bluuebunny/crossref_metadata_2025 huggingface dataset:
The Peruvian Alzheimer Disease Initiative (PeADI): An international effort model to increase diversity in AD research
Authors: Illanes‐Manrique Maryenela , Mena Pedro Ramon , Milla‐Neyra Karina , Adams Larry D. , Mejía Koni K. , Rios‐Pinto Julia , Isasi Rosario , Medina‐Colque Angel , Beecham Gary W. , Cornejo‐Herrera Ivan , Vance Jeffery M. , Ochoa‐Valle Edward , Castro‐Suarez Sheila , Cuccaro Michael L. , Sarapura‐Castro Elison , Cornejo‐Olivas Mario , Pericak‐Vance Margaret A.
Published: December 2022

Background

Peru is one of the five largest countries in Latin America and harboring a high Amerindian ancestry component in this population. The Latin American population, including Peruvians, are underrepresented in research studies of Alzheimer disease (AD).We have developed an international collaborative research initiative to ascertain a Peruvian cohort for AD and other related dementias for genetic studies of Amerindian individuals.

Methods

The Peruvian Alzheimer Disease initiative (PeADI) was developed to recruit and enroll Peruvian adults aged 65 and older to a comprehensive genetic AD study. Individuals will get whole genome sequencing and plasma biomarkers. Participants included cases with AD and ADD,healthy controls as well as multiplex AD families. Since 2019, we have established a multisource ascertainment approach including recruitment at main hospitals, outreach community activities and more recently due to the COVID19 pandemic remote recruitment and home visits. Our recruitment has expanded since our initial efforts in which we enrolled individuals from Lima, the capital city. We are now ascertaining participants in three regions from the Andes highlands (Puno,Huancayo, and Cusco) and one region from the southern coast (Tacna).All participants are enrolled using a standard protocol administered by neurologists and neuropsychologists. This protocol includes clinical interviews and neurocognitive assessment.

Results

As of December 2021, we have enrolled 103 AD and other dementia cases, 202 controls and 4 multiplex AD families. While the majority of participants are from Lima, 25% controls and 1% of cases have been recruited in regions outside Lima. We have confirmed a significant association between APOE and AD in Peruvian Population higher than we have observed in non‐Hispanics. In addition to ascertainment activities, we are working closely with the respective sites to develop a network for AD research across Peru. To date, we have developed local research capacities within each region,including training opportunities for investigators, coordinators and lab technicians. In addition, we are developing resources for health and medical support and basic equipment for all regions.

Conclusion

The PeADI study shows the importance of equitable international north‐south cooperation and local network cooperation to increase representation of understudied admixed populations to help us understand Amerindian ancestry in drug target discovery.
Investigating a CD8+ T cell age‐associated gene signature in Alzheimer's disease
Authors: Young Juan J , Park Hong‐Jai , Par‐Young Jennefer , Bartlett Hugh H. , Kim Hye Sun , Shin Min Sun , You Sungyong , Kim Min Hyung , Allore Heather G. , Mecca Adam P , Kang Insoo
Published: December 2022

Background

Neuroinflammation has been linked with the pathologic progression of Alzheimer’s disease (AD). Previous studies focused primarily on the innate immune system; however, there are few human studies evaluating the potential relationships between adaptive immune cells and the development of AD pathology. Alterations in the immune system occur with aging, likely contributing to increased infection, malignancy and inflammation in older adults. One of the most prominent immune changes with age includes the expansion of memory CD8+ T cells in peripheral blood. Notably, cytotoxic IL‐7 receptor alpha low (IL‐7Rα or CD127low) CD45RA+ effector memory (EM) CD8+ T cells (TEMRA) have been associated with dementia and mild cognitive impairment (MCI) due to AD. In addition, our lab recently discovered an age‐associated gene expression signature of IL‐7Rα low EM CD8+ T cells. Thus, we hypothesized that individuals with AD have altered levels of IL‐7Rα low EM CD8+ T cell aging gene expression.

