bluuebunny/crossref_metadata_2025 huggingface dataset:
ALFA+: A cohort study to understand and model the preclinical stage of Alzheimer’s disease
Authors: Minguillón Carolina , Fauria Karine , Soteras Anna , Menchon Tania , Meléndez Xavier , Freixa Jordi , Sánchez‐Benavides Gonzalo , Gispert Juan Domingo , Molinuevo Jose Luis ,   ALFA Study
Published: December 2020

Background

With the aim of shedding light into the pathophysiology and pathogenic factors involved in early preclinical Alzheimer’s disease (AD), we established the ALFA program for the prospective follow‐up of cognitively unimpaired, many offspring of AD patients, participants. The nested ALFA+ cohort study incorporates deep phenotyping, including blood and CSF sampling for biomarker determination, FDG, amyloid and tau PET, and extended MRI and cognitive testing protocols.

Methods

Baseline visit is split into the following sessions (S) performed within ∼3‐6 months: S1: clinical visit to gather risk factor information and blood sampling, cognitive testing and an MRI scan. S2: lumbar puncture (LP) to obtain CSF. S3: extended neuropsychological and MRI exploration. Finally, amyloid (S4) and FDG (S5) PET are performed. Participants undergo follow‐up visits approximately every 3 years.

Results

Baseline visit resulted in the inclusion of 450 participants (mean age 61.1 [4.7]; 3.3% screening failure rate; 3.8% discontinuation rate). Remarkably, the number of APOE‐ε4 heterozygotes and homozygotes in ALFA+ is significantly higher than in the general population (Figure 1). Most ALFA+ participants have undergone both CSF sampling and [18F]flutemetamol PET (81.9%); the remaining have only CSF sampling (13.3%) or PET (4.8%). The prevalence of the amyloid positivity in the ALFA+ population is of 34%, which is also much higher than reported for the general population of this age range (Figure 2). The rate of amyloid accumulation and incidence of amyloid positivity is currently under investigation.

Conclusions

To our knowledge, the ALFA+ cohort study is the biggest monocentric research platform of middle‐aged cognitively unimpaired individuals, representing a highly valuable cohort of thoroughly characterized middle‐age participants ALFA+ is enriched in genetic risk factors for AD resulting in a higher proportion of participants with altered biomarkers compared with other populations.
Decreases in slow wave sleep associate with a higher risk of incident Alzheimer’s disease dementia in a community sample
Authors: Himali Jayandra J , Beiser Alexa S , Baril Andree‐Ann , Seshadri Sudha , Pase Matthew P
Published: December 2020

Background

Sleep disturbance is common in dementia, although it is unclear whether changes in sleep architecture precede dementia onset. We examined the prospective association of changes in sleep architecture with the risk of incident Alzheimer’s disease (AD) dementia in the community‐based Framingham Heart Study (FHS).

Methods

Our sample comprised a subset of 294 FHS Offspring participants who participated in the Sleep Heart Health Study Visit 1 (1995‐1998) and Visit 2 (2001‐2003), were dementia‐free and aged over 60 years at the time of Visit 2. Stages of sleep were quantified using home‐based overnight polysomnography. Annualized change in the sleep metrics were computed by subtracting Visit 1 from Visit 2 measures divided by the time interval (in years) between the two visits. Surveillance for incident AD dementia commenced at visit 2 and continued for up to 17 years (mean follow‐up 11 (SD, 4)). We used a series of proportional hazards models to relate changes in sleep to the risk of incident AD dementia, adjusting for age, sex, APOE ε4 allele status, smoking status, and sleeping medication, antidepressant and anxiolytic use.

Results

Participant mean age was 69 years (SD, 6, 49% male). Over 17‐years follow‐up, we observed 27 cases of AD dementia. The two sleep assessments were separated by a mean of 5.2 years (SD, 0.4). Levels of wake after sleep onset increased by a mean of 4.8 minutes (SD, 11.7) per year whereas both sleep efficiency and the percentage of slow‐wave sleep declined by 0.4% (SD, 2.3) and 0.6% (SD, 1.5) per year, respectively. Each percentage reduction in slow‐wave sleep associated with a 30% increase in the risk of incident AD dementia (HR, 0.70; 95% CI: 0.54, 0.91, P=0.007). Changes in other stages of sleep (stage 1, 2 and REM), sleep fragmentation (sleep efficiency and wake after sleep onset), and respiratory disturbances (apnea‐hypopnea index) did not associate with dementia risk.

Conclusions

By linking decreases in slow‐wave sleep to the risk of clinical AD up to 17 years later, our results extend observations suggesting that slow‐wave sleep is important for synaptic plasticity underlying memory and for glymphatic clearance of neurotoxins that potentially lead to AD dementia.
Characterising the temporal relationship between Aβ and tau accumulation in AD using in vivo imaging data
Authors: Whittington Alex , Gunn Roger N
Published: December 2020

Background

In 2010 Jack et al. proposed sigmoidal curves for Amyloid‐β (Aβ) and tau accumulation in Alzheimer’s Disease (AD) progression with Aβ preceding tau. Our recent work has shown that a logistic growth model consistent with this can describe the accumulation of Aβ as measured by imaging data (Whittington et al. 2018). Here, we use Aβ and Tau imaging data combined with mathematical modelling to characterise the temporal relationship between the two key pathological hallmarks of AD.

