bluuebunny/crossref_metadata_2025 huggingface dataset:
The importance of Communication and Education: Lessons learned from AGREEDementia
Authors: Rosen Allyson C. ,   AGREEDementia
Published: December 2022

Background

When and how to communicate effectively the results of genetic and biomarker based prediction, detection, and quantification of the brain substrates of dementia involve important ethical and legal issues critical for precision medicine. AGREEDementia is an open working group that focuses on informed discussions and development of educational material to support communication and use of this information.

Method

Members attend two meetings monthly via videoteleconference. One meeting is a targeted working group that focuses on the following: 1. People with Symptoms, 2. People without Symptoms, 3. Research, 4. Ethics/Healthcare Law, 5. Diversity. Members also attend a monthly “all hands” meeting where they receive updates from other groups, partner organizations, and hear presentations on emerging research and resources.

Result

Over the past few years AGREEDementia has produced several collaborative papers, webinars, and decision tools for people considering undergoing biomarker testing that will be discussed. Membership continues to grow to over 120 though level of involvement varies. The group is largely comprised of academic researchers (76%) including neurologists, neuropsychologists, clinical trial coordinators, ethicists, and healthcare lawyers. The second largest subgroup was from advocacy groups and stakeholders (18%) and 6% are students. Collaborations with other organizations including the NIA, Alzheimer’s Association/ISTAART, the Lewy Body Dementia Association, Association for Frontotemporal Dementia, and Cohen Veterans Bioscience greatly enrich the group by publicizing conferences and collaborating on papers and products. The Alzheimer’s & Dementia Outreach, Recruitment & Engagement at NIA also disseminates decision tools and other materials. Over time, the stakeholder group developed from an audience providing consultation to a creative force that pioneered a program to support people with cognitive dysfunction attending AAIC and other scientific conferences. The Diversity workgroup was added in order to mentor and teach research staff in sensitive outreach to diverse cohorts. The ongoing, monthly, lecture series and links to all these materials are hosted at a website, AGREEDementia.com.

Conclusion

With controversies around how best to integrate biomarker and genetic information into clinical care, when to share research data with the public, and implement novel biomarker‐based therapies, AGREEDementia has provided an open forum for all to visit and consult.
Heterogeneity of response to methylphenidate in apathetic patients in the ADMET 2 Trial
Authors: Lanctôt Krista L. , Perin Jamie , Vieira Danielle , Rosenberg Paul B. , Herrmann Nathan , Shade David , Lerner Alan J. , Padala Prasad R , Brawman‐Mintzer Olga , van Dyck Christopher H , Porsteinsson Anton P. , Craft Suzanne , Levey Allan I. , Mintzer Jacobo E
Published: December 2022

Background

Apathy is the most common neuropsychiatric symptom in Alzheimer’s disease (AD), however there are no approved treatments. In the recent Apathy in Dementia Methylphenidate Trial 2 (ADMET 2), methylphenidate treatment resulted in a significant reduction in apathy with a small to medium effect size. Given these results and the clinical heterogeneity of apathetic AD patients, we assessed the heterogeneity of response to methylphenidate in ADMET 2 to identify individuals who may benefit particularly from this treatment.

Method

In this multicenter, randomized, placebo‐controlled clinical trial of 177 AD patients with clinically significant apathy, participants were randomized to receive methylphenidate or placebo for 6 months. Twenty‐one unplanned potential predictors of treatment outcomes were assessed. Predictors were chosen for multivariate modeling based on estimated effect difference, difference of change in the Neuropsychiatric Inventory (NPI)‐apathy subscale of two or more at the 6 month visit. Participants were then grouped into 10 subgroups by their index scores, which were constructed based on the predictors with the biggest difference in effect.

Result

Of the 21 predictors, six were chosen for multivariate modelling based on having an effect difference of 2 or more in the NPI apathy score. Four of these predictors had a significant interaction with the treatment. Methylphenidate was more effective in participants less likely to have baseline anxiety (‐3.1, 95% CI ‐5.7 ‐ ‐0.5, p = 0.023) or agitation (‐3.6, 95% CI ‐6.1 ‐ ‐1.1, p = 0.005) as measured by the NPI, taking a cholinesterase inhibitor (‐4.1, 95% CI ‐6.7 ‐ ‐1.3, p = 0.004), taking at least one AD medication (‐4.0, 95% CI ‐6.9 ‐ ‐1.1, p = 0.008), highly educated (‐2.1, 95% CI ‐5.4 – 1.3, p = 0.231), and low functional capacity (‐2.6, 95% CI ‐5.55 – 0.26, p = 0.076) as measured by the Activities of Daily Living scale.

Conclusion

Individuals who were less anxious or agitated, more highly educated, on treatment for Alzheimer’s disease, and with low functional capabilities were more likely to benefit from methylphenidate when compared to placebo. Consistent with its potential activating effects, methylphenidate may be particularly beneficial for subgroup of apathetic AD participants with lower baseline anxiety and agitation.
Cell‐type specific alterations in intrinsic excitability and neurotransmission in short‐term virally induced model of Alzheimer’s Disease
Authors: Goettemoeller Annie M , Rowan Matthew JM
Published: December 2022

Background

Alzheimer’s Disease (AD) is a neurodegenerative cascade resulting in neuronal dysfunction and memory loss, classically characterized by the deposition of amyloid plaques throughout the brain. Although deposition of these proteins correlates with cognitive loss in AD, these aggregates may not be causally related to initial neuronal and circuit pathology in AD. Interestingly, evidence in AD patients and mouse models has reported cortical circuit hyperexcitability prior to plaque pathology. The cell and molecular mechanisms underlying hyperexcitability in early‐stage AD remain unclear. In healthy brains, normal circuit operations are maintained through a fine‐tuned balance between excitatory (pyramidal) and inhibitory neuron activity. In several APP‐expressing mouse models, pyramidal and inhibitory neuron physiology are differentially affected and also evolve with disease severity. However, these parameters have not been explored in an adult‐onset APP model.

