bluuebunny/crossref_metadata_2025 huggingface dataset:
Tau pathology, relative cerebral flow and cognition in dementia with Lewy bodies
Authors: Wolters Emma E. , van de Beek Marleen , Ossenkoppele Rik , Verfaillie Sander C.J. , Coomans Emma M. , Timmers Tessa , Visser Denise , Tuncel Hayel , Golla Sandeep S.V. , Windhorst Albert D. , Scheltens Philip , van Der Flier Wiesje , Lemstra Afina W. , Van Berckel Bart N.M.
Published: December 2020

Background

Dementia with Lewy Bodies (DLB) is characterized by the presence of neuronal inclusions containing alpha‐synuclein proteins, and often co‐occurs with Alzheimer’s disease (AD) pathology. We aimed to determine the pattern of tau pathology and relative cerebral blood flow (rCBF) in DLB, compared to AD and controls, and their association with cognitive impairment using a single dynamic [18F]flortaucipir PET scan.

Method

Eighteen patients with DLB (66 ± 8 years, MMSE 25 ± 4, 44% amyloid positive (abnormal CSF (Aβ42 <813 pg/mL)/visual read amyloid‐PET), 100% FP‐CIT SPECT abnormal, Table 1), 65 amyloid positive cognitively impaired patients (MCI‐AD (n = 13), AD (n = 52)) and 50 controls underwent a dynamic 130‐minute [18F]flortaucipir PET scan. Receptor parametric mapping (cerebellar gray matter reference region) was used to extract (regional, Hammers based) binding potential (BPND) and R1, which reflect tau pathology and rCBF, respectively. We performed voxel‐wise comparisons (Puncorrected < 0.001) of [18F]flortaucipir BPND and R1 between diagnostic groups using SPM, adjusted for age and sex. DLB patients underwent extensive neuropsychological assessment covering memory, executive functioning, language, attention and visuospatial domains. For DLB only, we performed linear regression analyses between [18F]flortaucipir BPND, R1 and cognition in the following regions‐of‐interest (ROIs); medial and lateral temporal/ parietal, occipital and frontal cortex, adjusted for age, sex and education.

Result

Averaged [18F]flortaucipir BPND images across groups showed visually minimal tau uptake in the inferior temporal lobe in DLB (Figure 1). Voxel‐wise comparisons showed lower [18F]flortaucipir R1 in the occipital lobe in DLB compared to AD and controls (Figure 2). Regional [18F]flortaucipir BPND was lower in DLB compared to AD and comparable with tau binding in controls (Figure 3). Occipital and lateral parietal R1 was lower in DLB compared to AD and controls (all p<0.01, Figure 3). R1 but not BPND was related to cognition (language only); lower medial temporal (stß = 0.76, p = 0.001), medial parietal (stß = 0.64, p = 0.02) and frontal (stß = 0.64, p = 0.02) R1 was related to lower language score (Figure 4).

Conclusion

In our sample, tau load in patients with DLB did not differ from controls, but there were DLB‐specific occipital and lateral parietal flow reductions compared to both controls and AD patients. Our results indicate that rCBF may be of more clinical relevance than tau pathology in DLB.
Selective association of neurogranin gene expression with amyloid and tau pathology in the parahippocampal gyrus in Alzheimer’s disease
Authors: Sun Xiaoyan , Wang Qian , Blennow Kaj , Zetterberg Henrik , McCathy Micheline , Loewenstein David A. , Yue Zhenyu , Zhang Bin
Published: December 2020

Background

Brain region‐specific neuronal and synaptic damage is associated with clinical symptomatology and pathogenesis of Alzheimer’s disease (AD). The mechanism underlying such regional vulnerability in AD remains elusive.

Method

Public access datasets from the Mount Sinai NIH NeuroBioBank (MSBB), The Religious order Study and the Memory and Aging Project(ROSMAP) and the Harvard Brain Tissue Resource Center (HBTRC) were used in this study. Using a large‐scale transcriptomic dataset from the prefrontal cortex (BA 10, 261 samples), the superior temporal gyrus (BA 22, 240 samples), the parahippocampal gyrus (BA 36, 215 samples) and the pars opercularis (BA 44, 222 samples) of MBSS post‐mortem brains of AD and normal control subjects, we studied the association of the post‐synaptic protein neurogranin (NRGN) gene expression with amyloid and tau pathology (plaque and tangle counts), clinical dementia scale (CDR), and pathological diagnosis of AD. Integrative gene network analysis was conducted by using a combination of the datasets from three brain banks.

Result

We show that NRGN gene expression in post‐mortem brain is associated with the certainty of pathological diagnosis of AD, and negatively associated with amyloid and tau pathology only in parahippocampal gyrus among the four brain regions examined. NRGN gene expression in parahippocampal gyrus is also negatively associated with CDR scores. Integrative gene network analysis reveals that the positively correlated genes with NRGN in AD are associated with synaptic transmission and cation channel pathways.

Conclusion

Our results suggest that synaptic damage in selective brain regions contributes to the clinical phenotype in AD. Understanding of synaptic functional pathways associated with synaptic damage may provide another avenue to prioritize targets for AD.
A new functional biomarker of cognitive impairment in Alzheimer's disease
Authors: Stothart George , Smith Laura
Published: December 2020

Background

Fast Periodic Visual Stimulation (FPVS) provides a new objective electroencephalographic method for assessing an individual’s ability to discriminate between different categories of stimuli. Participants do not need to understand the task, or provide any response, making it ideal for the assessment of cognition in patient populations. We have adapted FPVS to examine a range of cognitive processes that deteriorate in Alzheimer’s disease, see Figure 1, with the ultimate aim of developing a functional biomarker to aid early diagnosis.

