bluuebunny/crossref_metadata_2025 huggingface dataset:
Cardiometabolic disorders are associated with reduced cerebral perfusion and white matter microstructure
Authors: Lockhart Samuel N. , Hughes Tim M. , Suerken Cynthia , Jung Youngkyoo , Whitlow Christopher T. , Bateman James R. , Williams Benjamin J. , Espeland Mark A. , Sachs Bonnie C. , Hayden Kathleen M. , Baker Laura D. , Craft Suzanne
Published: December 2021

Background

Cardiometabolic disorders (hypertension and diabetes) often co‐occur and are considered key modifiable risk factors for Alzheimer’s disease and related disorders; yet, the extent to which they each affect brain structure and function is unclear. We examined their associations with neuroimaging biomarkers of white matter microstructure, cerebral perfusion, and cognitive function in a diverse cohort of older adults.

Method

Participants aged 50‐85 years enrolled in Wake Forest Alzheimer’s Disease Research Center’s Clinical Core between 2016‐2020 received clinical evaluation, oral glucose tolerance testing (OGTT), neuroimaging, cognitive testing, and adjudication for mild cognitive impairment (MCI) and dementia. 3T brain MRI included T1 (for gray/white matter segmentation, regional volumes/thicknesses); FLAIR for white matter hyperintensity volume (WMHv); arterial spin labeling for cerebral blood flow (CBF); diffusion tensor imaging (DTI) for fractional anisotropy (FA); and neurite orientation dispersion and density imaging (NODDI) for Free Water. Hypertension (HTN) was staged using seated blood pressure (BP) and medications. Hyperglycemia was staged using OGTT 120 minute glucose levels (OGTT120), hemoglobin A1c, and fasting glucose as available. Cardiometabolic status was categorized (HTN only, hyperglycemia only, hyperglycemia+HTN, neither). Multivariable linear regression modeled associations with neuroimaging measures adjusted for age, gender, and race.

Result

MRI was available on 478 participants (35% MCI and 10% dementia) with mean age of 70±8 years, 74% with HTN, 61% with hyperglycemia (4% with non‐insulin treated diabetes), and 15% African‐Americans. The combination of hyperglycemia+HTN was associated with significantly higher NODDI Free Water and WMHv, lower FA, and lower gray matter perfusion, compared to neither factor (Table). Continuous levels of systolic BP and OGTT120 broadly correlated with WM microstructure, WMHv, and gray matter CBF (Figure). In adjusted models, systolic BP remained significantly associated with higher NODDI Free Water and WMHv, and CBF in gray and white matter. OGTT120 and WMHv remained significant in adjusted models. Cardiometabolic factors were not associated with gray matter macrostructure (e.g. volumes, temporal lobe cortical thickness) or cognitive status in this sample.

Conclusion

In this deeply phenotyped and racially diverse sample, individual cardiometabolic factors and the co‐occurrence of disorders was associated with reduced cerebral gray matter perfusion and reduced white matter microstructure.
Prevalence of modifiable risk factors for Alzheimer’s disease and related dementias, and association with cognitive disability among transgender and gender non‐binary adults in the U.S.: BRFSS 2019
Authors: Lambrou Nickolas H , Norton Derek L , Gleason Carey E , Flatt Jason D
Published: December 2021

Background

Subjective cognitive impairment (SCI) may represent an early sign of Alzheimer’s disease and related dementias (ADRD). Little is known about prevalence of SCI among people identifying as transgender men/women, or gender non‐binary (TNB). The Behavioral Risk Factor Surveillance System (BRFSS) defines cognitive disability as serious difficulty concentrating, remembering, or making decisions due to a health condition. Using report of cognitive disability as a surrogate for SCI, we aimed to: 1) characterize rates of morbidities considered modifiable risk factors for ADRD by gender identity, and 2) explore interactions between morbidities, cognitive disability and gender identity.

Method

We analyzed 2019 BRFSS data from 31 US states and Guam administering the optional sexual orientation and gender identity (SOGI) module. Chi‐squared tests characterized unadjusted associations between gender identity and health conditions (heart attack, stroke, diabetes, angina/coronary heart disease, and depression). Adjusted associations were investigated using logistic regression models. Models included cognitive disability as outcome, with gender identity, health condition, and age group as covariates, and interaction between gender identity and health condition. Likelihood ratio tests evaluated for interaction significance. Multiple correction controlled for false discovery rate at 5%.

Result

Of respondents providing a gender identity (n=231,414), 955 identified as TNB. Rates of depression were significantly higher for TNB respondents (37%) compared to cisgender (i.e. non‐TNB) counterparts (19.2%). Additionally, reports of cognitive disability were significantly higher in TNB respondents (24.7%) compared to cisgender counterparts (10.5%). Adjusted odds of cognitive disability with depression were highest for transgender men (aOR=11.48; 95% CI=20.70‐6.37) and cisgender men (aOR=9.22; 95% CI=9.65‐8.81), followed by cisgender women (aOR=7.50; 95% CI=7.79‐7.23), transgender women (aOR=4.71; 95% CI=7.93‐2.79), and non‐binary respondents (aOR=3.48; 95% CI=6.44‐1.88). Overall, TNB respondents were younger, with most between ages 18‐44 years (48.3%), compared to cisgender counterparts (26.8%).

Conclusion

Rates of depression and cognitive disability were significantly higher for TNB groups compared to cisgender counterparts. Interestingly, interaction analyses suggested that men, be it transgender or cisgender, demonstrated greatest cognitive disability associated with depression compared to other groups. Future directions include investigating psychosocial facets of gender identity and cognitive health, along with tailored interventions addressing modifiable risk factors and ADRD screening.
Iron intake, brain iron, and Alzheimer’s disease among community‐dwelling older adults
Authors: Agarwal Puja , Ayton Scott , Wang Yamin , Agrawal Sonal , Bennett David A , Barnes Lisa L , Leurgans Sue E , Bush Ashley I , Schneider Julie A
Published: December 2021

Background

Iron is an essential trace metal for brain health but maybe damaging when in excess, for example, through the regulated cell death program, ferroptosis. We earlier reported that higher brain iron levels are associated with faster cognitive decline and more neurofibrillary tangles, but the cause of iron elevation is unknown. This study investigates dietary and demographic factors associated with brain iron levels, Alzheimer’s Disease (AD) pathology, and cognitive decline.

