bluuebunny/crossref_metadata_2025 huggingface dataset:
The Association between Brain Age and Alcohol Use
Authors: Funk‐White Makaya , Wing David , Eyler Lisa T. , Moore Alison A. , Reas Emilie T. , McEvoy Linda K.
Published: December 2022

Background

Alcohol has been shown to have both beneficial and adverse associations with cognitive health in aging, dependent upon amount consumed, but associations with structural brain measures are less well understood. Here, we investigated whether predicted brain age, calculated using a voxel‐based algorithm trained on a large dataset, differs by alcohol use among a cohort of healthy older adults.

Method

Participants included 163 community dwelling older adults (aged 56‐97 years, mean 77 years, 60% females). We categorized individuals as: non‐drinkers (30.7%), light drinkers (1‐7 drinks/week; 47.2%) moderate drinkers (> 7‐14 drinks/week; 12.3%), or heavy drinkers (> 14 drinks/week; 9.8%). In secondary analyses, we explored the effect of differentiating the non‐drinker group into never drinkers (5.5%), former drinkers (10.4%), and occasional drinkers (14.7%). Brain age was calculated using structural MRIs processed with the BrainAgeR program (Cole et al, 2018). We calculated predicted brain age difference (PBAD) by subtracting predicted brain age (PBA) from chronological age. We used analysis of variance (ANOVA) to determine if PBAD differed across groups.

Results

PBA was highly correlated with actual age (r = .713). PBAD differed significantly across groups (F (3,150) = 3.20; p = 0.025): PBAD was significantly higher among heavy drinkers (average PBAD = 3.0 years) compared to all other groups. Non‐drinkers, light drinkers, and moderate drinkers showed younger than actual brain age, by 1.3, 2.9, and 3.3 years, respectively, with no significant differences across groups. Our secondary analysis showed that PBAD among former drinkers was not significantly different from that of heavy drinkers while never drinkers and occasional drinkers showed significantly younger PBAD relative to heavy drinkers.

Conclusion

Among this sample of healthy older adults, consumption of more than 14 drinks/week was associated with older than expected brain age. This is consistent with prior literature demonstrating that drinking above recommended guidelines is associated with brain volume loss. In contrast, never drinking and lighter drinking was associated with younger than expected brain age. While we found little evidence for a beneficial association of light or moderate drinking, drinking within guidelines does not appear to adversely affect brain health even among older adults.
Biological variation of Alzheimer’s disease plasma biomarkers in healthy individuals
Authors: Brum Wagner S. , van Doorn William , Ashton Nicholas J. , Montoliu‐Gaya Laia , Janelidze Shorena , Zimmer Eduardo R. , Zetterberg Henrik , Karikari Thomas K , Hansson Oskar , Meex Steven JR , Carobene Anna , Blennow Kaj
Published: December 2022

Background

Plasma biomarkers for Alzheimer’s disease (AD) have demonstrated great performance to identify AD pathology in research cohorts, and recent studies also support their potential to monitor effects of disease‐modifying treatments. To properly interpret these biomarkers in research settings and to inform power calculations of future trials using them as surrogate outcomes, information on their physiological variability over time is needed. We conducted a 10‐week biological variation (BV) study to assess the within‐individual (CVI; CV: coefficient of variation), between‐individual (CVG) and analytical variability (CVA) of blood‐based AD biomarkers. These parameters can provide the reference change value (RCV), which determines how much biomarker values must change to represent a significant abnormality‐related change, i.e. exceeding analytical and biological variation.

Method

Plasma samples were collected weekly for 10 weeks from 20 healthy individuals from the European Biological Variation Study (n=20; 50% female, median age 46.4). Biomarkers for tau pathology (p‐tau181), brain amyloidosis (Aβ42, Aβ40, Aβ42/40), glial activation (GFAP) and neurodegeneration (NfL) were quantified in duplicate using the Simoa technology. The CV‐ANOVA statistical method was used to compute BV estimates. To evaluate diurnal rhythm of these biomarkers, we also conducted a study with non‐demented older adults (n=24; 58‐82yo), with hourly blood collections during 26h in strictly‐controlled environmental conditions (NCT02091427). P‐tau217 (Lily) analyses are ongoing for both studies.

Result

Individual‐level (Figure 1) and pooled biomarker levels are shown (Figure 2), as well as BV estimates (Table 1). The 10‐week within‐individual physiological variation (CVI) was lower for Aβ42/40 (4.3%), followed by Aβ42 (6.0%), Aβ40 (6.4%), NfL (7.9%), GFAP (9.3%) and p‐tau181 (15.8%). Between‐individual variation (CVG) was lower for Aβ42/40 (8.8%), followed by Aβ42 (13.3%), Aβ40 (17.0%), p‐tau181 (20.5%), NfL (23.0%) and GFAP (31.5%). Analytical variation was low for all biomarkers (CVA range: 2.5‐6.6%). The RCV was higher for p‐tau181 (45.6%), followed by GFAP (31.7%), NfL (27.6%), Aβ40 (19.0%), Aβ42 (18.8%) and Aβ42/40 (15.6%).