Method

Healthy younger (n=42, ACE‐III=92 +‐ 6) and older adult controls (n=39, ACE‐III=95 +‐5), and Alzheimer’s disease patients (n=20, ACE‐III=62+‐15) completed a battery of FPVS and behavioural tasks designed to measure their recognition memory, semantic categorisation and visual object processing, see Figure 2.

Result

FPVS provided an objective measure of recognition memory, semantic categorisation and visual object processing in just 1min of EEG recording time with no behavioural response or comprehension of the task required. There were no significant differences between younger and older adults in any FPVS measures of cognitive function. Alzheimer’s disease patients showed significant FPVS decreases in all three cognitive domains compared to healthy controls, with the greatest deficits in recognition memory (Old vs Alzheimer’s, t(58)=3.68, p=0.001, Hedge’s g = 1.38). FPVS measures of recognition memory separated AD from healthy ageing in binary classification approaches, outperforming behavioural measures, see Figure 3.

Conclusion

We have demonstrated that FPVS can be adapted to measure a range of cognitive functions pertinent to dementia. It provides a fast, objective and implicit measure of cognitive function that remains stable in healthy ageing. Alzheimer’s disease has a significant impact on FPVS measures of cognition, and the approach holds promise for the development of new early diagnosis tools.
A novel MRI contrast agent for identifying hyperphosphorylative neurons as a marker of future tau pathology
Authors: Badachhape Andrew , Parekh Parag A. , Mu Qingshan , Bhavane Rohan , Srivastava Mayank , Stupin Igor , Bhandari Prajwal , Devkota Laxman , Tanifum Eric , Ghaghada Ketan , Annapragada Ananth
Published: December 2020

Background

Hyperphosphorylated tau (pTau) is a precursor to tau tangle formation in Alzheimer's disease (AD). We have identified aptamers that bind to specific cell membrane receptors of human neuronal cells that are hyperphosphorylating tau. In this work, we built a novel targeted nanoparticle magnetic resonance imaging (MRI) contrast agent, TauX, that binds such neurons, and tested its efficacy in vivo in the P301S mouse model of tau pathology.

Method

DNA aptamers preferentially binding on the cell membrane of hyperphosphorylative SH‐SY5Y cells were selected using a modified SELEX protocol. Mass spectrometric proteomic analysis of the bound aptamers was used to identify the binding targets on the cell‐surface, and target presence was validated on both mouse and Alzheimer’s disease patient brain tissues. P301S transgenic mice (n=8) and age‐matched wild type mice (n=6) were intravenously injected TauX contrast agent and imaged by MRI using a T1‐weighted spin‐echo (T1w‐SE) sequence at 2 months of age. An additional control group of transgenic mice (n=8) received untargeted gadolinium nanoparticle contrast agent. T1‐weighted images were acquired on 1T MRI scanner at pre‐ and 4 days post‐contrast injection. Receiver operator characteristic (ROC) curves were generated with a six‐point ordinal scale to assess sensitivity and specificity for TauX. Mice were aged to 8 months and their brains were histologically assessed with AT100 antibody to confirm pTau pathology.

Result

TauX‐enhanced post‐contrast images showed MR signal enhancement in most of the transgenic mice that went on to develop tau pathology 4‐6 months later, but not in wild type animals lacking tau pathology (Figure 1). Transgenic mice given untargeted nanoparticle contrast also did not show MR signal enhancement (Figure 1). AT100 staining of P301S cortical brain sections demonstrated elevated pTau levels related to wild type counterparts (Figure 2). ROC curve constructed over the entire tested group, including controls, showed overall AUC and accuracy ∼0.8 (Figure 3).

Conclusion

A novel MRI contrast agent that can identify mice that develop tau pathology several months in the future has been demonstrated. If successful in humans, this agent could advance the identification of patients at risk of tau pathology to a very early pre‐symptomatic stage of the disease.
Continuous and risk‐score‐based predictors of ATN Alzheimer's disease status among cognitively healthy individuals: Findings from the EPAD‐LCS study
Authors: Calvin Catherine M , de Boer Casper , Raymont Vanessa , Gallacher John , Koychev Ivan G ,   EPAD consortium
Published: December 2020

Background

The Amyloid/Tau/Neurodegeneration (ATN) framework has been proposed as means of evidencing the biological state of Alzheimer’s disease (AD). Predicting ATN status in pre‐dementia individuals therefore provides an important opportunity for targeted recruitment into AD interventional studies. We investigated the extent to which ATN phenotype can be predicted by known AD risk factors as well as validated risk scores.

Method

We used baseline data from the European Prevention of Alzheimer’s Disease Longitudinal Cohort Study (v1500.0). 1181 participants with complete data (mean age 65±7 years, 57% female) were categorised into four ATN subgroups: no pathology, AD pathologic change, AD pathology, and, non‐AD pathology. Multinomial logistic regression tested composite risk scores (CAIDE, Framingham Vascular and Stroke scores) and the following individual risk exposures for association with ATN subgroups: age, sex, education, APOE e4, family history of dementia, systolic blood pressure, body mass index (BMI), high cholesterol, physical inactivity, smoking, hypertensive medication, prior cardiovascular disease, atrial fibrillation, and white matter lesion volume. ROC curve models were used to estimate the added value of predicting each pathology group according to significant risk factors and composite scores.