Method

We examined rapidly emerging physiological changes in cortical PV interneurons and neighboring pyramidal neurons in an adult‐onset AD model. We analyzed contributions of overexpressed wild‐type human amyloid precursor protein (WT hAPP) using an AAV viral approach. We fluorescently targeted cell types for whole‐cell patch‐clamp electrophysiology using a PV‐specific enhancer labeling technique or an excitatory neuron‐specific AAV. Lastly, we optogenetically stimulated PV interneurons to assess neurotransmission onto neighboring pyramidal cells.

Result

We report alterations in cortical PV interneuron and pyramidal neuron intrinsic excitability, as well as PV‐to‐pyramidal neurotransmission, after short‐term induction of hAPP virally. Interestingly, each of these two neuronal subtypes displayed unique changes suggesting different cell‐type‐specific molecular alterations.

Conclusion

This breakdown of APP processing and its effects on PV interneuron and pyramidal neurons provides potential insights into early cell‐type‐specific mechanisms of the pathogenesis of Alzheimer’s Disease, thus providing specific interventions to ameliorate early symptoms and potentially slow the progression towards severe disease.
Cerebrovascular Dysfunction at the Intersection of Ischemia and Alzheimer’s Disease
Authors: Ismail Ozama , Pike Martin , Zhang Wenri , Mishra Anusha
Published: December 2022

Background

Cerebrovascular dysregulation is one of the earliest detectable changes in Alzheimer’s disease (AD) etiology that precedes the descent into dementia1. Ischemic events such as stroke and silent infarcts trigger cerebrovascular dysfunction2,3, accelerate cognitive decline4 and increase dementia risk5. Further, the resulting decrease in cerebral blood flow (CBF) can induce the formation of amyloid β6. Thus, we examined cerebrovascular function at the intersection of ischemia and AD by measuring CO2‐evoked hyperemia and neurovascular coupling (NVC) after small strokes in wild type and Tg2576 model of AD‐related amyloidosis.

Method

We established a model of small ischemic strokes by performing a short 30‐minute middle cerebral artery occlusion, yielding a mild subcortical infarct (MSCI). We performed MSCI in 6‐month old Tg2576 and littermate wild‐type mice (WT) and compared them to naïve mice. We used arterial spin‐labeling (ASL) MRI to quantify CBF and CO2‐evoked hyperemia at 10 and 14 months of age and Laser Doppler flowmetry (LDF) to measure NVC at 14 months of age. We also quantified hippocampal volumes.

Result

There was no apparent change in hippocampal volume after MSCI in either genotype. There was a reduction in NVC in WT+MSCI mice in both hemispheres, with a trend towards greater reduction in Tg2576+MSCI mice. The CO2‐evoked hyperemia was also reduced in WT+MSCI and Tg2576+MSCI mice compared to WT naïves. Curiously, naïve Tg2576 mice showed the most severe impairment in CO2‐evoked hyperemia, which appeared improved in Tg2576+MSCI. We are re‐examining this finding.

Conclusion

Using an innovative mixed model of mild ischemia and amyloidosis, here we report that the two pathologies can synergize to accelerate cerebrovascular impairments. Strikingly, we found that even a small one‐sided stroke can impair cerebrovascular function bilaterally. Future studies will determine the extent to which amyloid pathology and cognitive deficits are exacerbated by such impairments. Our findings suggest that targeting early cerebrovascular dysfunction after ischemia may prove useful in deterring the onset of dementia later in life.

References:

Iturria‐Medina, Y. et al. (2016) Nat. Commun. 7, 11934.

Salinet, A.S.M., Robinson, T.G. & Panerai, R.B. (2015) J. Appl. Physiol. 118, 170–177.

Li, Z., McConnell, H.L. & Mishra, A. (2021). Front Cell Nuerosci. 15: 762843.

Levine, D.A. et al. (2015) JAMA. 314, 41–51.

Vermeer, S.E., Longstreth, W.T. & Koudstaal, P.J. (2007) Lancet Neurol. 7, 611–9.

Wen, Y., Onyewuchi, O., Yang, S., Liu, R. & Simpkins, J.W. (2004) Brain Res. 1009, 1–8.
Multi‐parametric Neuroimaging in a Non‐Human Primate Model of Sporadic Cerebral Amyloid Angiopathy (Saimiri boliviensis boliviensis)
Authors: Murray Sean , Veraart Jelle , Karimi Sohail , Genovese Thomas S , Leung Jonathan , Goldman Hannah , Patel Akash G , Gray Stanton B , Zhang Jiangyang , Hopkins William D , Williams Lawrence E , Wisniewski Thomas , Zaim‐Wadghiri Youssef , Scholtzova Henrieta
Published: December 2022

Background

Squirrel monkeys (SQMs) are a unique non‐human primate model (NHP), which unlike other NHPs, develops extensive age‐associated cerebral amyloid angiopathy (CAA). The growing recognition of CAA contribution to clinical decline and CAA‐related complications in current clinical trials underscore the utility of the SQM model for studying CAA pathology development. Neuroimaging can play a key role in noninvasively detecting and monitoring disease progression in conjunction with histological methods. We have previously shown the utility of quantitative R2
* to map age‐related differences in SQM neuropathology cross‐sectionally and longitudinally. Here we aim to complement our protocol with advanced MRI approaches sensitive to brain microstructure to enable early and specific detection of alteration in tissue integrity. Our overarching goals aim to establish the in vivo and ex vivo MRI metrics profile of young and geriatric SQM cohorts.