Conclusion

Blood‐based AD biomarkers demonstrate good week‐to‐week stability, but their CVG and RCV’s can be rather high, with implications both for use in clinical routine (misclassification risk) and for future trial designs (high numbers of participants needed). Results for the diurnal variation study will also be presented.
Kidney function is associated to Alzheimer’s related blood biomarkers (NfL, P‐tau181, and GFAP) but not dementia risk in a community‐based cohort followed over 17 years
Authors: Stocker Hannah , Beyer Léon , Trares Kira , Perna Laura , Rujescu Dan , Holleczek Bernd , Beyreuther Konrad , Schöttker Ben , Gerwert Klaus Bernhard , Brenner Hermann
Published: December 2022

Background

In order to determine the future of Alzheimer’s disease (AD) related blood biomarkers in the clinical setting, it is crucial to identify factors that could affect the interpretation of biomarker levels. Kidney function has been shown to influence biomarker levels, but has also exhibited associations to dementia risk and it is unclear whether kidney function plays a role in AD pathology or is merely a factor influencing blood biomarker levels. Therefore, the aim of this study was to explore the association of kidney function with risk of incident AD/dementia diagnosis within 17 years and with the blood biomarkers, neurofilament light (NfL), phosphorylated tau (p‐tau181), and glial fibrillary acidic protein (GFAP), in a community‐based cohort study.

Methods

Kidney function was assessed through the estimated glomerular filtration rate test (2021‐CKD‐EPI creatinine‐cystatin C equation (eGFRcr‐cys)) at baseline in 6,256 participants aged 50‐75 years, of whom 510 received a dementia diagnosis throughout 17 years of follow‐up in a community‐based prospective cohort study in Germany (Figure 1). In a subset of participants (n=766, n=261 dementia cases), NfL, p‐tau181, and GFAP blood concentrations were measured at baseline using Simoa technology. Cox regression and linear regression models adjusted for age and sex were used to assess the association of kidney function with incident dementia risk and the log‐transformed blood biomarker concentrations.

Results

Impaired kidney function (eGFRcr< 60 mL/min/1.73m2) at baseline was not associated to incident dementia (p=.73) or AD diagnosis (p=.94) within 17 years (Figure 2). However, the blood biomarkers, NfL and P‐tau181, did exhibit significant associations to impaired kidney function (β, p‐value: NfL, 0.47, <.0001; P‐tau181, 0.21, <.01) and gender‐specific associations were evident in the association to GFAP (β, p‐value: Males, 0.31, <.01; Females, ‐.12, .11) (Table 1).

Conclusions

Reduced kidney function may result in increased concentrations of AD related blood biomarkers but not necessarily increased AD risk. Kidney function might influence the accuracy of AD blood biomarkers and should be considered in clinical translation. Additionally, the interaction between kidney function and sex in the association to GFAP including possible explanatory biological mechanisms should be further explored.
Results From a Multiple Ascending Dose Study in Healthy Volunteers of ACD856, a Positive Modulator of Neurotrophin Trk‐Receptors
Authors: Önnestam Kristin , Nilsson Boel , Rother Matthias , Rein‐Hedin Erik , Bylund Johan , Halldin Magnus , Forsell Pontus , Nordvall Gunnar , Sandin Johan , Segerdahl Märta
Published: December 2022

Background

ACD856 is a novel positive allosteric modulator of Trk‐receptors in clinical development for the treatment of Alzheimer’s disease and other disorders where cognition is impaired. The aim of this study was to assess the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of multiple ascending doses of ACD856.

Method

24 healthy volunteer subjects were administered ACD856 or placebo as a daily oral solution over 7 days in 3 cohorts of stepwise ascending doses. After each dose, the safety, tolerability, and pharmacokinetics of ACD856 were assessed by an internal Safety Review Committee to decide on the escalation of dose to the next cohort.

Result

There were no clinically significant changes from baseline in mean ECG, vital signs, physical examination findings, clinical chemistry, haematology, coagulation, or urinalysis parameters after receiving the 7 daily doses of ACD856. Occasional individual abnormal laboratory values were observed but all were assessed as not clinically significant. Most of the reported adverse events were of mild intensity, only a few were of moderate intensity and none of severe intensity. No serious adverse events were reported.

The pharmacokinetic data confirmed the findings from the previously performed single ascending dose (SAD) study, including that ACD856 has a rapid absorption, long half‐life, high bioavailability, and a linear dose‐dependent exposure. The Cmax at steady state was approximately 1.6‐fold higher than the initial dose administration and no time‐dependent clearance was observed. Moreover, initial CSF data confirms CNS exposure of ACD856. Further PK, CSF and pharmacodynamic data will be shown at the time of presentation.

Conclusion

ACD856 was shown to be safe and well tolerated in man at the tested dose levels and with a suitable pharmacokinetic profile for further clinical development. In the next step, ACD856 will be evaluated in a phase Ib study with the aim to further assess pharmacodynamic effects.
AlzoSure® Predict, a simple minimally‐invasive blood test to predict the early onset of Alzheimer’s disease before the manifestation of clinical symptoms
Authors: Piccirella Simona , Van Neste Leander , Fowler Christopher , Masters Colin L , Fripp Jurgen , Doecke James D , Xiong Chengjie , Uberti Daniela , Kinnon Paul
Published: December 2022

Background

Ongoing research seeks to identify blood‐based biomarkers able to predict the onset and progression of Alzheimer’s disease (AD). AlzoSure® Predict is a rapid, minimally‐invasive blood test that predicts the early onset of AD up to, at least, 6 years in advance of clinical symptoms.

Methods

The AlzoSure® Predict test, an IP‐LC‐MS/MS based method, was performed to quantify the AZ284® peptide of an unfolded variant of the p53 protein (U‐p53AZ). The data were compared with the neuropsychological diagnosis in a longitudinal cohort of 479 subjects between 60 and 85 years old from the Australian Imaging, Biomarkers, and Lifestyle (AIBL) study. The cohort consists of 237 cognitive normal, including both subjects with no and subjective memory complaints (NMC/SMC) and 98 mild cognitive impairment (MCI), 141 AD, and 3 other dementia patients that were followed‐up every 18 months.