Method

Under the assumption that tau accumulation can also be characterised by a logistic growth model, a pair of equations (Figure 1, Eqns 1 &2) for Aβ and tau accumulation can be derived. These equations can be solved by substitution to yield a function for Tau in terms of Aβ (Figure 1, Eqn 3) which has 4 parameters (rAβ & rTau: unconstrained exponential accumulation rates; T50Aβ & T50Tau : time of half maximal concentrations). rAβ and T50Aβ were previously estimated as 0.20 yrs‐1 and 14.9 yrs respectively (Whittington et al. 2018) and were fixed to these values in the current work. AmyloidIQ and TauIQ analysis (Whittington & Gunn, 2018) were performed on 233 subjects’ data downloaded from ADNI where each subject had both an Aβ ([18F]Florbetapir) and Tau ([18F]Flortaucipir) scan to derive estimates of Aβ Load and Global Tau Load. Equation 3 was fitted to these data to estimate the parameters rTau & T50Tau and consequently the temporal relationship between Aβ and tau including the temporal lag parameter TLAG (= T50Tau ‐ T50Aβ).

Results

The model fit described the data well (Figure 2A: Solid black line) and provided clear in vivo evidence that Tau accumulation follows Aβ (TLAG = 5.5+‐0.9SE yrs). The estimated tau exponential growth rate (rTau) was 0.13 yrs‐1 which was lower than that observed for Aβ (r Ab = 0.2 yrs‐1). These parameters then allowed for the generation of predicted population accumulation curves for Aβ and tau over time (Figure 2B).

Conclusion

Using the IQ analytics platform and temporal regression modelling we provide clear in vivo evidence that in AD tau accumulation follows Aβ and characterise this temporal relationship.
Longitudinal validation of Cognigram™ in mild cognitive impairment (MCI): First year of data
Authors: Frank Andrew R.
Published: December 2020

Background

It is estimated that 10‐16% of patients with mild cognitive impairment (MCI) transition to dementia each year[1], though it has been difficult to predict which patients are at highest risk of deterioration[2]. CognigramTM is a computerized card game that measures cognition, with results relatively unaffected by language, educational level, and cultural background[3]. Our three‐year longitudinal study aims to assess the capacity of Cognigram to predict future cognitive decline in MCI and cognitively normal (CN) subjects.

Method

One year data is presented here for the first 7 MCI (mean age 76.0, mean MoCA 21.0) and first 6 CN (mean age 69.5, mean MoCA 27.5) participants. Cognigram testing was performed at baseline, 3, 6, 9, and 12 months. Cognigram captured performance scores related to card detection, identification, one‐back, and card learning. Clinical change was assessed using blinded neuropsychological evaluations performed at baseline and 12 months.

Result

Based on the neuropsychological testing, MCI and CN participants were classified as either clinically “stable” (4 MCI and 5 CN) or “declining” (3 MCI, 1 CN). On Cognigram card learning accuracy, clinically declining participants showed an accuracy drop of ‐0.14 (0.89 to 0.75) compared to clinically stable participants who showed an accuracy increase of +0.05 (0.89 to 0.94) (p=0.013). There were no clear patterns in the other Cognigram sub‐tests.

Conclusion

The Cognigram card learning accuracy test may distinguish between clinically stable and declining participants. The stable participants’ improvement may be explained by a learning effect, which is absent in the decliners. This analysis is limited by the small number, and data will be reviewed with more participants over three years. At the conclusion of our longitudinal study, we hope to determine if Cognigram can identify early cognitive changes in CN and MCI which predict which patients eventually convert to dementia. References: (1) Moon Y, Oh‐Park M, Lee J.(2013). http://www.sciencedirect.com/science/article/pii/B9780323544542000133; (2) Brooks, L.G., Loewenstein, D.A. Alz Res Therapy 2, 28 (2010); (3) Cogstate Healthcare, LLC (2017). https://www.cognigram.us/cognigram/about/index/index0.
Derivation of a tau‐PET based pathology accumulation index to estimate global tau‐load
Authors: Leuzy Antoine , Lilja Johan , Ossenkoppele Rik , Palmqvist Sebastian , Janelidze Shorena , Stomrud Erik , Strandberg Olof , Smith Ruben , Hansson Oskar
Published: December 2020

Background

As cortical tau pathology in Alzheimer’s disease (AD) has been shown to correlate closely to neurodegeneration and onset of cognitive impairment, there is a growing interest in the further refinement of tau‐PET methods for clinical use. Similar to amyloid‐PET, tau‐imaging will likely be approved for visual‐read supported by quantification (i.e. standardized uptake value ratio [SUVR]). Recently, we showed that a spatial normalization‐based weighting‐parameter (w, termed Aβ‐index) derived from amyloid‐PET was highly correlated to SUVR. As this measure carries several advantages over SUVR (e.g. no need to define ROIs and no need for an MRI), we here aimed to extend this method to tau‐PET.

Method

Preliminary findings are based on 245 subjects with and without cognitive impairment scanned with [18F]flortaucipir as part of the Swedish BioFINDER study. The relationship between w (termed Tau‐index) and SUVR (temporo‐parietal target‐ROI (Vogels et al.,2018) and inferior cerebellar cortex as reference) was assessed via linear regression and coefficient‐of‐determination (R2). Additional analyses are ongoing with a larger cohort (AVID AO5 and Expedition‐3), including cases with antemortem [18F]flortaucipir and post‐mortem tau immunohistochemistry for neurofibrillary tangle pathology. Findings will also be validated in BioFINDER‐2 (n=800, scanned with the second‐generation tau tracer [18F]RO948). Both cohorts will also include longitudinal data. Diagnostic performance of Tau‐index and SUVR will be assessed against visual‐read and post‐mortem tau‐histopathology using area‐under‐the‐curve (AUC) values from receiver‐operating characteristic analyses. These results will be presented at AAIC2020.