Method

2D T2‐w (a) Turbo‐spin‐echo (TSE) and (b) FLAIR MRIs were acquired in vivo and ex vivo, while (c) multi‐shell diffusion‐weighted MRI (DWI) was limited to ex vivo imaging. Diffusion tensor imaging (DTI) and Diffusion kurtosis imaging (DKI) metrics were derived from comprehensive DWI datasets. Immunohistochemistry was subsequently performed to characterize the microstructural underpinnings of MRI abnormalities.

Result

Bothin vivo and ex vivo T2‐w TSE and FLAIR helped identify spontaneous asymmetric hyperintensities (ARIA‐E) in geriatric SQMs (21‐23yrs), predominantly in the parieto‐occipital WM, not seen in the young cohort (5‐yrs). Importantly, DKI‐derived mean kurtosis proved to be the most sensitive of DWI metrics for detecting lesions in the parieto‐occipital region. Widely adopted DTI metrics were far less sensitive in identifying microstructural changes. Histological assessment of region‐matched sections revealed Iba1 microgliosis, as well as immunoreactivity for both extravascular fibrinogen and decreased MBP when compared to the contralateral side. Aß immunohistochemistry (6E10/4G8) confirmed presence of CAA in the affected regions.

Conclusion

Advanced DWI models are sensitive and specific neuroimaging tools for identifying abnormalities associated with tissue integrity that are potentially linked to age‐associated cerebrovascular dysfunction. Ex vivo conventional MRI detected similar abnormalities observed in vivo and proved to be a useful step to validate the performance of advanced imaging strategies, which can help bridge the gap between in vivo MRI and histology.
Higher physical activity is associated with greater myelin content in older adults with cerebral small vessel disease and mild cognitive impairment
Authors: Silva Nárlon Cássio Boa Sorte , Dao Elizabeth , Hsu Chun Liang , Tam Roger , Lam Kevin , Alkeridy Walid Ahmed , Stein Ryan G , Laule Cornelia , Vavasour Irene M , Liu‐Ambrose Teresa
Published: December 2022

Background

Myelin loss is considered a marked feature of cerebral small vessel disease (cSVD). Although physical activity levels may exert protective effects over cSVD pathological changes, its specific relationship with myelin content in this population is unknown. Therefore, we investigated whether physical activity levels are associated with myelin content in community‐dwelling older adults with cSVD and mild cognitive impairment.

Method

We analyzed cross‐sectional data from older adults with cSVD and mild cognitive impairment in our laboratory. Myelin content was assessed using MRI with a multi‐echo gradient and spin echo T2 relaxation sequence, indexed as myelin water fraction (MWF). Physical activity levels were estimated using the Physical Activity Scale for the Elderly (PASE). Hierarchical regression models adjusting for total intracranial volume, age, sex, body mass index, and education were conducted to determine the associations between MWF and PASE. Significant models were further adjusted for white matter hyperintensity volume.

Result

Individuals (n = 102) with cSVD and mild cognitive impairment (mean [SD], age = 74.7y [5.5], Montreal Cognitive Assessment = 21.76 [3.2]), 63.7% female) were included. In adjusted models of tract‐specific cerebral white matter, physical activity was linked to higher MWF in the sagittal stratum (Unstandardized B [95% CI]: 0.014 [0.004 to 0.023], R2
change = 0.08, p = 0.004), anterior corona radiata (0.008 [0.000 to 0.015], R2
change = 0.04, p = 0.049), and genu of the corpus callosum (0.011 [0.002 to 0.020], R2
change = 0.05, pchange = 0.018). Similarly, physical activity also associated with MWF in whole‐brain white matter (0.007 [0.000 to 0.014], R2
change = 0.04, pchange = 0.046). White matter hyperintensity volume did not modify any of these associations.

Conclusion

Physical activity may be one important component of maintaining myelin in older adults with cSVD. Future research should address whether myelin content is a sensitive neuroplasticity marker sensitive to physical activity changes or exercise interventions.
Plasma Signatures of Lipid and Cellular Energy Metabolism in the 5xFAD Mouse
Authors: Gross Thomas J , Vu Michael M , Malhas Rond , Green Kim N , MacGregor Grant R , Tenner Andrea J , LaFerla Frank , Mapstone Mark
Published: December 2022

Background

Identifying early biomarkers of Alzheimer’s disease (AD) could help us understand mechanisms of AD and provide opportunities to develop novel therapeutics. The plasma metabolome is a rich source of potential biomarkers. Our goal is to analyze metabolomics in new models of AD being developed by MODEL‐AD. Here, we examine lipid and cellular energy metabolism via plasma metabolomics in the 5xFAD mouse.

Method

We examined age‐dependent changes in the abundance of plasma metabolites obtained from 10 (5M,5F) 5xFAD and 10 (5M,5F) wild type (WT) mice at 4‐, 12‐, and 18‐months. Blood was collected at time of death and the plasma fraction was analyzed using liquid chromatography mass spectrometry (LC‐MS). We measured 762 lipids and 204 polar metabolites. We used Metaboanalyst 5.0 for all analyses.

Result

We found increased abundance of acylcarnitines in 5xFAD mice relative to WT mice at 4‐months of age (q < 0.05) which reversed by 18 months of age where there was a relative depletion of acylcarnitines in the 5xFAD mice (q < 0.05). The best 10 discriminant features from Component 1 of a sPLS‐DA were acylcarnitines (4/10) and lipids (4/10) at 4‐months, lipids (8/10) at 12‐months, and acylcarnitines (6/10) at 18‐months. Using these 10 features, ROC area under the curve (AUC’s) was 0.95 (95%CI 0.78‐1.0) at 4‐months, 0.91 (95%CI 0.61‐1.0) at 12‐months, and 1.0 (95%CI 1.0‐1.0) at 18‐months.

We examined changes in multivariate lipid and metabolite patterns between the two groups over time. We found 30 metabolites with significant interactions between Time and Group. Pathway analysis using these 30 metabolites showed enrichment for Glycerophospholipid Metabolism (q < 0.05) indicating the 5xFAD mice show more rapid depletion of these particular lipids over time.