Result

53.4% of the sample showed no brain pathology, 24.0% showed AD pathologic change, 14.1% showed non‐AD pathology, and, 8.5% had biological AD. In age and sex‐adjusted multinomial logistic regression there were significant group effects for age, APOE e4, family history of dementia, BMI, and white matter lesion volume. In ROC models, discriminative accuracy (AUC) in predicting AD pathologic change and AD pathology (vs no pathology), was improved by 4% and 3% respectively after adding family history, BMI and white matter lesion volume to the most basic model (age, sex and APOE e4). Risk composite scores did not add to the models.

Conclusion

Low BMI and high white matter lesion volume but not established risk scores associated with AD pathology; white matter lesions were also greater in the AD pathologic change group. Specific vascular risk factors, particularly white matter lesion volume, may be of additional value to ATN profiling (i.e. ATN(V) for biological AD in a pre‐dementia stage.
Uncovering the multicausality of Alzheimer’s disease: A systems modeling approach
Authors: Uleman Jeroen , Melis René JF , Hoekstra Alfons , Quax Rick , Rikkert Marcel GM Olde
Published: December 2020

Background

In the onset and progression of Alzheimer’s disease (AD), many factors and processes are involved. Our understanding of the multicausal and complex nature of AD may benefit from computational modeling approaches that can be used for knowledge synthesis at the level of the whole system. We have developed a systems dynamics (SD) model of AD.

Method

We have applied the group model building methodology to develop from expert input and literature review a causal loop diagram (CLD) that graphically describes the relationships between important risk factors and proposed causal mechanisms in non‐familial AD from midlife onwards. This CLD was implemented computationally as a SD simulation model.

Result

For the resulting CLD, experts identified 38 variables and 144 connections between them. The experts modeled hypotheses about their relations with a multitude of important processes ranging from amyloid‐β accumulation and cerebral endothelial dysfunction, via physical activity and sleep to social functioning. The SD model was parametrized using empirical information taken from the Global Alzheimer’s Association Interactive Network (GAAIN) and is able to simulate preventive interventions on potentially modifiable risk factors.

Conclusion

The CLD and SD model described and quantified hypotheses about relationships and feedback loops implicated in AD onset in a comprehensive way. Our approach showed the potential of systems‐oriented simulation models for studying the complex etiology of AD.
A comparison of methods of defining objective cognitive impairment in preclinical Alzheimer’s disease based on Cogstate One Card Learning accuracy performance
Authors: Pudumjee Shehroo , Lundt Emily S. , Albertson Sabrina M. , Alden Eva , Machulda Mary M. , Kremers Walter K. , Jack Clifford R. , Knopman David S. , Petersen Ronald C. , Mielke Michelle M. , Stricker Nikki H.
Published: December 2020

Background

The numeric clinical staging scheme described by the NIA‐AA workgroup proposes evidence of subtle decline on longitudinal cognitive testing as one option to define transitional cognitive decline for individuals in the Alzheimer’s continuum. Few studies have compared longitudinal and cross‐sectional definitions of subtle objective cognitive impairment (sOBJ). The study aim was to compare the diagnostic accuracy of cross‐sectional sOBJ and longitudinal objective cognitive decline (ΔOBJ) for preclinical Alzheimer’s disease (AD) based on Cogstate One Card Learning (OCL) performance.

Method

We included Mayo Clinic Study of Aging cognitively unimpaired (CU) participants who were A+T+ by amyloid and tau PET assessment (n=32) and A‐T‐ (n=211); all had at least two follow‐up visits. sOBJ was defined as performance ≤ ‐1SD on OCL accuracy using age‐corrected normative data. ΔOBJ was measured using two different methods: (1) within subjects’ standard deviation (WSD) using a ≤ ‐1 z‐score for change to define decline based on Cogstate’s normative change data, and (2) extracted subject‐specific slopes from a linear mixed effects model (LME) which can be interpreted as approximate annual change; decline was defined as slope < 10%ile among a reference sample of CU participants aged 50‐65 at baseline (N=732).

Results

sOBJ and ΔOBJ‐WSD both showed low sensitivity in detection of A+T+ (9.4% and 12.5%, respectively). Total AUC values did not differ significantly (p=.31) across sOBJ (AUC = .64, CI = .53‐.75) and ΔOBJ‐WSD (AUC = .53, CI = .42‐.65) methods. Sensitivity of the ΔOBJ‐LME method to predict A+T+ was improved (37.5%) when using a conventional cutoff of <10%ile slope and was further improved (56%) when using an optimal derived cutoff equivalent to <17%ile slope within the reference group. Like the sOBJ method, the ΔOBJ‐LME method differentiated groups better than chance (AUC = .69, CI = .58‐.80). Despite increased sensitivity, total AUC values were not significantly different across sOBJ and ΔOBJ‐LME methods (p=.34). However, total AUC of ΔOBJ‐LME was significantly better than ΔOBJ‐WSD (p=.03).

Conclusions

ΔOBJ may be more sensitive to preclinical AD than sOBJ and may serve as a helpful method for identifying at risk CU individuals if advanced statistical methods are used for defining change.
Molecular alterations of protein tau in the cingulate cortex of human brain with Alzheimer’s disease
Authors: Apatiga‐Perez Ricardo , De la Cruz Fidel , Garcés‐Ramírez Linda , Hernandes‐Alejandro Mario , Ontiveros‐Torres Miguel Ángel , Luna‐Muñoz José
Published: December 2020

Background

Alzheimer's disease (AD) brain tissue at different stages were examined to compare the events of protein tau hiperphosphorilation and its assemble into Neurofibrillary tangles (NFT) in the hippocampus and the cingulate cortex and how this may be involved in the appearance of the Behavioral and Psychological Symptoms of Dementia (BPSD).