Results

The data confirms the strong diagnostic value of U‐p53AZ with a sensitivity of 95% for AD, discriminating it from NMC and SMC subjects with an AUC of 99.8% (95% CI: 99.6‐100.0%) and a specificity of 99.6%, and from MCI patients at the early symptomatic stage with an AUC of 95.7% (95% CI: 92.8‐98.5%) and a specificity of 91.8%.

In the prognostic setting, U‐p53AZ showed a significantly better performance (P<0.0001) with an AUC of 99.0% (95%CI: 98.2‐99.8%) compared to amyloid b‐PET (Ab‐PET) with an AUC of 83.5% (95% CI: 79.5‐87.5%). Due to unavailability of data, Ab‐PET performance was determined on a subset of 422 subjects. In a multifactorial Cox proportional hazards model, U‐p53AZ proved to be the major contributor and and the best performing, independent predictor for cognitive decline to neuropsychological AD over time. In this model with normalized continuous risk factors, U‐p53AZ was the most significant contributor (P<.0001) with a hazards ratio of 2.92, compared to Aβ‐PET (P<.0155), APOE ε4 (P<.2323), and age (P<.0106).

Conclusion

The present study confirms the diagnostic performance of U‐p53AZ for AD and expands its potential into the prognostic field. Additional studies are going to be performed based on both ADRC and ADNI samples to further prove the prognostic power and the utility of the AlzoSure® Predict test.
First‐in‐human [18F]D2‐Deprenyl‐PET imaging and GFAP evaluation as biomarkers of reactive astrogliosis in neurodegenerative diseases
Authors: Katzdobler Sabrina , Vogler Letizia , Eckenweber Florian , Nübling Georg , Palleis Carla , Lindner Simon , Fietzek Urban , Nuscher Brigitte , Mueller Andre , Koglin Norman , Stephens Andrew W , Haass Christian , Brendel Matthias , Levin Johannes
Published: December 2022

Background

Neuroinflammation is a process occurring in neurodegenerative diseases, such as Alzheimer’s Disease (AD) and parkinsonian syndromes. In light of emerging disease modifying trials, objective biomarkers are urgently needed. Here, we target reactive astrogliosis for biomarker development in a pilot cohort of Multiple System Atrophy (MSA), in which key pathology and associated neuroinflammation are regionally more restricted than in AD, but more pronounced than in Parkinson’s Disease (PD). We combine glial fibrillary acidic protein (GFAP) as fluid‐based biomarker with [18F]D2‐Deprenyl‐(DED)‐PET imaging, a novel PET tracer targeting MAO‐B, for comprehensive characterization of reactive astrogliosis in this model disease.

Method

GFAP levels were analyzed in plasma samples of 23 MSA and 22 PD patients, as well as in CSF samples of 14 MSA and 14 PD patients. In a subset of patients (4 MSA‐P, 7 MSA‐C and 3 PD), first‐in‐human [18F]DED‐PET imaging was performed. Fluid‐based and PET‐imaging biomarker levels were cross‐sectionally compared, followed by correlation to clinical disease severity as indicated by UMSARS (Unified Multiple System Atrophy Rating Scale) and MDS‐UPDRS (MDS Unified Parkinson’s Disease Rating Scale). Correlation between fluid‐based biomarkers and PET imaging signals was performed. Two additional patients were on rasagiline treatment and proved target engagement of [18F]DED‐PET imaging.

Result

[18F]DED‐PET imaging showed significantly higher SUVr signals in various regions of MSA when compared to PD. Signal increases were seen in phenotype‐specific target regions with higher putaminal tracer binding in MSA‐P and higher cerebellar tracer binding in MSA‐C patients (Fig. 1). Decreased [18F]DED‐PET tracer signal was detected in patients on rasagiline treatment, indicating sufficient blocking (Fig. 2). While CSF and plasma GFAP levels did not differ between MSA and PD, GFAP levels in both biofluids correlated with disease severity in MSA (p < 0.05), but not in PD.

Conclusion

We present first‐in‐human data on a novel PET tracer to detect reactive astrogliosis in MSA. While [18F]DED‐PET imaging identifies disease‐ and entity‐specific regional astrogliosis, fluid biomarkers representing the overall level of astrogliosis appear to reflect clinical disease burden. Translation of these biomarkers into other neurodegenerative diseases, such as AD, should be pursued.
Longitudinal hippocampal atrophy is associated with cognitive decline independently of amyloid and tau in neocortex
Authors: Hanseeuw Bernard , Jacobs Heidi I.L. , Schultz Aaron P , Buckley Rachel F. , Properzi Michael J , Becker Alex , Farrell Michelle E. , Sanchez Justin S , Papp Kathryn V. , Yang Hyun‐Sik , Chhatwal Jasmeer P. , Price Julie C , Fakhri Georges El , Rentz Dorene M. , Sperling Reisa A. , Johnson Keith A.
Published: December 2022

Background

Hippocampal volume (HV) atrophy is a well‐known biomarker of cognitive impairment. However, it is not specific for Alzheimer’s disease (AD). To disentangle the contributions of AD and other neuropathologies to cognitive decline, we investigated the longitudinal associations between HV and cognition, adjusting for Aβ and tau in participants from the Harvard Aging Brain Study who were clinically normal (CN) at inclusion.