Conclusion

We see changes in cellular energy and lipid metabolism in aging 5xFAD mice. These changes in energy metabolism may reflect an early compensatory shift as amyloid plaques appear which then fails as the plaques establish and the animal ages. We also find significant time‐dependent changes in lipid and metabolite abundances especially metabolites associated with glycerophospholipid metabolism. These age‐dependent changes in lipid and metabolomic profiles of the 5xFAD relative to WT suggest a dynamic and complex metabolic milieu.
Machine learning‐based prediction of cognitive outcomes in de novo Parkinson's disease
Authors: Harvey Joshua , Reijnders Rick A , Cavill Rachel , Duits Annelien , Köhler Sebastian , Eijssen Lars M.T. , Rutten Bart P.F. , Shireby Gemma , Torkamani Ali , Creese Byron , Leentjens Albert F.G. , Lunnon Katie , Pishva Ehsan
Published: December 2022

Background

Cognitive impairment is a debilitating symptom in Parkinson’s disease (PD), with high variability in onset and course of progression. This present study aimed to establish an accurate multivariate machine learning model to predict cognitive outcome in newly diagnosed PD.

Method

Using baseline measures from the Parkinson’s Progression Markers Initiative (PPMI) cohort we subset clinical, biofluid and genetic/epigenetic variables. Annual cognitive assessments over an eight‐year time span were used to define two outcomes of i) dementia conversion, and ii) cognitive impairment. Outcomes and variable subsets were tested using multiple machine learning (ML) algorithms (random forest, elasticnet, SVM‐linear and cforest) to predict prognosis of individual cognitive decline in PD. Prediction was assessed using multiple measures including Area under the Curve (AUC) and Mathews Correlation Coefficient (MCC).

Result

For both cognitive outcomes, irrespective of the of ML algorithm, models consisting of clinical variables alone performed best, with high specificity and the largest AUC's (0.88 ‐ 0.92) and MCC's (0.57‐0.80). Notably, cognitive impairment outcome showed better sensitivity than dementia conversion outcome (0.72 – 0.81 vs 0.29 – 0.64, respectively). Addition of biological and genetic variables did not largely improve the model performance. However, a number of cerebrospinal fluid (CSF) proteins and epigenetic markers showed high predictive weighting in multiple models, when included alongside clinical variables.

Conclusion

Machine learning algorithms can accurately predict cognitive impairment development in PD. Within the generated models, clinical predictors appear to play a more prominent role than biological predictors. We further present additional future study data, expanding epigenetic research into PD dementia.
High tau PET binding reveals a constellation of beta‐amyloid positivity and fast cognitive decline
Authors: Ioannou Konstantinos , Bucci Marco , Nordberg Agneta K , Chiotis Konstantinos
Published: December 2022

Background

Beta‐amyloid Positron Emission Tomography (PET) efficiently detects beta‐amyloid plaques supporting the presence of a pathophysiological landmark of Alzheimer’s disease (AD) continuum, but lacks specificity regarding the prediction of future cognitive status. The increasing validation of tau PET tracers raises questions about whether a tau PET biomarker could predict clinically relevant cognitive decline and its potentially beneficial role in the assessment of individuals who belong to the AD continuum.

Method

We identified 335 subjects [cognitive normal (CN; n=217), mild cognitive impairment (MCI; n=99), dementia (n=19)] with baseline beta‐amyloid and tau PET scans that have completed a follow‐up of at least two years, from the Alzheimer’s Disease Neuroimaging Initiative dataset. First, we assessed the accuracy of tau PET to discriminate the MCI patients that will convert to AD. Based on Alzheimer’s Disease Assessment Scale–Cognitive Subscale, we used linear mixed‐effects models to define the annual rate of cognitive change of all individuals and Gaussian mixture modelling to cluster them as either fast or slow decliners. Next, group comparisons and the accuracy of tau PET to discriminate between them were tested. Finally, the association between baseline tau PET SUVR and cognitive rate of change was assessed with linear models

Result

The individuals with beta‐amyloid positivity and fast cognitive decline showed the highest tau PET binding values independently of baseline cognitive status, compared to the other groups (beta‐amyloid negative with fast or slow decline and beta‐amyloid positive with slow decline). Baseline tau PET binding could determine fast decliners with a beta‐amyloid positive scan with an accuracy of 85% (composite temporal region of interest). Similarly, tau PET binding accuracy was high in determining MCI patients that would be both beta‐amyloid positive and show progress in their diagnosis. Linear models showed that baseline tau PET binding is related to the annual rate of cognitive decline in beta‐amyloid positive individuals.

Conclusion

High baseline tau load is coupled with both beta‐amyloid pathology and an accelerated profile of cognitive decline. Tau PET imaging could offer substantial advantages over beta‐amyloid PET imaging since it provides important information about both the underlying pathophysiology and the prognosis of the disease.
Temporal Characterization of the Amyloidogenic APP/PS1dE9;hAPOE4 Mouse Model of Alzheimer’s Disease
Authors: Grenon Martine , Bathini Praveen , Papavergi Maria‐Giusy , Schroeder Maren K , Lemere Cynthia A.
Published: December 2022

Background

The development of immunotherapies against Aβ is burdened by clinical adverse events (AEs) observed as amyloid‐related imaging abnormalities (ARIA) on magnetic resonance imaging scans. The vascular inflammatory AEs have been reported in AD clinical trials administrating certain anti‐Aβ plaque‐binding antibodies and are thought to represent cerebral microhemorrhages and vasogenic edema. ARIA incidence appears apolipoprotein (APOE) genotype‐dependent, wherein APOE E4 allele carriers are at higher risk when compared to non‐carriers. With hopes to robustly model patients most at risk for the vascular complications of anti‐Aβ immunotherapy, we selected a relatively new transgenic mouse model bearing the human APOE E4 gene. The model has not yet been extensively characterized at multiple age points. To assess the face validity of the mouse model, we are conducting a battery of histological and biochemical tests.