Result

Strong associations were observed between [18F]flortaucipir Tau‐index and SUVR (R2=0.933, P<0.001;Figure 1). No significant difference was seen between AUC‐values from Tau‐index and SUVR for the separation of AD from CU controls (Tau‐index=0.913, SUVR=0.920;Figure 2).

Conclusion

The proposed Tau‐index is simpler to implement clinically and may also facilitate the comparison of tau‐PET across different tracers/processing approaches. The proposed Tau‐index showed a clear association to SUVR and carries an advantage over the latter in that it does not require ROI definition nor the use of an MRI, which is important considering that many elderly subjects have contraindications for MRI. The findings require replication in the larger data sets as well as against neuropathology, which will be presented at the conference.
Detection of attenuated dynamic cerebrovascular function in aging and cognitive decline using a novel neuroimaging approach
Authors: Yew Belinda , Dutt Shubir , Li Yanrong , Ho Jean K , Jang Jung Yun , Blanken Anna E , Sible Isabel J , Marshall Anisa J , Gaubert Aimee , Shao Xingfeng , Wang Danny JJ , Nation Daniel A
Published: December 2020

Background

Cerebrovascular contributions to aging and cognitive decline have been increasingly recognized, yet the impact of changes in dynamic cerebrovascular function remain unclear. Breath holding and hyperventilation elicit alterations in end‐tidal carbon dioxide (etCO2) and cerebrovascular functions underlying cerebral blood flow (CBF). Manipulation of breathing during neuroimaging may therefore enable assessment of dynamic cerebrovascular changes implicated in cognitive decline.

Method

Community‐dwelling younger (n=15) and older (n=40) adults performed guided 15‐second breath holds to induce hypercapnia and paced breathing (alternating between 5‐second inhalation and exhalation) to induce hypocapnia, while undergoing pseudo‐continuous arterial spin labelling (pCASL) MRI. Continuous blood pressure and end‐tidal carbon dioxide (etCO2) were simultaneously collected. Cerebrovascular resistance index (CVRi), was estimated by dividing mean arterial blood pressure by pCASL‐derived CBF. Carbon dioxide reactivity (CO2R) was calculated by dividing change in CBF by change in etCO2. Older adults also underwent neuropsychological assessment of global and domain‐specific cognition. Relationships between dynamic cerebrovascular function, aging, and cognition were analyzed, controlling for hypertension and education.

Result

Across age groups, paced breathing decreased etCO2, CBF, and CO2R, while increasing CVR. Breath‐holding increased etCO2, CBF, and CO2R, while decreasing CVR. Older adults demonstrated attenuated cerebrovascular autoregulation (i.e. changes in CBF, CO2R, and CVR) in response to hypo‐ and hypercapnia, despite equivalent changes in etCO2 and blood pressure. Among older adults, weaker cerebrovascular response was associated with worse performance on measures of global cognition, memory, and executive function. Effects were preserved even after controlling for hypertension.

Conclusion

Through instigation of mild hypercapnia and hypocapnia during MRI, cerebrovascular reactivity deficits were detected in community‐dwelling older adults. Hemodynamic response was attenuated in older relative to younger individuals, suggesting that acute autoregulatory capacity may diminish with aging, above and beyond changes associated with hypertension. Reduced hemodynamic response was also associated with poorer global cognition and performance on tests of executive function and memory. Results suggest that age‐related vascular changes may hamper the proficiency with which changes in blood pressure and CO2 are met with cerebrovascular responses, potentially compromising CBF and neuronal function. This noninvasive method may therefore enable detection of cerebrovascular changes characterizing the earliest stages of cognitive decline.
Levels of amyloid β in cerebrospinal fluid predicts cognition five years later: A population‐based study of 70‐year‐olds
Authors: Skoog Johan , Bodin Timothy Hadarsson , Zetterberg Henrik , Kern Jurgen , Zettergren Anna , Blennow Kaj , Kern Silke , Thorvaldsson Valgeir , Skoog Ingmar
Published: December 2020

Background

Few studies have investigated the relationship between cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease (AD) and later cognitive function in the general population. The aim of this study was to study the association between Aβ42/40‐ratio, total‐tau (t‐tau) and phosfo‐tau (p‐tau) at age 70 and cognition at age 75 in a population‐based sample without dementia at baseline.

Method

The sample was derived from the population‐based Gothenburg H70 Birth Cohort Studies. A representative sample of 70‐year‐olds (N=1203, response rate=72%) were examined between 2014‐2016. A subsample of 316 individuals (26%) consented to a lumbar puncture and were free from dementia at age 70. Data have so far been collected on 72 individuals with CSF‐measures at age 70 and cognitive data at the follow‐up at age 75. CSF measures included Aβ42/Aβ40‐ratio, T‐tau and P‐tau, while cognitive tests comprised the Ray Auditory Verbal Learning Test (RAVLT), Semantic Fluency (animals) and Trail Making Test (TMT) A and B.

Result

At age 70, the prevalence of amyloid pathology was 22.8%, total tau pathology 33.2%, and phosphorylated tau pathology 6.9% in cognitively unimpaired individuals. Lower Aβ42/Aβ40‐ratio at age 70 was associated with lower verbal learning score (p<0.01), lower delayed recall (<0.0001) and lower verbal fluency score (p<0.05) at age 75. Aβ42/Aβ40‐ratio was not significantly associated with TMT, and T‐tau and P‐tau was not significantly related to any of the cognitive measures.