Methods

A total of 40 genes which include 9 IL‐7Rαlow aging genes and 31 genes previously reported to be associated with AD and/or memory were analyzed in peripheral blood of 82 participants with AD and 40 cognitively normal age‐balanced participants by quantitative polymerase chain reaction (qPCR). Gene expression data was analyzed utilizing one‐way ANOVA, principal component analysis (PCA), and unbiased hierarchical clustering analysis.

Results

Eight genes were differentially expressed (P < 0.05) between cognitively normal participants and participants with MCI or dementia due to AD. These genes included 5 IL‐7Ralow aging genes (GZMH, NUAK1, TGFBR3, PRSS23, OSBPL5), 2 genes related to AD and/or memory (CD163, CYP4F3) and a gene related to both aging and AD (PADI4). The expression levels of IL‐7Ralow aging genes moderately correlated with those of AD and memory genes. PCA and clustering analysis suggest IL‐7Ralow aging genes may be associated with disease status in a subset of AD subjects.

Conclusions

An altered CD8+ T cell age‐associated gene signature is present in AD patients, warranting further studies investigating biological implications of CD8+ T cells, especially highly cytotoxic and inflammatory IL‐7Rαlow EM CD8+ T cells, in AD.
Pilot Randomised, Double‐Blind, Placebo‐Controlled Crossover Trial Evaluating the Feasibility of an Intranasal Oxytocin in Improving Social Cognition in Individuals Living with Alzheimer’s Disease
Authors: Michaelian Johannes C , McCade Donna , Hoyos Camilla M , Brodaty Henry , Harrison Fleur , Henry Julie D , Guastella Adam J , Naismith Sharon L
Published: December 2022

Background

Individuals living with Alzheimer’s disease (AD) demonstrate global deficits in social cognition. These deficits have been associated with impaired interpersonal relationships amongst caregivers, in turn contributing to a greater sense of caregiver ‘burden’. In other areas of neuropsychiatric disease (i.e., autism spectrum disorder), intranasal oxytocin (INOT) administration has shown replicable improvements in social cognitive function, particularly in Theory of Mind. Recently, randomised controlled trials (RCTs) in frontotemporal dementia have reported that repeated INOT administration may be regarded as safe and well tolerated at higher doses ‐ resulting in changes to apathy and improvements in empathic concern, as rated by a caregiver. To date, no studies have investigated the feasibility of an INOT treatment in individuals living with AD. Here, we conducted a pilot feasibility trial to determine the feasibility of recruitment, the acceptability of enrolment and the adherence to an INOT treatment in order to inform the subsequent design of a future RCT. Secondly, we sought to determine the effect size estimates on key potential social cognitive function outcome measures related to both the participant and their caregiver.

Method

Four individuals living with AD were enrolled in a single‐centre, randomised, double‐blind, placebo‐controlled crossover trial involving a one‐week treatment period with both INOT (72 IU) and placebo.

Result

All participants reported no treatment‐causative or serious adverse events, following repeated INOT administration. While acceptability of enrolment was excellent (100%), as well as INOT treatment adherence (placebo, 95%; INOT, 98%), our feasibility of recruitment was not acceptable (i.e., only 7% of fifty‐eight individuals with dementia screened met inclusion criteria). However, positive/large effects were associated with expected secondary outcomes around self‐reported health and wellbeing, caregiver ‘burden’, intimacy and interpersonal bonding, following repeated INOT administration.