Methods

Serial MRI (HV [1.3‐7.0y], PiB‐PET (Aβ, [1.9‐8.5y]), Flortaucipir‐PET (tau, [0.8‐6.0y]), and the Preclinical Alzheimer Cognitive Composite (PACC, [3.0‐8.8y]) were observed over an average five‐year follow‐up in 128 CN participants, including ten who progressed to symptomatic AD during the study. Longitudinal HVs were processed using Freesurfer v.6 and adjusted for intracranial volume. PiB was measured in a neocortical aggregate, Flortaucipir in inferior temporal (IT) and entorhinal cortex (EC). PET data were expressed as PVC‐SUVr scaled to subcortical white matter. We predicted cognition and imaging data over time with random intercept and slope in linear mixed‐models and extracted PACC, PiB, FTP, and HV slopes for each subject. Baseline imaging and slope data were entered in age‐adjusted linear regressions to evaluate their associations with PACC slope.

Results

Without covariate, faster HV atrophy was correlated with faster PACC decline (Fig.1, R2=0.28, p<0.0001). Adjusting for age, the correlation was reduced, but significant (R2=0.20, p<0.0001, Table 2). Entering all predictors into sequential regression models, we observed that HV atrophy was associated with PACC decline independently of PiB and Tau (Table 3, model‐D). HV atrophy was explained by EC Tau, but not by PiB or IT Tau (model‐C, Fig.2). When comparing all biomarkers, HV slope uniquely accounted for 10% of the variance in PACC decline. IT Tau explained most of the association between EC Tau, PiB, and PACC. Altogether, 45% of the variance in PACC decline was explained by longitudinal changes in imaging biomarkers.

Conclusions

In older adults, longitudinal hippocampal atrophy is associated with cognitive decline, independently of amyloid and tau, suggesting that non‐AD neuropathologies (TDP43, vascular) contribute to hippocampal‐mediated cognitive decline. Serial HV measures, in addition to AD‐specific biomarkers, may help evaluate the contribution of non‐AD pathologies that cannot be measured in‐vivo but are important for cognition.
Current diagnostic pathways for Alzheimer's Disease ‐ A comparison of six countries
Authors: Carboni Margherita , Suridjan Ivonne , Yan Jessie , Roth Sophie
Published: December 2022

Background

Diagnostic pathways from cognitive impairment (CI) to Alzheimer’s disease (AD) are complex and vary geographically. This study aimed to quantify and compare the current diagnostic pathways in six countries.

Methods

A real‐world, cross‐sectional survey of 1,694 health care professionals (HCPs) was conducted in six countries (US, China, UK, France, Germany and Spain) from October to November 2021. HCPs provided data for 6,744 patients including patient demographics, presenting symptoms, and diagnostic tests and procedures. Descriptive analyses were conducted for all patients and further stratified by countries and HCP types (primary care physicians (PCP) versus specialists (geriatricians, neurologists and psychiatrists)).

Results

Most common presenting symptoms included problems with memory (89.9%), physical/behavioral (87.1%), executive functioning (72.2%) and language (71.4%). 42.1% of patients were presenting to HCPs the first time for their symptoms.

96.0% of patients with data on diagnostic tests by country and specialty (n=6,525), underwent clinical and 95.5% cognitive tests, including tests at scheduled follow‐up visits. Mini‐Mental State Examination (MMSE) was the most frequently used cognitive test (n=5,141). About half the patients (n=3,329) received blood‐tests, mainly to rule out other causes of CI (n=2,687) (Table 1).

Diagnostic test use varied by country and specialty. In China, cognitive tests, especially MMSE, were more commonly used by specialists (81.9%) than PCPs (41.6%). In the UK blood tests were more commonly used by PCPs (62.5%) than specialists (46.2%).

Conclusion

Diagnostic pathways varied largely by country and specialty. This study is relevant to populate diagnostic pathways, fill data gaps and advance patient care in AD by supporting future evidence generation, especially when new treatment options arrive.
A pilot study to investigate postural sway and saccadic eye movements comprehensively for MCI classification
Authors: Imaoka Yu , Hauri Laura , Flury Andri , de Bruin Eling Douwe
Published: December 2022

Background

While single assessment of postural sway or saccadic eye movements is potentially useful for dementia screening at clinical settings [1, 2], multimodal assessment of the two movements could improve the screening accuracy [3‐5]. We have developed a novel comprehensive assessment system of posture and saccades, with integrated additional cognitive tasks of visuospatial memory and spatial orientation. We hypothesised that the new system would improve the classification of mild cognitive impairment (MCI).

Method

23 older adults joined the experiment and were split into two group based on the score of Montreal Cognitive Assessment (MoCA) [6]: 20 healthy older adults (HA) (70.35±4.93 years, 11 men / 9 women) and 3 older adults with MCI (74.7±4.04 years, 1 man / 2 women). The assessment system consists of stabilometer (GP‐5000, ANIMA Corporation, Japan) and a head‐mounted display virtual reality (VR) technology (VIVE Pro Eye, HTC Corporation, Taiwan). We measured postural sway and pro‐ or anti‐saccadic eye movements simultaneously in each of three different VR environments: #1) no additional cognitive task, #2) with visuospatial memory task, and #3) with spatial orientation task. We compared the parameters of saccades and postural sway between HA and MCI groups.

Result

HA group achieved the MoCA score of 27.2±1.64, while MCI group scored 20.3±2.08 (P=0.006). Our analysis did not find significant differences between the two groups in all parameters. However, we observed moderate effect on standard deviation of centre of pressure in medio‐lateral direction in two test conditions: 1) the condition with pro‐saccade and visuospatial memory tasks (P=0.14; effect size = 0.32) and 2) the condition with anti‐saccade and spatial orientation tasks (P=0.09; effect size = 0.36).

