuoperceptual/executive spheres, using the Rey‐Osterrieth figure copy/recall (ROSC) test. Regression analysis was used to establish correlation.

Result

The mean age was 85 years (SD 4.06). The mean level of education was 12.12 years (SD 2.93). Only 28% of participants lived alone. Semantic evaluation was the most difficult task, with only 48% of patients able to pass. Patients who answered 3 memory tasks right, had a mean score of 21 (SD 4.6) on the ROSC recall. Those who pass 2 memory tasks, had a mean score of 18.75 (SD 5.20) on the ROSC recall, and those who pass only one, or failed all of them, had a mean score of 9. We identified the ROSC recall as the most powerful predictor of cognitive resiliency. Age correlated well with ROSC recall (p 0.0017, CI 45‐126), but no years of education (p 0.21, CI 2.32‐21). Hemoglobin had a significant effect on ROSC copy (p 0.0019, CI 5‐26), but no ROSC recall (p 0.84, CI ‐14‐12). No correlation was found between ROSC recall and MCV, RDW, or albumin level.

Conclusion

We corroborate that age is the single most important factor for cognitive decay, whereas a normal hemoglobin level appears to be protective. Level of education seems to lose its protective effect in the old‐old and oldest‐old population. Patients able to perform well on the three types of memory, showed great proficiency on the ROSC recall.
The PIONEER Study: A multi‐center, randomized, double‐blind, placebo‐controlled phase 2 trial of the effects of T3D‐959 on safety, cognition, function and plasma biomarkers in mild to moderate Alzheimer’s disease subjects: Rationale and study design
Authors: Didsbury John , Strittmatter Warren , Chamberlain Stan , Gabriel Hoda
Published: December 2020

Background

Dysfunctional glucose and lipid metabolism are key drivers underlying pathological pathways ultimately resulting in Alzheimer’s disease (AD). T3D‐959 is a small molecule, orally delivered, brain penetrating, novel PPAR delta agonist with 15‐fold lower PPAR gamma potency that acts to maintain homeostasis of glucose and lipid metabolism. Ubiquitous brain expression of PPAR‐delta, its critical role in regulating glucose and lipid metabolism and phenotype of PPAR‐delta null mice, coupled with a promising safety profile and multiple efficacy signals in an exploratory Phase 2a clinical trial (NCT02560753) in patients with mild‐to‐moderate AD, provide the foundation for the next Phase 2 clinical trial, the PIONEER Study [Prospective therapy to Inhibit and Overcome Alzheimer's Disease Neurodegeneration via Brain EnErgetics and Metabolism Restoration].

Methods

PIONEER is a randomized, double‐blind, placebo‐controlled, Phase 2 trial involving 256 mild to moderate AD patients (MMSE=16‐26) dosed orally once‐a‐day for 24‐weeks in 4 parallel arms (T3D‐959 active arms of 15mg, 30mg and 45mg QD and a placebo arm in a 1:1:1:1 ratio). Co‐primary outcome measures include the ADAS‐cog11 cognition and global function CGIC measures. Secondary and exploratory outcome measures include change from baseline in plasma Aβ 42/40 ratio, NfL and tau between subjects treated with T3D‐959 compared to placebo, evaluation of the effect of T3D‐959 compared with placebo on apathy as measured by the NPI, on functional decline as measured with ADCS‐ADL, on executive function as measured using the DSCT, on verbal fluency, on plasma metabolomic and proteomic biomarkers and change in absolute regional, and whole brain, cerebral metabolic rate for glucose (CMRgl) as assayed by FDG‐PET.

Results

Cognitive and functional endpoints, as well safety data will be presented and discussed.

Conclusions

PIONEER is designed to evaluate the efficacy and safety of multiple dose strengths of T3D‐959 in patients with mild to moderate severity AD.
Group therapy for family caregivers of PWD at risk for complicated grief: A feasibility and efficacy analysis of pre‐loss group therapy
Authors: Supiano Katherine P , Andersen Troy C , Beynon Cynthia , Luptak Marilyn , Iacob Eli
Published: December 2020

Background

Our previous evaluation of Complicated Grief Group Therapy (CGGT) in bereaved dementia family caregivers demonstrated efficacy and identified intervention elements suitable for adaption into a preventative care approach.