Method

Brain tissue previously fixed with 4% paraformaldehyde from 7 patients with different stages of AD were examined in this study. Sections were blocked with 0.2% IgG free albumin and the primary antibody (Table 1) was incubated overnight. Secondary antibody HRP was incubated considering the specie and isotype. Finally, the reaction was revealed with 0.0006% 3´3´diaminobenzidine and 0.006% H2O2

Result

The cases with early stages of AD are morphologically characterized by diffuse and granular deposits of tau aggregate in a non‐fibrillar state in the transentorhinal region of the hippocampus and to a lesser extent in the cingulate cortex. Following this pattern, in cases with mild stage was found in less proportion extracellular NFT (E‐NFT) in CA1 region of the hippocampus, in contrast, there was a major labelling for this antibody in the cingulate cortex but for intracellular NFT. Finally, in moderate AD cases was found E‐NFT both in the cingulate cortex and hippocampus, being the latter where it was observed to a greater extent.

Conclusion

There is a direct relationship in the processes of NFT formation and subsequent disease progression between the cingulate cortex and the hippocampus, having its origin in the latter.
Panel discussion: DIAN‐TU trial collaborative effort
Authors: Bateman Randall J. , Ryan Laurie M. , Carrillo Maria C. , Kerchner Geoffrey A. , Farlow Martin R. , Salloway Stephen P. , Yaari Roy
Published: December 2020

Background

Dr. Bateman is principal investigator of a therapeutic trial evaluating two investigational drugs, gantenerumab and solanezumab, for dominantly inherited Alzheimer’s disease. Washington University is also the regulatory sponsor for this trial. Funding for DIAN‐TU clinical trials includes the National Institute on Aging of the National Institutes of Health, Alzheimer's Association, Eli Lilly and Co, Hoffman La‐Roche/Genentech, Janssen, Avid Radiopharmaceuticals, GHR Foundation, and an anonymous foundation. Discussion session with leaders from the collaborative group: Randall Bateman (DIAN‐TU, PI), Laurie Ryan (NIH/NIA), Maria Carrillo (Alzheimer’s Association), John Sims (Eli Lilly and Co.), Geoff Kerchner (F. Hoffman‐La‐Roche, Ltd.), Marty Farlow (DIAN‐TU Project Arm Leader, Sola), and Steve Salloway (DIAN‐TU Project Arm Leader, Gant). Trial results discussed.
The Generation program: Baseline characteristics of cognitively unimpaired APOE4 carriers recruited for Generation study 1 and Generation study 2
Authors: Tariot Pierre N. , Borowsky Beth , Liu Fonda , Riviere Marie‐Emmanuelle , Rouzade‐Dominguez Marie‐Laure , Cazorla Pilar , Quinn Matt , Ricart Javier , Langbaum Jessica B. , Viglietta Vissia , Sui Yihan , Caputo Angelika , Reiman Eric M. , Graf Ana
Published: December 2020

Background

The Alzheimer Prevention Initiative (API) Generation Program evaluated the effectiveness of the BACE1 inhibitor, umibecestat, and the active immunotherapy, CAD106, in delaying the onset of AD symptoms in APOE4 carriers. The Generation Program included two studies implemented in 23 countries at 207 sites. Recruitment in the program and treatment with umibecestat was terminated in July 2019 after detecting an early signal of mild worsening in some measures of cognitive function with umibecestat. We will summarize the baseline characteristics of participants in the Generation Program.

Method

Treatment duration was planned for 5‐8 years in two double‐blind, placebo‐controlled, parallel design studies (Lopez Lopez et al., 2019) in cognitively unimpaired participants aged 60‐75 years, at risk for onset of clinical symptoms due to AD. Generation Study 1 (NCT0256551) recruited APOE4 homozygotes (HMs) while Generation Study 2 (NCT03131453) enrolled both HMs as well as APOE4 heterozygotes (HTs) if they also had elevated brain amyloid (assessed by either PET and/or CSF). Both studies included a 12‐week screening phase starting with genotyping. Amyloid testing was the last screening assessment performed before randomization.

Result

Among the 9623 participants recruited, more than 2700 completed the 12‐week Screening phase with amyloid testing. Approximately 27% were HMs. About 60% of HMs and 35% of HTs had elevated brain amyloid. A total of 1623 participants were randomized: 478 to Generation Study 1 (all HMs) and 1145 to Generation Study 2 (including 20% HMs and 80% HTs with elevated amyloid). Education, sex, family history of AD, clinical scales (including MMSE, RBANS total score and indices, CDR sum of boxes, and ECog), brain volumes and amyloid status will be shown. Scores from cognitive scales will be presented by sex, genotype (E4/E4, E3/E4, E2/E4), age group and amyloid status.

Conclusion

The Generation program collected a broad set of parameters for the world’s largest cohort of cognitively unimpaired APOE4 carriers. Baseline characteristics of participants enrolled in the Generation Program were consistent with the target population at risk for AD. Findings in relation to genotype, age, sex and amyloid status will be discussed.
Umibecestat in the API Generation program: Worsening in RBANS and/or CDR on treatment reverses after wash‐out
Authors: Graf Ana , Riviere Marie‐Emmanuelle , Liu Fonda , Rouzade‐Dominguez Marie‐Laure , Cazorla Pilar , Quinn Matt , Arkuszewski Michal , Ricart Javier , Langbaum Jessica B. , Piccard Hernan , Sui Yihan , Quarg Peter , Caputo Angelika , Reiman Eric M. , Tariot Pierre N.
Published: December 2020

Background

Recruitment in the API Generation program and treatment with umibecestat were terminated in July 2019 after detection of an early signal of mild worsening in some measures of cognitive function with umibecestat. Participants were followed to assess the reversibility of these and other observed effects. We will summarize the key clinical results for umibecestat vs placebo during treatment and follow up.