Conclusion

Moderate effect was observed on postural sway behaviours in the two test conditions. Since these conditions theoretically activate wider areas of the brain, our comprehensive assessment approach could be useful for dementia screening. Future research requires more sample size of MCI population for further analysis.
Exploratory evaluation of 18F‐MK‐6240 tau PET positivity in TANGO phase 2 clinical trial of gosuranemab (BIIB092) in Mild Cognitive Impairment and mild Alzheimer’s disease
Authors: Racine Annie M , Collins Jessica A. , DuBois Jonathan M , Seibyl John , Kong Jessica , Li Yumeng , O'Gorman John , Makaretz Sara J. , Jones Stephanie , Graham Danielle , Rajagovindan Raj , Shulman Melanie , Haeberlein Samantha Budd
Published: December 2022

Background

TANGO was a randomized, placebo‐controlled, phase 2 study evaluating gosuranemab, an investigational anti‐tau antibody, for potential treatment of mild cognitive impairment (MCI) due to Alzheimer’s disease and mild Alzheimer’s disease. We explored the feasibility and validity of assessing 18F‐MK‐6240 tau PET positivity in post hoc exploratory analyses, to inform evaluation of treatment effect in future clinical trials.

Method

TANGO enrolled 654 individuals aged 50‐80 years, diagnosed with MCI due to Alzheimer’s disease or mild Alzheimer’s disease, positive for amyloid pathology. 357 participants enrolled in an optional 18F‐MK‐6240 tau PET substudy. Two expert neuroradiologists read each baseline scan as visually tau positive (Tau+) or negative (Tau‐); discrepant cases were resolved by consensus. Exploratory regional SUVR quantitative thresholds (>2 standard deviations from the mean) were derived on an external 18F‐MK‐6240 sample of N=103 elderly, cognitively unimpaired, amyloid negative adults. TANGO baseline tau PET scans were classified as quantitatively Tau+ if SUVR was above a threshold in composite regions for Braak I‐II (SUVR >1.22) and/or Braak III‐IV (SUVR > 1.29). Baseline demographics and clinical characteristics were compared between the Tau+ and Tau‐ groups and concordance between the two tau positivity approaches (visual read vs. quantitative SUVR thresholds) was assessed.

Results

85%‐90% of the TANGO tau PET substudy population was Tau+ at baseline using quantitative or visual read approaches, respectively. Interrater agreement for the two visual readers was high (97%). Agreement between the visual read and quantitative methods was also high (93%). Tau+ and Tau‐ groups overlapped in their baseline clinical and demographic characteristics, but the Tau+ group trended toward indicators of more advanced disease at baseline (e.g. worse clinical scores).

Conclusions

Based on this study of patients diagnosed with MCI due to AD and mild Alzheimer’s disease, patients who are amyloid positive also have a high probability of having tau pathology as measured by either visual read or quantitative assessment. These exploratory analyses suggest the criteria for 18F‐MK‐6240 tau PET positivity using either visual read or SUVR quantitative thresholds are feasible and valid and provides opportunities to incorporate evaluation of 18F‐MK‐6240 tau positivity into clinical trials.
VIVIAD, A Phase 2b Study Investigating Varoglutamstat in Patients with MCI and Mild AD: Dose Selection and Interim Safety Results
Authors: Weber Frank , Fuchs Katharina , Schaeffer Michael , Bihlet Asger Reinstrup , Alexandersen Peter , Axelsen Tobias Melton , Scheltens Philip , Vijverberg Everard G.B.
Published: December 2022

Background

Varoglutamstat (PQ912), a small molecule glutaminyl cyclase (QPCT) inhibitor, reduces the brain levels of pyroglutamate‐3‐Aβ (N3pE‐Aβ), a toxic Aβ variant shown to play a pivotal role in the development and progression of Alzheimer’s disease (AD). Encouraging results reported in a prior Phase 2a study (NCT02389413) led to the initiation of a state‐of‐the‐art Phase 2b trial investigating multiple cognitive, safety and biomarker endpoints.

Methods

VIVIAD (NCT04498650) is a multicentre randomized, placebo‐controlled, double‐blind, parallel group dose finding Phase 2b study in patients with cognitive impairment (MCI) and mild AD. Objectives are to evaluate the longterm efficacy (primary endpoint Cogstate NTB), safety and tolerability of oral varoglutamstat. The study will recruit 250 patients. The first 90 patients are randomised 1:1:1 (600 mg twice daily, (BID) or 300 mg BID varoglutamstat or placebo BID). An independent DSMB will unblind safety results after 90 patients have completed 24 weeks of treatment in June 2022 and decide on the varoglutamstat dose to be carried forward. The data remain blinded outside the DSMB. After the DSMB decision, all patients will be randomised 1:1 between the final dose of varoglutamstat and placebo and continue treatment up to 48‐96 weeks dependent on study entry date.

Results

The study is currently enrolling patients in 22 AD study centers in 5 European countries (160 patients are randomised as of April 25, 2022). The safety data providing the base for the DSMB dose decision, the DSMB decision itself and the baseline characteristics of the patients enrolled into the trial so far will be reported at AAIC.

Conclusion

The state‐of‐the art Phase 2b study VIVIAD is designed to yield important results in early AD for varoglutamstat, the first small molecule and only project in clinical development selectively targeting the de novo production of neurotoxic N3pE‐Aβ. The DSMB decision represents an important milestone within the Phase 2b study as it will recommend the dose of varoglutamstat considered to be safe for being carried forward to the study completion.
Free water imaging in healthy brain aging and first signs of brain pathology
Authors: Berger Martin , Pirpamer Lukas , Hofer Edith , Ropele Stefan , Pasternak Ofer , Enzinger Christian , Schmidt Reinhold , Koini Marisa
Published: December 2022

Background

Brain aging is associated with cerebral small vessel disease (SVD). Recently, it was suggested that SVD is mainly driven by increases of extracellular free water (FW). The aim of the present study was to examine the association of FW, conventional and FW‐corrected diffusion tensor imaging (DTI) parameters (fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD), axial diffusivity (AD)) with aging. The second aim was to determine if differences in FW and DTI parameters exist between individuals with first signs of pathology and healthy elderly controls regarding metrics that are not associated with age.

