bluuebunny/crossref_metadata_2025 huggingface dataset:
Proteomic interrogation of human hippocampal CA1 pyramidal neuron sublayers in Alzheimer’s disease
Authors: Reyes Isabel , Kanshin Evgeny , Ueberheide Beatrix , Masurkar Arjun V.
Published: December 2020

Background

Hippocampal CA1 pyramidal neurons (PNs) are highly vulnerable to Alzheimer’s disease (AD). There is increasing evidence that superficial and deep CA1 PNs are molecularly and functionally distinct. Yet, it is unknown if these sublayers show differential molecular profiles in human AD.

Method

Laser capture microdissection was used to extract superficial and deep CA1 PN sublayers from hippocampal slices derived from formalin‐fixed, paraffin‐embedded (FFPE) Braak VI human AD brains (n = 8). Proteomics was performed using label‐free, quantitative liquid chromatography‐mass spectrometry (LC‐MS). Paired t‐test was used to identify protein hits whose abundance was significantly different (permutation‐based FDR correction, FDR cutoff at 5%) between neuron types.

Result

LC‐MS on these samples was high yield, with detection of 3159 unique proteins spanning ∼6 orders of magnitude in abundance, with ∼15% of identifications related to synaptic and ion channel function. Differences between superficial and deep CA1 PN sublayers included those related to AMPAR regulation (SIRT2), synapse function (ARHGAP23, SEPTIN4), neurodegeneration markers (NEFH), and markers of late versus early vulnerability in AD (INA). Differences that were nearly significant included CNTN2, associated with hippocampal PN Kv1 channels, components of the postsynaptic density dysregulated in AD (DLG4 and variants), and KCTD16, which impacts GABAB currents.

Conclusion

Proteomics combining LCM and LC‐MS from FFPE samples can be readily applied to address differences between PN sublayers. As such, these data support novel molecular differences between these layers in advanced AD, as related to physiologic dysfunction and disease‐related changes.
Fiber density and cross‐section correlates with tau burden in entorhinal cortex in healthy older adults
Authors: Gazes Yunglin , Mensing Ashley , Luo Linggang , Razlighi Qolamreza , Kreisl William Charles
Published: December 2020

Background

Tau PET imaging, while highly predictive of the onset of dementia, requires injection of radioactive compound and costs much more than MRI scans. The goal of this study was to test whether multi‐shell diffusion MRI can generate diffusion measures that predict tau burden. While DTI measures such as fractional anisotropy (FA) and mean diffusivity have been examined in aging and dementia studies, the DTI model is now recognized as being too simplistic and has been shown to mistakenly calculated higher FA than controls in atrophied white matter. Multi‐shell diffusion MRI allows more accurate modeling of crossing fibers and has been demonstrated to detect atrophy in Alzheimer’s disease.

Method

In the current study, a sample of 14 healthy older adults was scanned with multi‐shell diffusion MRI and tau PET imaging using [18F]MK‐6240 tracer. For 10 of the participants, diffusion was obtained on average 222 days before tau PET while the 4 other participants were scanned with diffusion MRI 211 days after tau PET. Standardized uptake value ratio (SUVR) for the left and the right entorhinal cortex were quantified relative to the cerebellar mean uptake. Diffusion data were processed through MRtrix’s fiber‐based analysis pipeline to obtain the whole brain fiber density and cross‐section (FDC) measure. Using tracts connected to the parahippocampal gyrus as masks, we tested whether FDC of the fibers in the white matter tracts connected to the parahippocampal gyrus correlated negatively with the tau SUVR in the entorhinal cortex within each hemisphere, correcting for age.

Result

After correction for multiple comparisons using family‐wise error approach, FDC for fibers connected to the left parahippocampal gyrus were negatively correlated with the left entorhinal tau SUVR as shown in figure attached. The mean FDC over the significant fibers and EC tau SUVR showed that r = ‐.707, p=0.007.

Conclusion

The negative correlation supports our hypothesis that greater tau burden is associated with lower fiber density and cross‐section in white matter tracts directly connected to the parahippocampal cortex. This encouraging result demonstrates the potential for multi‐shell diffusion as an alternative to PET for early detection of tau burden in cognitively healthy older adults.
Evaluation of class C CpG ODN immunomodulatory potential in a non‐human primate model of sporadic CAA
Authors: Patel Akash G. , Nehete Pramod N. , Nehete Bharti P. , Guttman Daniel Ezra , Kwak Yena , Dowling‐Campbell Kathryn Leigh , Tibensky Miroslav , Williams Lawrence E. , Wisniewski Thomas , Scholtzova Henrieta
Published: December 2020

Background

A number of studies have shown that the stimulation of innate immunity in transgenic mouse models can ameliorate AD‐related pathology. The failures of many immunotherapeutic clinical trials for AD has been related to poor translatability of promising transgenic mouse data to humans. Our recent data from a non‐human primate (NHP) model of sporadic cerebral amyloid angiopathy (CAA), squirrel monkey (SQM), indicate that treatment with TLR9 agonist, class B CpG ODN, results in reduction of CAA without toxicity. Here, we advanced our study using class C CpG ODN, which is currently being explored in a variety of human disease conditions and has shown favorable safety profiles. The present study is first to assess the effectiveness of class C CpG ODN to elicit an immune response in aged population whose immune system might be senescent.

Method

Elderly female SQMs received either CpG ODN or vehicle (saline) every 4 weeks as part of an ongoing chronic‐treatment study (14 injections so far). Phenotypes and frequency of lymphocyte/monocyte subsets were examined by flow cytometry (FC) in whole blood collected prior‐ and at multiple intervals post‐CpG ODN injection. SQM PBMCs were tested for functionality after incubation with CpG ODN (ELISPOT). Plasma taken at specific injection intervals was analyzed to identify cytokine/chemokine profiles and autoantibody responses toward Aβ40/42.