Method

The study was conducted in 614 decedents (age‐at‐death:91.2±7.2years; education:14.6±3years;70% females) of the Rush Memory and Aging Project. AD pathology was assessed using standard criteria. Brain iron levels were evaluated in four brain regions (inferior temporal, mid frontal, and anterior cingulate cortices, and cerebellum) using Inductively Coupled Plasma Mass Spectrophotometry, and a composite mean z‐score was generated. Cognitive performance measured with 19 tests examined annually until death. Mean annual dietary iron intake was obtained from a validated food frequency questionnaire. Linear and logistic regression models with stepwise selection were used to investigate associations.

Result

The mean dietary iron intake (up to>10 years of follow‐up before death) was not associated with postmortem brain iron levels, cognitive decline, or global AD pathology. Age‐at‐death (β=‐0.01,p=0.001), sex (β=0.30,p<0.0001), smoking (β=‐0.20,p=0.0008), and APOE‐ε 4 status (β=1.65,p=0.01) were each associated with higher brain iron levels. Except for APOE‐ε 4 status, these associations were retained when further controlled for AD pathology. Among dietary factors, in the age‐adjusted model, total fat (β=0.007,p=0.04) was positively, and omega‐3 fat (β=‐0.18,p=0.001) was negatively associated with higher brain iron levels. However, with further adjustment for age, sex, smoking, and APO‐ε 4 status, only the omega‐3 association, was retained.

Conclusion

Unlike brain iron, dietary iron intake does not relate to AD pathology or cognitive decline. This may not be surprising since the blood‐brain barrier is relatively impermeable to fluctuations in blood iron levels. Brain iron accumulation in older adults relates to demographic factors independent of AD pathology. Overall, brain iron was not associated with dietary iron but was inversely associated with omega‐3 fats. Further studies on fat intake, dietary fat and iron interaction, and its relationship with brain measures are warranted.
Laser speckle‐based retinal imager as a potential screening tool for mild cognitive impairment
Authors: DeBuc Delia Cabrera , Kandukuri Jayanth , Sinha Avigyan , Lee Wen‐Hsiang , Crocco Elizabeth , Sapahia Rishav , Mendoza‐Santiesteban Carlos , Smiddy William E. , Garg Rajesh K. , Kostic Maja , Alfonso Michelle Marrero , Baumel Bernard , Rege Abhishek
Published: December 2021

Background

As the overall population's life expectancy rises, so does the prevalence of age‐related cognitive impairment (CI). Recent evidence has shown that cognitive impairment (CI) is not limited to the brain and affects the retina. In this study, we characterized dynamic retinal blood flow (RBF) patterns using the XyCAM RI (Vasoptic Medical, Inc.), a non‐invasive, laser speckle‐based retinal imager, in cognitively normal subjects (CN), patients with mild cognitive impairment (MCI), and individuals with diabetes mellitus (DM) including those with diabetic retinopathy (DR).

Method

A total of thirty‐four individuals (68 eyes) were imaged using the XyCAM RI. Normal cognitive function was determined using neuropsychological tests. High frame‐rate (82 Hz) RBF data was acquired over six seconds from each eye. As described and defined in Fig. 1, various dynamic RBF metrics were computed from the shape of the temporal waveform of blood flow velocity indices (BFVi) averaged within multiple arterial and venous segments intersecting a circular track around the optic disc. One‐way ANOVA was used to compare group means (p<0.05).

Results

Dynamic RBF metrics were computed using BFVi data from arterial and venous segments of 8 CN, 12 DM, 5DR, and 9 MCI eyes for comparison. Statistical comparisons (Table 1) confirmed significant differences between Dip BFVi in MCI vessels and CN/DR vessels but not DM vessels suggesting similar reduced RBF in both MCI and DM vessels. Compared with the Dip BFVi, no group‐wise differences were observed in Peak BFVi and Mean BFVi, suggesting the usefulness of assessing temporally‐resolved RBF data. A significantly higher arterial VRI (p < 0.002) and smaller venous VFI in MCI subjects demonstrated increased contractility compared to CN and DM subjects. The ANOVA test confirmed a statistically significant difference in the VFI of MCI subjects from each of the CN/DM/DR groups.

Conclusion

Individuals with MCI have different RBF characteristics compared to CN and DM subjects. These results may be related to systemic changes in arterial stiffness and increased blood pressure, which have been correlated with a decline in cognition. Non‐invasive dynamic RBF metrics using the XyCAM RI should be further investigated as potential biomarkers for classifying individuals with MCI.
Plasma Aβ40, Aβ42 and Aβ‐clearance proteins as blood biomarkers for Alzheimer's disease, subjective cognitive decline, and MCI
Authors: Ito Hitomi , Shan Liu , Hata Naoko , Korenaga Tatsumi , Suzuki Hideaki , Meno Kohji , Takihara Takanobu , Akatsu Hiroyasu , Matsukawa Noriyuki , Asada Takashi , Arai Tetsuaki , Uchida Kazuhiko
Published: December 2021

Background

For early intervention and prevention of dementia, diagnostic biomarkers for MCI and preclinical Alzheimer's disease (AD) are important. amyloid β (Aβ) and tau are known as biomarkers for AD, and the CSF Aβ40 / Aβ42 ratio is clinically useful for diagnosis of AD. We have reported that three proteins in serum related to Aβ clearance: ApoA1, complement protein C3 and transthyretin (TTR) are useful as blood biomarkers for MCI (Triple marker). Plasma Aβ has been shown to correlate with amyloid PET, however, its clinical utility in MCI and AD diagnosis is unclear. Therefore, we investigated usefulness plasma Aβ in addition to the triple marker as blood test for MCI and AD. Here we analyzed plasma levels of Aβ40, Aβ42 and Triple marker in MCI and AD as diagnostic markers.