Conclusion

These data provide the first evidence demonstrating the safety and tolerability of INOT administration in individuals living with AD. Despite limitations in sample size, moderate‐to‐large effect size improvements were identified in participant health outcomes as well as core social cognitive functions and burden as reported by a caregiver. This suggests potential broad‐ranging beneficial effects of INOT which should be assessed in future RCTs from multiple perspectives.
Objectively measured physical activity and cognition in cognitively normal older adults: A longitudinal analysis of the Australian Imaging Biomarkers and Lifestyle (AIBL) study
Authors: Sewell Kelsey R , Rainey‐Smith Stephanie , Villemagne Victor L , Peiffer Jeremiah J , Sohrabi Hamid R , Taddei Kevin , Ames David , Maruff Paul , Laws Simon M , Masters Colin L. , Rowe Christopher , Martins Ralph N , Erickson Kirk I. , Brown Belinda M
Published: December 2022

Background

Physical inactivity is one of the greatest modifiable risk factors for dementia and research shows physical activity can delay cognitive decline in older adults. However, much of this research has used subjective physical activity data and a single follow‐up cognitive assessment. Further studies using objectively measured physical activity and comprehensive cognitive data measured at multiple timepoints are required.

Methods

Participants were 199 community‐dwelling cognitively normal older adults (68.7 5.9 years) from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study. Actigraphy was used to measure physical activity at baseline, yielding measures of intensity (peak counts), total activity (total counts) and energy expenditure (kilocalories; k/cal). Cognitive function was assessed using a cognitive battery administered every 18‐months from baseline (3‐11 years follow‐up), yielding composite scores for episodic memory, executive function, attention and processing speed, and global cognition.

Results

Higher baseline energy expenditure predicted improvements in episodic memory and maintained global cognition over time (β = 0.011, SE = 0.005, p = 0.031; β = 0.009, SE = 0.004, p = 0.047, respectively). Both physical activity intensity and total activity predicted global cognition, such that those with higher peak and total counts had better cognition over time (β = 0.012, SE = 0.004, p = 0.005; β = 0.012, SE = 0.004, p = 0.005, respectively). Finally, higher total activity predicted improved episodic memory over time (β = 0.011, SE = 0.005, p = .022).

Conclusion

These results suggest that physical activity is associated with preserved cognitive function over time, and that activity intensity may play an important role. This research further highlights the importance of early intervention to prevent cognitive decline and may aid in informing lifestyle interventions for dementia prevention.
Identification of a dual Aβ‐tau disaggregator for the treatment of Alzheimer’s disease
Authors: Han Seung Hoon , Kim Koeun , Park Suji , Jeong Jaehoon , Ko Yeon Uk , Kim Hye‐Ju , Kim Seong Muk
Published: December 2022

Background

The accumulation of misfolded protein aggregates is connected with neurodegenerative diseases such as Alzheimer’s disease (AD), and Parkinson’s disease. Because of the accumulation of amyloid β (Aβ) plaques and tau tangles (NFTs) in the brain, neurons slowly degenerate and lose their functions in AD. Recently, many clinical trials for AD therapy with single‐target drugs, especially targeted for Aβ or tau aggregates, have failed. As a therapeutic strategy for AD, we therefore propose to introduce a multifunctional anti‐AD agent to disaggregate the Aβ plaques and NFTs.

Method

Hit compound was selected with disaggregation of Aβ and tau aggregates in various concentrations and half maximal effective concentration by thioflavin T (ThT) fluorescence assay. In vitro study, we examined the effects of our hit compound on the accumulation of intracellular Aβ or tau in over‐expressing cells. In vivo study, we administrated orally our hit compound to AD mouse model for 12 weeks (100mg/kg by weekly). Analysis of Aβ and tau was performed by molecular biological and histological experiments.

Result

Our results show that the hit compound had dual disaggregation capacity for Aβ and tau aggregates. We observed significant decrease of Aβ and NFTs in hit compound treated AD mice compared to vehicle treated. Also, we found the restoration of cognitive decline in compound treated AD mice.

Conclusion

The study demonstrate that our hit compound was identified as dual functional drug for Aβ and NFTs disaggregator. These findings may help to design the next generations of dual or selective disaggregators.
Association between multimorbidity, subjective memory decline and cognitive performance in older adults.
Authors: Souza‐Talarico Juliana Nery , Santos Jair Lício Ferreira , Buck Harleah , Duarte Yeda Aparecida de Oliveira
Published: December 2022

Background

High multimorbidity rates co‐existing with Alzheimer’s disease (AD) have been interpreted as a consequence of dementia progression. Little is known about multimorbidity’s relationship with cognition as an underlying factor capable of accelerating the progression and onset of the disease. Here we examined the relationship between multimorbidity, cognitive performance and subjective memory decline in older adults in a large representative dataset.