Result

FC enumeration of major lymphocyte/monocyte populations revealed significant decreases in the absolute numbers across study days with days 3 and 7 being significantly lower than baseline. These results likely reflect transient redistribution of cells out of peripheral blood. Further validation of CpG ODN immunostimulatory potential was demonstrated by increased levels of plasma cytokines/chemokines in vivo, and an increase in the numbers of PBMCs producing IL12, IFNγ, and IFNα in vitro. CpG ODN did not lead to increased production of IgG/IgM autoantibodies against Aβ when assessed periodically. Additionally, longitudinal MRI monitoring for ARIA will enhance the evaluation of CpG ODN efficacy and safety.

Conclusion

Overall, the present study provides essential information regarding immune response patterns of CpG ODN in this NHP model, enabling potential future clinical applicability of CpG ODN for AD therapeutics.
HOPE4MCI trial: First trial targeting reduction of hippocampal overactivity to treat mild cognitive impairment due to Alzheimer’s disease with AGB101
Authors: Rosenzweig‐Lipson Sharon , Barton Russell , Gallagher Michela , Edgar Chris J. , Maruff Paul T. , Mohs Richard
Published: December 2020

Background

Evidence from preclinical models and human patients demonstrates that neuronal circuits become hyperactive in prodromal AD contributing to the accumulation of Alzheimer’s pathology and subsequent cognitive decline. Such data support the hypothesis that neural overactivity in the medial temporal lobe/hippocampus is a critical driver of AD neuropathology, including the deposition of amyloid and spread of tau along connectional pathways. AGB101 (low dose levetiracetam) demonstrates efficacy on a range of molecular, synaptic, electrophysiological, functional and behavioral endpoints across models and species. In a Phase 2 study measuring hippocampal activity during a pattern separation memory test in patients with aMCI, AGB101 normalized hippocampal activity and improved performance on this specific memory assessment of hippocampal function. The HOPE4MCI trial is investigating the effects of AGB101 (220 mg) vs placebo in patients with MCI due to AD. The objective of the study is to assess the efficacy of AGB101 (low‐dose levetiracetam, 220 mg, extended release tablet) compared to placebo in subjects with mild cognitive impairment (MCI) due to Alzheimer’s disease (AD) using Clinical Dementia Rating‐Sum of Boxes (CDR‐SB) scores as the sole primary outcome. A substudy will evaluate levels of tau protein in the brain using tau PET ([18F]MK‐6240) at baseline and end of protocol.

Method

This is a multicenter, randomized, double‐blind, placebo‐controlled, 78‐week, fixed‐dose study evaluating AGB101 versus placebo as a treatment for slowing the progression of MCI due to AD. Inclusion criteria: Subjects must meet the following inclusion criteria at screening: 1) Subjects between 55 and 85 years old; 2) Have MCI due to AD consistent with the NIA‐AA criteria: MMSE (24‐30); CDR (0.5); Impaired delayed recall on the ISLT; essentially preserved ADLs' 3) Evidence of an amyloid‐positive PET scan

Result

The HOPE4MCI trial is currently underway. Sites are currently enrolling in the US and Canada with plans to expand to Europe. Up to date subject demographics, screen failure information, safety and dropout information will be presented at the meeting.

Conclusion

HOPE4MCI represents the first and only Phase 3 clinical trial targeting the reduction of hippocampal overactivity for slowing the progression of MCI due to AD.
Family quality of life in dementia and caregiver burden are associated with different caregiver personal characteristics
Authors: Pilonieta Giovanna , Jablonski Rita A , Winstead Vicki , Geldmacher David S
Published: December 2020

Background

Most care for persons with dementia takes place in the context of family. Dementia is associated with diminished quality of life for both affected persons and their caregivers, as well as increased burden. There is a growing consensus in dementia care that service‐delivery models for persons with dementia need to be family‐centered, but few studies have explored the concept of “family quality of life” (FQOL) in dementia. As part of a planned coaching intervention to reduce burden in caregivers of people with behavioral and psychiatric symptoms of dementia (BPSD) associated with care resistance, we collected baseline data on factors that might influence burden, FQOL, and response to the intervention.

Method

The 42‐item Family Quality of Life in Dementia (FQOL‐D) questionnaire, Connor‐Davidson Resilience scale (CD‐RISC), Pearlin Mastery scale, and neuroticism items from Eysenck Personality Inventory(EPI) were collected from 26 family caregivers of people with AD who endorsed BPSD with care resistant behaviors. The Spearman correlation between caregiver personality traits and FQOL‐D was calculated. In addition, relationships between caregiver burden, measured with the Zarit Burden Interview (ZBI), and caregivers' personality characteristics were ascertained.

Result

Of the 26 enrolled caregivers, 14 (53.85) were female, their mean age was 64.5 years and 24 (92%) were college‐educated. Their care recipients were 61% female, 77% white, mean age of 76 years, and college‐educated (88%). Mean scores were CDRISC 76.03 (+/‐12.05), EPI 6.30 (+/‐1.95), Pearlin 20.23 (+/‐3.26) and FQOL 173.80 (+/‐24.92). There were moderate correlations between FQOL and CDRISC (r=0.5). Secondary analysis showed moderate correlations between ZBI and Pearlin (r=–0.42) and EPI (r=0.48). All reported associations are P<.05