Conclusion

Our findings indicate that amyloid pathology precedes decline in cognition with at least five years while T‐tau and p‐tau does not.
Genome‐wide gene‐based analysis of episodic memory trajectories in the Mexican Health and Aging Study (MHAS)
Authors: Barral Sandra , Gao Yizhe , Arango Silvia Mejia , Obregon Alejandra Michaels , Samper‐Ternent Rafael , Wong Rebeca , Mayeux Richard , Reyes‐Dumeyer Dolly , Rentería Miguel Arce , Tosto Giuseppe
Published: December 2020

Background

Understanding genetic modulation of memory will yield insight into the biological mechanisms underlying memory decline and dementia. The cognitive genetics field has largely focused on populations of European descent. Including genetically diverse populations, such as the Mexican population, the largest USA minority group, will increase our understanding of the genetic architecture of memory function.

Method

The analysis sample consisted of 17,650 participants from the Mexican Health and Aging Study for whom socio‐demographic and longitudinal scores on episodic memory were available. Adjusted trajectories of memory performance were estimated using Latent Class Mixed Models. Genome‐wide gene‐based analyses were carried out in the sub‐sample of participants (n = 2,433) with imputed genotyped data (Haplotype Reference Consortium reference). The slope of episodic memory scores was used as the outcome in gene‐based analyses adjusted for sex, age, education, kinship matrix and principal components. Secondary analyses were restricted to participants with Native‐American ancestry (n = 1,842).

Result

The majority of the participants (77%) clustered as Stables, those who maintained their memory performance over time. Compared to those classified within the Stable memory trajectory, the prevalence of dementia was higher among Decliners. Zinc metabolism appear to be essential for neurogenesis, and neural migration and dietary zinc deficiency has been associated with memory impairment. The Zinc Finger CCHC Domain‐Containing Protein 2 (ZCCHC2) gene yielded the strongest association (p = 4.1 × 10−5). A less strong association with ZCCHC2 was also observed (p = 0.003) in the Native‐American ancestry sub‐sample. However, among the Native‐American participants, a different gene yielded the strongest association (p = 1.3 × 10−4), the Intraflagellar Transport 74 (IFT74) gene. The gene is a member of the IFT complex implicated in the vesicular trafficking to axons and dendrites. Sequence variants in IFT74 have been linked to a form of amyotrophic lateral sclerosis accompanied by progressive cognitive impairment.

Conclusion

Genetic variation influence longitudinal changes in episodic memory in a sample of Mexican population. Our results suggest that the indigenous Native American ancestry of Mexican population harbors novel and unique genetic variation underlying memory decline. Future work will include a larger sample (approximately 10,000 participants) and trans‐ethnic meta‐analysis with additional Caribbean‐Hispanics, African‐Americans and non‐Hispanic Whites cohorts.
OWOW! Six years on, what have we learned? Experience and perspectives on a cognitive interventional programme for persons with dementia
Authors: Choong Tanya‐Marie Yuen Oi , Yong Ting Ting , Satish Vaynii , Wilbur Koh Zhi Hao , Mei Nyu Mei , Lim Levinia , Silva Eveline , Kandiah Nagaendran
Published: December 2020

Background

Cognitive stimulation is an effective non‐pharmacological intervention shown to support cognitive function in persons with dementia (PwD). In 2014, we initiated the OWOW! programme as a multidisciplinary platform to address the physical and cognitive needs of our patients and offer opportunities for proactive behavior and social interaction. In this study, we draw further insights to the programme by examining staff experience and perspectives.

Method

Semi‐structured interviews were conducted with past and existing facilitators of the OWOW! programme (n=8). Questions were pertained to facilitators’ (1) rationale for programme participation, (2) personal experiences and emotions, and (3) feedback regarding organizational and administrative efficiency, and areas of improvement. Responses were examined and analyzed using a systematic thematic analysis approach.

Result

Three main themes were identified from preliminary thematic analysis: (1) gaining fresh insight into the level of personhood retained in PwD, (2) relevance of facilitators’ competency and skill, and (3) challenges with respect to programme logistics and organization. All facilitators also emphasized the need to incorporate PwDs' autonomy and personhood in the programme.

Conclusion

Our findings demonstrate that empowering PwD and reinforcing their personhood is the driving factor behind the effectiveness of the OWOW! programme. The various issues brought up by facilitators will also direct the team to better prepare for future runs of OWOW!
Association of brain copper with Alzheimer’s disease neuropathology: A community‐based neuropathologic study
Authors: Agarwal Puja , Dhana Klodian , Schneider Julie A. , Ayton Scott , Wang Yamin , Agrawal Sonal , Bennett David A. , Barnes Lisa L. , Leurgans Sue E. , Bush Ashley I. , Morris Martha Clare
Published: December 2020

Background

Copper (Cu) is an essential element for brain health. There is increasing recognition that altered Cu homeostasis is related to the development of Alzheimer’s disease (AD). Neuropathologic findings of amyloid plaque and neurofibrillary tangles are the hallmarks of Alzheimer's disease process. Whether brain Cu is associated with AD neuropathology in humans is unknown. This study examines the relationship between brain Cu levels and AD neuropathology in autopsies from a community sample of older adults.