Methods

Cross‐sectional data from 1,103 individuals (60.1% female), between 60 – 97 years old, enrolled in the Health, Wellbeing and Aging Study (SABE), a Brazilian population‐cohort study, were assessed for multimorbidity and cognitive performance. Multimorbidity was defined as the co‐occurrence of at least two chronic conditions. Cognitive performance was determined using the MMSE, verbal fluency (number of animals per minute), and backward digital span. For the subjective memory performance, participants were asked whether their memory for daily activities was better, the same, or worse compared to the last ten years.

Results

Multimorbidity was present in 36.8% of the participants, with the highest rates observed in the participants with subjective memory decline (p < 0.001). Multivariate analysis adjusted for age, sex, education and depression symptoms showed that the higher the multimorbidity rate, the lower the MMSE (B = ‐0.365; p = 0.025) and the digit span scores (B = ‐0.232; p = 0.003; F = 68.3; p < 0.001).

Conclusion

In older adults, multimorbidity was associated with higher subjective memory decline, lower short‐term memory, and global cognitive performance. These findings support future longitudinal studies investigating multimorbidity in moderating dementia pathology and progression.
Bead‐based electrochemical gap sensors for detection of tau protein in blood to diagnosis and monitoring the tauopathy
Authors: Kwon SunSang , Yun Mijin , Lee Soo Hyun
Published: December 2022

Background

Recently, there is a need for a method for detecting biomarkers in blood that can be collected relatively easily for diagnosis and monitoring of dementia symptoms in Alzheimer's disease (AD) patients. Tau protein, a typical hallmark of AD, has six isoforms, and is divided into four repeating microtubule binding domains (4R) and three microtubule binding domains (3R) depending on whether exon 10 is included. According to the balance of 3R‐ and 4R‐tau, tauopathy can be distinguished. It is expected to be able to differentiate normal (NC) from AD and other dementias by measuring the tau protein in the blood.

Method

In this study, an electrochemical sensor with a novel structure was employed to detect tau in the plasma of living patients. The nanogap sensor consists of a gap electrode and a SU‐8 microwell for loading a single magnetic bead (Figure 1). A sample was prepared by reacting the surface of the magnetic beads with an antibody (total tau or anti 3R‐ or 4R‐tau antibody) and an antibody functionalized with a secondary O‐glycosylated tau (O‐g tau) antibody or phosphorylated tau (p‐tau) antibody.

Result

As a result of O‐g/p‐tau measurement, the impedance change by O‐g tau was large in NC (n=4), whereas the impedance change by p‐tau was large in AD (n=13). Patients with idiopathic Parkinson's disease (IPD) (n=3) also had more impedance changes due to p‐tau (Figure 2). As a result of measuring 3R‐ or 4R‐tau protein, the impedance change by 4R‐tau in NC was larger than that by 3R‐tau, whereas the opposite result was shown in AD. similar to the previous results, the impedance change by 3R‐tau was larger in IPD (Figure 3),

Conclusion

We used a novel electrochemical gap sensor to detect tau protein in blood samples collected from living patients. As a result, it is expected to be able to differentiate NC from tauopathy and other dementias by measuring the tau protein in the blood (Figure 4).
QEEG‐based differentiation between Alzheimer’s disease with or without alpha synucleinopathy
Authors: Park Ukeob , Kang Seung Wan , Baik Kyoungwon , Ye Byoung Seok
Published: December 2022

Background

As existence of alpha synucleniopathy could affect progression of cognitive impairment in Alzheimer’s disease (AD), it’s very important to differentiate comorbidity of alpha synucleniopathy in AD to predict progression. To develop affordable EEG‐based discriminating machine‐learning(ML) algorithm for existence of alpha synucleniopathy, we explore differences between AD with vs without it.