Methods

To evaluate age‐ and sex‐related pathological changes, we collected brain and blood plasma from euthanized male and female APP/PS1dE9;hAPOE4 (APP/E4) mice across 3 ages: 8‐, 12‐ and 16‐months. General‐ and pGlu3‐Aβ levels were quantified using enzyme‐linked immunoassays (ELISA). Prussian Blue hemosiderin staining was used to examine microhemorrhages.

Results

Immunoassays of brain homogenates exhibited significantly higher insoluble Aβx‐40, Aβx‐42 and pGlu3Aβ levels in 16‐month‐old mice compared to 8‐ and 12‐month‐old mice. Moreover, the 16‐month‐old females demonstrated significantly higher levels of Aβx‐40 and pGlu3Aβ than age‐matched males. Hemosiderin staining was observed in all 12‐ and 16‐month mice, however no significant differences in abundance was found between the 2 age points. Immunostainings for plaque deposition of various Aβ species, vascular amyloid, dystrophic neurites and gliosis are ongoing.

Conclusions

Age‐ and sex‐dependent increases in Aβ deposition were revealed in the APP/E4 mouse model. Preliminary evidence for microhemorrhage was observed. Subsequent analyses will better characterize the translational credibility of APP/E4 as a model for future nonclinical immunotherapies targeting Aβ. (1RF1AG058657‐CAL)
Quantifying Extent, the Spatial Distribution of Flortaucipir PET Uptake, in an Autopsy Cohort and its Correspondence to Post‐Mortem Staining of Alzheimer’s Disease Biomarkers
Authors: Kennedy Ian Andrew , Kotari Vikas , Southekal Sudeepti , Pontecorvo Michael J.
Published: December 2022

Background

In Alzheimer’s disease, neurofibrillary tangle (NFT) burden can be characterized in postmortem staining and in vivo NFT‐specific flortaucipir PET by increases in intensity and spatial distribution. Previous work compared intensity based standard uptake value ratios (SUVRs) from Early Tau and MUBADA volumes of interest (VOIs) in detecting Braak stage pathology. We propose a measure called Extent to quantify the spatial distribution of NFT‐specific uptake in flortaucipir PET from the Phase III study AV‐1451‐A16 and compare against Early Tau and MUBADA SUVRs in detecting Braak stage pathology and post‐mortem amyloid burden.

Methods

This retrospective analysis of the AV‐1451‐A16 study included 60 subjects that underwent ante‐mortem flortaucipir imaging and post‐mortem assignment of Braak stages and Thal/CERAD scoring for amyloid burden. The processing of the flortaucipir scans and the recording of neuropathological findings were performed as previously described except cerebellum crustaneous was used as a reference region. Extent was calculated by 1) creating a Z‐score image using 16 young cognitively normal controls, 2) retaining voxel clusters with Z‐scores smaller than a false discovery corrected p‐value of 0.01, and 3) calculating the ratio of the number of surviving voxels against the total number of voxels in the mask. Flortaucipir positivity was defined as greater than 2.5 SD of the mean of young controls for Early Tau and MUBADA SUVRs and as non‐zero for Extent. Amyloid positivity was defined by a Thal/CERAD scoring of 2 or higher and compared to flortaucipir positivity using sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV).

Results

Extent detected subjects with flortaucipir positivity comparably to Early Tau in Braak stages I, II, and III while detecting more subjects with flortaucipir positivity in Braak stages V and VI than Early Tau and MUBADA (Table 1 and Figure 1). For amyloid positivity, Extent had the highest sensitivity (79.62%) and NPV (29.42%) while MUBADA had the highest specificity (87.50%) and PPV (97.06%) (Table 2).

Conclusion

Based on the Correspondence to post‐mortem staining, the Extent measure of flortaucipir spatial distribution may provide benefit over intensity based SUVRs in detecting flortaucipir and amyloid positive subjects for inclusion in future studies.
Tau PET imaging with 18F‐PI‐2620 in patients with corticobasal syndrome: a case series
Authors: Santibanez Rodrigo A , Mendez‐Orellana Carolina , Juri Carlos , Escobar Sebastian , Bustamante Gabriel , Quiroga Cosme , Contreras Nicolas , Haeger Arlette , Amaral Horacio , Kramer Vasko
Published: December 2022

Background

Corticobasal syndrome (CBS) is the clinical phenotype originally described for corticobasal degeneration (CBD), a rare sporadic neurodegenerative 4‐repeat tauopathy, clinically characterized by the presence of asymmetric parkinsonism, apraxia, cortical sensory deficits, dystonia, myoclonus, and cognitive dysfunction. However, patients with CBS can have neurodegenerative pathology other than CBD, like progressive supranuclear palsy (PSP), Alzheimer's Disease (AD), Vascular Dementia, and Lewy body dementia. Selective tau tracers have made it possible to detect the presence of abnormal tau deposits in vivo. 18F‐PI‐2620 is a tau‐specific positron emission tomography (PET) tracer with a high binding affinity for aggregated tau. This study aims to investigate the potential role of 18F‐PI‐2620 as a biomarker in patients with CBS.

Method

Four participants with clinical features consistent with probable CBS according to the 2013 Armstrong diagnostic criteria underwent dynamic PET scans for 75 min after injection of 18F‐PI‐2620. Specific binding ratios were derived from averaged PET images from 45‐75 min post‐injection.

Result

First two patients had robust increases in 18F‐PI‐2620 uptake in temporal, parietal, and occipital cortical regions with relative sparing of globus pallidus and putamen. In the third patient, 18F‐PI‐2620 uptake was observed in the globus pallidus and putamen with relative sparing of cortical regions. The fourth patient had low 18F‐PI‐2620 uptake localized in the globus pallidus, temporal, and parietal regions.