Method

A total of 909 cases consisting of 354 non‐demented control (NDC), and 76 subjective cognitive decline (SCD), 312 MCI, and 167 AD diagnosed according to ADNI neuropsychological criteria were selected in the multicenter clinical study. The positron emission tomography (PET) using with [18F] Florbetapir was performed 24 APOE4‐carring SCD and MCI subjects. Plasma Aβ40, Aβ42 were measured by ELISA (EUROIMMUN, Lübeck). Plasma levels of ApoA1, TTR, complement C3 was measured as described previously (Liu et al., Alzheimer Dement (Amst) 2019).

Result

Plasma ApoA1 and complement C3 levels were decreased in progression of the disease. Plasma Aβ40 / 42 ratio showed ROC AUC = 0.82 and 0.67 in AD vs. NDC and MCI vs. NDC, respectively. Combination of plasma levels of Aβ40 / 42 ratio and Triple marker (ApoA1, TTR, C3) showed AUC = 0.85 (80% sensitivity and 85% specificity) in AD vs. NDC and AUC = 0.76 (76% sensitivity and 70% specificity) in MCI vs. NDC. Aβ40 / 42 ratio and TTR were significantly decreased in amyloid‐positive subjects (SUVR≥1.10) compared to amyloid‐negative subjects (SUVR<1.10).

Conclusion

Combination of plasma Aβ40 / Aβ42 ratio and Triple marker is a useful blood test for not only AD but also the early stages of cognitive decline.
Cognitive correlations with amyloid, tau and neurodegeneration PET across the Alzheimer’s disease age spectrum
Authors: Tanner Jeremy A , Iaccarino Leonardo , Edwards Lauren , La Joie Renaud , Strom Amelia , Pham Julie Q. , Mellinger Taylor J. , Soleimani‐Meigooni David N. , Rosen Howard J. , Kramer Joel H , Miller Bruce L. , Rabinovici Gil D.
Published: December 2021

Background

In Alzheimer’s disease (AD), cognitive symptoms have varying associations with tau, amyloid and neurodegeneration. Patients with early‐onset AD (EOAD, age<65) have more non‐amnestic symptoms, greater AD pathological burden, and less co‐pathologies than late‐onset AD (LOAD, age≥65). It is unknown whether the association between cognitive symptoms and Alzheimer’s disease biomarkers differs with age, and this has implications for clinical trials. The goal of this study was (1) to evaluate the association between domain‐specific cognitive performance and PET‐based pathology in AD, and (2) to compare whether theses associations differ in EOAD versus LOAD.

Method

Amyloid‐positive patients meeting criteria for mild cognitive impairment or AD dementia (Total n=71; EOAD n=33, mean age 58±4, MMSE 20±7, 61% female; LOAD n=38, mean age 74±6, MMSE 24±5, 45% female) underwent neuropsychological testing, 18F‐flortaucipir (FTP‐PET), 11C‐PIB‐PET (PIB‐PET), and a subset underwent 18F‐fluorodeoxyglucose‐PET (FDG‐PET, n=57). Composite scores were calculated for episodic memory, semantic memory, language, executive function and visuospatial domains. Voxelwise regressions (thresholded at uncorrected p<0.001 voxel‐level, FWE p<0.05 cluster‐level) evaluated PET/cognition correlations, and EOAD versus LOAD differences were tested with a PET*group interaction. Mediation analyses assessed direct and FDG‐PET‐mediated associations between FTP‐PET and cognitive performance in regions‐of‐interest based on the voxelwise regressions.

Results

FTP‐PET and FDG‐PET (lesser extent), but not PIB‐PET, showed significant domain‐specific voxelwise associations with cognitive performance that aligned with known brain‐behavior relationships (episodic memory/medial temporal lobe, semantic memory/anterior temporal, language/perisylvian, executive/frontal, visuospatial/occipital) (Figures 1‐3). There were no significant interactions between age and PET correlations across all modalities. Mediation analysis revealed that FDG‐PET mediated the relationship between FTP‐PET and cognition in all domains except episodic memory (Table 1). FTP‐PET also had a direct effect on executive function (p<0.001) and visuospatial (p=0.02) performance.

Conclusion

In AD, cognitive performance correlated with tau and neurodegeneration, but not amyloid, in similar patterns across the age spectrum. The relationship between tau and cognition was in part mediated by glucose metabolism. These findings provide support for inclusion of EOAD patients in clinical trials, for tau PET as a biomarker that captures molecular specificity and aligns with clinical performance, and for the shared potential of disease‐modifying therapies across the AD age spectrum.
A randomised placebo‐controlled study on the effects of anthocyanins for maintaining cognitive functioning in individuals at increased risk for dementia
Authors: Khalifa Khadija Nasralla , Aarsland Dag
Published: December 2021

Background

Anthocyanins are found in dark berries, that have antioxidant and anti‐inflammatory effects and can cross the blood‐brain barrier. This study aims to evaluate the safety and efficacy of anthocyanins in modifying key dementia‐related mechanisms and maintaining cognitive functioning in older people at risk for dementia.