Method

Based on pattern of cognitive impairment and 3 types of PET scan [18F‐Florbetaben brain amyloid‐beta, FDG, DAT‐PET] , dementia due to Alzheimer’s disease [pure ADD] or Lewy Body (pure LBD) or mixed type (AD with LB disease) were clinically classified.

We measured 19ch resting state EEG based on international 10‐20. Quantitative analysis of EEG was done by iSyncBrain®.

Result

Pure ADD showed the characteristics that general EEG slowing with low total power, relative delta enhancement and desynchronized alpha with low amplitude. Pure LBD showed the pattern of slow alpha peak frequency with intact synchronization, relatively higher EEG total power and frontotemporal theta enhancement. Compared to pure ADD, ADD with LB showed mixed pattern of ADD and LDB. Total power was higher, alpha wave showed intact synchronization but theta power was rather enhanced at frontal(Fz; p‐value < 0.05) and bilateral temporal(T3,5, T4,6; p‐value < 0.05) area that was reported as characteristic pattern of progressive type of AD by previous studies.

Conclusion

These findings imply that ADD could have different EEG oscillation characteristics according to the Lewybody disease. Next step, we will develop the machine‐learning algorithm to discriminate the Lewybody disease based on specific EEG features and validate it.
Tau Pathology induces Whole‐Brain Subcritical Brain Dynamics across the spectrum of Alzheimer’s Disease
Authors: Kobeleva Xenia , Ritter Petra , Patow Gustavo , Deco Gustavo
Published: December 2022

Background

Cognitive dysfunction in Alzheimer’s Disease (AD) is caused by dysfunctional brain region interactions. Although functional connectivity alterations in AD have been described in several studies, their associations to tau pathology have not been completely understood. Using whole‐brain network modeling we can mechanistically associate the functional impact of tau on brain function in silico.

Method

Using tau PET and fMRI data from the ADNI3 study, we linked regional tau burdens to fMRI activity using a Hopf dynamical model of brain activity using linear regressions. The Hopf model faithfully recreates oscillatory brain activity and adjust the bifurcation of the regional oscillations to either to a noisy (subcritical) or a more regular (supracritical) regime (Deco et al., 2017). The similarity of simulated and empirical time series was assessed by comparing the resulting (dynamical) functional connectivity differences using root mean squared error and Kolmogorov‐Smirnov statistics (as described in Kobeleva et al., 2021). We compared the resulting bifurcation parameters of the Hopf model between healthy controls with no SUVR above 2, healthy controls with at least one region with a SUVR above 2 (considered as at‐risk subjects with a high tau burden) and patients with mild cognitive impairment (MCI).

Result

We achieved a good fit of the tau‐dependent model of brain activity, ensuring a realistic representation of brain activity in the model. Mean bifurcation parameters differed across the three groups (controls with low and high tau burden, and MCI patients). Specifically, we found increasingly more subcritical bifurcation parameters in controls with high tau burden and MCI patients, quantitatively associating a higher tau burden associated with noisier brain oscillations.

Conclusion

Our results show that biology‐inspired models of AD contain parameters with clinically relevant information. We observed a shift to a more subcritical regime in subjects with high tau and even more so in MCI, showing that tau is associated with nosier brain oscillations, possibly contributing to impaired information transmission and observed cognitive dysfunction. These results constitute a missing link to the branching process theory of cortical network function in AD and contribute to understanding impaired cortical excitability in AD.
QEEG‐based discernment of dementia pathologies through machine learning: Lewy body and Alzheimer’s disease
Authors: Jeong Taegyun , Park Ukeob , Kang Seung Wan
Published: December 2022

Background

Alzheimer’s disease is the most common cause of dementia, which destroys nerve cells in the brain through the formation and accumulation of amyloid plaques. However, various other pathologies of dementia also exist, such as Lewy body pathology where the destruction is caused by the accumulation of Lewy body peptides. Differing dementia pathologies carry distinguishing symptoms and treatment methods; hence we cannot disregard the importance of correct identification of the pathology.