Conclusion

In the first two patients, 18F‐PI‐2620 binding distribution resembles what was described for Alzheimer's disease. In the third patient, 18F‐PI‐2620 uptake pattern suggests PSP. In this particular case, we hypothesize the definitive diagnosis is PSP‐CBS, a rare clinical presentation of PSP with CBS features. Finally, the fourth patient had low 18F‐PI‐2620 uptake but in areas clearly related to AD, PSP, and probably CBD. Our findings support CBS's heterogeneous pathological basis and suggest that 18F‐PI‐2620 could represent a valuable tool in the assessment of CBS, establishing an underlying tauopathy in most cases. However, we suspect 18F‐PI‐2620 in CBS is insufficient to distinguish, in some cases, AD pathology from other tauopathies. Therefore, the use of additional biomarkers to establish the presence of amyloid pathology should be considered. Further studies are needed to confirm these preliminary results.
Biological characterization with CSF proteomics of dementia with Lewy bodies (DLB) according Alzheimer's disease (AD) biomarker profile
Authors: Vermunt Lisa , Lemstra Afina W. , Doelkahar Brian S , Irwin David J. , van de Beek Marleen , Chen‐Plotkin Alice , van der Flier Wiesje M. , Peeters Carel F.W. , Pijnenburg Yolande A.L. , Tijms Betty M. , Visser Pieter Jelle , del Campo Marta , Teunissen Charlotte E.
Published: December 2022

Background

In dementia with Lewy bodies (DLB), Alzheimer co‐pathology is common, and associated with an unfavorable prognosis. For targeted treatment development it is crucial to understand the biological underpinnings of DLB with Alzheimer co‐pathology, and how it differs from Alzheimer disease (AD). We performed a cerebrospinal fluid (CSF) proteome profiling to biologically characterize DLB with and without AD co‐pathology in vivo.

Method

Patients from Amsterdam Dementia Cohort, Twin60+, and UPENN, we selected individuals with DLB (n=109), and subcategorized them in CSF Aβ42 (A‐/A+) and pTau‐181 (T‐/T+) biomarker groups (A‐T‐ n=29; A‐T+ n=16; A+T‐ n=29; A+T+ n=36), and patients with AD dementia (A+T+ n=230) and cognitively normal controls (A‐T‐ n=246). CSF levels of 810 proteins were measured with the Olink proximity extension assay. We compared protein profiles from the DLB subgroups and AD dementia with controls with ANCOVA adjusted for age and sex. Proteins with significant FDR‐controlled p‐values were used to perform functional enrichment analyses in KEGG and GO Biology and Cellular components using STRING‐DB.

Result

DLB A‐T‐ exhibited least abnormalities compared to controls, with 6 proteins dysregulated (Figure 1). DLB A‐T+ had 12 upregulated proteins. DLB A+T‐ exhibited the most distinct protein dysregulation, with 16 upregulated proteins, and 312 downregulated proteins. DLB A+T+ had 3 downregulated and 18 upregulated proteins. Of the DLB groups, DLB A+T+ had with 15 proteins the largest overlap in dysregulated proteins with AD dementia patients (Figure 1). In functional enrichment analysis for DLB A‐T‐ no enrichment was present. DLB A‐T+ and DLB A+T+ groups were enriched for proteins involved cytokine‐cytokine interactions. The DLB A+T‐ group had top enrichment for basement membrane components and phenylalaline metabolism upregulation, and cell adhesion molecules, VEGF, and axon guidance and morphogenesis downregulation.

Conclusion

The CSF proteome in DLB varied depending on the CSF AD profile. The overlap in CSF proteome between AD dementia and DLB with signs of AD seems to cover mostly immune‐mediated processes. The biological abnormalities in DLB with isolated abnormal CSF Aβ42 were most distinct, possibly pointing to a unique subtype. Using biomarkers and proteomics for understanding the biology behind AD co‐pathology could guide treatment development for DLB.
Longitudinal cerebrospinal fluid phosphorylated tau181 and total tau do not reflect tau PET retention in dominantly inherited Alzheimer disease
Authors: McDade Eric , Wang Guoqiao , Li Yan , Gordon Brian A. , Benzinger Tammie L.S. , Fagan Anne M. , Llibre‐Guerra Jorge J , Cruchaga Carlos , Clifford David B. , Xiong Chengjie , Perrin Richard J. , Bittner Tobias , Holdridge Karen C. , Yaari Roy , Bateman Randall J. ,   Dominantly Inherited Alzheimer Network
Published: December 2022

Background

Although Alzheimer disease (AD) related changes of tau can be measured in fluids and by positron emission tomography (PET), it remains unclear how these two are associated across the AD spectrum. To further explore the association between soluble tau related biomarkers‐ cerebrospinal fluid (CSF) total tau and p‐tau181‐ and neurofibrillary tangles (NFT) (flortaucipir PET), we compared longitudinal change of each in the dominantly inherited AD trials unit (DIAN‐TU) trial of solanezumab and gantenerumab.

Method

73 Mutation carriers (MC) (31 CDR>0) from the DIAN‐TU‐001 study (30 gantenerumab, 20 solanezumab, 23 shared placebo) underwent longitudinal collection of CSF for measurement of p‐tau181 and total tau, and flortaucipir tau PET over 2.3 (0.92) mean (SD) years; tau PET was available at baseline for 26% of participants. Individual rates of change for CSF measures and tau PET retention were estimated using the method of least squares. Spearman correlations of the rate of change were used to assess the association between CSF and tau PET.

Result

For all MCs the change of CSF p‐tau181 and tau had no association with change in tau PET standard uptake value ratio SUVR (r = 0.01, p‐0.95 and r = 0.10, p‐0.43), figure. When limiting the correlations to those in the gantenerumab arm, where a significant reduction in p‐tau181 and total tau was previously identified, there remained no clear association between a reduction in soluble tau measures in CSF and change in tau PET SUVR (r=‐0.21, p‐0.27 and r= ‐0.08, p‐0.71).