Method

We adapted CGGT treatment elements into a manualized 10 session pre‐loss group psychotherapy—Pre‐Loss Group Therapy (PLGT)—for dementia caregivers at risk for Complicated Grief (CG). We implemented and evaluated three PLGT cohorts in three long‐term care facilities with family caregivers at‐risk for CG whose care recipient had a life expectancy of 6 months or less and resided in a long‐term care facility (NT = 24).

Result

Evaluation of participant preparedness for the death of the person with dementia (PWD), self‐care and grief outcomes showed significant improvement across domains between pre and post‐group. Notably, there was a statistically significant decrease in grief as measured by the Inventory of Complicated Grief score from baseline (M = 25.67, SE=1.80) to post‐group (M = 14.41, SE=1.65) t(21)= 6.280, p<0.001 and a statistically significant increase in meaning making as measured by the Grief and Meaning Reconstruction Inventory score from baseline (M = 111.74, SE=1.96) to post‐group (M = 116.46, SE=1.65) t(21)= ‐3.197, p<0.01. Clinician‐rated grief severity declined (N=22, β = –0.472, SE = 0.018, p < 0.001) per week and grief improvement increased (N=22, β = 0.259, SE = 0.023, p < 0.001) per week, as assessed on the Clinician Global Impressions Scale. We evaluated Early‐Stage intervention feasibility components of recruitment, retention, treatment fidelity, as well as PLGT participant acceptability, tolerability, satisfaction and treatment adherence. Of participants, 75% completed at least 80% of sessions, and 91% completed all assessments. Each feasibility target was achieved.

Conclusion

This is the first known application of proven therapeutic strategies to address CG applied to high‐risk dementia caregivers prior to the death of the PWD. Caregivers at risk for CG may benefit from group therapy targeting preparedness and pre‐loss grief experience, as we provide with PLGT. PLGT holds promise for translation into comprehensive caregiver support programs and delivered to active caregivers of living PWD at risk for CG across community and in the settings of hospice and long‐term care.
Investigating predictive models for earlier diagnosis of cognitive impairment using multimodal eye biomarkers
Authors: DeBuc Delia Cabrera , Arthur Edmund , Feuer William , Persad Patrice , Somfai Gabor Mark , Kostic Maja , Oropesa Susel , Mendoza‐Santiesteban Carlos
Published: December 2020

Background

The purpose of this study is to investigate predictive models for earlier diagnosis of cognitive impairment (CI) using the eye.

Method

Prospective age‐matched subjects (n = 69, 55+ years) w/o CI and the presence of any ophthalmic history were recruited. The Montreal Cognitive Assessment scores, retinal images (EasyScan, iOptics) and full‐field electroretinogram (RETevalTM, LKC Technologies, Inc.) were obtained. The multifractal behavior in the skeletonized optic‐disc region was analyzed using the generalized dimensions (D0, D1 & D2) and singularity spectrum f(α) vs. α, both calculated with the ImageJ program. The lacunarity (Λ) was also calculated by measuring the gap dispersion inside each retinal image. Logistic regression was used to construct predictive models to discriminate between phenotypes obtained from individuals w/o CI. Independent variables were divided into sets (see Table 1). Then, five hierarchical set models were fitted with all independent variables forced in. For each model, predicted probabilities were used to construct Receiver Operating Characteristic (ROC) curves. In a separate analysis, all independent variables were allowed inclusion in a parsimonious forward stepwise fashion, and a ROC curve was also constructed with its model‐predicted probabilities. Efficacy of discrimination was summarized with the area under the ROC curve (AUROC) and Youden’s index.

Result

Of the 69 participants, 32 had CI (46%). Figures 1 and Table 1 shows that the overall predictive accuracy of the model 5 in discriminating patients with CI from cognitive healthy subjects may be better (AUROC∼0.95) than that of the other combined measurements AUROC range∼[0.73 ‐ 0.88]. In the separated analysis with all independent variables, the singularity exponent a2 was the most significant predictor of CI. Once this was accounted for, none of the other parameters was statistically significant except Flicker IT. Therefore, a2 and Flicker IT were included in a single model to obtain a powerful predictive index: Xlinear = 18.387 + (0.736) × (Flicker IT)‐(26.887) x (a2) being the Predictive probability of CI = expXlinear/(1+expXlinear). The AUROC for this predictive model was 0.897 (SE = 0.050) and was highly significant (p < 0.001).