Conclusion

A relationship between Family Quality of Life and caregiver personal characteristics was identified. Higher baseline FQOL‐D was associated with greater self‐reported resilience. Similarly, higher mastery scores were associated with lower burden on the ZBI. Higher caregiver neuroticism was associated with higher reported burden. No relationships between mastery or neuroticism and FQOL‐D were established in this small sample. We identified that the positive construct of FQOL‐D may be associated with different caregiver characteristics than the negative emotional valance attributed to burden.
TOMM40 has genomic effects on hippocampal volume in mid‐life adults independent of APOE ε4 status
Authors: Pappas Colleen , Wang Qian , Lee Ling Yi , Le Scott T. , Klinedinst Brandon S. , Pollpeter Amy , Larsen Brittany , Willette Auriel A.
Published: December 2020

Background

The Apolipoprotein E ε4 (APOE ε4) haplotype is the strongest genetic risk factor for developing late‐onset Alzheimer’s disease (AD). Part of this risk may be due to APOE ε4 carriers showing progressive hippocampal atrophy decades before disease onset. It is unclear if genes next to APOE, such as Translocase of Outer Mitochondrial Membrane 40 (TOMM40), exercise an APOE ε4‐independent effect on hippocampal volume, which could better identify asymptomatic adults at risk for AD.

Method

We leveraged participants from UK Biobank (N = 10,130) with complete genetic, brain magnetic resonance imaging (MRI), and sociodemographic data. ANOVA and multiple linear regression tested the relationship between a priori identified TOMM40 Single Nucleotide Polymorphisms and hippocampal volume. For preliminary data, we focus on rs2075650 (‘650) genotype of neutral vs. high risk (AA vs. AG + GG genotypes). Main effect and mediation‐moderation analyses were conducted across and within APOE ε4 vs. non‐APOE ε4 carriers. Specifically, mediation‐moderation included age, sex, and serum metabolic markers.

Result

Among APOE ε4 carriers, TOMM40 ‘650 did not exercise independent effects. For non‐APOE ε4 carriers, among women, TOMM40 AG and GG genotypes had 0.16% more atrophy in mid‐life but 1.8% less atrophy in late‐life. Among men, these genotypes showed 0.90% less atrophy in mid‐life but 4.5% more atrophy in late‐life. Biomarkers of energy metabolism and amyloid clearance mediated these associations.

Conclusion

Among non‐APOE ε4 carriers, TOMM40 had an independent effect on hippocampal volume as a function of sex and age, acting as an ultimately protective factor in women but detrimental in men.
Cultural validity of cognitive markers for Alzheimer’s disease (AD): Evidence for global strategies
Authors: Parra Mario A. , Custodio Nilton , Montesinos Rosa , Pintado Caipa Maritza , Reynoso‐Guzman Wylliams , Slachevsky Andrea
Published: December 2020

Background

Availability of culture‐free cognitive tests with marker properties for AD has proved a barrier to global harmonization strategies. The European Neurodegenerative Diseases Working Group suggested that the Short‐Term Memory Binding Test (STMBT) and the Free and Cued Selective Reminding Test (FCSRT) are useful tests for the early detection of AD (Costa et al., 2017). Yassuda et al. (2019) showed that STMB is insensitive to age and education among healthy Brazilian adults. Parra et al. (2019) suggested that these tests should enter global strategies to aid the early detection of AD. Evidence is still needed to ascertain that such a validity translates to the assessment of affected individuals from underrepresented populations. The current study aimed to shed new light on such an outstanding question.

Methods

We recruited 64 healthy controls (HC), 60 patients with Mild Cognitive Impairment (MCI), and 63 patients with mild AD from Lima, regional area health clinics (DIRESA) between 06/2018‐05/2019. They were all illiterate. We considered Illiterate individuals who (1) attended no school or were enrolled for less than one year and (2) could not read or write (a booklet was given which showed a simple sentence). We assessed them with the STMBT, the visual FCSRT, and a brief clinical‐neuropsychological protocol.

Results

The assessment confirmed the healthy (CDR=0.0, pFAQ=2.2, BDI=5.9), MCI (CDR=0.5, pFAQ=3.7, BDI=6.2), and dementia (CDR=1.3, pFAQ=16.5, BDI=7.2) status of our groups. Significant between‐group differences were found with both the STMBT (F(2,184)=590.1, p<0.001) and Free Recall during the visual FCSRT (F(2,184)=3936.2, p<0.001), with HC>>>MCI>>>AD. ROC analysis with STMB revealed AUC=0.98 for HC vs. MCI, AUC=1.00 for HC vs. AD, and AUC=0.97 for MCI vs. AD. For the visual FCSRT, an AUC=1.00 was found for HC vs (MCI & AD), and AUC=0.99 for MCI vs AD.

Conclusion

The two cognitive markers recently recommended for harmonisation of neuropsychological assessment in neurodegenerative dementias in Europe seem suitable to support such practices in illiterate populations. Parra et al. (2019) recently suggested that only global strategies will help meet global challenges. Here we provide evidence of cognitive markers for AD that can reliably enter such strategies.
Performance comparison of automated white matter lesion segmentation algorithms in the DELCODE Study
Authors: Gaubert Malo , Zimmermann Isabella , Lange Catharina , Dyrba Martin , Li Hongwei , Duering Marco , Ziegler Gabriel , Teipel Stefan J. , Peters Oliver , Priller Josef , Schneider Anja , Wiltfang Jens , Bürger Katharina , Laske Christoph , Spottke Annika , Jessen Frank , Düzel Emrah , Wirth Miranka ,   the DELCODE Study Group
Published: December 2020

Background

White matter hyperintensities (WMH), derived from T2‐weighted MRI, represent a sensitive imaging marker of cerebrovascular disease. To investigate WMH in large‐scale multicenter clinical studies, appropriate automated WMH segmentation algorithms are required. Therefore, prior evaluation of these methods is important, especially due to additional challenges posed by the multicenter acquisition. We assessed performance of different WMH segmentation algorithms compared to manual segmentation (reference) in the multicenter DZNE‐Longitudinal Cognitive Impairment and Dementia Study (DELCODE).