Conclusion

In dominantly inherited AD, soluble p‐tau181 and total tau changes in CSF appear to reflect disease processes that are distinct from the change in NFT pathology measured by tau PET. These results suggest the need for caution in extrapolating treatment related changes of soluble tau to those of NFT pathology.
Brain metabolism changes in middle‐aged asymptomatic APOE‐ε4 carriers. The PESA Study
Authors: Tristão‐Pereira Catarina , Toribio‐Fernández Raquel , Sanchez‐Gonzalez Javier , Gispert Juan Domingo , Ibañez Borja , Cortes‐Canteli Marta , Fuster Valentin
Published: December 2022

Background

Apolipoprotein E (APOE) is the major genetic risk factor for late‐onset Alzheimer’s disease (AD) and is implicated in cardiovascular disease. TheAPOE‐ε4 allele is associated with brain hypometabolism in AD, mild cognitive impairment (MCI) (Mosconi et al. Neurology 2004) and in cognitively unimpaired middle‐aged individuals (Reiman et al. NEJM 1996). Greater longitudinal decreases in brain metabolism were reported in APOE‐ε4 carriers with MCI (Paranjpe et al. Neuroimage Clin 2019), but studies on brain metabolism longitudinal changes in unimpaired middle‐aged APOE‐ε4 carriers are scarce and with relatively small sample sizes (Reiman et al. PNAS 2001). The Progression of Early Subclinical Atherosclerosis (PESA) study is a longitudinal study following >4000 asymptomatic middle‐aged subjects deeply screened for cardiovascular risk factors (CVRFs) (Fernandez‐Ortiz et al. AHJ 2013). Individuals with the highest burden of atherosclerosis underwent FDG‐PET at baseline and CVRFs were associated with hypometabolism in AD regions (Cortés‐Canteli & Gispert et al. JACC 2021). Those individuals underwent a 6‐year follow‐up FDG‐PET. Here, we investigate the effect of APOE genotype on brain metabolism progression in middle‐aged asymptomatic individuals.

Method

365 cognitively unimpaired adults (mean age 50 years old) were genotyped for APOE and underwent two FDG‐PET studies (Table). Baseline and follow‐up images were spatially normalized to a group template in the MNI space. FDG‐uptake was normalized to the pons and images were subtracted, yielding a measure of brain metabolic change. An ANOVA model was carried out to compare brain metabolism change between APOE‐

Result

At the global level, we observed significantly greater decreases in FDG uptake in ε4 carriers compared to the reference ε3/ε3 genotype (p=0.024). Voxelwise analysis showed greater decreases between ε4 carriers and non‐ε4 carriers in the precuneus, supramarginal gyrus, hippocampus and anterior cingulate gyrus (Figure).

Conclusion

Asymptomatic middle‐aged APOE‐ε4 carriers have a greater decline in brain metabolism in regions known to display hypometabolism in AD, suggesting an increased vulnerability. Further analysis will reveal the extent to which AD pathology and/or other risk factors may mediate this association.
MIND diet associated with less hippocampal sclerosis: A Community‐Based Neuropathologic Study
Authors: Agarwal Puja , Agrawal Sonal , Cherian Laurel J , Aggarwal Neelum T. , James Bryan D , Holland Thomas Monroe , Bennett David A , Barnes Lisa L. , Leurgans Sue E. , Schneider Julie A
Published: December 2022

Background

Mediterranean‐DASH Intervention for Neurodegenerative Delay (MIND) diet is associated with slower cognitive decline, reduced Alzheimer’s dementia risk, and greater brain volume. We have also shown MIND diet is associated with less Alzheimer’s disease (AD) pathology. Hippocampal sclerosis (HS, severe neuronal loss and astrogliosis in CA1/subiculum), is increasingly recognized as an important pathologic finding associated with TDP‐43 (“LATE‐NC), AD pathology, and dementia. The pathogenesis of HS is not clear but may be neurodegenerative and/or vascular. This study investigates the association of the MIND diet with hippocampal sclerosis in autopsied brains from a community sample.

Methods

The study was conducted among 581 deceased participants (age at death = 91.3 ± 6.1 years; 72% female, education = 14.8 ± 2.8 years) of the Rush Memory and Aging Project. The coronal section of the mid hippocampus CA1 and subiculum were assessed for severe neuronal loss and gliosis to define HS. Mean MIND diet scores were obtained from a validated food frequency questionnaire administered annually during follow‐up years prior to death. We used logistic models adjusted for age at death, sex, education, and total calories to examine associations of MIND diet (continuous and grouped in tertiles) with HS. Further models controlled for APOE‐ε4 status, and other pathologies including global AD pathology, arteriolosclerosis, and LATE‐NC stage.

Results

High and moderate adherence to MIND diet was associated with 69% (OR (95% CI) = 0.31(0.15, 0.64)) and 54% (OR (95% CI) = 0.46 (0.24, 0.79)) lower odds of HS. After adjusting for APOE‐ε4 status and AD pathology, the association was retained (T3 vs. T1: OR (95% CI) = 0.30 (0.15, 0.62); T2 vs. T1: (95% CI) = 0.46 (0.24, 0.87); p for trend = 0.0007). Further adjusting for arteriolosclerosis and LATE‐NC did not appreciably change the effect estimates.

Conclusion

The MIND diet is associated with a lower likelihood of hippocampal sclerosis. Further studies are needed to more fully understand the role of diet on hippocampal structure and function in the context of AD and related brain pathologies.
Global brain venous oxygenation is associated with cardiorespiratory fitness in older adults
Authors: Green Zachary D. , John Casey S. , Brooks William M , Lee Phil , Burns Jeffrey M. , Morris Jill K.
Published: December 2022

Background

T2‐Relaxation‐Under‐Spin‐Tagging (TRUST) is an MRI technique which allows for the measurement of brain blood oxygenation. Global venous oxygenation has been shown to decrease over the course of life and may prove useful as a measure of brain aging. No studies to date have examined the association between cardiovascular fitness and brain venous oxygenation.