Conclusion

Our results showed that the predictive model using multimodal eye biomarkers has potential to target cognitive screening toward individuals at increased risk of CI.
Exposure to low output power laser with transcatheter intracerebral photobiomodulation therapy reduces mental and cognitive disorders and dementia in Alzheimer's disease
Authors: Maksimovich Ivan V.
Published: December 2020

Background

Transcatheter Intracerebral Photobiomodulation Therapy (PBMT) using low output power laser is a promising area in AD treatment. The method is aimed at stimulating angiogenesis, restoring cerebral microcirculation, stimulating metabolic processes and ATP metabolism in neuronal mitochondria, stimulating neurogenesis and regenerating cerebral tissues.

Method

The treatment was performed for 93 patients suffering from various AD stages with dementia, cognitive and mental disorders aged 34‐80 (average age 67.5), men ‐ 32 (34.40%), women ‐ 61 (65.59%). The examination included: CDR determination, MMSE testing, CT, MRI with calculation of temporal lobe atrophy degree and determination of dementia stage using the Tomography Dementia Rating scale (TDR), cerebral scintigraphy (SG), rheoencephalography (REG), cerebral MUGA. Test Group: 48 (51.61%) patients underwent transcatheter intracerebral Photobiomodulation Therapy (PBMT) using a helium‐neon laser. According to atrophy and dementia degree, cognitive and mental disorders severity, the patients were divided: preclinical AD stage (TDR‐0) ‐ 4 (8.33%); early AD stage (TDR‐1) ‐ 16 (33.33%); medium AD stage (TDR‐2) ‐ 21 (43.76%); severe AD stage (TDR‐3) ‐ 7 (14.58%) patients. Control Group: 45 (48.39%) patients underwent conservative treatment (Memantine 5‐20mg or Rivastigmine 3‐12 mg daily). According to atrophy degree, the severity of dementia, cognitive and mental disorders, the patients were divided: preclinical AD stage (TDR‐0) ‐ 6 (13.33%); early AD stage (TDR‐1) ‐ 13 (28.89%); medium AD stage (TDR‐2) ‐ 15 (33.34%); severe AD stage (TDR‐3) ‐ 11 (24.44%) patients.

Result

An early follow‐up period of 6‐12 months. Test Group: all 48 (100%) patients showed improvement in cerebral microcirculation and signs of cerebral temporal lobes volume increase, which indicates neurogenesis and cerebral regenerative changes. The process was accompanied by clinical condition improvement, dementia decline, cognitive and mental functions restoration. Control Group: during the treatment, there was no stable improvement in the patients’ condition but a tendency to further increase in cerebral involutive changes, which was accompanied by dementia growth, cognitive and mental impairment.

Conclusion

Transcatheter intracerebral PBMT is a promising, effective AD treatment. It diminishes dementia, cognitive and mental disorders, and allows improving the quality of patients’ life and restoring their daily activity.
Saccadic eye movements associated with executive function decline in mild cognitive impairment and Alzheimer’s disease
Authors: Pereira Marta Luisa Goncalves de Freitas , Villa Martina , Koh Do Hyong , Camargo Marina von Zuben de Arruda , Belan Ariella Fornachari , Radanovic Marcia , Pomplun Marc , Forlenza Orestes Vicente
Published: December 2020

Background

Abnormalities in eye movement metrics have been related to cognitive decline in dementia (Garbutt et al., 2008; Crawford et al., 2005), however, little is known about its association with executive dysfunction prior to the onset of Alzheimer’s disease (AD). The objective of this study was to determine whether older adults with mild cognitive impairment (MCI) or incipient dementia due to AD display subtle signs of impairment in executive functioning as compared to healthy controls, through the analysis of eye movement behavior.

