bluuebunny/crossref_metadata_2025 huggingface dataset:
Clinico‐genetic study of two Japanese pedigrees with hereditary spastic paraparesis and Alzheimer's disease
Authors: Rumore Roberto , Montecchiani Celeste , Gaudiello Fabrizio , Miele Marialuisa , Kawarai Toshitaka , Orlacchio Antonio
Published: December 2020

Background

Mutations in the SPG4/SPAST gene are the major cause of hereditary spastic paraplegias (HSPs), a group of genetic disorders leading to progressive spasticity and weakness of the lower limbs. Alzheimer's disease (AD) is a degenerative disorder of the central nervous system. Early‐onset familial AD (EOFAD) accounts for 3‐5% of all AD cases and denotes families in which onset is reliably before age 60 to 65 years and often before age 55 years. The present study reports a second Japanese pedigree in which a SPG4/SPAST mutation co‐segregates with HSP and EOFAD.

Method

Whole exome sequencing (WES), Sanger sequencing, Multiplex Ligation dependent Probe Amplification (MLPA) analysis, bioinformatics, neurological evaluation, diagnostic imaging, and pathological assessment. An SPG4/SPAST Japanese family with similar genotype‐phenotype findings was already described by our research team. Haplotype analysis was conducted on the two pedigrees.

Result

One Japanese man was diagnosed as certainly affected by slowly progressive autosomal dominant HSP, according to the Harding criteria. The age at onset of the first motor symptoms was 31 years. At 52 years, phenotype was complicated by cognitive impairment; a diagnosis of probable EOFAD following the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer’s Disease and Related Disorders Association (NINCDS‐ADRDA) criteria was formulated. The case was definite Alzheimer’s disease (autopsy proven): the brain pathology revealed plaques with a congophilic core and neuritic pathology. Both the brother and the son of the proband revealed the same initial symptoms of dementia and HSP was diagnosed, respectively, at age 55 and 34 years. WES revealed in all the patients a heterozygous change in SPAG4/SPAST. MLPA analysis excluded the presence of deletions/duplications in SPG4/SPAST. Haplotype analysis disclosed a founder effect for the mutation in the two families sharing the same clinico‐genetic characteristics. Bioinformatic analyses and population study confirm a pathogenetic role of such mutation. Screening of PS1, PS2, and bAPP genes did not reveal any coding mutation. No affected subject carried out APOE genotype ε4/ε3 or ε4/ε4.

Conclusion

This work describes the second Japanese family with a SPAG4/SPAST mutation and association of HSP and EOFAD. A possible founder effect was confirmed by haplotype analysis.
Precise morphological mapping of high plex neurodegenerative and neuroinflammation protein targets in human and mouse FFPE brain tissue with the GeoMx™ digital spatial profiler
Authors: Rosenbloom Alyssa , Bahrami Arya , Kuhar Jamie , Miller Kelly , Liang Yan , Geiss Gary , Beechem Joseph M.
Published: December 2020

Background

Neurodegenerative diseases, including Alzheimer’s, Parkinson’s, and amytrophic lateral sclerosis (ALS), affect millions of people worldwide and represent an increasing burden in terms of healthcare economics and societal impact. The investigation and characterization of the abundance, specific spatial distribution and co‐localization of neurodegenerative and neuroinflammatory targets within the human brain are critical for the advancement of our understanding of progressive degenerative disease.

Method

NanoString’s GeoMx Digital Spatial Profiler (DSP) platform allows for simultaneous analysis of >70 proteins from discrete regions of interest (ROI) in FFPE tissue sections, providing morphological context to high plex molecular analysis. The assay relies upon antibody probes coupled to photocleavable oligonucleotide tags. After hybridization of probes to slide‐mounted formalin fixed paraffin‐embedded (FFPE) tissue sections, the oligonucleotide tags are released from discrete regions of the tissue via UV exposure. The size and shape of the UV exposure pattern is adjustable allowing for precise investigation into rare or specific cell populations, disease microenvironments, or neural sub‐regions. Released tags are quantitated on the standard nCounter® platform, and counts are mapped back to tissue location, yielding a spatially‐resolved digital profile of analyte abundance.

Results

In this study, we validate the GeoMx Human Neural Cell Profiling Core panel (∼20‐plex, RUO) and five add‐on Modules (∼10‐plex each, RUO) covering Alzheimer’s Pathology, Parkinson’s Pathology, Autophagy, and Glial Cell Subtyping on GeoMx DSP platform. In addition, diseased human brain tissue was mapped with fluorescent morphology markers highlighting amyloid beta plaques, microglia, and astrocytes to select ROIs for high plex profiling using the validated antibody set. In comparable studies, mouse neurodegenerative disease models were evaluated with the GeoMx Mouse Neural Cell Profiling Core panel and Alzheimer’s and Parkinson’s Pathology Modules in both FFPE and fresh frozen samples.

Conclusion

Specific cell population sampling was demonstrated by masking for multiple or individual microglia, neurons, and astrocytes. Concentric masks around plaques (Contour Profiling) allowed for spatially distinct sampling of the amyloid beta plaque microenvironments. Ongoing efforts will expand the neuroscience‐specific human and mouse antibody catalogues validated for the GeoMx DSP platform.
Novel characterization of vascular amyloid in CAA via CLARITY
Authors: Nackenoff Alex , Schrag Matthew S.
Published: December 2020

Background

Alzheimer’s Disease (AD) is a costly and expanding medical crisis that represents the major form of β‐amyloidosis affecting our aged population. Another form of cerebral β‐amyloidosis is Cerebral Amyloid Angiopathy (CAA), where β‐amyloid deposits into the cerebrovasculature instead of—or in addition to—distinct parenchymal plaques, independently contributing to cognitive decline. CAA is thought to produce weakened vascular network, eventually producing miniature cerebrovascular hemorrhagic events, microbleeds, and progressive deteriorating cognitive function.