Method

We examined 87 healthy elderly (age: M = 66.34, SD = 9.82) and 87 individuals with first signs of cerebral pathology (age: M = 68.14, SD = 9.18) of the Austrian Stroke Prevention Family Study. Individuals with first signs of cerebral pathology were defined as having WMH score >1, presence of lacunes and/or microbleeds. FW in global normal appearing white matter (NAWM) as well as conventional and FW‐corrected DTI parameters were used in correlation analyses to assess their association with age. ANOVA adjusted for multiple comparison was used to determine the differences in FW and FW‐corrected DTI metrics between individuals with initial signs of SVD and healthy controls.

Result

FW in NAWM as well as non‐FW‐corrected DTI were significantly associated with age in the total sample and both stratified groups (range of |r|: 0.24‐0.49). No correlation between FW‐corrected DTI measures and age were found. Differences between individuals with and without first signs of pathology were only identified for FW in NAWM.

Conclusion

The association between uncorrected conventional DTI parameters and age is mainly driven by the amount of FW, calling for caution when interpreting uncorrected DTI scores. In contrast, FW appears to be a sensitive marker at very early, clinically silent, signs of SVD.
Functional Interpretation of Alzheimer’s Disease Genetic Risk and Systematic Gene Prioritization
Authors: Küçükali Fahri , Sleegers Kristel ,   EADB
Published: December 2022

Background

Genome‐wide association studies (GWAS) of Alzheimer’s disease (AD) risk identified over 100 genome‐wide significant susceptibility loci in the past 15 years, but remaining challenges include resolving the mechanism of action of how these associations functionally contribute to AD risk and prioritizing the candidate risk genes in the complex risk loci. To address these, we have recently developed a systematic gene prioritization pipeline that nominated highly likely candidate risk genes within the majority of 42 new loci identified by our recent AD GWAS meta‐analysis. In this subsequent work, we investigated the complete landscape of AD risk‐associated molecular phenotypes and further extended our analyses to known AD risk loci and subthreshold significant loci.

Method

We investigated downstream effects of AD‐associated variants on molecular phenotypes (e.g. gene expression, splicing, methylation, protein expression, histone modifications) through molecular quantitative trait loci (QTL) catalogues measured in disease‐relevant tissues and cells. We queried the lead variants in these QTL catalogues and performed genetic colocalization analyses (coloc) & transcriptome/methylome/proteome‐wide association studies (TWAS/EWAS/PWAS) using the EADB stage I meta‐analysis GWAS on 85,934 cases and 401,577 controls. Evidence for candidate genes in new, known, and subthreshold loci were assessed by the gene prioritization pipeline that was updated with new analyses. Moreover, we investigated AD‐associated cryptic splicing events using Nanopore sequencing.

Result

Our results implicated >140 protein‐coding genes with AD risk in 42 new loci, >275 in 34 known loci, and over >65 in 31 subthreshold loci. Within MINDY2 known locus, evidence from multiple QTL‐GWAS integration domains confirmed ADAM10 as a prioritized gene. Moreover, we obtained first QTL‐based evidences for candidate genes within previously‐unresolved new risk loci such as RASGEF1C. In a subthreshold locus, fine‐mapped expression TWAS associations were observed for SNX31 (a member of sorting nexins together with SNX1 in novel loci) consistently across multiple brain expression reference panels, implicating genetic upregulation of SNX31 with increased AD risk. Furthermore, we could confirm AD‐associated novel splicing events within prioritized genes such as DOC2A.

Conclusion

Our comprehensive study effectively and systematically prioritized AD risk genes and aided functional interpretation of AD GWAS by contributing to better understanding of genetically‐associated molecular mechanisms underlying AD risk.
Second‐generation fully automated Elecsys cerebrospinal fluid immunoassays demonstrate high precision, reproducibility, and sample stability suitable for clinical use to aid Alzheimer’s disease diagnosis
Authors: Rutz Sandra , Manuilova Ekaterina , Müller‐Hübner Laura , Grimmer Timo , Powers Jennifer , Christenson Robert H. , Karpova Maria , Winter Carla , Teunissen Charlotte E.
Published: December 2022

Background

Beta‐amyloid(1–42) (Abeta42) and phosphorylated tau 181 (pTau) cerebrospinal fluid (CSF) biomarker analysis is recommended alongside cognitive evaluation to aid Alzheimer’s disease (AD) diagnosis. For clinical use, CSF biomarker assays should demonstrate high precision/reproducibility and sample stability. This study evaluated precision, reproducibility, and sample stability of second‐generation fully automated Elecsys® CSF immunoassays.

Method

Frozen/pooled CSF and PreciControl samples were analyzed using Elecsys β‐Amyloid(1–42) CSF II/Phospho‐Tau (181P) CSF immunoassays on cobas e 601 (Roche Diagnostics International Ltd). pTau/Abeta42 ratios were calculated. Precision was evaluated at one site per Clinical and Laboratory Standards Institute (CLSI) EP02‐A3 (two runs/day in duplicate over 21 days; n=84). Reproducibility was determined per CLSI EP05‐A3 over five days using a single lot across three sites (site‐to‐site)/three lots at one site (lot‐to‐lot). Coefficients of variation (CVs)/standard deviations (SDs) for repeatability/intermediate precision/reproducibility were calculated using variance component analysis. Sample stability was determined from fresh CSF, collected per manufacturer's instructions. Baseline measurements were taken <6 hours after lumbar puncture and follow‐up measurements (from stored aliquots) at defined intervals for ≤8 days at room temperature (RT; 25°C; n=13), ≤15 days at 6°C (n=14), and ≤13 weeks at ‐20°C (n=25). Storage stability was determined from percent recoveries/ordinary linear regression.