Method

WMH segmentations were performed on a preliminary randomly‐selected dataset of 20 participants that included FLAIR images from different diagnostic groups across the AD continuum, various study sites and Siemens 3T scanner models. We used freely‐available and fully‐automated WMH segmentation methods, i.e. LST‐LGA, LST‐LPA, and Sysu_Media, the winner of the MICCAI WMH segmentation challenge. Performance of the algorithms was compared to reference segmentation using volumetric and spatial correspondence indices, intraclass correlation coefficient (ICC), Dice’s similarity coefficients (DSC), recall (sensitivity), and precision (positive predictive value), across the whole brain and with respect to the number of detected clusters.

Result

Preliminary analyses (n=20, example in Fig.1) indicated that mean WMH volumes, estimated by the algorithms, were lower compared to reference, except for Sysu_Media. Volumetric agreement with reference segmentation was moderate‐to‐high across methods (best: Sysu_Media, ICC=0.9). Mean global DSCs were moderate (best: Sysu_Media, DSC=0.6±0.2), with better performance for larger compared to lower WMH load. Mean number of clusters, detected by the algorithms, was lower compared to reference, except for Sysu_Media that overestimated this value. Mean DSCs for clusters were also moderate for all algorithms (best: Sysu_Media, DSC=0.5±0.2). Mean precision of detected WMH load and number of clusters was higher than mean recall (sensitivity) across all methods, except for Sysu_Media.

Conclusion

These preliminary findings show that performance of different automated WMH segmentations is relatively similar. Although most algorithms correctly identify WMH (higher precision), the methods underestimate total WMH load (lower sensitivity). The Sysu_Media algorithm performs best in many indices, however, it yielded lowest precision in number of clusters. Results of the final sample (n=40) will be presented, intended to serve as a method guide for conducting WMH segmentations in the multicenter DELCODE study.
Global Council on Brain Health: Recommendations to promote brain health through music enrichment
Authors: Lock Sarah Lenz , Chura Lindsay Rachel , Parkes David ,   Global Council on Brain Health
Published: December 2020

Background

The Global Council on Brain Health (GCBH) is an independent collaborative of scientists, clinicians, scholars, and policy experts convened by AARP to provide evidence‐based advice on what people and professionals can do to maintain and improve brain health. The Council translates scientific research into actionable recommendations for the public that will help drive behavior change in individuals across communities and cultures. In 2020, the Council will focus on the topic of music specifically as it relates to brain health. Music offers natural and accessible strategies for older adults who wish to exercise their full creative potential or cope with issues related to dysfunction or isolation.

Method

Experts from around the world were brought together to analyze the body of evidence on the impact of music and brain health, build consensus, and issue recommendations. AARP’s original research captures data from surveys highlighting adult engagement with music as it relates to their brain health.

Result

This presentation will feature consensus on whether and how music impacts cognitive health. Recommendations and practical tips based on the latest research advancements will also be showcased to help the public understand the potential that music holds for supporting and enriching brain health. Data from surveys fielded by AARP research, developed in consultation with the GCBH, will be featured.

Conclusion

This presentation highlights findings from the Council’s examination of the impact of music on brain health. Music and dance/movement interventions can positively impact health outcomes, including cognition, quality of life, psychological impact, mental well‐being, etc. Participation in music therapy and experiences can regulate stress and arousal, thus affecting overall health. The scientific and policy dimensions of music and brain health on aging adults will also be addressed.
Associations among family stigma, type of dementia, caregiver burden and other negative psychological outcomes
Authors: Velilla Lina M , Acosta‐Baena Natalia , Calle Andres , Allen Isabel Elaine , Lopera Francisco , Kramer Joel H
Published: December 2020

Background

There is very little research about the impact of family stigma and the type of dementia on the mental/physical health, and Quality of life (QoL) in early‐onset Alzheimer's disease (EOAD) and Frontotemporal dementia (FTD) caregivers. Thus, we aimed to address the question of whether family stigma and the type of dementia are predictors of depression, QoL and caregiver burden.

Methods

This is an analytical study with a cross‐sectional design. 140 Participants who are family caregivers of patients with the diagnosis of EOAD, FTD and late‐onset AD (LOAD) completed questionnaires about family stigma, caregiver burden (Zarit Burden), depression (CES‐D), anxiety (STAI), and QoL (SF36). Multivariable linear regression models were used with LOAD as a reference category to examine associations between depression, QoL and caregiver burden as outcomes predicted by family stigma and type of dementia.

Results

After adjusting by age and patient’s dementia stage, the cognitive component of family stigma (Cog‐stigma) and type of dementia were good predictors of role limitations due to emotional problems (EOAD type b= ‐0,34 p<0,001; FTD type b= ‐0,36 p<0,001; Cog‐stigma b= ‐0,23 p<0,001), general health performance (FTD type b= ‐0,25 p=0,007; Cog‐stigma b= ‐0,34 p<0,001), energy/fatigue (EOAD type b= ‐0,27 p=0,003; FTD type b= ‐0,27 p=0,001; Cog‐stigma b=0,38 p<0,001), emotional wellbeing (EOAD type b= ‐0,28 p=0,004; Cog‐stigma b= ‐0,38 p<0,001), depressive mood (EOAD type b= 0,22 p= 0,028; Cog‐stigma b= 0,35 p<0,001), and depression (EOAD type b=0,24 p=0,018; Cog‐stigma b= 0,35 p<0,000). The Cognitive aspect of stigma was a good predictor of role limitation due to physical problems (b= ‐0,31 p<0,001) and caregiver burden (b=0,51 p<0,001).