Method

All previous attempts to characterize CAA microscopically have utilized thin brain sections, which are unable to discern the discrete relationship between these β‐amyloid structures and the surrounding vasculature along the entire blood vessel. We attempt to solve this limitation with the use of CLARITY, an advanced fixative technique which preserves intact cellular network structure and allows for diffusion of unfixed lipids, rendering contiguous transparent 3D tissue samples

Result

Through this technique, we have qualitatively determined the near‐ubiquitous nature of β‐amyloid deposition in CAA and gross vascular abnormalities of stratified intensity. Furthermore, we have determined that β‐amyloid is present at sites of microhemorrhage, a question that has remained controversial to date

Conclusion

This methodology will allow us to evaluate specific markers associated with vascular fragility and microhemorrhage risk and map the microvascular network to identify morphological and molecular features associated with vascular fragility. This work will provide the throughput necessary to discover tractable vascular markers for novel future therapeutics for CAA, potentially generalizable to AD.
Subjective cognitive decline is associated with longitudinal cerebral blood flow reductions and gray matter atrophy in older adults
Authors: Kresge Hailey A. , Liu Dandan , Khan Omair A. , Pamidimukkala Ujwala , Cambronero Francis E. , Moore Elizabeth E. , Bown Corey W. , Pechman Kimberly R. , Hohman Timothy J. , Jefferson Angela L. , Gifford Katherine A.
Published: December 2020

Background

Subjective cognitive decline (SCD), a potential harbinger of Alzheimer’s disease (AD), has been cross‐sectionally associated with neurodegeneration and cerebrovascular disease markers on brain MRI. However, longitudinal associations are less clear with few existing studies that yield inconsistent findings. Here, we related baseline SCD to longitudinal structural and hemodynamic markers of brain health in older adults free of clinical dementia and stroke.

Methods

Vanderbilt Memory & Aging Project participants (n=299,72±7 years, 58% male) completed a baseline SCD protocol and multimodal 3T brain MRI, including T
1‐weighted imaging (grey matter volumes) and pseudo‐continuous arterial spin labeling (cerebral blood flow (CBF)) at baseline and multiple follow‐ups (18‐months, 3‐years, 5‐years). Baseline SCD (total and subdomain memory, language, and executive functioning scores) was longitudinally related to global and regional grey matter volumes and CBF (mL/100g/min). Linear mixed effects models, with random intercepts and slopes and a follow‐up time interaction, covaried for baseline age, sex, race/ethnicity, education, diagnosis, mood, and apolipoprotein E (APOE)‐e4 status. Grey matter volume models covaried for intracranial volume. CBF models covaried for associated tissue volume.

Results

Mean follow‐up time was 3.8 years. Higher total SCD predicted hippocampal volume reductions (p=0.04), increased inferior lateral ventricular volume (p<0.001; Figure 1A), and global CBF reductions (p<0.001; Figure 1B). Higher scores within each SCD domain predicted hippocampal volume reductions, increased inferior lateral ventricular volume, and global CBF reductions (p‐values<0.04). Higher executive functioning‐SCD related only to frontal and occipital CBF reductions (p‐values<0.003; Figure 1C) but not temporal CBF or lobar atrophy (p‐values>0.07). Language‐SCD predicted reduced frontal CBF (p=0.01; Figure 1D) and temporal lobe volume (p=0.02). Surprisingly, memory‐SCD was not associated with temporal lobe volume or CBF (p‐values>0.05). Sensitivity analyses excluding outliers revealed the same associations.

Conclusions

Higher baseline SCD predicted multiple pathways of longitudinal brain changes, including cerebral hemodynamics and volume loss within areas first affected by AD. Executive functioning‐SCD predicted hemodynamic changes and language‐SCD related to alterations within the frontal and temporal lobes. Results suggest the relevance of considering the type of SCD, as specific domains may predict different pathologies over time with important prognostic implications. Future research is needed to understand the clinical consequences of these findings.
Associations between white matter hyperintensities and cognitive dysfunction in Alzheimer’s, vascular and mixed dementias
Authors: Lee Hyunwoo , Wiggermann Vanessa , Rauscher Alexander , Beg Mirza Faisal , Popuri Karteek , Tam Roger , Lam Kevin , Liu‐Ambrose Teresa , Dao Elizabeth , Keridy Walid Ahmed Al , Jacova Claudia , Sossi Vesna , Pettersen Jacqueline , Benavente Oscar R. , Hsiung Ging‐Yuek Robin
Published: December 2020

Background

Increased burden of white‐matter hyperintensities (WMHs) on MRI is common among different types of dementia. WMHs can be caused by various underlying etiologies and are non‐specific markers of tissue abnormality. Therefore, global measures such as WMH burdens may not distinguish between degrees of cognitive impairment. We explored the associations between lobar‐specific WMH volumes and cognitive dysfunction across different dementia subtypes.