Result

Repeatability CVs were <2.4% and <1.9% for Abeta42 and pTau immunoassays, respectively, and <2.4% for pTau/Abeta42 ratio. Intermediate precision CVs were <3.3% and <3.7% for Abeta42 and pTau immunoassays, respectively, and <3.9% for pTau/Abeta42 ratio. Site‐to‐site reproducibility CVs were <5.1% and <3.6% for Abeta42 and pTau immunoassays, respectively, and <6.5% for pTau/Abeta42 ratio (Table 1). For the Abeta42 immunoassay, lot‐to‐lot reproducibility CVs were <5.4%, except for one sample pool (mean concentration: 322 pg/mL; SD: 34.1 pg/mL; Table 2). Lot‐to‐lot reproducibility CVs were <3.6% for the pTau immunoassay and <6.0% for pTau/Abeta42 ratio. At maximum sample storage duration (8 days at RT/15 days at 2−8°C), median recoveries of 95%/98% were observed for Abeta42 and 97%/99% for pTau immunoassays. Stability assessment at ‐20°C is ongoing.

Conclusion

The Elecsys immunoassays demonstrated high precision/reproducibility, supporting clinical use in AD diagnosis. Conservative recommendations for sample storage are 5 days at RT/14 days at 2−8°C.
Novel circling SWAT for deep learning based diagnostic classification of Alzheimer’s disease: Application to metabolome data
Authors: Jo Taeho , Kim Junpyo , Bice Paula , Huynh Kevin , Wang Tingting , Meikle Peter J , Kaddurah‐Daouk Rima , Nho Kwangsik , Saykin Andrew J.
Published: December 2022

Background

Recent advances in deep learning have allowed multi‐omics data to be used to detect early stages of Alzheimer's disease (AD). The metabolome, as the end‐product of biological cascades including the genome, transcriptome, and proteome, may have informative elements that could serve as potential AD biomarkers. We report a novel two‐step deep learning method to detect AD and progression using lipidomics data.

Method

We used serum‐based cross‐sectional lipidome data with 781 lipids from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) including 216 cognitively normal (CN), 635 MCI, and 382 dementia (AD). Phenotype influence scores (PIS) was derived by deep learning‐based circling Sliding Window Association Test approach (Circling SWAT) (Fig. 1‐A), an extension of SWAT (Jo et al., 2022) with correlation heatmap and dendrogram analysis for omics data with minimal features. We used convolutional neural networks (CNN) to classify AD from CN based on top‐scoring metabolites. The AD classification model was used to predict conversion of MCI to AD within two years using 146 MCI‐convertors who developed AD and 190 MCI‐Stable who did not develop AD over two years from baseline. We removed two deDE lipids, deDE(18:2) and deDE(20:4), because their associations with AD were driven mainly by AD‐related medication.

Result

Phenotype influence scores (PIS) were calculated for each lipid using circling SWAT to determine their impacts on AD. The metabolites with the highest PIS were LPE(22:6), PC(39:5), and PC(15‐MHDA_22:6). When CNN was applied to the top 50 lipids by PIS, AD and CN classification accuracy was 73.6% (Fig. 1‐B), which was 5.1% higher than the accuracy obtained using only age, sex, and APOE ε4. For MCI conversion to AD, the AD/CN classifier accuracy was 69.9% or 8.8% higher than a model using only age, sex, and APOE ε4.

Conclusion

The circling SWAT method appears promising for the analysis of lipidome data as it was able to identify several AD‐related lipids and predict disease progression.
Association between recollection and familiarity‐based memory measures and plasma biomarkers for Alzheimer’s disease
Authors: DiCalogero Michael , Lane Jacqueline , Kelley Melissa , Tropea Thomas F. , Shaw Leslie M. , Chen‐Plotkin Alice , Wolk David A.
Published: December 2022

Background

Normal aging and preclinical Alzheimer’s Disease (AD) share common features, such as structural changes to medial temporal lobe regions and declining episodic memory. However, prior work suggests qualitative differences between AD‐related memory changes and those due to aging. Specifically, recollection‐based, or contextual, memory declines with both normal aging and AD. Alternatively, familiarity‐based, or item, memory is more specific to preclinical AD and atrophy in the perirhinal cortex. In the current analysis, we examined the relationship between these forms of memory with plasma biomarkers associated with AD and neurodegeneration.

Method

At the Penn Alzheimer’s Disease Research Center, 127 cognitively‐normal participants (age=73.12±6.62, 59% female, years of education=16.40±2.62, 80% Caucasian) completed an experimental memory paradigm assessing recollection and familiarity along with standard neuropsychological testing. In this paradigm, pictures of common objects were presented in 80 pairs at study and participants were told to pick the object they preferred. At test, 40 intact, 40 re‐arranged, and 40 novel object pairs were presented. Recollection was defined as the probability(intact)–probability(rearranged), while familiarity was defined as the probability(rearranged)/(1‐R). To account for differences in base rates of false alarms (‘‘old’’ responses to novel pairs), familiarity was calculated using a measure of discrimination (d’) derived from signal detection theory. Whole blood samples were collected in EDTA‐tubes, spun‐down, and stored at ‐80°C. Measures of glial fibrillary acidic protein (GFAP), neurofilament light chain (Nfl), and plasma tau (p‐Tau181) were generated with the Simoa HD‐X analyzer system.