Currently, the correct pathology can be identified through positron emission tomography (PET), which is expensive and results in exposure to harmful ionizing radiation. Therefore, the present study aims to overcome the disadvantages of current screening methods and distinguish the quantitative electroencephalography (QEEG) of two dementia pathologies through machine learning.

Method

EEG data employed in the present study were recorded at the 19 electrode locations defined by the international 10‐20 system, in eyes‐closed resting‐state condition. The acquired data were then re‐referenced to a common average reference. Hereafter, bandpass filtering at 0.1‐45.5Hz, bad epoch rejection and independent component analysis (ICA) was performed to remove noise components from the data. Standardized low resolution brain electromagnetic tomography (sLORETA) was further used for mathematical estimation of source cortical activity, yielding data for 68 cortical regions based on the Desikan‐Killiany atlas.

Gamma wave (30‐45Hz) features were excluded from the data due to is vulnerability to electromyography. Further feature reduction was also performed, through the designated criteria on p‐value threshold (0.05) and feature importance threshold determined by shapely values. The final dataset (N = 104; 30 ADD, 74 DLB) was established, where 20% of the data (N =21; 6 ADD, 15 DLB) were randomly selected and excluded as test data for model verification.

Result

The final machine learning model trained and tested through the dataset yielded test accuracy at 85.7% with ADD sensitivity at 83.3%, DLB sensitivity at 86.7%. The 5 fold cross validation accuracy was at 82.1%.

Conclusion

The model developed in the present study yielded a promising classification performance, through EEG data which is cheap and harmless to record. Such QEEG‐based classification models may sufficiently replace the PET in future, resolving current disadvantages.
Longitudinal evolution of neuropathological substrates of Alzheimer’s disease in obese patients
Authors: Debatisse Justine , Schindler Louise , Nowell Joseph , Edison Paul
Published: December 2022

Background

Obesity is a metabolic condition with increasing prevalence all over the world. Patients with a body mass index (BMI) higher than 30 are considered obese. Obesity is also a risk factor for chronic morbidities such as type 2 diabetes and may increase the risk of developing Alzheimer's disease (AD). Not much is known about longitudinal changes in Alzheimer’s pathology in these patients. We hypothesised that BMI would predict longitudinal pathological alterations derived from imaging parameters.

Method

252 participants (n=107 obese non‐diabetic patients with BMI>30) cognitively normal (n=80) and with mild cognitive impairment (n=172) were evaluated from the Alzheimer’s Disease Neuroimaging Initiative (Mean age = 73.6 years, SD = 8.0). All participants had two T1‐weighted MPRAGE MRI scans within two‐years (Mean gap=718 days, SD=107). Regional cortical thickness was measured on T1‐MPRAGE using FreeSurfer v.6.0. Individual gray matter density maps were computed using voxel‐based morphometry (VBM) and regional values were sampled in various cortical regions. Regional cortical thickness and gray matter density are expressed as delta values between baseline and followup (Value followup ‐ Value Baseline). Spearman’s correlation coefficients were calculated to assess the relationship between BMI and imaging biomarkers.

Result

In the whole cohort, we found that BMI is significantly negatively correlated with longitudinal changes in cortical thickness in anterior cingulate (ACC, p=0.0073, r=‐0.17) and posterior cingulate (PCC, p=0.0147, r=‐0.15) cortical thickness. We also found that BMI is significantly negatively correlated with longitudinal changes in frontal (p=0.0184, r=‐0.15), parietal (p=0.0057, r=‐0.18) and temporal (p=0.0141, r=‐0.16) gray matter density. When looking only at MCI participants, we found similar results with even stronger correlations. BMI is significantly negatively correlated with delta anterior cingulate (ACC, p=0.0008, r=‐0.25) and posterior cingulate (PCC, p=0.004, r=‐0.22) cortical thickness.