Method

N=57 participants (7 Alzheimer’s disease [AD]/5 subcortical vascular dementia [SVaD]/7 mixed dementia [MixD]/38 vascular cognitive impairment [VCI]; Sex:34M/23F; Age:73±8yrs; pooled from three independent studies) were scanned on 3T MRI. WMHs were segmented on 3D‐FLAIR (MixD/AD/SVaD) or dual‐echo PD/T2‐weighted (VCI) images. T1‐weighted images were processed with Freesurfer 6.0. Left and right frontal, temporal, occipital and parietal lobes plus basal ganglia volumes were constructed using the Freesurfer segmentation outputs. We calculated the proportion of WMH burden within each lobe, i.e. the ratio of lobar WMH volume over the lobar volume. The Montreal Cognitive Assessment (MoCA) was used as a measure of cognitive function. We used a general linear model to determine the association between the WMH/lobar volume ratios and the MoCA scores. Covariates included age, sex, and presence of AD‐related (yes for MixD/AD, no for rest) and vascular‐related conditions (yes for SVaD/VCI/MixD, no for AD). Additionally, we assessed the relationship between the MoCA scores and the ratio of total WMH burden over the whole‐brain parenchymal volume.

Result

The model yielded a significant association between the MoCA scores and WMH/lobar ratios within the left (p=0.031) and the right (p=0.035) frontal lobes, with higher ratios predicting lower MoCA scores. The effect was not significant within the temporal, occipital, parietal lobes and the basal ganglia. The effect was insignificant at the whole‐brain level (p=0.08).

Conclusion

We found a significant association between the frontal lobe WMH burden and the MoCA scores, especially sensitive to frontal executive functions. This suggests that region‐specific assessments of WMHs may provide improved imaging‐cognitive correlations over the global WMH burden. Future studies with more consistent imaging protocols and broader cognitive/clinical assessments are warranted to further characterize the relationship between WMHs and cognitive impairment.
Multimodal screening for neurodegeneration in preclinical Alzheimer’s disease using EEG, APOE4 genotype, neuropsychological and MRI data
Authors: Gaubert Sinead , Raimondo Federico , Houot Marion , Corsi Marie‐Constance , Naccache Lionel , Sitt Jacobo Diego , Hermann Bertrand , Oudiette Delphine , Gagliardi Geoffroy Pierre , Habert Marie‐Odile , Dubois Bruno , Fallani Fabrizio De Vico , Bakardjian Hovagim , Epelbaum Stéphane ,   Alzheimer’s Disease Neuroimaging Initiative, MEMENTO Study Group, and INSIGHT‐preAD Study Group
Published: December 2020

Background

Early biomarkers are needed to identify individuals at high risk of preclinical Alzheimer’s disease (AD) (Jack et al., 2018). Electroencephalography (EEG) is a non‐invasive and cheap technique that would be an interesting screening tool for the preclinical stage of AD.

Method

We included participants from the INSIGHT‐preAD cohort, which is an ongoing single‐center multimodal observational study designed to identify risk factors and markers of progression to clinical AD in 318 cognitively normal individuals aged 70–85 years with a subjective memory complaint (Dubois et al., 2018). We divided the subjects into four groups, according to their amyloid status (on 18F‐florbetapir PET) and neurodegeneration status (on 18F‐fluorodeoxyglucose PET). We analysed 314 baseline 256‐channel high‐density eyes‐closed 1‐minute resting‐state EEG recordings. We extracted 10 quantitative EEG biomarkers, including spectral measures, algorithmic complexity and functional connectivity metrics. We evaluated three different classifiers (random forest, decision tree and logistic regression) to predict amyloid and neurodegeneration status from multimodal data, combining EEG, ApoE4 genotype, demographic, neuropsychological and MRI data. We divided the dataset into a training set (n=258) and validation set (n=46). We used a 5‐fold cross‐validation on the training set to identify the optimal combination of features.

Result

As recently published (Gaubert et al., 2019), the most prominent effects of neurodegeneration on EEG metrics were localized in fronto‐central regions with an increase in high‐frequency oscillations (higher beta and gamma power) and a decrease in low‐frequency oscillations (lower delta power), higher spectral entropy, higher complexity and increased functional connectivity measured by weighted Symbolic Mutual Information in theta band. In the machine learning analysis, among the different features, EEG was the most strongly predictive of neurodegeneration. Similar predictive performance was obtained when reducing the number of electrodes from 256 to 8. EEG biomarkers combined with hippocampal volumetry had a high negative predictive value (91%) and high sensitivity (82%) to predict neurodegeneration. The combination of ApoE4 genotype with demographic data was most strongly predictive of amyloid status.

Conclusion

EEG could be a valuable tool to screen for or rule out neurodegeneration in elderly memory complainers. This procedure has been patented under the following PCT number: PCT/EP2019/086629.
Cohousing for people living with dementia: The Modena experience
Authors: Fabbo Andrea , Neviani Francesca , Valentini Laura , Luppi Emanuela , Bertolotti Marco
Published: December 2020

Background

Social isolation, caregiving burden and costs, loss of quality of life related to increasing disability, loss of agency and personhood, are some of the main unmet needs for people with dementia (PwD) and their caregivers. Objective: In order to support people with dementia and their caregivers we implemented a cohousing model. 5 PwD were encouraged to live together. Caregivers were supported in the care according to person centred approach.

Method

Participation in the project (supported by Modena City Council and local Alzheimer association, had been on a voluntary basis. The only exclusion criteria for PwD had been bedridden .Each PwD has his own bedroom with personal belongings and furniture, while the dining and living room are furnished according to prosthetic environment principles. Caregivers turn up in order to both maintain familial environment and reduce global care burden, while formal caregivers, provided by social service and employed by relatives, contribute to PwD care. According to carers expressed needs, voluntaries and an occupational therapist have been engaged to weekly involve PwD in leisure activities and psychosocial intervention. A granted psychologist is available to support Caregivers. A cost analysis, PwD and caregiver quality of life evaluation and caregiving burden were checked. Two control groups of PwD living at home with relatives or family assistant were considered in order to evaluated this cohousing model effectiveness. The first control group was supported by local dementia association. PwD were follow by a memory clinic in cohousing group and in both control groups.