Method

Following randomization to umibecestat or placebo, clinical assessments were scheduled at month 3, month 6 and every 6 month thereafter. After discontinuation of study medication, participants underwent a full evaluation within 3 months of the last dose. Data will be presented for visits on‐ and off‐treatment. For visits off‐treatment, results will be compared for visits occurring before vs after wash‐out of umibecestat (> 31 days after last dose). Analysis of cognitive scales in relation to age, sex, genotype and amyloid status, and a safety summary will also be presented.

Result

At termination about 650 participants had reached week 26. The final evaluation was performed on most of the 1561 ongoing participants (45% after wash‐out). Worsening was detected in a group‐level comparison at month 3 and month 6 in both studies for the two doses of umibecestat (effect size 0.2‐0.3 for RBANS Total, Immediate and Delayed Memory indices). Analysis from the visits conducted after wash‐out indicated that key cognitive findings seen before wash‐out were reversible: we saw no more between‐group differences in RBANS and no more imbalance in the proportion of participants having a >14‐point decrease in total RBANS or > 1‐point increase in CDR‐SB after wash‐out. Similar findings were also seen in homozygotes without elevated amyloid.

Conclusion

The negative effect of umibecestat vs placebo on RBANS and CDR‐SOB was detected as early as month 3 and was detectable throughout the treatment period, but was no longer present after wash‐out of umibecestat. This effect seems to be independent of the presence of brain amyloid. Confirmation of the contemporary reversibility of worsening in measures of cognition is an important result to inform development of future prevention therapies for Alzheimer’s disease (AD).
Persistent challenges in Alzheimer’s disease modeling: Pragmatic solutions to inform the road forward
Authors: Herring William L , Mauskopf Josephine M
Published: December 2020

Background

The credibility of economic evaluations of emerging Alzheimer’s disease (AD) therapies will depend on addressing persistent structural and data challenges with transparent and evidence‐based approaches. This study describes methodological challenges recurring throughout the AD modeling literature and recommends practical solutions for future researchers.

Method

Systematic literature reviews of economic models in AD were supplemented by a targeted review of recently published models. The findings from the reviews and the approaches used in recent models were synthesized to identify remaining structural and data challenges. Data availability and anticipated health technology assessment requirements were used to inform potential solutions to these challenges.

Result

We identified four fundamental challenges for models used to evaluate emerging AD therapies: (1) quantifying heterogeneity in population characteristics and the natural history of disease progression and dementia onset; (2) assembling evidence supporting the extrapolation of short‐term trial endpoints to long‐term benefits; (3) addressing data gaps in costs, utilities, and mortality by disease severity accounting for age; and (4) bridging differences in populations, endpoints, and care settings across datasets and markets. We recommend analyses of existing longitudinal datasets to understand variability and prognostic factors within and between datasets, matching patient characteristics and progression patterns across datasets and clinical trials (challenges 1, 4). Existing longitudinal datasets also can be used to generate evidence of correlation between short‐term clinical trial endpoints and long‐term progression in support of model extrapolations (challenge 2). Long‐term follow‐up of clinical trial participants should be planned to validate findings from these analyses. Previously collected data on costs, utilities, and mortality should be reanalyzed to isolate AD‐specific estimates across disease severity levels accounting for the impact of aging (challenge 3). Crosswalks between study populations, symptom measures, and biomarker criteria should be created to support adaption of economic models to local markets (challenges 1, 3, 4). Finally, models should be developed with flexibility in their structural assumptions to address uncertainty inherent in these recommended solutions.

Conclusion

Pragmatic solutions tailored to the available data and the anticipated profiles of therapies in late‐stage development should be pursued to support near‐term decision making and inform the design of long‐term evidence‐generation efforts.
Sensory gamma frequency stimulation in cognitively healthy and AD individuals safely induces highly coordinated 40 hz neural oscillation: A preliminary study of non‐invasive sensory stimulation for treating Alzheimer’s disease
Authors: Suk Ho‐Jun , Chan Diane , Jackson Brennan , Fernandez Vanesa , Stark Danielle , Milman Noah , Beach Sara , Uitermarkt Brandt , Gander Phillip , Boes Aaron D , Brown Emery , Boyden Ed , Tsai Li‐Huei
Published: December 2020

Background

Our lab previously showed that 40 Hz sensory stimulation can modulate neural oscillations, ameliorate Alzheimer’s disease (AD) pathology, and improve cognition in AD mouse models (Iaccarino, Singer et al., Nature, 2016; Martorell, Paulson et al., Cell, 2019; Adaikkan et al., Neuron, 2019). To determine the safety and feasibility of 40 Hz sensory stimulation as a potential therapeutic for AD, human subjects, including AD patients, were exposed to various stimulation modalities and their electrophysiological responses were studied.

Method

We developed a device that delivers light and sound at desired frequencies for human use. Cognitively healthy (24 males, 22 females; age range 20‐75) and AD subjects (7 males, 10 females; age range 55‐88) were stimulated with our device while their scalp electroencephalogram (EEG) was recorded. Epilepsy patients with intracranial electrodes (1 male, 1 female; age 19) were also exposed to our device for sensory stimulation while recording the intracranial EEG (iEEG). The EEG signals were screened for interictal/ictal spikes and analyzed to evaluate spectral characteristics.