Result

Familiarity correlated with GFAP (r(125) =‐0.24, p<0.05) (Figure 1) and NfL (r(125) =‐0.23, p<0.05) (Figure 2). Further, a partial correlation controlling for age and days between the experimental and plasma measure remained significant for GFAP (r(125)=‐0.25, p<0.05). Additionally, recollection correlated with Nfl (r(125) =‐0.25, p<0.05) (Figure 3). Correlations with standard neuropsychological tests revealed no significant results.

Conclusion

This study reveals that within the normal aging spectrum, familiarity‐based memory correlates with molecular measures that have been associated with amyloid (GFAP), while both measures correlated with a non‐specific measure of neurodegeneration (NfL). This supports the notion that familiarity may be sensitive to preclinical AD.
Large‐Scale Network Dysfunction in Dementia with Lewy Bodies: Preliminary Results from an fMRI Connectomic Mapping Study
Authors: Kashyap Bhavani , Wyman‐Chick Kathryn A , Hanson Leah R , Sherman Samantha J , Svitak Aleta L , O'Keefe Lauren R , Chrenka Ella A , Sughrue Michael Edward , Rosenbloom Michael H
Published: December 2022

Background

The diagnosis of dementia with Lewy bodies (DLB) is often delayed in clinical practice. The sensitivity and specificity of structural MRI is suboptimal: a multisite study with autopsy confirmation demonstrated 64% sensitivity and 68% specificity for differentiating DLB from Alzheimer's Disease (AD; Harper et.al, 2016). There is an urgent need to develop additional reliable biomarkers for DLB. We describe resting state functional MRI (rsfMRI) results using an automated connectome mapping program (Infinitome).

Method

Participants meeting criteria for probable DLB (McKeith et al, 2017) aged between 40 ‐90 years with a MMSE >15 were recruited from a multidisciplinary dementia clinic in this cross‐sectional study. MRI imaging was performed using a 3T Siemens scanner. DTI (diffusion tensor imaging), rsfMRI and structural images were gathered and analyzed through Infinitome (Rosenbloom et al, 2021), a program that creates a machine learning‐based, subject‐specific version of the Human Connectome Project‐Multimodal Parcellation atlas based upon diffusion tractography structural connectivity.

Result

Twenty‐six participants were contacted, of which 14 (54%) were consented and one withdrawn by the investigator. Of the 13 subjects that completed the study, 77% were male, 100% white and non‐Hispanic origin, with mean age 73.29 years (± 5.8), and average MMSE score 23.14 (±4.3). All participants demonstrated abnormal connectivity in regions involving visuospatial attention (areas 8Av, PGs, TE2a) and language processing (areas 55b, TGd, TGv; Table 1; Baker et al, 2018). Five parcellations were part of the extended default mode network (DMN) whereas one was part of the extended central executive network. Seven participants demonstrated changes in connectivity of area 46 (R & L; cognitive processing and mood) within the salience network (SN).

Conclusion

Preliminary findings suggest reduced connectivity in regions involved in visuospatial attention, language processing, and mood within in large‐scale networks such as the DMN and SN, consistent with previously published fMRI studies in DLB (Nicastro 2021; Schumacher 2018). The use of rsfMRI and connectome mapping may enable identification of a distinct radiological “signature” for DLB. Future research will evaluate rsfMRI features that distinguish DLB from AD.
Testing the association of resting‐state functional connectivity of the hippocampus and prefrontal cortex with AD‐vulnerable executive functions in periadolescent children
Authors: Zatkalik Abigail L , Phipps Connor J , Ramirez Meghan K , Sexton Jennifer N , Heller Abi , Behm Lillian , Nickolas Kristen , Maerlender Arthur C. , Phatak Vaishali S , Cramer Justin A. , Blair James , Murman Daniel L , Warren David E
Published: December 2022

Background

Alzheimer’s disease (AD) is an insidious neurodegenerative disease that is frequently associated with deficits in both memory and executive functions (EFs). EFs consist of a diverse range of cognitive processes, including inhibition, working memory, and cognitive flexibility. In AD and other disorders, dysfunction in EFs can result in attention deficits, decreased inhibition, and impaired decision‐making abilities. EFs have been historically linked to the prefrontal regions of the brain, but recent studies of brain networks and their functional connectivity have broadened these links to include brain regions such as the hippocampus (Hc). Building upon prior work, the current project investigated the association between decision making and hippocampal resting state functional connectivity (rs‐FC) in periadolescent children.

Method

A cohort of healthy periadolescent children aged 8‐13 (N = 80) was sampled from the ongoing NIA‐funded Polygenic Risk of Alzheimer’s Disease in Nebraska Kids (PRANK) study. PRANK participants completed an array of cognitive and behavioral measures, in addition to an MRI of the brain. Decision making ability was assessed via the NIH Toolbox Dimensional Change Card Sorting (DCCS) task. The rs‐FC between the Hc and regions of the prefrontal cortex (PFC) was measured, and its covariance with DCCS was assessed.

Result

rs‐FC of the Hc covaried with performance on the DCCS in the left dorsolateral prefrontal cortex (dlPFC) and dorsal anterior cingulate cortex (dACC). These anatomical regions are in line with larger intrinsic brain networks, such as the frontoparietal network (FPN) and the cingulo‐opercular network (CON).

Conclusion

These preliminary results suggest the Hc is associated with anatomical regions and intrinsic brain networks that are important for EFs. A better characterization of the process by which EF occurs within the brain may drive further research that can assess ways to limit the decline of these cognitive abilities associated with healthy aging or brain pathology such as AD.