Method

We conducted a 24‐week randomised, double‐blind, placebo‐controlled Phase II study. A total of 208 participants aged 60‐80 years with cardiometabolic disorders (n=143) or mild cognitive impairment (n=68), were randomised to either purified anthocyanins (Medox® capsules, 320mg/day) or placebo for 24 weeks. The primary outcome is the Quality of episodic memory score, a composite measure from the online cognitive test battery CogTrack®, administered monthly. Secondary outcomes include other cognitive scores, neuroimaging (MRI and FDG‐PET), blood and CSF biomarkers. Medication compliance was measured by counting returned capsules, and anthocyanin metabolite levels will be measured in serum and CSF. Longitudinal measures of Quality of episodic memory will be subject to Mixed Model for Repeated Measures ANCOVA. Cognitive data are currently being analysed but still blinded.

Result

Treatment groups are shown in Table 1. Retention in the study was very good; only one participant discontinued the study due to adverse event (AE), diarrhoea, another four due to pre‐defined protocol deviation (Figure 1). AEs were reported in 34 participants, five of which were serious adverse event (hospitalisation for constipation, hypertension, MRI finding of acute ischemic stroke at final assessment, and two anginas). There were minor differences in the proportions of participants reporting AEs (18 vs 15%; p=0.58). There were no notable changes in safety blood tests and the medication compliance was high (median 98% of planned doses, IQR 93‐99%).

Conclusion

This is one of the most ambitious trials of anthocyanins and cognitive impairment. Anthocyanin capsules were well‐tolerated and safe, with no significant differences in adverse events between the treatment groups. The analysis of the cognitive outcome measures is ongoing, and the results will be presented at the meeting. The study may contribute to further improvement of intervention strategies to prevent or delay the onset of dementia, including a potential decision to take anthocyanins toward phase III trials.
Quantitative amyloid PET in the AMYPAD diagnostic and patient management study
Authors: Buckley Christopher , Gispert Juan Domingo , Altomare Daniele , Moro Christian , Bullich Santiago , Caprioglio Camilla , Scheltens Philip , Van Berckel Bary N.M. , Collij Lyduine E. , Alves Isadora Lopes , Berkhof Johannes , Garibotto Valentina , Delrieu Julien , Molinuevo Jose , Drzezga Alexander , Jessen Frank , Nordberg Agneta K. , Walker Zuzana , Demonet Jean‐François , Gismondi Rossella , Battle Mark R. , Farrar Gill , Stephens Andrew W. , Barkhof Frederik , Frisoni Giovanni ,   AMYPAD Consortium
Published: December 2021

Background

AMYPAD‐DPMS is a European, multicenter, prospective, interventional, randomized controlled study. It aims to assess clinical utility and cost‐effectiveness of amyloid‐PET. It recruited individuals with Subjective Cognitive Decline plus (SCD+), and syndromic diagnosis of Mild Cognitive Impairment (MCI) and dementia. Here, we describe the quantitative results of the basal amyloid PET performed in these participants.

Method

Until end of recruitment on October 30th, 2020, 844 participants were included in AMYPAD‐DPMS from 8 clinical sites. Of those, 186 are from the Geneva site, 143 from Amsterdam, 130 from Toulouse, 101 from Barcelona, 94 from Cologne, 73 from Stockholm, 64 from London and 53 from Lausanne. Amyloid PET was performed with either 18F‐florbetaben or 18F‐flutemetamol and analysed with AmyPype, a PET‐only Centiloid‐calibrated pipeline running on a GE Advantage Workstation, to render comparable estimates of global amyloid load for both tracers. The standard Global Cortical Average region of interest was used as target region and the whole cerebellum as reference. Distributions as well as Mean and Standard Deviations (SD) of CL values by tracer, site and by diagnostic groups were computed.

Result

From the 844 recruited participants, 245 (29%) were SCD, 341 (40%) MCI and 258 (31%) dementia. By January 19th, 2021, 661 scans had been analyzed with AmyPype and had passed quality control. Of them, 308 (47%) were scanned using 18F‐florbetaben and 353 (53%) with 18F‐flutemetamol. The global mean (SD) [range] of Centiloid (CL) values was 45.0 (49.0) [ ‐52.4, 221.9] CL. By clinical group, the average (SD) CL values were 25.5(39.1) for SCD+, 45.8(47.9) for MCI, and 66.3(51.1) for dementia patients. CL distributions by clinical group are shown in Figure 1, and per‐site and tracer in Figures 2‐3 for the MCI and Dementia groups.

Conclusion

Quantitative amyloid PET in AMYPAD‐DPMS shows a very well‐balanced tracer use. As expected, CL values increased with increasing disease severity. The consistent distribution of the majority of CL values within/across clinical groups suggest that the Centiloid transformation implemented in AmyPype allowed the direct comparison of estimates of amyloid burden across the two tracers used in this trial.
CSF and PET biomarkers for noradrenergic dysfunction in neurodegenerative disease: A systematic review and meta‐analysis
Authors: Lancini Elisa , Bartl Franziska , Haag Lena , Rühling Maren , Ashton Nicholas J , Zetterberg Henrik , Düzel Emrah , Hämmerer Dorothea , Betts Matthew
Published: December 2021

Background

Alterations to the noradrenergic system may occur in the early stages of Alzheimer’s disease (AD) and Parkinson’s disease (PD) and could contribute to clinical symptoms. The aim of this study was to conduct a meta‐analysis of noradrenergic differences in AD and PD assessed using cerebrospinal fluid (CSF) and positron emission tomography (PET) measures

Method

CSF noradrenaline (NA) and its metabolite 3‐Methoxy‐4‐hydroxyphenylglycol (MHPG) as well as NA transporter availability (PET MeNER) levels in controls, AD and PD patients were pooled across studies. Differences between controls and patients were calculated with Hedge’s g and combined using a random‐effects model meta‐analysis. A random‐effect meta‐regression was conducted using the volume of the CSF samples, the sample sizes, the years post diagnosis, the severity of the diseases as covariates using laboratory analysis technique as a between‐study factor.