Method

The study was conducted in 679 deceased participants from the Rush Memory and Aging Project, a cohort study. Brain Cu levels were measured using ICP‐MS in gray matter from inferior temporal, mid frontal, anterior cingulate, and cerebellum. Diffuse and neuritic plaques and neurofibrillary tangles were assessed in multiple brain regions and summarized as standard measures of AD pathology, including Braak, CERAD, NIA‐Reagan, global AD pathology. Linear regression analyses were used to evaluate the associations of brain Cu (grouped in tertiles) with the AD pathology in models controlled for age at death, sex, education, and APOE‐ ε 4 status.

Result

The mean age at death was 90.2 (±6.2) years, 70% were women, and 25% carriers of the APOE4 allele. Higher brain Cu levels were associated with less AD neuropathology. Participants in the middle and highest tertile of overall brain Cu levels had less global AD pathology (T3 vs. T1:β = ‐0.10; T2 vs. T1 = ‐0.11; p trend = 0.007) and Braak stage (T3 vs. T1: β = ‐0.31; T2 vs. T1 = ‐0.22; p trend = 0.005) when compared to those in the lowest tertile. Similar associations were found between inferior temporal brain Cu levels and AD neuropathology: global AD pathology (T3 vs. T1: β = ‐0.17, p = <0.0001); Braak (T3 vs. T1: β = ‐0.42, p = 0.0001); CERAD (T3 vs. T1: β = ‐0.17, p = 0.008); NIA‐Reagan (T3 vs. T1: β = ‐0.21, p = 0.002)). Brain Cu levels in mid‐frontal and cerebellum had a marginal association, whereas anterior cingulate Cu levels had no association with AD neuropathology.

Conclusion

Higher brain copper levels are associated with fewer AD neuropathology, suggesting that brain Cu levels either may reflect the severity of the disease or may indicate its potential beneficial effect on the disease process.
Comparison of static and dynamic analysis techniques for longitudinal analysis of amyloid PET
Authors: Cash David M , Markiewicz Pawel J , Jiao Jieqing , Coath William , Modat Marc , Lane Christopher A , Parker Thomas D , Keuss Sarah E , Buchanan Sarah M , Burgos Ninon , Dickson John , Barnes Anna , Cardoso Jorge , Alves Isadora Lopes , Barkhof Frederik , Thomas David L , Beasley Daniel , Wong Andrew , Schöll Michael , Richards Marcus , Ourselin Sebastien , Fox Nick C , Schott Jonathan M
Published: December 2020

Background

Amyloid PET is a robust biomarker of cortical β‐amyloid accumulation and a candidate endpoint for Alzheimer’s prevention trials. Quantification typically uses Standard Uptake Value Ratio (SUVR) measures acquired over 10‐20 minutes at steady‐state. SUVR may be more susceptible to altered blood flow than modelling of dynamic uptake data from injection to steady state. This may influence quantification, particularly change over time. Here we compared cross‐sectional measures and longitudinal rates of β‐amyloid change from static and dynamic analyses in individuals free of dementia.

Method

All participants were from Insight46, a sub‐study of the British 1946 birth cohort. Florbetapir PET scans were acquired on a single Biograph mMR PET/MR scanner and reconstructed using pseudo‐CT attenuation maps. Static SUVR images were acquired 50‐60 minutes post‐injection. Distribution Volume Ratio (DVR) was obtained from the Simplified Reference Tissue Model (SRTM) over 0‐60 minutes post‐injection. Both analyses used the same reference (cerebellar grey) and target (composite cortical grey) regions with no partial volume correction. Amyloid positivity was determined from a Gaussian Mixture model of the baseline data, taking the 99th percentile of the amyloid negative distribution. Amyloid accumulators were individuals with annual rates of change above 1.8%/year, representing the mean annualised rate of change in 37 cognitively normal CSF Aβ42 positive ADNI participants (doi:// 10.2967/jnumed.114.148981).

Result

390 participants had suitable PET data for cross‐sectional static and dynamic analysis; 195 participants had longitudinal data. DVR and SUVR exhibited high agreement cross‐sectionally (r2=0.79) with similar cut‐points (Table 1) and amyloid positivity rates (94% concordant classification, Figure 1). Longitudinal DVR resulted in more converters and accumulators in the amyloid negative group (Figure 2 and 3). However, comparing baseline amyloid positive/negative groups, longitudinal SUVR provided a larger effect size (Cohen’s d=1.02) than longitudinal DVR (d=0.28) (Table 1), with a sample size of 241 needed to detect a 25% reduction in SUVR per arm (compared to amyloid negatives) at 95% significance, 80% power.

Conclusion

Static and dynamic PET measures provide similar “state measures” at baseline, but have different longitudinal properties. SUVR may be more sensitive for quantifying accumulation in amyloid positive individuals; dynamic measures may be better at detecting earlier accumulation and conversion.
Diagnostic lumbar puncture in people with Down syndrome: The experience of the Jerome Lejeune Institute
Authors: Rebillat Anne‐Sophie , Hiance‐Delahaye Anne
Published: December 2020

Background

People with Down syndrome (DS) face an extremely high risk to develop dementia due to Alzheimer’s disease (AD) (Ballard C et al., 2016). The diagnosis of dementia in this population is complex given the pre‐existing intellectual disability, behaviour and co‐morbidities (Esbensen AJ et al, 2018). Contribution of biomarkers is crucial. However there are many reservations on the feasibility of lumbar puncture in this population. Nethertheless, this medical procedure should be accessible for people with DS (Carmona‐Iragui M., 2017)