Method

Global venous oxygenation (Yv) and cardiorespiratory fitness were measured in sixteen older adults. Yv was measured from voxels within the superior sagittal sinus (SSS) using the TRUST sequence. The four voxels with the highest measured signal had their intensities averaged within each volume of the sequence. These values were fitted to an exponential function to yield a quantitative T2 and an estimate of Yv. Cardiorespiratory fitness was measured as the VO2 peak (mL/kg/min) during a cardiopulmonary exercise test to maximal capacity or volitional termination following the Cornell modified Bruce protocol.

Result

Using a linear regression with age and sex as covariates (F = 4.410, p = .31), Yv was shown to associate significantly with peak VO2 (b = .444, p = .020). Yv did not differ between male and female participants (t = 1.758, p = .101), and did not appear to associate independently with age (R = .182, p = .499). However, our sample was small and only included older adults.

Conclusion

This study shows for the first time that whole body cardiorespiratory fitness is associated with global brain venous oxygenation. Future work will examine the utility of this neuroimaging biomarker to monitor changes in fitness with measures of cognitive aging
SORL1 regulates the generation of APOE selectively in human neurons
Authors: Lee Hyo , Aylward Aimee J , II Richard V Pearse , Hsieh Yi‐Chen , Augur Zachary M , Knupp Allison , Goberdhan Srilakshmi , Pan Cheryl , Seyfried Nicholas T. , Bennett David A , De Jager Philip L , Young Jessica E. , Young‐Pearse Tracy
Published: December 2022

Background

SORL1 is a neuronal sorting receptor that has been strongly implicated in the pathogenesis of Alzheimer’s disease (AD). While SORL1 has structural similarities to low‐density lipoprotein (LDL) receptors, it is unclear if it plays a role in regulating lipoprotein levels in the brain. We aimed to utilize human induced pluripotent stem cells (iPSCs) to understand the intersection of SORL1 and APOE biology and interrogate the potential role of SORL1 as an LDL receptor.

Method

We differentiated iPSC lines derived from the ROS and MAP cohorts that span the cognitive and neuropathological spectrum of aging to neuron and astrocyte fates and performed unbiased proteomic profiling, Western blotting, and ELISA to quantify protein levels of SORL1 and APOE. We next used CRISPR/Cas9 to generate SORL1 null iPSC lines and differentiated to neuron, astrocyte, and microglial fates. In neurons and astrocytes, AD‐relevant phenotypes such as APOE, Abeta, and phospho‐tau were assessed. Rescue experiments were performed in SORL1 KO neurons using pharmacological perturbations and shRNA to elucidate the pathways downstream of loss of SORL1 that lead to altered Abeta, tau and APOE.

Result

We observed a strong correlation between SORL1 and APOE protein expression in neurons derived from ROSMAP cohort individuals that was not apparent in astrocytes. Next, we validated previously reported findings that loss of SORL1 in neurons results in an elevation in Abeta levels. We expanded upon these findings to show that SORL1 null neurons display elevated phospho‐tau levels and a significant reduction of extracellular and intracellular APOE. While enhancing retromer and autophagy function rescued the elevation of phosphorylated tau in SORL1 null neurons, these treatments did not rescue reduced APOE levels. Rather, loss of SORL1 resulted in a reduction in APOE RNA expression, suggesting that loss of SORL1 leads to a downregulation of APOE at the transcriptional level. Integration of profiling data from ROSMAP iNs and SORL1 knock out iNs implicate the transcription factors NFkB and REV‐ERB as potentially mediating the effect of loss of SORL1 on APOE RNA levels.

Conclusion

SORL1 has a neuron‐specific function in regulating APOE levels that is separable from its role in regulating Abeta and phospho‐tau levels.
In vivo downregulation of pancreatic amylin improves brain function and reduces brain β amyloid pathology in APP/PS1 mice
Authors: Viswanathan Velmurugan Gopal , Kotiya Deepak , Verma Nirmal , Despa Florin
Published: December 2022

Background

Amylin is a systemic hormone that is co‐secreted with insulin from pancreatic β‐cells. Amylin co‐aggregates with brain parenchymal and vascular b‐amyloid in persons with Alzheimer’s dementia. Cross‐sectional data show higher CSF and blood amylin levels are associated with increased frequency of cognitive impairment. The present study sought to determine how in vivo downregulation of amylin influences brain function during the development of Aβ pathology.

Method

Because mouse amylin is nonamyloidogenic, we developed an APP/PS1 mouse model in which the mouse amylin gene is replaced by the human amylin gene and is conditionally regulated by tamoxifen (TMX) injection, intraperitonially. At 3 months of age, human amylin‐expressing male mice were randomly assigned to either amylin downregulation group or control group (maintained amylin expression) (n = 10/group). Two months later, we assessed brain function with the novel object recognition test and performed comparative immunochemical Aβ analyses of hippocampal tissue by using MSD ELISA and immunohistochemistry (IHC).

Result

Mice with downregulated human amylin show enhanced recognition memory index (p < 0.001) and lower plasma amylin levels (p < 0.001) compared to those that continued to express human amylin. This was associated with decreased hippocampal levels of Aβ42 (p < 0.05) measured by MSD ELISA and decreased number of plaques (P < 0.01) measured by IHC.

Conclusion

Amylin downregulation in APP/PS1 mice improves memory. Molecular processes associated with improved memory involve decreased hippocampal Aβ pathology. Further studies are needed to understand how altered secretion of pancreatic amylin may influences the balance between brain Aβ accumulation and Aβ elimination from the brain.