Result

Twenty‐seven studies met the inclusion criteria. Seven studies with extreme effect sizes influencing between‐study heterogeneity were identified as outliers and subsequently removed from further analyses. In PD patients, significant reductions in CSF NA (n= 132, g= ‐0.26, p=0.01) and MHPG (n=257, g = ‐0.27, p<0.01), in addition to reduced PET MeNER binding in the hypothalamus (n=29, g = ‐0.87, p<0.05), were observed compared with control subjects (n=166 for NA, n=227 for MHPG respectively). In AD patients, no significant difference in CSF NA levels (n=194, g= ‐0.06, p= 0.78) and only a trend for increased MHPG levels (n=208, g= 0.24, p= 0.07) were observed compared with controls (n=196 for NA, n=218 for MHPG respectively), see Figure 1. The number of articles addressing PET MeNER in AD was not sufficient to conduct a meta‐analysis. The hypothesized explanatory variables, namely the volume of CSF samples, the sample size, the years post diagnosis and the severity of the disease, were not significant (p>0.05) in any of the investigated groups.

Conclusion

Our results indicate that noradrenergic dysfunction in neurodegenerative diseases can be detected using CSF or PET measures and may be more pronounced in PD compared to AD. Further studies using longitudinal CSF and PET measures are required to elucidate the relationship between noradrenergic dysfunction and the progression of neurodegenerative diseases.
Longitudinal examination and validation of the latent dementia phenotype factor in 10 harmonized cohort studies
Authors: Lam Ben CP , Crawford John D , Lipnicki Darren M , Mewton Louise , Sachdev Perminder S
Published: December 2021

Background

Previous studies have developed a latent continuous indicator of dementia phenotype, referred to as delta (δ), capturing the overlap of cognition and functional status in dementia (Royall & Palmer, 2012. J Neuropsy Clin Neurosci; Gravett et al., 2015. Neuropsy). To investigate this as a potential tool for harmonizing cognitive test and function data and identifying dementia cases in heterogeneous samples of older adults across studies, the current research constructed and examined the latent dementia factor (LDF) in 10 longitudinal population‐based studies from the Cohort Studies of Memory in an International Consortium (COSMIC).

Method

A total sample of 19,208 older individuals (mean age = 73 years; 58% females) with a median follow‐up of 6 years was analysed. Longitudinal confirmatory factor analysis was first conducted to establish measurement invariance of LDF constructed by available neuropsychological tests and instrumental activity measures in each study (see Figure 1). The LDF scores were then standardised at common values of age, sex, and education to ensure comparability. Latent growth curve analysis was then conducted to estimate the initial level of and per year change in LDF. Measures for examining validity included dementia diagnosis, the Mini‐Mental State Examination (MMSE), and the Clinical Dementia Rating Scale Sum of Boxes (CDR‐SOB).

Result

A significant linear increase in LDF in the overall sample was observed (an increase of 0.13 standard deviation per year). Mixed effects cox regression revealed significant associations between initial level of and change in LDF and incident. Further, one standard deviation increase in LDF was associated with 0.72 point decrease in MMSE and 0.34 point increase in CDR‐SOB over time. Change in LDF accurately discriminated diagnosed dementia cases in all except two studies with limited neuropsychological data (average ROC area under the curve = 0.84).

Conclusion

This research shows the validity of a latent dementia indicator with dementia risk in a geographically and ethnoculturally diverse sample of older adults. This supports the utility of this approach to harmonise studies with different cognitive and functional measures to identify cases at risk of dementia (based on cutoffs of LDF).
Developments in clinical testing of cerebrospinal fluid biomarkers of Alzheimer’s disease in the UK
Authors: Keshavan Ashvini , Chapman Miles D. , Hart Melanie , Lunn Michael P. , Zetterberg Henrik , Schott Jonathan M.
Published: December 2021

Background

Guidance from the UK National Institute for Health and Care Excellence now incorporates CSF biomarkers in certain circumstances when a diagnosis of Alzheimer’s disease (AD) is considered. To improve testing speed and reliability, we validated the fully‐automated Lumipulse platform against existing Innotest ELISAs, by measuring amyloid‐β 1‐42 and 1‐40 (Aβ42 and Aβ40), tau and phospho‐tau181 (p‐tau181), and deriving cut‐points for reporting all routine clinical tests in the UK.

Method

In a prospectively‐collected cognitive clinic cohort, 56 samples were tested using Innotest ELISAs for Aβ42 and total tau, and the Lumipulse platform for Aβ42 and Aβ40. The Lumipulse Aβ42/Aβ40 cut‐point that gave the best concordance with an Innotest definition of AD‐like CSF (Aβ42<630 pg/ml and tau/Aβ42≥0.88) was selected and compared to values derived in the Insight 46 cohort by concordance with 18F‐florbetapir PET (Keshavan et al. 2020, Alz Dem (Amst.) doi:10.1002/dad2.12097). A subset of 20 samples from the clinic cohort assayed on both platforms for p‐tau181, and a further 42 samples from routine clinical testing, were also examined for concordance of Lumipulse p‐tau181 with Aβ42/Aβ40.

Result

A Lumipulse Aβ42/Aβ40 cut‐point of 0.065 gave 95% sensitivity and 89% specificity for distinguishing AD‐like from non‐AD‐like CSF (area under the curve (AUC) 0.959). Applying this cut‐point to data from Insight 46, where the Lumipulse Aβ42/Aβ40 AUC for amyloid PET was 0.966, yielded 85% sensitivity and 94‐96% specificity. Innotest and Lumipulse measurements of p‐tau181 were highly correlated (r=0.897, β=1.261, intercept=‐1.001). Applying the manufacturer's recommended Lumipulse p‐tau181 cut‐point of 56.5 pg/ml to the clinical samples gave 72% sensitivity and 86% specificity for distinguishing those with Lumipulse Aβ42/Aβ40≤0.065.