Method

Description of the procedure performed at the Jerome Lejeune Institute using standard guidelines, pictograms and nitrous oxide analgesia

Result

About a third of the patients refused the procedure. For the others, the puncture was very well tolerated but sometimes made difficult by the anatomical particularities of the patients

Conclusion

It is a well accepted and well tolerated procedure, requiring time.
Young adult cognitive ability moderates effects of lifestyle behaviors on brain aging in late midlife: A longitudinal study of cognitive reserve
Authors: Franz Carol E. , Hatton Sean N. , Lyons Michael J. , Puckett Olivia K. , Whitsell Nathan , Kremen William S.
Published: December 2020

Background

Recent studies have reported significant associations between modifiable lifestyle factors and dementia (Licher et al, 2019; Lourida et al, 2019). We sought to extend those findings by examining whether the effect of lifestyle on brain age, a possible risk factor for dementia, is moderated by one’s level of general cognitive ability (GCA). Additionally, we examined associations between brain aging and mild cognitive impairment (MCI).

Method

At mean age 68 (SD 2.6; range 61‐72), 356 participants from the Vietnam Era Twin Study of Aging (VETSA) underwent structural MRI which was used to create predicted brain age difference (PBAD) scores (Liem et al., 2017). MCI at age 68 was determined using Jak/Bondi criteria. At mean age 40 (SD 2.7; range 34‐44), a positive lifestyle index was created comprising three self‐reported behaviors: not smoking, ≤ moderate alcohol consumption, and high social engagement. GCA at mean age 20 was assessed with the Armed Forces Qualification Test. Linear mixed models included GCA, lifestyle and their interaction as IVs, and adjusted for age, ethnicity, APOE genotype, height, and family membership.

Result

Age 20 GCA and age 40 lifestyle were significantly associated with PBAD [F=5.83; p=.02 and F=15.14; p<.001, respectively]. Having a higher GCA or more positive lifestyle behaviors predicted having less advanced brain age. The GCA‐lifestyle interaction was significant, indicating moderation. Having both lower GCA and few positive behaviors predicted having an older brain age relative to chronological age [F=5.00; p=. 03], but GCA made no difference when more positive behaviors were present (Figure 1). At age 68, non‐amnestic MCI participants had significantly more advanced brain aging compared with cognitively normal or amnestic MCI participants [F=3.10; p=.05].

Conclusion

Risk reduction remains a major component in the fight to prevent/delay dementia. Early positive lifestyle behaviors appeared to be protective against brain aging nearly three decades later for those with low or moderate GCA. High GCA appeared to be protective regardless of lifestyle behaviors. These results suggest that the negative effects of lifestyle start early, particularly for those who have lower cognitive reserve. Early intervention may help promote healthier brain aging and possibly delay dementia onset.
Study partner‐ and self‐reported difficulties in cognitively complex everyday activities in participants without objective cognitive impairment
Authors: Verrijp Merike , Dubbelman Mark A , Nijhuis Elke W , Visser Leonie NC , Zwan Marissa D , Jutten Roos J , Van Hout Hein PJ , van Der Flier Wiesje , Scheltens Philip , Sikkes Sietske AM
Published: December 2020

Background

Study partner report is used to assess cognitively complex everyday activities, or instrumental activities of daily living (IADL). Because a study partner is not always available, the question arises whether IADL can also be evaluated using self‐report. The aim of this study is to investigate the relationship between study partner‐ and self‐report IADL in individuals without objective cognitive impairment, and to explore its associated factors.

Method

Participants (N=3,295; mean age 61.0±12.1 years, 70.3% female; Table 1.) and their study partners (N=1,225) were recruited from the Dutch Brain Research Registry. They completed self‐ and study partner‐report versions of the Amsterdam IADL Questionnaire. For the 1,225 dyads, linear regression analyses were used to investigate the relationship between self‐ and study partner report. Age, sex, cohabitation, marital status, education and subjective memory complaints were explored as potential confounders and effect‐modifiers.

Result

A total of 1,544 (46.9%) participants and study partners (n=497, 40.6%) reported an increased level of difficulty in at least one IADL activity (Figure 1). Absolute agreement between self and study partner on item level was high, ranging from 93.3–99.2%. Participants self‐reported more IADL difficulties (M=65.9±SD=4.7), compared to their study partners (M=66.1±SD=4.6; p<0.05). The study partner‐ and self‐ reported IADL scores were significantly associated (B=0.54). When participants experienced memory complaints, both the participant and study partner reported more IADL difficulties (both p<0.001, Figure 2). Furthermore, we found an interaction effect indicating that the association between self and study partner was lower for those without memory complaints (B= 0.42, Figure 3). In addition, the association between self‐ and proxy was slightly lower for highly educated participants (B=0.47).