Method

93 elderly individuals were allocated into three groups according to cognitive status: normal controls (CTRL, n=28), mild cognitive impairment (n=44) and Alzheimer’s disease (n=21). All groups were tested with an eye tracking‐assisted protocol composed of a prosaccade (PS) and an anti‐saccade (AS) task. The PS task required a fast, automatic saccade towards a peripheral target stimulus. In the AS task (measure of executive functioning), subjects had to inhibit an prosaccade towards the target stimulus and initiate a voluntary saccade in the opposite direction.

Result

The PS task revealed a similar saccadic performance across the three groups. The AS task had a greater impact on the frequency and latency of eye movement metrics in each group, with AD subjects showing a greater executive decline than CTRL and with MCI group performing intermediately. MCI were similarly impaired as AD in their voluntary saccadic reaction times, with a longer time to correct erroneous saccades. Correlations revealed relationships between eye movement metrics in the AS and measures of inhibitory control, attention, working memory and self‐monitoring.

Conclusion

The three groups showed a similar pattern of eye movements in the PS task, with both patients groups revealing a preserved automatic saccadic control compatible with the pattern observed in healthy ageing. AS task confirmed that cognitive impairment in the MCI‐AD continuum affects eye movement patterns reflecting executive deficits in inhibitory control, working memory and executive‐attention control subjacent to voluntary saccades. MCI revealed an intermediary impairment in these executive domains, as compared to AD (highest impairment) and CTRL. However, they showed significant increased response times similar to AD subjects, in order to overcome these deficits.
Behavior and amyloid profiles modify the association of tauopathy/neurodegeneration and cognitive decline in Alzheimer’s disease
Authors: Ge Xinting , Qiao Yuchuan , Zhang Jiong , Shi Yonggang
Published: December 2020

Background

Tau tangles and amyloid plaques are specific biomarkers that define dementia of Alzheimer’s disease (AD). However, behavioral changes or neuropsychiatric symptoms (NPS) are the natural course of AD, which impact the patients’ quality of life and caregivers’ burdens. Relationship between tau tangles or changes of cortical thickness and ‘noncognitive’ symptoms such as behavioral changes were understudied.

Method

497 subjects were selected from Alzheimer’s Disease Neuroimaging Initiative (ADNI) project. Participants underwent tau positron emission tomographic (PET) scanning with 18F AV‐1451, Aβ PET scanning with florbetapir or florbetaben, magnetic resonance imaging, and cognitive and behavioral testing. A 4‐group division approach was proposed using both amyloid (A‐/A+) and behavior (B‐/B+) status: A‐B‐, A‐B+, A+B‐ and A+B+. Multivariable linear regression model was used to delineate the relationship of tauopathy/neurodegeneration and cognitive decline for each group.

Result

The tau deposition increased significantly from the A‐ group to the A+ group, and the associated regions spread into nearly the whole brain. No correlations of the cortical thickness with cognitive decline were found for both the A‐ and A+ groups. Considering the behavior status, no associations were found for both the A‐B‐ group and the A+B‐ group. The association of cognitive decline with tau deposition was observed in the temporal lobe (entorhinal cortex, para‐hippocampal gyrus, et., al) for the A‐B+ group and spread into nearly the whole cerebrum for the A+B+ group. For cortical thickness, the associations with cognitive decline show similar spreading patterns of tau deposition for the A‐B+ group while nearly no difference of the associated regions for the A+B+ group.

Conclusion

The association of cognitive decline with tauopathy/neurodegeneration were driven by the subjects with abnormal behavior status (B+ groups), while there were nearly no associations for B‐ groups (A‐ and A+). NPS may have the ability to improve the differentiation sensitivity of Aβ on the severity of tauopathy/neurodegeneration. Several factors such as tau tangles, amyloid plaques, cortical atrophy, and behavior symptoms should be considered together for neuropsychiatric disorder diagnosis.
Correlation analysis between magnetic susceptibility in MRI and amyloid β in PET
Authors: Sato Ryota , Kudo Kohsuke , Yamaguchi Akinori , Udo Niki , Matsushima Masaaki , Yabe Ichiro , Sasaki Makoto , Harada Masafumi , Matsukawa Noriyuki , Amemiya Tomoki , Kawata Yasuo , Bito Yoshitaka , Ochi Hisaaki , Shirai Toru
Published: December 2020

Background

Studies on quantitative susceptibility mapping (QSM) have reported increased susceptibility in the brain of Alzheimer’s disease patients, reflecting the pathological accumulation of iron in Aβ plaques. Previously, we revealed moderate correlation between increased magnetic susceptibility in QSM and Aβ deposition in PET by using a region of interest (ROI) analysis in a relatively small cohort (26 patients) (Kudo K., et al. AAIC 2019). In this study, we examine the correlation in a larger sample size by using the ROI analysis and a whole‐brain voxel‐based analysis.