Result

The EEG signals from cognitively healthy and AD subjects as well as epilepsy patients did not show any interictal/ictal spikes during or after the stimulation. In all subject groups, our sensory stimulation increased the spectral power and coherence at 40 Hz, with the concurrent visual and auditory stimulation leading to more widespread and coordinated 40 Hz oscillations than visual or auditory stimulation alone. iEEG signals showed that our sensory stimulation can entrain deeper brain regions. An hour‐long continuous 40 Hz stimulation using concurrent visual and auditory stimuli in healthy older subjects showed 40 Hz power and coherence both increasing over time. Following the hour‐long stimulation, gamma power and coherence were elevated compared to the pre‐stimulation levels.

Conclusion

Our non‐invasive sensory stimulation at gamma frequency safely induces highly coordinated 40 Hz oscillations in cognitively healthy and AD subjects. This serves as a preliminary study for a placebo‐controlled, randomized control trial to test the effect of our sensory stimulation on AD. The application of non‐invasive techniques to modulate gamma oscillations in the human brain is a novel and potentially very powerful disease modifying therapeutic for the treatment of dementia.
White matter hyperintensities, gray matter atrophy and cognitive deficits in Parkinson’s disease
Authors: Dadar Mahsa , Gee Myrlene , Duchesne Simon , Camicioli Richard
Published: December 2020

Background

MRI features of grey matter atrophy and White Matter Hyperintensities (WMHs) of cerebrovascular origin have been linked to cognitive symptoms in Parkinson’s disease (PD) (Yau 2018, Dadar 2018). Here we assess the relationship between WMH burden, gray matter atrophy in the Hippocampi and cognitive symptoms in PD.

Method

Data included 50 PD patients and 45 age‐matched controls with T1‐weighted and FLAIR scans at baseline, month18, and month36. WMHs were segmented using T1‐weighted and FLAIR images and a random forests classifier (Dadar et al. 2017, Figure 1.a). SNIPE (Scoring by Nonlocal Image Patch Estimator) was used to measure Alzheimer’s‐disease‐like atrophy patterns in the left and right hippocampi (Figure 1.b, Coupé et al. 2019). The relationship between MRI features and clinical scores was assessed using mixed‐effects models: where Cohort denotes a categorical variable contrasting PD versus controls, and ID denotes the categorical random effects. The variables of interest were MRI‐Feature (implying an overall association between the MRI feature and clinical score of interest) and the interaction term Cohort:MRI‐Score (implying an additional PD‐specific impact of the MRI‐Feature on the Clinical‐Score). Log‐transformed WMH volumes and SNIPE grading in the left and right Hippocampi were used as MRI features. Total Dementia Rating Scale (DRS) was the dependent variable of interest reflecting cognitive performance.

Result

WMH load significantly increased with age in both groups (t=9.95, p<0.0001). We did not find a significant group difference in WMH volumes. We did not find a significant association between WMH load and Total DRS score in either group. Total DRS significantly decreased with age (t=‐2.23, p<0.04) and decrease in Hippocampal grading (tLeftHC=2.83, pRighHC=0.005, tLeftHC=2.55, pRighHC=0.01), with a marginally greater impact in PDs (Figure 2, tLeftHC=1.80, pRighHC=0.07, tLeftHC=1.58, pRighHC=0.10).

Conclusion

In our cohort, hippocampal atrophy was significantly associated with cognitive deficits in both controls and PD patients, with a slightly greater impact in the PD group. We did not observe an impact of vascular disease burden on cognitive performance.
Mechanisms of neuroinflammation with APOE4 implicate CPLA2
Authors: Wang Shaowei , Solomon Victoria A. , Sullivan Patrick M. , Yassine Hussein N.
Published: December 2020

Background

APOE4 is the strongest genetic risk factor for late‐onset Alzheimer’s disease (AD) and is associated with increased susceptibility to neuroinflammation, however the reasons for this association are not very clear. Increased phosphorylation of calcium‐dependent cytosolic PLA2 (cPLA2) is evident in amyloid plaques of human brains. Enhanced cPLA2 activity promotes the release of arachidonic acid (AA) and prostaglandin E₂ (PGE2) to initiate an inflammatory response. Our primary aim is to determine if ApoE4 increases cPLA2 activity.

Method

Cellular, animal models and human brain tissue were employed

Result

We found greater cPLA2 expression and phosphorylation in ApoE4 immortalized and primary astrocytes compared to ApoE3. Greater levels of phosphorylated cPLA2 and higher cPLA2 activity were found in the brains of ApoE4‐TR mice (vs ApoE3) at 8‐months of age. In addition, phosphorylated cPLA2 level was increased in hippocampus of APOE4/E4 carriers with AD compared to cognitive healthy APOE3/E3 carriers. To examine the mechanisms for phosphorylation of cPLA2, we examined its regulation by the mitogen‐activated protein kinase (MAPK) pathway. We found that the p38 pathway (but not ERKs pathway) was more activated in cells, mouse and human brain samples with ApoE4 genotype compared to ApoE3.

Conclusion

Our research implicates an ApoE4‐driven cPLA2 activation as a mechanism for the increased susceptibility to neuroinflammation in AD and a potential target for treatment.
A systematic review of short cognitive assessments for diagnosing dementia and MCI in clinical settings in Chinese‐speaking countries
Authors: Yu Ruan‐Ching , Lai Jen‐Chieh , Mukadam Naaheed , Kapur Narinder , Stott Joshua , Livingston Gill
Published: December 2020

Background

Mandarin Chinese is one of the most widely spoken languages in the world, and is used as a primary or secondary language in China, Hong Kong, Singapore and Taiwan. These countries differ in historical, economic and societal contexts so that cognitive assessments validated in one country may not be valid in another. The aims of this study are to compare the short diagnostic assessments (<15 minutes) used to assist in diagnosing dementia and Mild cognitive impairment (MCI) in Chinese‐speaking countries through rating the translation and cultural adaptation and reporting the sensitivity and specificity of assessments.