Result

A significant cost reduction was found in cohousing group (1879 €/month vs 2502€/month and 2662€/month in control groups). Moreover caregiving burden reduction and an improved PwD and caregivers quality of life were found in cohousing group.

Conclusion

This is the first cohousing experience for PwD, in our Country. Relatives improved caregiving experience, reduced financial burden, isolation and time spent for assistance. PwD reduced the risk of institutionalization and improved their quality of life. According to this study results another cohousing experience was open 6 month ago by our community social services.
Daily stressful experiences, depressive symptoms, and behavioral responses of ADRD family caregivers
Authors: Puga Frank , Wang Danny , Pickering Carolyn E
Published: December 2020

Background

Family caregivers of individuals living with Alzheimer’s disease or related dementias (ADRDs) are at a higher risk for serious mental illness, specifically depression. Caring for individuals living with ADRDs can be stressful due to the behavioral symptoms of dementia (BSD). Over time, stressors, such as BSDs, can contribute to the onset of depressive symptoms. Few studies have examined BSDs as contextual triggers contributing to variations in daily mental health symptom experiences of caregivers. Further, it is unclear how behavioral adaptations to caregiving‐specific stressors, such as engaging in elder abuse and neglect (EAN), impact caregiver mental health. In this study, we identified specific individual vulnerabilities, daily environmental stressors, and caregiver behaviors that increase the daily odds of experiencing depressive symptoms.

Method

Using a micro‐longitudinal design and ecological momentary assessment methods, we examined daily environmental stressors (BSDs), caregiver behaviors (i.e., EAN events), and individual vulnerabilities (i.e., demographics, early life adversity, social isolation, social support, and coping strategies) that impact daily odds of experiencing depressive symptoms. Data were collected from a national sample of family caregivers (N=50) who completed daily diaries over a 21‐day period (n=841). Multi‐level modeling was used to test a series of hypotheses on the relationship between daily environmental stressors, caregiver behaviors, individual vulnerabilities, and depression symptom experiences.

Result

Family caregivers were more likely to report depressive symptoms on a given day when a BSD was present and perceived as bothersome (OR = 1.22, 95% CI: 1.09‐1.43, p = 0.002). Additionally, when an EAN event occurred on a given day, caregivers were more likely to report depressive symptoms (OR = 1.27, 95% CI: 1.02‐1.58, p = 0.034) . Individual‐level factors also interacted with BSD, EAN events, and daily depressive symptoms.

Conclusion

The results from this study help elucidate factors that contribute to variations in the daily mental health symptom experiences of ADRD caregivers. The interactions between BSDs, EAN events, and depression identified in this study will inform interventions to better support family caregivers and improve mental health outcomes for an at‐risk population.
Cortical plasticity assessment predicts decline in patients with mild cognitive impairment
Authors: Lorenzo Francesco Di , Motta Caterina , Bonnì Sonia , Caltagirone Carlo , Martorana Alessandro , Koch Giacomo
Published: December 2020

Background

Alzheimer`s disease (AD) is characterized by loss of synaptic connections, cell death and disruption of structural and functional networks. One of the most consistent findings is the impairment of cortical plasticity, especially Long Term Potentiation (LTP) mechanisms. Recently, the use of new diagnostic criteria allowed to considered AD as a clinico‐biological entity identifiable in vivo on the presence of biomarkers. In light of these new criteria, aim of the current work is to investigate cortical plasticity in patients with hippocampal type memory impairment admitted for the first time in the memory clinic and stratified according to CSF biomarkers profile; moreover we followed patients up to a period of three years to explore the relationship between neurophysiological, neuropsychological and CSF biomarkers and clinical progression.

Method

Seventy‐three patients were recruited and followed up for 36 months. They underwent CSF sampling and Transcranial Magnetic Stimulation to investigate LTP and intracortical circuits. According to the new AD criteria we divided patients in three groups: 1) Mild Cognitive Impaired (MCI) patients (n=21); Prodromal AD (PROAD) patients (n=24); AD Dementia (ADD) patients (n=28).

Result

In neurophysiological evaluations only iTBS protocol was different among the different groups showing a paradoxical reversal of LTP for ADD and PROAD and a poor response for MCI patients. ProAD worsened faster than MCI. Regression analyses showed that LTP impairment was related to clinical progression. Kaplan‐Meyer analyses showed that patients expressing the worst LTP values were the ones to progress faster in a 3 year time.

Conclusion

The new criteria based on the presence of biomarkers and dementia allow us to identify patients at a prodromal stage that will develop dementia due to AD. LTP impairment drives the clinical progression in patients at prodromal stages confirming its pivotal role in determining cognitive decline. These results pave the way for the identification of new therapeutic targets such as synaptic plasticity modulators.
Multilevel and network analysis in patients with mild cognitive impairment: Cognitive assessment as a predictor of biomarkers
Authors: Fernández Rodrigo S , Clarens Maria Florencia , Mendez Patricio Alexis Chrem , Crivelli Lucia , Allegri Ricardo F
Published: December 2020

Background

The extracellular aggregation of the amyloid protein and hyperphosphorylated tau in neurons are biomarkers of Alzheimer's disease. Their use the clinical settings allowed to improve the diagnosis, in patients with cognitive impairment. The objective of this study was to evaluate the extent to which multivariate and network analysis of a neuropsychological battery are sensitive to predict and classify patients with mild cognitive impairment with positive (MCI +) and negative (MCI‐) amyloid markers.