Conclusion

Clinical testing of AD CSF biomarkers in the UK has now moved to the Lumipulse platform, reducing the result turnaround time from 20‐25 to 10 working days. As certified reference materials for each biomarker become available, future cut‐point refinements may allow for standardisation across laboratories and even countries.
Mass spectrometric measurement of six site‐specific tau phosphorylations in CSF and blood of Alzheimer's disease patients
Authors: Montoliu‐Gaya Laia , Ashton Nicholas J. , Benedet Andréa Lessa , Rodriguez Juan Lantero , Brinkmalm Gunnar , Karikari Thomas K. , Kern Silke , Rosa‐Neto Pedro , Zetterberg Henrik , Blennow Kaj , Gobom Johan
Published: December 2021

Background

Hyperphosphorylation of tau is responsible for its loss of normal physiological function, gain of toxicity and its aggregation to form NFTs. Increased phosphorylated tau is detected in Alzheimer´s disease (AD) CSF and blood, and changes in the tau phosphorylation pattern may reflect different stages of the disease progression. A better understanding on how the levels of site‐specific phosphorylations are modulated across the AD continuum in these biofluids may help to provide with a more accurate diagnosis.

Method

We developed an LC‐MS method based on parallel reaction monitoring (PRM) using Orbitrap MS to measure tau phosphorylations at positions pT181, pS199, pT205, pT217 and pT231 in CSF and plasma, and additionally p396 in CSF. Tau enrichment prior to LC‐MS differed between biofluids. For CSF, 250 µl of sample were prepared by performing partial PCA protein precipitation, followed by SPE and tryptic digestion. For plasma, 1 ml samples were subjected to immunoprecipitation using a combination of several tau antibodies, followed by tryptic digestion and SPE.

Result

The performance of the method was first evaluated by analysis of CSF from neurochemically characterized AD patients and controls (n=40). All measured phosphorylations showed significant separation between groups (p<0.001) (Fig. 1). In addition, pT181, pT217 and pT231 showed good correlations with SIMOA immunoassays. In plasma, a set of AD patients and controls (n=26) were analysed. All phosphorylations showed an increase in AD, and most significantly pT205 (p=0.003) and pT231 (p=0.008) (Fig 2). Interestingly, these two phosphorylations were the ones that showed higher correlation with p‐tau CSF (Spearman r=0.52 and r=0.63, respectively). Plasma values were also compared to the respective SIMOA immunoassays. Finally, the method was used to measure samples from the Translational biomarker In Aging and Dementia (TRIAD) cohort (n=209), consisting of young individuals (<30 years old), cognitive unimpaired, mild cognitive impairment (MCI) and AD patients.

Conclusion

With our LC‐MS method to quantify site‐specific p‐tau levels, we have established the tau phosphorylation pattern in AD biofluids. Our data indicates that phosphorylation at position T231 is the one that shows a higher fold change between AD and controls both in CSF and blood.
A novel regional centiloid atlas to investigate the relationship between the quantification of [18F]flutemetamol amyloid PET and CSF Aβ42/40 in patients with SCD or MCI
Authors: Battle Mark R , Buckley Chris J , Farrar Gill , Pillay Lovena Chedumbarum , Ossenkoppele Rik , Smith Ruben , Hansson Oskar
Published: December 2021

Background

Visual assessment of [18F]flutemetamol amyloid PET images, performed regionally (frontal, lateral temporal, posterior cingulate/precuneus, temporo‐parietal, striatum), is recommended, with a positive (abnormal) classification if any one of these regions is clearly positive. Changes in the striatum, known to contain extensive fibrillar amyloid deposits in AD, could identify likely converters in Subjective Cognitive Decline (SDC) or Mild Cognitive Impairment (MCI) subjects. CSF biomarkers are proven to detect abnormal amyloid metabolism in early stages of AD, with Aβ42/40 more reliable than Aβ42 alone. We applied a novel regional Centiloid Atlas, based on standard Centiloid (CL) cortical VOIs with additional striatal , aiming to better stratify amyloid abnormalities. Correlation between CL and Aβ42/40 was also investigated.

Methods

The regional Centiloid atlas, developed by overlaying standard CL cortical VOI on AAL atlas and incorporating additional striatal regions, was applied to 394 [18F]flutemetamol subjects from the Swedish BioFINDER I study following the methods of Klunk et.al. (Alzheimer’s & Dementia, 2015). In total, 387 Subjects with CSF Aβ42/40 information from the ADx analysis platform available, were included for analysis.

Results

Average Aβ42/40 and CL values are presented (Table 1). Statistically significant differences in Aβ42/40 between control and MCI (p=0.0004), and SCD and MCI (p=0.0031) were observed (Fig. 1). Statistically significant differences in CL were also found in the cortical (p=0.007 or less) and striatal (p=0.028 or less) regions across all groups. Correlation between CL and Aβ42/40 for controls was moderate in both cortical (R2=0.35, Fig. 1) and striatal (R2=0.33, Fig. 2) regions. Similar correlations were found for SCD (Cortical: R2=0.52, Striatal: R2=0.48) and MCI (Cortical: R2=0.52, Striatal: R2=0.54).

Conclusions

Standard Centiloid PET quantification provides global values across the cortical region. Identifying combined striatal differences in [18F]flutemetamol retention may provide additional information, aiding . Detecting these abnormalities and understanding their relationship to CSF biomarker changes may be useful in identifying those subjects for progression to AD. Further work to identify differences between cortical and striatal uptake in within subjects is ongoing.
An analysis of the study participant and study coordinator experience utilizing an electronic consent (eConsent) in REDCap
Authors: Chin Erin , Suver Christine , Lah James J , Goldstein Felicia C , Manzanares Cecelia , Cobb Nichelle L , Blazel Hanna , Edwards Dorothy Farrar
Published: December 2021

Background

The informed consent (IC) process offers an opportunity for researchers to promote participant autonomy and facilitate decision making. However, the traditional IC experience is often tedious, requiring study coordinators to present information in long IC documents. Paper IC documents can be difficult to understand and do not necessarily meet the needs of participants or study coordinators. The COVID‐19 pandemic underscores the need to provide an alternative to the in‐person, paper‐based IC process to minimize person‐to‐person contact. We worked with IRBs to revise how we engage and consent people in Alzheimer’s Disease Research Centers at the University of Wisconsin‐Madison and Emory University.