Method

We searched for terms relating to "assessments" and "dementia" or "MCI" and "Chinese‐speaking populations” in electronic bibliographic databases, including Embase, Ovid MEDLINE(R), PsycINFO, PsycTESTS, Web of Science, The Cochrane Library from inception to 3th July 2019. Two raters independently screened titles and abstracts, rated the translation and cultural adaption according to published guidelines by judging whether the details described are sufficient for replication and evaluated the quality of studies with a diagnostics critical appraisal sheet developed by the Centre for Evidence‐Based Medicine (CEBM).

Result

The searches retrieved 11763 articles, of which 74 articles were included after full‐text screening: 29 articles from China, 18 articles from Hong Kong, 12 articles from Singapore and 15 articles from Taiwan. We found 41 different short cognitive assessments used, but only two assessments ‐ the Mini‐Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) have been validated in the four countries. The NUCOG cognitive screening tool in China specifically was shown to have the highest validity in screening 44 dementia diagnosed with DSM‐IV from 260 normal controls with a sensitivity of 100% and specificity of 98.5%. Reporting of cultural adaptation was achieved in approximately two third of the studies analysed.

Conclusion

There are wide range of tools available to assess cognitive impairment in the Chinese‐speaking populations most of them are not validated in all Chinese speaking populations. Their psychometric properties vary and translation and cultural adaptation procedures are poorly reported.
Protective low expression of PU.1 reduces microglial inflammatory and phagocytic response
Authors: Pimenova Anna A. , Herbinet Manon , Gupta Ishaan , Machlovi Saima , Marcora Edoardo , Goate Alison M.
Published: December 2020

Background

The genetic risk for sporadic Alzheimer’s disease (AD) is polygenic, driven by more than 40 loci. Pathway analysis implicates immune response in the etiology of AD, and given that genetic risk alleles are enriched in myeloid cell types, it has been proposed that impaired microglial function is a major contributing factor to AD risk. Microglial homeostasis is affected by the myeloid lineage‐determining transcription factor SPI1/PU.1, with lower SPI1 expression associated with protection and higher expression with risk for AD based on the rs1057233 genotype.

Methods

To understand how modulation of PU.1 expression affects microglial function we generated stable Spi1/PU.1 overexpression and knock‐down BV2 mouse microglial cell lines and assessed their response in functional assays under baseline and challenged conditions using staurosporine, rotenone and LPS.

Result

Analysis of RNA sequencing data from BV2 lines showed that knock‐down of PU.1 repressed the microglial homeostatic gene signature in a manner similar to that described in disease‐associated microglia in AD mouse models. Pathways of LXR/RXR signaling, antioxidant action and protein translation were upregulated, while inflammatory gene expression was decreased, which may underlie the protective effect of microglia with reduced PU.1 expression. BV2 microglial cells with PU.1 overexpression showed increased, while PU.1 knock‐down led to decreased phagocytosis of bioparticles independent of their type, e.g. zymosan, myelin, early or late apoptotic cells. PU.1 overexpression led to resistance to staurosporine‐induced apoptosis because of decreased caspase cascade activity, while PU.1 knock‐down cells were more susceptible to apoptosis‐induced cell death independent of caspase activation. Increased viability of PU.1 overexpressing cells resulted in potentiation of production of reactive oxygen species, nitric oxide and inflammatory cytokines under stimulated conditions. Furthermore, conditioned media from these cells led to propagation of the reactive phenotype to mouse primary astrocytes in culture. In contrast, PU.1 knock‐down repressed the inflammatory response of BV2 cells after LPS stimulation, and repressed the reactive phenotype in astrocytes.

Conclusion

Reduced expression of PU.1 represses the homeostatic signature of microglia and decreases stimulus‐mediated cell viability, phagocytic and inflammatory responses, which may lead to increased turnover of microglia in the brain underlying the protective effect of SPI1 genotype against AD risk.
Relationship between serum TSH level and Alzheimer disease pathology
Authors: Choi Byung Wook , Kang Sungmin , Kim Hae Won
Published: December 2020

Background

Thyroid dysfunction is one of the risk factors associated with cognitive impairment, including Alzheimer disease (AD). The aim of this study was to evaluate the association between serum TSH level and AD pathology through biochemical assays, positron emission tomography (PET) imaging, and cognitive performance tests.

Method

Sixty‐nine subjects without overt hypothyroidism who underwent [18F]‐florbetaben PET were included in this prospective cross‐sectional study. The serum levels of free thyroxine (fT4) and thyroid stimulating hormone (TSH) were quantified using radioimmunoassays. The Mini‐Mental State Examination, Digit Span Memory Test, Boston Naming Test, and the Rey‐Osterrieth Complex Figure Test and Recognition Trial were performed to assess cognitive function. Differences in cerebral amyloid‐β (Aβ) burden, which is represented by standardized 18F‐florbetaben uptake value ratio (SUVR), were compared between high‐normal TSH (TSH ≥ 2.5 μIU/mL) and low‐normal (TSH < 2.5 μIU/mL) groups. Multiple linear regression analyses, adjusted for age and sex, were performed to evaluate the relationship between thyroid hormone levels and cerebral Aβ burden, and between thyroid hormone levels and cognitive function.