Method

Patients with MCI‐ (n = 32) and MCI + (n = 54), performed a standard neuropsychological battery (UDS2). A multivariate Analysis of Variance (MANOVA) was performed to compare the performance of each group, followed by a Linear Discriminant Analysis analysis (LDA) to detect the tests that best classify groups. Moreover, an analysis of networks and centrality measures was carried out, with the objective of characterizing the way in which the different tests characterize the groups

Result

The MANOVA revealed that MCI‐ and MCI + groups significantly differ in their overall neuropsychological performance (P <0.001). Likewise, the LDA showed that a function (P <0.05) explains 60% of the variance (R2) and accurately classified group membership in 71% of patients. Network analysis showed that, the groups were similar in the number of connections, but differ in their type and strength. Finally, these analyzes suggested, that the tests of orientation, verbal‐immediate memory, logical‐deferred memory and semantic fluency, would be those that best separate groups.

Conclusion

The neuropsychological evaluation was capable of 1) Separating the MCI‐ and MCI + groups according to their relative performance; 2) Accurately characterize how the neuropsychological tests are associated with each other and 3) Predict whether MCI patients have positive / negative amyloid biomarkers.
Elevated levels of synaptic protein GAP‐43 associate with brain tauopathy, atrophy and cognition in Alzheimer’s disease
Authors: Dhiman Kunal , Villemagne Victor LL , Eratne Dhamidhu , Graham Petra L , Fowler Christopher J , Bourgeat Pierrick , Li Qiao‐Xin , Collins Steven , Bush Ashley I , Rowe Christopher C , Ames David , Masters Colin L , Blennow Kaj , Zetterberg Henrik , Martins Ralph N , Gupta Veer Bala
Published: December 2020

Background

Synaptic dysfunction is an early pathophysiological event, which associates with cognitive aberrations in Alzheimer’s disease (AD). Growth associated protein 43 (GAP‐43) is a nervous tissue specific protein, which plays a crucial role in axon formation, growth and synaptic plasticity. The current study evaluated the utility of cerebrospinal fluid (CSF) GAP‐43 in diagnosing AD, and its association with neuropathological and cognitive changes in AD, using CSF samples of participants from the Australian Imaging, Biomarkers and Lifestyle study of ageing (AIBL).

Method

The study participants (n=218) were clinically classified into healthy controls (HC, n=156), mild cognitive impairment (MCI, n=34) and AD (n=28). CSF levels of core CSF biomarkers (amyloid beta‐42, Ab42; total‐tau, T‐tau; phosphorylated‐tau, P‐tau) were assessed using commercial enzyme linked immunosorbent assays (ELISA). CSF GAP‐43 levels were assessed using a sandwich ELISA, based on the monoclonal antibody NM4 (Fujirebio, Ghent, Belgium) and a polyclonal GAP‐43 antibody (ABB‐135, Nordic Biosite, Täby, Sweden). Association of GAP‐43 with core CSF biomarkers was assessed via a linear correlation analysis. Multiple regression analyses were undertaken to assess the utility of GAP‐43 for predicting baseline amyloid load (measured by standardized uptake value ratio, SUVR), brain atrophy (measured by hippocampal volume) and cognition (measured by Mini‐Mental State Examination, MMSE and Clinical Dementia Rating Sum of Boxes, CDR‐SB).

Result

GAP‐43 levels were significantly elevated in AD compared to HC (p=0.001) and MCI (p= 0.036) and distinguished AD from HC with an area under the receiver operating characteristic curve (AUC) of 0.72. CSF GAP‐43 levels were significantly correlated with CSF T‐tau (r=0.84, p<0.001) and P‐tau (r=0.87, p<0.001), but not with CSF Ab42 (r=0.05, p=0.470). CSF levels of GAP‐43 significantly predicted baseline hippocampal volume (b =−0.05, standardized b=−0.16, p=0.027), and cognition as measured by MMSE (b =−0.28, standardized b =−0.14, p=0.039) and CDR‐SB (b =0.28, standardized b =0.22, p=0.001), after controlling for covariates. CSF GAP‐43 levels also significantly predicted baseline amyloid (b =0.05, standardized b=0.24, p<0.001).

Conclusion

As an AD biomarker, CSF GAP‐43 could be used to track the stage‐ and state‐associated synaptic aberrations that occur in the AD brain, and to understand the impact of stage‐associated synaptic aberrations on cognition and brain atrophy.
Deferiprone to delay dementia (the 3D trial)
Authors: Ayton Scott , Woodward Michael , Ellis Kathryn A. , Lim Yen Ying , Maruff Paul T. , Desmond Patricia M. , Salvado Olivier , Fazlollahi Amir , Rowe Christopher C. , Churilov Leonid , Bush Ashley I. ,   3D Trial Investigators
Published: December 2020

Background

Potential therapeutic targets for Alzheimer’s disease (AD) outside of β‐amyloid are of increased interest. Brain iron has been reported to predict accelerated AD progression when measured using fluid biomarkers (CSF ferritin), quantitative susceptibility mapping MRI, or directly in post‐mortem tissue, and is one potential therapeutic target. Brain iron may contribute to neurodegeneration by becoming pro‐oxidant (e.g. ferroptosis), or by promoting an inflammatory phenotype of microglia. Deferiprone is an orally bioavailable, BBB‐penetrant moderate iron chelating drug approved for the peripheral iron overload in β‐thalassemia. Deferiprone reported promising evidence for disease modification of Parkinson’s disease in two phase II studies; here we report the status of a phase IIb clinical trial of deferiprone for AD.