Conclusions

The cognitive aspect of stigma (negative self‐attribution about the caregiver role or the own perception of been treated as less worthy by others) and the type of dementia are significant predictors of higher caregiver burden, greater depression and reduced QoL among caregivers. The EOAD caregivers showed a higher occurrence overall of negative caregiver outcomes. Family stigma should be addressed as a potential risk factor for both emotional and physical health among caregivers and as a potential factor that increases the burden among early‐onset dementia caregivers.
Asymmetric caudate hypometabolism in the absence of frontal involvement on FDG‐PET in patients with semantic dementia and behavioral symptoms
Authors: Choudhury Parichita , Savica Rodolfo , Radford Jonathan Graff , Duffy Joseph R , Machulda Mary M. , Schwarz Christopher G. , Spychalla Anthony J. , Senjem Matthew L. , Gunter Jeffrey L. , Lowe Val J , Whitwell Jennifer L , Josephs Keith A
Published: December 2020

Background

Although semantic dementia (SMD) presents with language decline, patients often develop behavioral changes. Behavioral symptoms in SMD are attributed to both cortical (orbitofrontal cortex atrophy) and subcortical (nucleus accumbens) degeneration in imaging and neuropathological studies. The caudate nucleus has been implicated in early behavioral changes in some phenotypes of frontotemporal dementia. The objective of this study was to determine whether asymmetric ipsilateral caudate nucleus hypometabolism on [18F]‐fluorodeoxyglucose positron emission tomography (FDG‐PET) is associated with early behavioral changes in the absence of frontal hypometabolism in SMD.

Method

Fifteen patients with a diagnosis of SMD evaluated by the Neurodegenerative Research Group (NRG) at the Mayo Clinic, Rochester from 2006‐2016, who had FDG‐PET, were included in this study. Clinical data was extracted from the medical records including age at presentation, sex, behavioral symptoms and duration of symptoms. Automated average Z‐scores generated from CortexID (GE Healthcare, WI, USA) using 3D stereotactic surface projections were obtained for the following regions bilaterally: temporal lobes, frontal lobes and caudate nucleus. Patients were categorized as left or right hemisphere lateralized based on the higher temporal lobe Z‐scores. Caudate nucleus and frontal lobe Z‐scores were then compared between the two sides for each patient. Hypometabolism was considered present if Z‐scores were greater than 2.

Result

Of our cohort, 9/15 (60%) were females with a median age of 68 at presentation and had 3.5 years symptom duration. 13/15 had at least 1 behavioral symptom at presentation. Eleven patients were considered to have left‐lateralized whereas 4 were right‐lateralized in their temporal lobe hypometabolism. Median Z‐scores were significantly different for ipsilateral and contralateral caudate nuclei at 2.5 and 1.6, respectively (p=0.02, Wilcoxon nonparametric test). Frontal lobe median Z‐scores were 1.2 (ipsilateral) and 0.59 (contralateral) with no statistical difference between two sides (p=0.13).

Conclusion

In SMD patients who exhibit behavioral symptoms with no frontal hypometabolism on FDG‐PET, asymmetric caudate nuclei hypometabolism should be explored as a possible imaging marker. This implicates abnormal frontal‐striatal circuitry in the development of behavioral symptoms even in the absence of frontal hypometabolism in early behavioral changes in SMD.
Cerebral amyloid deposition correlates with objectively measured sleep dysfunction
Authors: Tissot Cécile , Blais Hélène , Thompson Cynthia , Benedet Andréa Lessa , Pascoal Tharick A. , Therriault Joseph , Chamoun Mira , Lussier Firoza Z. , Savard Melissa , Rahmouni Nesrine , Stevenson Jenna , Gauthier Serge , Gosselin Nadia , Rosa‐Neto Pedro
Published: December 2020

Background

Sleep and circadian problems are known to be common along the Alzheimer’s disease (AD) spectrum. Previous research correlated an increase in CSF Aβ with poor sleep quality through self‐reported questionnaires in cognitively unimpaired (CU) individuals. Research on AD patients however showed an increase in tau‐PET. Today, there is increasing evidence that sleep disturbances are an early marker for AD pathology and marker of future risk of cognitive impairment. Our main objective was to study the relationship between sleep efficiency as assessed with polysomnography and amyloid, tau and neuroinflammation.

Method

28 individuals (21 CU and 7 mild cognitive impairment (MCI)) underwent a [18F]AZD4694 amyloid‐PET scan, [18F]MK6240 tau‐PET scan, [11C]PBR28 neuroinflammation‐PET scan, an MRI a full neuropsychological evaluation as well as a polysomnography. [18F]AZD4694, [18F]MK6240 and [11C]PBR28 standardized uptake value ratios (SUVRs) used the cerebellum grey matter as the reference region and were calculated between 40‐70 min, 90‐110 min and 0‐90 min post‐injection respectively. A voxel based regression model evaluated the relationship between the different pathophysiologies of AD, amyloid, tau and neuroinflammation, and sleep efficiency. The model’s covariates were age and diagnosis.

Result

We found a negative correlation between sleep efficiency as measured with a polysomnography and amyloid. The most impacted regions were the temporal poles, the inferior parietal cortex and subcortical regions such as the thalamus. However, we did not find a correlation with [18F]MK6240 and [11C]PBR28. When we corrected for apnea‐hypopnea index, sex and years of education, results were similar.