Result

The cerebral Aβ burden in the high‐normal TSH group was significantly higher than in the low‐normal TSH group (SUVR 1.53 vs. 1.35, p = 0.009). The fT4 levels were negatively correlated with cerebral Aβ burden (β = ‐0.250, p = 0.033), and TSH levels were positively correlated with cerebral Aβ burden (β = 0.243, p = 0.018). The fT4 level was also positively associated with cognitive function, as inferred from cognitive performance evaluation.

Conclusion

Serum TSH level is associated with cerebral Aβ burden. The fT4 and TSH levels showed negative and positive correlation with cerebral Aβ burden, respectively. Our findings suggest that serum TSH level, especially in subject with high‐normal serum TSH level, may contribute to AD development.
Gender and sex bias in clinical trial recruitment in Alzheimer's disease: Findings from Fundació ACE
Authors: Abdelnour Carla , Valero Sergi , Rosende‐Roca Maitee , Lafuente Asuncion , Hernandez Isabel , Tartari Juan Pablo , Santuccione Antonella , Ferreti Maria Teresa , Maguire Peggy , Buendía Mar , Pancho Ana , Tarraga Lluis , Benaque Alba , Gurrutxaga Miren , Ruiz Agustín , Boada Mercè
Published: December 2020

Background

FDA has made great efforts to promote inclusion of women in clinical trials. The aim is to protect specific biological gender and sex issues and encourage drug developers to consider specific clinical outcomes and drug‐safety profiles in terms of gender and sex. Alzheimer’s disease (AD) affects predominantly women, who double men in the number of patients diagnosed with dementia. Therefore, we explored gender and sex bias in the inclusion criteria for clinical trials in AD. Here our aim was to compare main inclusion criteria for clinical trials in MCI and dementia patients in terms of sex.

Method

Patients evaluated at FACE from 1996 to 2019 with CDR 0,5 to 2 evaluated from 1996 to 2019 were analyzed. Then, we used the main inclusion criteria for AD clinical trials to compare the sample in terms of sex and syndromic diagnosis. The chosen variables were age, sex, education, comorbidities, treatment and MMSE score. Logistic regression analysis was used accounting for these variables.

Result

From a total sample of 20,203 MCI and dementia patients, we selected potential candidates for clinical trials with complete information regarding age, years of education, MMSE, comorbidities and treatment. After adjusting for age, years of education, comorbidities and treatment, in the dementia sample only age and years of education showed statistically significant differences. Whereas in the MCI sample: age, years of education, treatment and comorbidities showed statistically significant differences (Table 1 and 2).

Conclusion

Women with MCI and dementia are less likely to participate in a clinical trial due to older age and less years of education than men. Another factor that prevent women for participating in clinical trials is their comorbidities when compared to men, whereas men are excluded due to treatment criteria more often than women. These results show that there is a pre‐selection bias against women in AD clinical trials because of demographic characteristics. Therefore, participation of women in clinical trials does not reflect the prevalence of AD among women and is not representative of reality. Efforts should be made to provide equal opportunities to potential clinical trials candidates regardless of gender.
An ultrasensitive immunoassay for detection of p‐tau181 in blood
Authors: Chen Yao , Chang Lei , Blennow Kaj , Zetterberg Henrik , Ball Andrew J.
Published: December 2020

Background

A high‐sensitivity blood‐based p‐tau181 assay could potentially provide a valuable tool for Alzheimer’s disease (AD) research and drug discovery. In this study we describe development of a high‐performance blood‐based p‐Tau181 assay using Simoa technology.

Method

A fully automated bead‐based digital Simoa immunoassay was developed to detect p‐tau181 in serum, plasma and CSF. A monoclonal antibody targeting p‐tau181 was used as capture antibody and a biotinylated antibody against tau was used as detector. Antibody selection was based on specificity for target analyte and generation of quantifiable signal in human serum and plasma samples. Assay conditions were optimized for maximal sample detection and analytical performance. The assay was evaluated for sensitivity, parallelism, cross‐reactivity to total tau, spike recovery, and analyte detectability in normal human serum, plasma and CSF.

Result

Analytical performance was characterized for sensitivity (LLOD 1.0pg/mL), quantifiability (100% of samples above LLOQ for CSF and plasma, 87% for serum), cross reactivity (<5% cross reactivity to total tau), linearity of sample dilution (81%‐122% in plasma (n=11) and 78%‐152% in serum (n=6)) and recovery of sample spike (70%‐94% in plasma (n=10) and 68%‐126% in serum (n=5)). Disease differentiation was studied by measuring plasma p‐tau181 level in 20 age‐matched AD patients and 20 healthy control samples obtained from a commercial source. Mean p‐tau181 was significantly higher in the AD patients than in the healthy controls (78.61pg/ml in AD versus 42.18pg/ml in HC, p=0.01). Differentiation power of p‐tau181 in CSF was also evaluated in 11 healthy control and 13 age‐matched AD patients (samples from U. Gothenburg). Mean CSF p‐tau181 level was significantly higher in the AD patients than in the controls (8551pg/mL in AD; 973pg/ml in healthy controls, p<0.05). A strong correlation (R² = 0.9293) between 20 matched serum and plasma samples was also observed.

Conclusion

This Simoa p‐tau181 assay enables measurement of this important analyte in blood and CSF samples. Efforts are underway to bring make this assay widely available as a new tool to facilitate research in AD and other neurodegenerative diseases. Ongoing studies using a larger cohort of clinical samples will determine the clinical utility of this assay.