Methods

The primary outcome of this trial is to compare the cognitive performance in a neuropsychological test battery of subjects with mild Alzheimer’s disease (confirmed using β‐amyloid PET) treated for 12 months with either deferiprone (15 mg/kg) administered orally twice a day or a matching placebo. Secondary outcomes include adverse events (safety analysis), change in brain iron burden measured by quantitative susceptibility mapping MRI (target engagement), and brain volume changes (secondary efficacy measure). 171 participants will be recruited and randomized in a 2:1 ratio (drug:placebo).

Results

Ten clinical trial sites have been established in Victoria (6), New South Wales (3), and Western Australia (1). The first patient was randomized in March 2018. As of January 2020, 101 patients have been screened and 45 randomized. 18 patients have completed the treatment protocol of 1 year.

Conclusions

The outcome of this trial is scheduled to report in 2021.
Longitudinal changes in resting‐state EEG are correlated with cognitive decline in Alzheimer’s disease and related dementia
Authors: Meghdadi Amir H. , Berka Chris , Richard Christian , Karic Marija Stevanovic , Rupp Greg , Mcconnell Marissa , Poole Jared , Fink Abigail , Hamilton Joanne M , Salat David H
Published: December 2020

Background

Resting‐state EEG measures such as spectral power in Theta (3‐7 Hz) and Alpha (8‐13 Hz) bands have been previously linked to cognitive decline in Alzheimer’s disease (AD) and other dementias. However, routine use of EEG in clinical settings has not been widely practiced. In this ongoing longitudinal study, we demonstrate how changes in EEG measures after 1‐year are correlated with actual changes in cognitive decline as measured by MMSE score of cognitive assessment.

Method

Five minutes of eyes‐closed resting‐state EEG were recorded during both an initial and one‐year follow‐up visits from Healthy Controls (n=67), individuals with Mild Cognitive Impairment (n=16), Alzheimer’s Disease (n=4), Dementia with Lewy‐body (n=1), Parkinson’s disease dementia (n=1), and subjects reporting memory problems without a clear diagnosis (n=7). A generalized‐linear‐model (GLM) was used to regress the relationship between predictors (MMSE and age at initial visit as well as longitudinal changes in 9 EEG measures that were selected a priori) and the outcome variable (actual changes in MMSE score after 1‐year). EEG measures included Theta‐Alpha Ratio (TAR) and relative power at 5 Hz (theta5) at temporal channels as well as relative power at 10Hz at POz channel.

Result

MMSE scores fell in 32% of participants and improved in 8% (Figure 1). A GLM using logarithmic link‐function with 11 predictors and 21 terms (EEG predictors and their interaction with age) was fitted to the data (F=4.24, p=2.44x10‐6). The most significant (p<0.01) predictors were age, theta5, TAR and their interaction with age, all at channel T6. Predicted and actual decline in MMSE were highly correlated (r=0.73, p=10‐5) (Figure 2). A simpler model with 12 terms (no interaction between predictors) resulted in (F=4.34, p=3.98x10‐5).

Conclusion

Predictive power of EEG in modeling cognitive decline was demonstrated in a cohort of patients with known or possible dementia diagnosis as well as controls. These results support the utility of EEG as a biomarker of cognitive decline. These markers could supplement other neuropathological biomarkers (such as beta‐amyloid and tau), particularly because changes in cognition may not necessarily happen at the same rate as pathological changes.
Microglial autophagy‐mediated clearance of amyloid‐beta plaques is dysfunctional in Alzheimer’s disease mice
Authors: Daily Kylene P. , Amer Amal
Published: December 2020

Background

Autophagy is a conserved homeostatic cellular process for clearing dysfunctional organelles, pathogens, and protein aggregates. Neurons in patients with Alzheimer’s disease (AD) exhibit accumulation of immature autophagic vacuoles, which is thought to contribute to amyloid‐beta (Aβ) plaque build‐up and neurotoxicity. However, it is still unclear what causes autophagic dysfunction in neurons and how it contributes to disease progression. Moreover, the role of autophagy in microglia, the innate immune cell and phagocyte of the CNS, has not been explored. We hypothesized that autophagy in microglia in AD is dysfunctional, leading to the inability of microglia to effectively clear Aβ plaque protein aggregates.

Method

We purify microglia from adult mice of an AD mouse model (5xFAD – 5 familial mutations of AD). We are utilizing a novel method developed in our lab to quantify Aβ internalization and degradation which does not require radioactive or fluorophore labeling. Additionally, we are able to visualize Aβ autophagic trafficking utilizing microglia from a mouse with GFP+ LC3, a key autophagy protein involved in the elongation of the autophagosome. Lastly, to understand the components at play in autophagy processing of Aβ in microglia, we are able to reduce expression of various autophagy proteins and microRNAs which target autophagy utilizing a magnetic nanoparticle transfection reagent.

Result

Microglia from AD mice and age‐matched wild‐type littermates internalize the same amount of Aβ, but AD microglia do not efficiently degrade Aβ in vitro. When stimulating autophagy using rapamycin, degradation of Aβ in AD microglia improves. We are able to see that microglia traffic Aβ to an LC3+ autophagosome, and that this trafficking and subsequent Aβ‐degradation is dependent on the expression of various autophagy molecules. Furthermore, we have reduced expression of microRNAs which downregulate autophagy and are overexpressed in AD, and recovered the degradative capacity of AD microglia in vitro.