Conclusion

These preliminary results show that poor sleep quality correlates with amyloid deposition in the brain of CU and MCI individuals. The regions impacted have been related to sleep regulation, such as the thalamus. They are also known to be vulnerable to AD pathophysiology, for example, temporal and inferior parietal cortices. Our study adds to previous research by identifying anatomical correlates, and also using objective assessment of sleep quality. It also corroborates with the idea that sleep deprivation promote Aβ deposition.
Data‐driven characterization of tau accumulation across the Alzheimer’s disease spectrum
Authors: Groh Jenna Rae , Svaldi Diana , Stage Eddie , Sanjay Apoorva Bharthur , Logan Paige E. , Risacher Shannon L. , Saykin Andrew J. , Apostolova Liana G.
Published: December 2020

Background

While tau imaging is showing promise as a prognostic biomarker in Alzheimer’s disease (AD), additional work is needed to fully characterize its clinical usefulness. Using a data‐driven approach, we classified individuals based on tau deposition in Braak regions and assessed how demographic, cognitive, and imaging biomarkers behaved in relation to tau deposition in the brain.

Method

We included 317 ADNI participants (126 cognitively normal, 152 mild cognitive impairment, 39 dementia) with available AV1451 PET, FDG PET, AV45 PET, and MPRAGE MRI. Imaging summary variables for PET and MRI were downloaded form ADNI (http://adni.loni.usc.edu). Average AV1451 SUVR maps (Figure 2) were created in SPM 12. We used k‐means clustering to derive a two‐group solution for each Braak stage (Figure 1A) and the 75th percentile + interquartile range of the negative group from each clustering solution to define tau‐positivity. Subjects were grouped by tau positivity in Braak regions 1&2, 3&4 and 5&6. Group 000 is negative in all six regions; group 100 is negative in all regions except Braak 1&2; group 110 is only negative in Braak regions 5&6; and lastly, group 111 is positive in all regions (see Table 2). We used ANOVA with Bonferroni correction for multiple comparisons to compare demographic and cognitive, imaging biomarker measures across the groups.

Result

Tau‐positive Braak 1&2 individuals (group 100) were significantly older compared to individuals with more diffuse tau positivity. Mean cortical AV45 SUVR, prevalence of amyloid positivity, and cortical hypometabolism increased with increase in tau burden (group 000<100<110<111, Table 1 and Figure 1B). Absence of significant tau binding in group 000 did not indicate lack of amyloid deposition or hypometabolism (Figure 1B). In contrast, global tau deposition (group 111) showed higher global amyloid deposition and hypometabolism (Figure 1B).

Conclusion

Greater tau deposition makes individuals more likely to exhibit cognitive deficits. Absence of tau didn’t correlate with absence of cognitive impairment.
The association between migraine genetic risk and dementia: A Mendelian randomization study
Authors: Ackley Sarah F. , Rist Pamela M. , Brenowitz Willa D. , Graff Rebecca E. , Glymour M. Maria
Published: December 2020

Background

Although some studies have suggested a possible link between migraine and dementia, there have been concerns that these associations may be due to diagnostic bias or unmeasured confounding. We tested whether migraine causes an increased risk of dementia using Mendelian randomization, which leverages genetic variability in migraine risk to estimate effects independent of confounding.

Method

In a sample of 259,839 individuals of European Ancestry aged 55 years or older from the UK Biobank, we calculated a migraine genetic risk score (MGRS) for each individual based on 38 known genome‐wide significant risk single nucleotide polymorphisms. Using algorithmically defined dementia diagnosis and migraine diagnosis from hospital and primary care sources, 2,069 and 11,357 individuals were diagnosed with dementia and migraine, respectively. Fluid intelligence score (score on a 13‐item test to assess logic and reasoning ability) and total brain volume normalized for skull size (TBV) were used as outcomes in addition to dementia diagnosis and were available for 174,609 and 10,229 individuals, respectively. Linear, logistic, and linear mixed‐effects models were used to assess the associations between the MGRS and TBV, dementia diagnosis, and fluid intelligence, respectively. Using instrumental variable regression with the MGRS as the instrument, we estimated the causal effect of migraine on dementia diagnosis, fluid intelligence, and TBV. All analyses were adjusted for the first 10 genetic ancestry principal components, orthogonal polynomials of degrees 1‐4 for age at time of outcome assessment, and genetic sex.

Result

The MGRS was strongly associated with migraine (p < 0.0001), but not dementia diagnosis (p = 0.22), fluid intelligence (p = 0.15), or TBV (p = 0.12). The estimated causal effect of migraine was a 3% (95% CI: [‐2%, 8%]) increase in absolute risk of dementia, a 1.1 (95% CI: [‐1.0, 3.1]) point increase in total fluid intelligence score, and a 123 (95% CI: [‐50, 296]) cubic centimeter decrease in TBV.

Conclusion

The MGRS was not significantly associated with dementia diagnosis, fluid intelligence, or TBV. Using a Mendelian randomization approach, we did not find evidence that migraine causes dementia.
fMRI complexity is associated with tau‐PET and cognitive decline in Alzheimer’s disease
Authors: Jann Kay , Kim Hosung , Albrecht Daniel , Wang Danny J.J. ,   Alzheimer’s Disease Neuroimaging Initiative
Published: December 2020

Background

Amyloid‐PET is considered an early marker for the preclinical stage of AD, while the neurofibrillary tangle pathology detected with tau‐PET imaging correlates more closely with neuronal injury and cognitive decline. However, PET scans are expensive and involve radiation exposure. Recently, entropy measures have been explored as indices of the complexity of rs‐fMRI time‐series. Reduced entropy values were associated with aging, APOE ɛ4 genotype and cognitive decline in AD. Here we use complexity of BOLD signals as an index of the information processing capacity of regional neuron populations, and test the hypothesis that it is sensitive to tau‐related neuronal injury and cognitive decline in the AD processes.