Conclusion

Subtle difficulties in IADL were present in about half of the population, and a high level of agreement between self and study partner was observed on both item and scale level IADL. We found several factors influencing the level of agreement, and in a next step we will include objective cognitive markers to explore the etiology of these differences. These findings provide support for the use of IADL self‐report in cognitively unimpaired individuals, in particular for use in primary or secondary prevention trials.
Identification of differential regulation of European versus African local ancestry haplotypes surrounding ApoEε4
Authors: Vasquez Marina Lipkin , Celis Katrina , Van Booven Derek , Hofmann Natalia K. , Rajabli Farid , Griswold Anthony J. , Brown Christopher D. , Pericak‐Vance Margaret A , Nuytemans Karen , Vance Jeffery M.
Published: December 2020

Background

The risk for late‐onset Alzheimer disease (AD) in ApoEε4 carriers differs between ancestral groups. ApoEε4 Non‐Hispanic White (NHW) homozygotes have an odds ratio of 14.9 while the risk is much lower in Africans (AF) (OR 2.2‐5.7). Local ancestry (LA) analyses in ApoEε4 carrier populations have shown the protective effect in Africans relative to NHW is due to factors lying in the LA surrounding ApoEε4. No coding differences between genes in the LA have been observed between AF and NHW ancestries. Thus regulatory differences in LA non‐coding regions are most likely involved in the protective factor(s) lowering the risk for AF carriers of ApoEε4. Enhancers are the most common regulatory element, and thus we sought to identify if any of these variants had functional enhancer effects between the two ancestries. Little functional characterization of genetic regulation in AF ancestries has been investigated.

Method

We identified 56 significant sequence differences among AF and ApoEε4 haplotypes from the 1000 genomes in a topologically associated area (56kb) surrounding ApoE. None of these differences were identified to be protein coding. We applied Massively Parallel Reporter Assay (MPRA) supplemented with single variant reporter assays using Promega Dual Glo‐Luciferase System in AD relevant cell lines to identify the regulatory potential of these variants and their surrounding regions and to assess the differential effect sizes of the variant alleles on enhancer activity.

Result

For MPRA and complementary single variants reporter assays, we generated ∼900bp PCR fragments surrounding these variants to ensure full representation of potential regulatory elements. MPRA vector library or single reporter vectors were transfected in three cell lines (SHY‐SY5Y neuronal cells, U‐118 astrocytes and HMC3 microglia). We identified evidence for differential regulation between AF and EU variant haplotypes in intron 5 of PVRL2, TOMM40 intronic regions and a large region located 3’ of APOC1. The latter encompasses a putative enhancer identified through ENCODE analyses in brains with NHW ancestry.

Conclusion

Our results indicate several areas of differential regulation in this LA region on ApoEε4 haplotypes. Follow‐up of the identified regulatory regions is currently ongoing using publicly available data and in‐house iPSC derived cell lines.
Urine dicarboxylic acids reflect loss of energy capacity and hippocampal volume in pre‐symptomatic Alzheimer's disease
Authors: Castor Katherine , Tran Thao , King Kevin , Chui Helena C. , Fonteh Alfred N. , Harrington Michael G
Published: December 2020

Background

Non‐invasive biomarkers will expedite widespread screening and early diagnosis of Alzheimer’s disease (AD). We hypothesized that the considerate loss of brain tissue in AD will result in detection of brain lipid components in urine, and that these will change in concert with CSF and brain biomarkers of AD.

Methods

Study participants (> 70 years) classified as cognitively healthy (CH, n=64) or AD (n=26) after neuropsychological assessment were recruited into HMRI’s Brain Aging Study. Urine dicarboxylic acids (DCA) of carbon length 3‐10 that reflect oxidative damage and energy generation or balance that may reveal changes in brain function were quantified using gas chromatography coupled with negative ion chemical ionization mass spectrometry. Brain volumes were obtained using a GE 3 or 1.5 Tesla MRI scanner. MRI data was analyzed using Freesurfer 6.0 to obtain left and right volumes (mm3) of seven brain regions including the hippocampus.

Results

Mean C4‐C5 DCAs were lower and mean C7‐C10 DCAs were higher in the urine from AD compared to cognitively healthy (CH) individuals. Moreover, mean C4‐C5 DCAs were lower and mean C7‐C9 were higher in urine from CH individuals with abnormal compared to normal CSF amyloid and Tau levels; i.e., the apparent urine changes in AD also appeared to be present in CH individuals that have CSF risk factors of AD pathology. In examining the relationship between urine DCAs and AD biomarkers, we found short chain DCAs positively correlated with CSF Aβ42, while C7‐C10 DCAs negatively corelated with CSF Aβ42 and positively correlated with CSF Tau levels. Furthermore, we found a negative correlation of C7‐C10 DCAs with hippocampal volume (p<0.01), while there was no significant correlation with the occipital volume. Urine measure of DCAs have an 82% ability to predict cognitively healthy participants with normal CSF amyloid/Tau.

Conclusions

These data suggest that urine measures of increased lipid oxidation and dysfunctional energy balance reflect early AD pathology manifest by brain and CSF biomarkers. Measures of urine DCAs may contribute to personalized healthcare by indicating AD pathology and may be utilized to explore population wellness and monitor the efficacy of therapies in clinical trials.
Ascertaining perturbations in microglial expression profiles using single‐nuclei RNA‐seq from human brains
Authors: Brase Logan , Del‐Aguila Jorge L. , Benitez Bruno A. , Karch Celeste M. , Cruchaga Carlos , Harari Oscar
Published: December 2020

Background

Alzheimer’s disease (AD) is a complex and heterogeneous trait in which multiple molecular pathways are disrupted in different cell‐types culminating in disease. Genetic variants in TREM2, a gene expressed in microglia, have been associated with high‐risk with AD, and similarly soluble TREM2 (sTREM2) levels in the cerebrospinal fluid (CSF) have been associated with AD. In a previous Genome‐wide association study (GWAS) of CSF sTREM2 levels, a genetic variant near the MS4A gene cluster accounted for 6 percent of the protein’s variance (rs1582763 p = 1.15 × 10−15). This finding suggests that TREM2 is involved in AD risk in the general population, beyond TREM2 risk‐variant carriers, as the minor allele frequency of rs1582763 > 0.30. rs1582763 is also a cis‐eQTL for both MS4A4A and MS4A6A genes in bulk RNA‐seq of blood.