Conclusion

Together these results indicate that Aβ is degraded via autophagy and that autophagy is defective in AD microglia. Our projects in the lab are seeking to establish additional consequences beyond failure of Aβ‐clearance, such as inability to regulate expression of inflammatory cytokines, and mechanisms behind dysregulated autophagy, such as epigenetic changes.
2020 annual report of Japanese brain bank network for neuroscience research
Authors: Murayama Shigeo , Saito Yuko
Published: December 2020

Background

The Japanese Society of Neuropathology (JSNP) stared the Brain Bank Committee in 1986 and has made continuous effort to establish all Japan Brain Bank Network.

Method

The Brain Bank for Aging Research was established in 1999, including 1,200 frozen brain and peripheral tissues from cohort of aging community and 130 neurodegenerative disorders from all over Japan. BBAR invited members of JSNP to form a brain bank network of Western style, consisting of brain donation, open resource, quality control including neuropathological diagnostic criteria in 2010.

Result

Three brain banks: National Center of Neurology and Psychiatry (NCNP), Mihara Memorial Hospital (MMH) and Fukushimura Hospital (FH) participated the Japanese Brain Bank Network for Neuroscience Research (JBBNNR) and received funding of Ministry of Education, Culture, Sports and Technology, Japan. All resources were from general autopsy and had clinical and radiological information. NCNP was for neurodegenerative and muscle disorders, MMH for ALS, cerebrovascular disorders and prion disease and FH for terminal cases of dementia and aging. In 2020, the Graduate School of Medicine, Osaka University will participate the network for developmental disorders. In japan, autopsy was the main source of human research and our project will be effective for ADNI‐ type clinical study constructing bioresource as well as postmortem human tissue.

Conclusion

Our brain bank project contributes to establish neurobiobank in Japan, bridging genome, bioresource, neuroimages and postmortem human tissue. The main target is human aging and the next step will be human development.
Integrated memory care clinic: Primary care for people living with dementia
Authors: Clevenger Carolyn K , Medders Laura J
Published: December 2020

Background

The Integrated Memory Clinic (IMCC) serves individuals with a dementia diagnosis, such as Alzheimer’s disease or a related disorder, and their care partners who reside in a community setting. The IMCC is America’s first and only comprehensive primary and dementia care practice. The IMCC addresses a primary concern for nearly 6 million Americans living with dementia: How to identify a primary care practice that is knowledgeable about, and sensitive to, the complex medical and social issues associated with a dementia diagnosis and also that can manage the co‐morbidities common in aging. The model takes a primary palliative care perspective, emphasizing aggressive symptom management, advance care planning, and holistic care that focuses on improving the quality of life for the person living with dementia and their care partner. The IMCC’s patient‐centered approach allows patients to receive a broad array of health care services in a single visit from an interdisciplinary team. The IMCC team supports families living with dementia by focusing on the care recipient and care partner well‐being and quality of life, by processes designed to avoid inappropriate acute and emergency care utilization, and through stage‐based support and psychoeducational programs. The IMCC launched a Patient Family Advisory Council simultaneously with enrolling its first patient. The Council meets monthly to review and advise health care providers about clinic operations, communications, billing practices, and sustainability. Currently, four nurse practitioners deliver care to approximately 550 patients. The average age of the patient population is 78 years; 65% of patients are female; 42% of patients are non‐white. The ambulatory care sensitive admission rate ranges from 1.56% to 2.87% for the past 12 months. Performance in hypertension and diabetes management outperforms health system benchmark goals for primary care practices. The IMCC nurse practitioners’ overall patient experience scores are at 97th percentile, representing a meaningful and positive caregiver experience. The IMCC has earned national recognition as a patient‐centered medical home from the National Commission on Quality Assurance. The IMCC represents a novel model of care for people living with dementia and their caregivers and may be a more sustainable model for this growing vulnerable population.
Daily functioning and cognition: Results from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) and Study of Latinos‐Investigation of Neurocognitive Aging (SOL‐INCA)
Authors: Stickel Ariana , Tarraf Wassim , Wu Benson , Marquine Maria J , Vasquez Priscilla M , Daviglus Martha , Estrella Mayra L , Perreira Krista , Gallo Linda , Lipton Richard B , Isasi Carmen R , Kaplan Robert , Zeng Donglin , Schneiderman Neil , Gonzalez Hector M
Published: December 2020

Background

Hispanics/Latinos are at increased risk for Alzheimer’s disease and related dementias (ADRD). Impairments in both cognition and daily functioning are required to meet clinical criteria for ADRD. Poorer cognition and female sex have been associated with greater declines in daily functioning with age. However, predictors of daily functioning among older Hispanics/Latinos are seldom investigated.

Method

Participants included 6292 cognitively healthy adults from the Study of Latinos ‐ Investigation of Neurocognitive Aging (SOL‐INCA), an ancillary study of a subset of participants 50+ years old in the Hispanic Community Health Study/Study of Latinos (HCHS/SOL). Cognitive data (learning and memory, executive functioning, processing speed) were collected at Visit 1 (HCHS/SOL). Daily functioning was assessed using the self‐rated version of the Instrumental Activities of Daily Living (IADL) questionnaire at Visit 2 (SOL‐INCA), an average of 7 years later. We used survey two‐part models (mixture of logit and generalized linear model with Gaussian distribution) and ordered logistic regression to examine whether cognitive performance (on individual tests and a cognitive composite z‐score) was associated with later functioning (risk of any impairment and degree of impairment) and tested for modifications by age (50‐59/60‐69/70+ years: Unweighted ns =2,659, 2,576, 1,057) and sex (male/female: Unweighted ns = 2239, 4053).