Method

Data used in this study were obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Our cohort consisted of a sample of 50 subjects form ADNI‐3 (age = 72.4±8.2, 19M/31F, 25CN, 19MCI, 6AD) with a T1 structural, a tau‐PET (tracer: 18F‐AV1451) and two fMRI scans. FMRI data underwent standard preprocessing before computing Multi‐Scale Entropy (MSE). Parametric SUVR images were calculated with a cerebellar reference region. Correlations between SUVR tau‐PET and MSE were calculated for 195 ROIs (Craddock atlas parcellation) including age, gender and regional gray matter volume as covariates. To evaluate if MSE and PET can be used to classify AD from CN we trained and tested a random‐forest classifier (via 10‐fold cross‐validation).

Result

We found significant negative correlations between low frequency MSE and tau‐PET measures in hippocampus, parahippocampal gyrus and posterior cingulate cortex (Figure 2). The classification model revealed that MSE and PET have similar prediction accuracy and sensitivity (Table Figure 3A). The most informative areas for the prediction revealed a large degree of overlap between MSE and tau‐PET (Figure 3B).

Conclusion

Correlation and classification results for MSE in relation with tau‐PET revealed areas in PCC, temporal and parietal lobes. These areas are implicated in tau pathology and cognitive decline. Hence, these overlapping findings support our hypothesis that the complexity of rs‐fMRI is associated with regional tau protein accumulation measured by PET and could provide a marker for information processing capacity of regional neuron populations and prediction of cognitive decline in the AD processes.
Tau‐first subtype of Alzheimer’s disease progression consistently identified through PET and CSF
Authors: Aksman Leon M. , Oxtoby Neil P. , Scelsi Marzia Antonella , Wijeratne Peter A. , Young Alexandra L. , Alves Isadora Lopes , Alexander Daniel C. , Barkhof Frederik , Altmann Andre
Published: December 2020

Background

Several studies contend that some Alzheimer’s disease (AD) subjects develop early‐stage tau pathology before amyloid pathology1,2, supporting a hypothesis that there are multiple distinct subtypes of amyloid and tau pathology progression within AD. We investigated this hypothesis, applying data‐driven disease subtyping models to both amyloid and tau PET as well as CSF measures.

Method

We performed two separate analyses using cross‐sectional data from ADNI. The first was a tau‐PET‐based analysis, which used eight regional amyloid PET (AV‐45) SUVRs and ten tau PET (AV‐1451) SUVRs from 402 subjects with both scans at the same visit. The second was a tau‐CSF‐based analysis, substituting CSF‐based prediction of tau PET SUVR (see Figure 2) in place of actual tau PET to give a larger dataset of 996 subjects. We used the Subtype and Stage Inference (SuStaIn3) algorithm to infer disease progression subtypes and individuals’ disease stages, and characterized demographic, cognitive and CSF differences across subtypes.

Result

We found two PET‐based subtypes in the tau‐PET‐based analysis: an amyloid‐first (84% of subjects) subtype and a tau‐first (16% of subjects) subtype in which Braak stage I‐III related tau SUVRs (hippocampus, amygdala, entorhinal cortex) become abnormal first (Figure 1A,B). The tau‐CSF‐based analysis confirms these subtypes: amyloid‐first (83% of subjects) and tau‐first (17% of subjects; Figure 2A,B). There were no significant differences in demographics or subject stages between subtypes in the tau‐PET‐based analysis (Figure 1C,D). In the tau‐CSF‐based analysis there was a small difference in age (amyloid‐first subjects 2.4 years older, Cohen’s f2 = 0.02, p < 0.05). Amyloid‐first individuals also had slightly worse executive function (Cohen’s f2 = 0.02, p < 0.05; Figure 3C) and, as expected, more abnormal CSF amyloid (Cohen’s f2 = 0.10, p < 0.001; Figure 3D) while tau‐first individuals had more abnormal CSF tau (Cohen’s f2 = 0.06, p < 0.001; Figure 3D).

Conclusion

We identified amyloid‐first and tau‐first AD subtypes consistently across PET and CSF biomarkers. Our data‐driven approach supports the existence of a subtype of AD with tau accumulation prior to amyloid pathology. References: 1. Duyckaerts, et al., 2015, Acta Neuropath; 2. Weigand, et al., 2019, Brain Comm; 3. Young, et al., 2018, Nature Comm.
Sleep inefficiency is associated with altered hippocampal functional connectivity during encoding in postmenopausal women
Authors: Maki Pauline M , Wu Minjie , Aizenstein Howard J , Derby Carol A. , Thurston Rebecca C
Published: December 2020

Background

In a recent systematic review, the Alzheimer’s Association concluded that it is yet unclear whether sleep disturbance may be a modifiable risk factor for cognitive decline and dementia. This conclusion underscored the gap in understanding of which specific aspects of sleep (e.g., amount or quality) are associated with that risk and whether the sleep problems are a cause or precursor of dementia. To address that gap, we examined objective (actigraphy) measures of sleep in relation to hippocampal functional connectivity during a memory task. We focused on community‐dwelling postmenopausal women, a population with frequent poor sleep and a heightened lifetime risk of Alzheimer’s disease. We hypothesized that lower sleep efficiency but not sleep quantity would be associated with alterations in connectivity between the hippocampus and prefrontal cortex.

Method

A total of 109 women (mean age=59.11 years; mean MOCA= 26.36; 78.0% white) from the MsBrain study completed 72‐hour sleep actigraphy assessments (Phillips Actiwatch‐A2) and blood‐oxygen‐level‐dependent (BOLD) fMRI assessments of verbal encoding and recognition. A generalized psychophysiological interaction (gPPI) analysis estimated task‐based hippocampal functional connectivity using SPM12 and Conn. The design matrix included principal time series of the seed region (left or right hippocampus), task conditions (novel words, familiar words), interaction variables (seed times series × task condition), and motion parameters. Sleep efficiency (% of time in bed spent sleeping) and total sleep time (hours slept) were regressed on patterns of brain connectivity in a region of interest confined to the hippocampus and prefrontal cortex, controlling for age, education and body mass index.