Method

In an ongoing effort to improve the IC process for adults at risk of developing memory and cognitive deficit, our team has been building and testing an electronic IC experience. We interviewed a total of 63 participants with a median age of 72. Participants underwent both the eConsent prototype and the paper consent. Seventy (70) percent of those participants preferred the eConsent over the traditional paper copy. We adapted into REDCap the electronic IC experience (eConsent). We collected input on the project from IRBs and study coordinators, and measured participant’s understanding of key elements of the IC through questions distributed throughout the eConsent.

Results

Each interested study participant received a unique link to the eConsent in REDCap. We observed which participants selected to review the eConsent information on their own, and which ones preferred to be guided remotely with the Study coordinators. We evaluated level of engagement with the eConsent and scored comprehension. The insights provided by this informed consent approach were used to determine whether it would be well suited for at‐home self‐administration across a diverse population.

Conclusion

Study participants and study coordinators alike prefer an electronic consent process and participants retain information better as opposed to the typical paper consent form. While the REDCap consent survey is a temporary solution for our study team, it is a cost‐effective solution that facilitates a better experience for the participants. We believe that this REDCap eConsent could be a beneficial solution for the virtual recruitment and consent process at other ADRC sites.
[11C]PiB and [18F]AV45 PET radiotracers show different rates of amyloid‐β clearance
Authors: Chen Charles D. , McCullough Austin A. , Gordon Brian A. , Joseph‐Mathurin Nelly , Wang Guoqiao , Li Yan , Xiong Chengjie , Pontecorvo Michael J. , Klein Gregory , Shcherbinin Sergey , Higgins Ixavier A. , Masters Colin L , Clifford David B. , van Dyck Christopher H , Masellis Mario , Hsiung Ging‐Yuek Robin , Gauthier Serge , Bateman Randall J. , McDade Eric , Salloway Stephen P. , Benzinger Tammie L.S.
Published: December 2021

Background

Results from the first Dominantly Inherited Alzheimer Network Trials Unit (DIAN‐TU) clinical trial showed Gantenerumab reduces amyloid‐β deposition in autosomal dominant Alzheimer disease individuals. However, it is uncertain whether these initial findings from [11C]PiB PET generalize to other amyloid‐β PET radiotracers.

Method

We acquired [11C]PiB and [18F]AV45 PET in mutation positive DIAN‐TU participants in the gantenerumab (n=30) and placebo drug arms (n=19). Participants were assessed at baseline and Year 4; at each visit, [11C]PiB and [18F]AV45 PET were acquired, with at most 28 days between imaging sessions. Regional standardized uptake value ratios (SUVRs) were quantified using the PET Unified Pipeline. Annualized SUVR percent change between baseline and Year 4 for both radiotracers in both drug arms were calculated. Differences in SUVR change between radiotracers/drug arms were assessed using the Wilcoxon signed‐rank/rank‐sum test. Each test statistic is reported as a rank‐biserial correlation r accompanied by p‐values adjusted for false discovery control by the Benjamini‐Hochberg procedure at level q=0.20.

Result

We observed a decrease from baseline to Year 4 SUVR in the gantenerumab arm, which was larger when studied with [11C]PiB than with [18F]AV45 PET in several regions, including the striatum and cingulate gyrus (r=[‐0.79,‐0.31], FDR‐adjusted p‐values=[0.00086,0.19], Figure 1). In contrast, we observed an increase in SUVR in the placebo arm, comparable in magnitude between [11C]PiB and [18F]AV45 PET (r=[‐0.15,0.68], FDR‐adjusted p‐values=[0.29,0.86]).

Conclusion

Differences seen between the effects of gantenerumab in [11C]PiB versus [18F]AV45 PET suggest several regions, such as the striatum and cingulate gyrus, may be inappropriate for radiotracer harmonization in studies involving gantenerumab. More practically, the finding that anti‐amyloid‐β therapies may have different effects on signal across radiotracers suggests multi‐site studies of anti‐amyloid‐β treatments should agree on a single radiotracer for best results. Follow‐up postmortem studies will be conducted to determine the binding affinity of various amyloid‐β radiotracers to amyloid‐β plaques in this cohort.
Functional connectivity measurements in APP/PS‐1 mice revealed hypo‐connectivity with transient hyper‐connectivity
Authors: Cover Christopher G , Klunk William E , Vazquez Alberto L
Published: December 2021

Background

Changes in brain functional connectivity (FC) have gained traction as an early event in Alzheimer’s disease (AD), especially reports of hyper‐connectivity preceding hypo‐connectivity.1 In the present study, we characterized changes in neuronal and hemodynamic connectivity in AD mice from 3‐12 months of age.

Method

Amyloid precursor protein/presenlin‐1 (APP/PS‐1) mice (n=8) were injected with AAV‐Syn‐GCaMP6f into cortical regions. Mice were head‐fixed and imaged monthly from 3‐12 months of age. Simultaneous neuronal and hemodynamic signals were measured using wide‐field optical imaging (Fig 1a). Plaque characterization was performed via methoxy‐04 labelled images (Fig 1b). Resting‐state connectivity was calculated via Pearson correlation derived from the average timeseries of functionally clustered brain regions using a K‐means algorithm (Fig 2). Repeated measures Wilcoxon Rank Sum was used to assess statistical differences. Findings were considered significant for p<0.05.