Result

After covariates adjustment, higher Visit 1 global cognitive (z‐score units) performance (OR= 0.56; 95% CI=[0.47;0.67]; p<0.001), as well as higher domain specific cognitive function, were associated with lower risk of any IADL dysfunction at Visit 2. Associations were stronger for the oldest group (70+ years) relative to the youngest group (50‐59 years), and this was consistent for all measures, except word fluency. Sex did not modify any associations between cognition and later functioning. Across the full sample, higher scores on learning, memory, and the cognitive composite were also associated with lower degree of IADL impairment.

Conclusion

Our findings confirm that cognitive health is an important predictor of everyday functioning among Hispanics/Latinos 7‐years later, especially in older adulthood. Additionally, IADL functioning among female Hispanics/Latinas was no more or less impacted by cognition as compared to their male counterparts.
Preventive strategy against PM2.5‐induced neuronal cell death
Authors: Kwon Kyoung J.A. , Kim Ryeung‐Eun , Han Seol‐Heui
Published: December 2020

Background

Particulate matter 2.5 (PM2.5) can gain access to the lungs and the circulatory system and may sequentially cross the blood brain barrier (BBB). Recent data suggested that these particles reaching the brain may cause neurological disorders including AD and PD. However, there is no study on how to prevent PM2.5‐induced inflammation and neurotoxicity.

Objective

In this study, we have demonstrated that PM2.5 increases the neuroinflammation and neuronal cell death, and that natural products such as astaxanthin and chlorophyll can prevent the subsequent neurotoxicity, mainly based on its anti‐oxidative and anti‐inflammatory properties. In this study, we have demonstrated that PM2.5 increases the neuroinflammation and neuronal cell death, and that natural products such as astaxanthin and chlorophyll can prevent the subsequent neurotoxicity, mainly based on its anti‐oxidative and anti‐inflammatory properties.

Method

In this regard, we measured 1) the mRNA expression of inflammatory mediators including iNOS, IL‐1b, and IL‐6, 2) the nitric oxide and reactive oxygen species production, 3) signaling molecules such as MAPKs and PI3K, 4) neurite extension and neuronal cell death using the immunocytochemistry and MTT assay. We used a well‐characterized Diesel particulate matter, PM2.5, from SIGMA‐Aldrich.

Result

PM2.5 increased inflammatory cytokines such as IL‐6 and IL‐1b production in rat astrocytes and microglia. Natural products including astaxanthin, chlorophyll and olive oil components attenuated PM2.5‐induced increased NO and other inflammatory cytokines expressions and prevented neuronal cell death in rat primary cortical neurons.

Conclusion

Our results show that PM2.5 activates the glia through inflammation leading to neurotoxicity, and natural products we tested can prevent this through the inhibition of glial activation. These results demonstrate natural products such as astaxanthin, chlorophyll and olive oil components as the candidate against air pollution exposure such as PM2.5.
The Digital Choice Anxiety Survey (DCAS): Initial development and validation
Authors: Hall Aidan , Mak‐McCully Rachel , Glenn Jordan M. , Madero Erica N. , Fuseya Nami , Gills Joshua L. , Gray Michelle , Bott Nick
Published: December 2020

Background

Psychiatric symptomatology, including anxiety, partially comprise the clinical prodrome of dementia. Moreover, increased anxiety may represent a risk factor associated with neurodegenerative disease. Efficient, longitudinal measurement of anxiety remains difficult with traditional paper‐pencil measures. As few digital measures of anxiety symptomatology exist, we aimed to develop and validate a digitally native, efficient and repeatable, anxiety survey to measure self‐reported anxiety in adults: the Digital Choice Anxiety Survey (DCAS).

Method

Development of the DCAS included three studies: Study one included adult participants (n=407) who completed a larger set of anxiety questions, alongside the Penn State Worry Questionnaire (PSWQ) and General Anxiety Disorder 7‐item (GAD‐7) survey. Factor analysis then reduced the larger set of DCAS questions and investigated convergent validity and accuracy of the DCAS. Study two recruited a sub‐sample of the original cohort (n=70) who completed the reduced DCAS survey to investigate convergent validity with the Geriatric Depression Scale (GDS). Study three recruited a separate sample of adults (n =58), who were administered the DCAS at baseline and again approximately two weeks after initial administration to examine test‐retest reliability.

Result

Study one: Mean participant age was 42.92±12.86 years. After removing questions with a Spearman’s correlation greater than or equal to 0.6, DCAS was shortened from 20 to 7 items. The 7 items showed strong internal reliability (Cronbach’s α=0.86), with a one factor solution found utilizing factor analysis (all factors r>0.56). There were positive associations with the PSWQ and GAD‐7 (r=0.82 & r=0.85), with overall accuracy of 0.93 for moderate anxiety on both PSWQ & GAD‐7. Study two: Mean participant age was 48.94±14.63 years. A positive association was found between the 7‐item DCAS and the GDS‐15 (r=0.58, p<0.01). Study three: Mean participant age was 54.79±12.53 years. Participants completed the DCAS an average of 11.7 days apart (SD=1.2) and showed robust test‐retest reliability (Pearson’s r=0.81).

Conclusion

This study provides evidence for psychometric validity and reliability of the DCAS. Follow‐up studies will investigate performance of the DCAS on clinically characterized populations and examine participant‐associated meta‐data.