Method

Forty‐two patients were prospectively recruited in four centers. The clinical diagnoses were as follows: 23 dementia cases, 18 mild cognitive impairment cases, and one cognitively normal case. Magnetic resonance imaging was performed using 3‐T scanners (Hitachi, Ltd.). Amyloid PET imaging was performed using 18F‐flutemetamol. Both QSM and PET images were spatially normalized, and the ROI and voxel‐based analyses were performed to examine correlation between these two images. In the ROI analysis, the correlations were analyzed for 47 regions (defined by an automated anatomical labeling atlas) by using Pearson’s correlation coefficient. In the voxel‐based analysis, the correlation coefficients were calculated between spatially smoothed QSM and PET images on a voxel by voxel basis. This research was supported by AMED under Grant Number JP18he1402002.

Result

Based on amyloid PET, 20 patients were Aβ positive and 22 were Aβ negative. In the ROI analysis, positive correlations were noted in 24 of the 47 regions, and moderate correlations (r>0.30) were noted in four regions: the supramarginal gyrus (r=0.35), anterior cingulate gyrus (r=0.32), rectal gyrus (r=0.31), and medial orbitofrontal cortex (r=0.30). When averaged for these four regions, the correlation was moderate (r=0.59), and receiver operator characteristic analysis to predict Aβ positivity revealed that the area under the curve was 0.79. In the voxel‐based analysis, three clusters were found as positively correlated regions (r>0.30) in the parietal and frontal cortices. When averaged for these three clusters, the correlation was high (r=0.80).

Conclusion

The ROI‐based and voxel‐based analysis results suggest that the increased susceptibility of QSM was correlated with amyloid PET.
Effective interventions for potentially modifiable dementia risk factors: Their costs and cost‐effectiveness
Authors: Mukadam Naaheed , Anderson Robert , Knapp Martin Richard John , Wittenberg Raphael , Karagiannidou Maria , Gonzales Sergi Costafreda , Tutton Madison , Alessi Charles , Livingston Gill
Published: December 2020

Background

The potential economic value of interventions to prevent dementia is unknown. We modelled this for potentially modifiable dementia risk factors.

Method

We searched PubMed and Web of Science from inception to July 2018 and included interventions that (a) successfully targeted any of nine pre‐specified potentially modifiable risk factors (hypertension, diabetes, hearing loss, obesity, physical inactivity, social isolation, depression, cigarette smoking and less childhood education), (b) had robust evidence that the intervention improved risk or risk behaviour and (c) are feasible in an adult population. We established when in the life‐course each intervention would be delivered. We calculated dementia incidence reduction from: annual incidence of dementia in people with each risk factor; population attributable fraction for each risk, corrected for risk factor clustering, and how effectively the intervention controls the risk factor. We calculated the discounted value of lifetime health gain (including reduced dementia mortality) and impact on cost (including NHS, social care and carer costs) per person eligible for treatment. We estimated annual total expenditure on the fully operational intervention programme in England.

Result

We found effective treatments for hypertension, stopping smoking, diabetes prevention and hearing loss. Treatments for stopping smoking and provision of hearing aids reduced cost. Treatment of hypertension was cost‐effective by reference to standard UK thresholds. The three interventions when fully implemented would save £1·863 billion annually in England, reduce dementia prevalence by 8·5% and produce QALY gains. The intervention for diabetes was unlikely to be cost‐effective in terms of impact on dementia alone.

Conclusion

There is a strong case for implementing the three effective interventions on grounds of cost‐effectiveness and quality of life gains, as well as for improvements in general health. While some people will decline or discontinue interventions, there is considerable room for the interventions to remain cost‐saving or cost‐effective even if adherence is lower.