Result

Amyloid plaques were predominately seen after 6 months old (mo) and increased linearly till 12‐mo (Fig 3). The average neuronal connectivity (Fig 4a) steadily declined between 3‐ to 12‐mo, with the steepest decrease occurring around 6‐mo (r=0.65 ± 0.01 @ 3‐mo to r=0.57 ± 0.01 @ 6‐mo; p=0.01). The exception being around 9‐mo, connectivity spiked (r=0.63 ± 0.01; p=0.94, compared to 3‐mo) before returning to r=0.55 ± 0.03 (p = 0.005, 10‐mo compared to 9‐months). Hemodynamic connectivity decreased between 3‐ to 12‐mo to r= 0.43 ± 0.01 (p=0.32; compared to 3‐mo; Fig 4b) with a trough around 9‐mo r=0.41 ± 0.02 (p=0.28; compared to 3‐mo). Average correlation between neuronal and hemodynamic activity remained stable but spiked around 9‐mo, though the transient hyper‐connectivity was not significant (Fig 5).

Conclusion

The observed neuronal transient hyper‐connectivity coincides with an acceleration in insoluble amyloid plaque deposition. Though insoluble amyloid continues to accumulate in the form of plaque and around blood vessels as the mouse ages, the steepest change in regional hypo‐connectivity seemed to occur around 6‐mo. We are currently exploring the decline in hemodynamic FC overtime and the detection of hemodynamic changes around the transient neuronal hyper‐connectivity at 9‐mo.

Reference: Schultz et al., J Neurosci. 2017 Apr 19; 37(16): 4323–4331.
Developing a novel peptide aptamer‐based treatment of Alzheimer’s disease
Authors: Ali Tahir , Klein Antonia N. , Vu Alex , Gilch Sabine
Published: December 2021

Background

Alzheimer’s disease (AD) is a major cause of dementia and age‐related neurodegenerative disease with no current treatment. Pathologically, AD is characterized primarily by accumulation of amyloid‐β (Aβ) in the brain. The interaction of Aβ‐oligomers (Aβo) with the cellular prion protein (PrPC) subsequently mediated AD pathologies. The interference with Aβo‐PrPC interaction is a valuable strategy for developing therapeutics for AD. Previously, we developed peptide aptamers (PAs) binding to the PrPC, partially covering the binding site of Aβo . In this study, we aimed to investigate the PAs effects on preventing Aβo‐PrPC interaction and toxicity in vitro and pathologies in AD models.

Method

Wild type mouse neuroblastoma N2a cells (overexpressing mouse PrP) were treated with Aβ (1 mM) and PAs (10 µg/ml), and after 24 hr performed the MTT assay. Following these in vitro experiments, we carried out in vivo experiments using transgenic 5xFAD (expressing human APP and PSEN1 transgenes harboring in total 5 mutations associated with familial AD) mice. The 5xFAD mice were treated with PAs at a 14.4 ug /day dosage for 6 weeks by intraventricular infusion using Alzet® osmotic pumps. After completion of treatment, fear conditioning test (FCT) was performed for consolidated leaning and memory functions of the 5xFAD mice.

Result

The MTT results indicated that PA treatment significantly reduced Aβo‐induced toxicity. Overall, our in vitro results indicated that PAs reduced Aβ‐induced neurotoxicity. In the FCT, we observed that PAs increased the time of freezing percentage as comparted to the non‐treated 5xFAD mice. The FCT results represented that PAs significantly improved consolidated learning and memory functions of 5xFAD mice as compared to the non‐treated 5xFAD mice.

Conclusion

Our results demonstrate that treatment with PAs targeting Aβo‐PrPC interaction would be valuable and novel strategy to treat AD.
Sleep disruption and disorders in former college and professional American football players
Authors: Alosco Michael L. , Adler Charles , Dodick David W. , Balcer Laura , Bernick Charles B. , Palmisano Joseph , Tripodis Yorghos , Cummings Jeffrey L. , Reiman Eric M. , Shenton Martha E. , Stern Robert A. , Banks Sarah J.
Published: December 2021

Background

Little is known about sleep in those with a history of contact sports, who are at increased risk for neurodegenerative disease(s). Sleep disruption and disorders are increasingly recognized as having a bidirectional relationship with Alzheimer’s disease neuropathology. Here, we investigated self‐reported sleep disruption and disorders in male former college and professional American football players.

Method

116 former National Football League (NFL) players, 60 former college football players, and 60 asymptomatic men without a history of traumatic brain injury or repetitive head impacts (controls), all between 45‐74 years, completed the Mayo Sleep Questionnaire (MSQ) which includes the Epworth Sleepiness Scale (ESS). Former American football players were enrolled across the spectrum of symptom severity (asymptomatic to mild dementia). Using binary logistic regression or analysis of covariance, comparisons (controlling for age, racial identity, body mass index, APOE e4 status) on each of the MSQ items and the ESS were made between each of the study groups.

Result

Compared to controls, former NFL players were more likely to restless legs (OR = 7.32, 95% CI = 1.63‐32.97*), sleepwalking (OR = 8.65, 95% CI = 1.08‐69.22*), observed apnea (OR = 2.25, 95% CI = 1.04‐4.85*), lower alertness levels (marginal mean diff. = 0.90**) and had higher ESS (marginal mean diff. = 2.37**). Former college football players reported greater sleep disturbances compared with controls: restless legs (OR = 10.82, 95% CI = 1.86‐62.89**), sleepwalking (OR = 10.45, 95% CI = 1.12‐97.58*), alertness levels (marginal mean diff. = 1.48**) and ESS (marginal mean diff. = 2.76*). There were no college vs control differences for observed apnea. There were no differences between former NFL players and former college football players on any sleep metric. **p<.005, *p<.05.

Conclusion

Sleep disturbances may be an important factor to investigate in those with a history of participation in American football.