Result

Sleep inefficiency but not sleep quantity was associated with lower hippocampal‐prefrontal connectivity during encoding (corrected p < .05). During encoding, sleep inefficiency was associated with lower connectivity between the /right hippocampus and left/right middle frontal gyrus and dorsal anterior cingulate cortex (ACC). No effects were evident for recognition.

Conclusion

The well‐established association between poor sleep and memory dysfunction in aging may be driven by poor sleep efficiency, which in turn may influence memory performance through decreased hippocampal‐prefrontal connectivity during encoding. Findings indicate a need for sleep interventions that help older adults to sleep better rather than longer.
HARMONY: Response to pimavanserin in the 12‐week, open‐label treatment phase
Authors: Foff Erin P. , Devanand Davangere P. , Ballard Clive , McEvoy Bradley , Stankovic Srdjan
Published: December 2020

Background

Dementia‐related psychosis (DRP) is common in patients with Alzheimer’s disease (AD), dementia with Lewy bodies (DLB), Parkinson’s disease dementia (PDD), vascular dementia (VaD), and frontotemporal dementia (FTD). However, no therapies have been approved. Current guidelines and real‐world practice involve a trial of off‐label antipsychotics when other interventions fail, with assessment of response in an individual patient and taper within 4 months in patients who have responded. Pimavanserin is an inverse agonist/antagonist at the 5‐HT2A receptor and is approved in the U.S. for treating hallucinations and delusions associated with Parkinson’s disease psychosis. The objective of this analysis was to examine the response (≥30% reduction on the SAPS‐H+D Total Score AND a CGI‐I score of 1=very much improved or 2=much improved) to pimavanserin during open‐label treatment of patients with DRP.

Method

HARMONY was a placebo‐controlled, randomized, Phase 3, relapse prevention study in patients with dementia (NIA‐AA criteria) and moderate to severe psychosis associated with PDD, DLB, AD, FTD or VaD. Eligible patients who failed brief psychosocial therapy during screening entered into a 12‐week open‐label (OL) period where they received pimavanserin 34 mg once daily. Patients were assessed for response at Weeks 8 and 12. Only patients who demonstrated sustained response (response at both Weeks 8 and 12) were eligible to randomize into the double‐blind portion of the trial. OL response rates and changes in psychotic symptoms were assessed in various subgroups within the study population

Result

392 patients were enrolled into the open‐label period; 41 patients were ongoing at the time of early study termination. Overall, 61.8% of patients demonstrated sustained response (59.8% AD, 71.2% PDD, 71.4% VaD, 45.5% DLB, and 50.0% FTD). Mean change in the SAPS scores across the OL period was similar regardless of dementia subtype or baseline characteristics. The response rate was similar regardless of age, dementia severity, or previous drug therapy, with more than 50% patients meeting response criteria at Week 4 across most factors.

Conclusion

In this Phase 3 study, during the OL treatment phase, pimavanserin produced a robust reduction in psychosis symptoms, irrespective of most likely clinical diagnosis of dementia subtype or baseline MMSE/dementia severity.
Brain connectivity and metacognition in persons with subjective cognitive decline (COSCODE): Retrospective analyses on the Geneva Memory Clinic cohort
Authors: Ribaldi Federica , Altomare Daniele , Garibotto Valentina , Mendes Aline , Assal Frederic , Eshmawey Mohamed , Chicherio Christian , Frisoni Giovanni B
Published: December 2020

Background

Advances in the Alzheimer’s disease (AD) field have enhanced awareness on brain health and prevention. This brings an increasing number of adults to ask for help in memory clinics for mild forgetfulness, leading to the increased use of health care resources. Nowadays, about 25% of memory clinics patients complain of cognitive decline in absence of objective deficits (subjective cognitive decline,SCD), and they are expected to increase in the coming years. Some patients with SCD later develop cognitive impairment and dementia, often due to AD, but the majority have psychiatric conditions, physical diseases, polypharmacy, or normal brain ageing. Differentiating these potential causes is often a difficult exercise even for expert physicians. The COSCODE project, funded by Swiss National Science Foundation and led by the Geneva Memory Clinic, aims to identify possible subgroups of SCD and their associated risk of decline. This abstract is focused on the retrospective analyses of SCD patients, to develop and future validate the recruitment criteria and SCD categorization.

Methods

We included 42 SCD from the Geneva Memory Clinic cohort with the following criteria:(i)Amyloid‐PET;(ii)MRI;(iii)clinical and neuropsychological evaluation;(iv)at least 1 follow‐up planned. To evaluate the representativeness of our sample we assessed the correlation between age, episodic memory and medial temporal lobe atrophy scale; Amyloid SUVr and Episodic memory. Then, a neuropsychologist and a neurologist evaluated the clinical reports in order to identify possible aetiologies of the cognitive complaint.

Results

In the whole sample (age, mean±SD:71±7years; 54% female; education:16.3±4.1; MMSE:28.8±0.8; 24% A+) age is inversely correlated with episodic memory (Free‐and‐cue‐selective‐reminding‐test, p=0.003) and positively with medial temporal lobe atrophy scale (p=0.017). Amyloid SUVr correlates negatively with episodic memory performance (p<0.05). On the other hands, the clinicians found 3 different aetiologies of the SCD: Comorbidity (stroke, brain injury, cardio‐vascular risk factors, physical disability,...), Psychopathology (depression, anxiety, personality trait); Unknown (apparently, no reason associated to the complaint). The prevalence of the 3 groups is respectively:29%,33%,38%.

Conclusions

Our SCD sample can be considered representative of a memory clinic population, indeed it’s a very heterogeneous group. The 3 groups categorization will be validated using a data driven approach and studying longitudinal trajectory of each subgroup to better understand their associated risk of decline.