Method

We generated unsorted single‐nuclei RNA‐seq from human brain tissue from the Knight‐ADRC brain bank. We collected the parietal lobe for 30 AD brains (19 are carriers of the rs1582763 minor allele), 18 autosomal dominant AD brains (ADAD) (9 carriers) and 7 neuropath‐free (6 carriers) for a total of 55 brains (34 carriers). Using the 10X Chromium 3’ chemistry v3 we generated high quality data for over 287,000 nuclei from 54 brains (after QC) to identify the transcriptomic effects of this variant at a cell specific resolution. We identified 13,880 microglial nuclei to analyze microglial subtypes, activation states, cell‐type specific eQTLs, and differential gene expression between carriers and non‐carriers of rs1582763.

Result

We identified microglia expression states that are specific to ADAD subjects, an increased proportion of total microglia on controls, and a shift in microglia expression state for AD subjects that are carriers of rs1582763. Using linear mixed models to account for subject of origin, we will analyze these nuclei to determine which subset of genes are differentially expressed.

Conclusion

Both ADAD status and rs1582763 status in AD subjects alter microglia gene expression states.
Effects of cognitive training program on brain connectivity in older adults with subjective cognitive complaints and mild cognitive impairment
Authors: Soto Marcio , Vilca Brenda Nadia Chino , Camlla Rosangela , Dengri Lucia , Fernández Ricardo Bruña , Maestú Fernando , Parra Mario A
Published: December 2020

Background

Cognitive intervention programs have achieved improvements at the behavioral level at different stages of dementia, especially in the preclinical phases, what is not yet clear is the neurophysiological correlate of these improvements, especially at the level of resting brain connectivity. Our objective was to analyze the changes at the neurophysiological level after the application of a cognitive training program in pre‐clinical phases of dementia using high density electroencephalography (hdEEG).

Method

An intrasubject design was applied. All subjects underwent clinical and cognitive measurements and resting state records in a hdEEG at baseline and 3 months later when the cognitive training sessions ended. The final sample was composed of 7 older adults with subjective cognitive complaints (mean age = 62.08, SD = 6.48) and 8 with mild cognitive impairment (mean age = 62.93, SD = 6.75); whom were evaluated with a large neuropsychological battery which include the domains of executive function and memory. Electrophysiological signals were recorded with a high density EEG (160 channels). The cognitive training program lasted 24 sessions distributed in 8 sessions for each cognitive domain (attention, executive function and memory).

Result

The results show a significant improvement of the cognitive domains trained and a greater clustering and a more efficient processing of the default brain network. These changes seem to be associated with greater efficiency in information processing and a reduction in random physiological activation in preclinical stages of dementia

Conclusion

These programs show clear evidence of changes at the brain level due to cognitive intervention, it is recommended to do follow‐up studies to assess their stability over time.
Brain bioavailable microbiome derived flavonoid metabolite attenuates neuroinflammation in C9orf72 associated frontotemporal dementia
Authors: Iqbal Umar Haris , Smith Chad , Trageser Kyle J. , Pasinetti Giulio Maria
Published: December 2020

Background

Familial frontotemporal dementia (FTD) has been associated with mutations in the G4C2 promoter of C9orf72 leading to production of dipeptide protein repeats (DPRs), the most neurotoxic being Glycine‐Arginine (GR). Previous studies have found a parallel relationship with the accumulation of DPRs and a neuroinflammatory response. Specifically, studies have determined microglia proliferation and persistent activation plays a role in disease progression and neurodegeneration. The current study investigated the effect of the bioavailable microbiome derived flavonol metabolite, 3‐hydroxybenzoic acid (3‐HBA) (Wang D. et al, 2015), on microglia morphology and proliferation in mice harboring the AAV9‐GFP(GR)100 virus in the brain recapitulating FTD type neuropathology and behavior.

Method

Mice were divided into three groups: GFP control, GR100, and GR100 with 3‐HBA. The GFP control group was transfected with AAV9‐GFP through intra‐cerebroventricular injection, whereas the other two groups were transfected with AAV9‐GFP(GR)100. The virus was administered on postnatal day 0, and the treatment of 3‐HBA began on day 28 for a period of 10 weeks. Immunofluorescence staining of microglia was performed on sections spanning the prelimbic/infralimbic cortex, primary somatosensory cortex (S1), and the hippocampus in order to stereologically quantify microglia proliferation and to reconstruct the microglia in 3D using the imaging software Imaris.

Result

Stereological counting determined an increase in microglia density of approximately 40% (p < 0.05) in the S1 of mice transfected with AAV9‐GFP(GR)100. In addition, there was approximately 30% (p < 0.0001) reduction in S1, and hippocampal volume in groups transfected with AAV9‐GFP(GR)100. 3D reconstruction and Sholl analysis determined a change in microglia morphology from a surveilling state, as seen in the GFP control group, to that of activation characterized by increased branching closer to the soma, as observed in the GR100 group. This increased complexity/activation was found to be attenuated with the administration of 3‐HBA which was associated with a significant reduction in branch complexity compared to both the control and GR100 group.

Conclusion

This study identifies a novel microbiome derived polyphenol that displayed potential in attenuating microglia activation, and hence reducing the neuroinflammatory response in FTD.