Conclusion

In this cohort of obese and non‐obese participants cognitively normal and with MCI, we found that obesity was associated with a longitudinal 2‐years worsening of macrostructural changes. Higher BMI was associated with a higher reduction of cortical thickness and with a decreased gray matter density in several brain regions.
Colocalization of cortical diffusivity changes and microglial activation in dementia
Authors: Debatisse Justine , Leng Fangda , Brooks David J , Edison Paul
Published: December 2022

Background

There is growing evidence that microglial activation plays a crucial role in the early pathological changes reported in Alzheimer’s disease (AD). Multimodal neuroimaging can be used to detect micro‐ and macrostructural alterations together with molecular imaging to quantify metabolism and proteins expression. Diffusivity map, reflecting neuronal integrity, can be derived from diffusion‐weighted imaging, and is thought to be increased in AD following pathological alterations. We hypothesised that changes in diffusivity could be colocalized with microglial activation at different stages of the disease.

Method

56 patients (mean age=70.4, SD=8.5) cognitively normal (CN, n=15), with mild cognitive impairment (MCI, n=28) and with AD (n=12) were included in this study. All participants underwent diffusion tensor imaging (DTI), amyloid PET ([18F]flutemetamol) and TSPO PET ([11C]PBR28). DTI data were processed with FSL v.6.0 to compute mean diffusivity (MD) maps. Standard uptake ratio (SUVR) values were calculated in SPM12 to identify the amyloid deposition and microglial activation within cortical regions. Amyloid status (Aβ‐positive/Aβ‐negative) was determined from processed data using a cerebellar gray matter ratio with a binding value greater than the CN mean+2SD. Z score maps of MD and [11C]PBR28 SUVR were computed using CN amyloid negative participants as reference. Z score maps were then correlated using SPM8 and the BPM toolbox. Significance was set at a threshold of p<0.05 with an extended threshold of 50 voxels.

Result

We found a significant positive correlation clusters between MD and PBR28‐SUVR Z score maps (higher diffusivity correlated with higher microglial activation) in MCI amyloid negative subjects in the temporal lobe (coordinates: 28 ‐3 ‐32, corrected p<0.001, k=7363). In MCI amyloid positive subjects, we found positive correlation in the parietal lobe (coordinates: ‐47 ‐41 39, corrected p=0.008, k=5712).

Conclusion

We found colocalized diffusivity and microglial changes in the early stage of the disease, in the temporal lobe of MCI amyloid negative participants and in later stages of the disease, in the parietal lobe of MCI amyloid positive participants. These results suggest the potential of DTI diffusivity and microglial activation imaging in detecting early neuronal damage occurring in dementia.
Executive functioning and attention in amnestic mild cognitive impairment are related to widespread grey matter integrity
Authors: Lejko Nena , Enriquez‐Geppert Stefanie , Reesink Fransje E , De Deyn Peter Paul , Spikman Jacoba M , Aleman André
Published: December 2022

Background

Memory problems that are characteristic of amnestic mild cognitive impairment (aMCI) are often accompanied by difficulties in attention and executive functions (EF). Studies have consistently reported atrophy of the hippocampus and its association with memory decline in aMCI. However, it is less clear whether differences in grey matter volume (GMV) also contribute to difficulties in attention and EF. To that end, we investigated whether GMV is related to performance on a series of cognitive tests in people with aMCI.

Method

GMV of 29 people with aMCI (mean age = 73.8 ± 7.6 Y, 5 F) was measured with voxel‐based morphometry and regressed against measures of task‐switching (Trail Making B‐A), inhibition (Stroop interference score), working memory (Symbol Digit Modalities), and attention (Vienna Reaction Time S1, S2, S3). Analyses were controlled for age and total intracranial volume. Because of the small sample, we used a lenient significance threshold of p < 0.001 (uncorrected) and cluster size (k) >= 20.

Result

Better task performance was related to higher GMV in widespread cortical regions. Task‐switching was mainly related to GMV in the bilateral insula (k = 924, 456, Z = 4.87, 3.79) and prefrontal areas (k = 846, Z = 4.35). Inhibition was related to volume in left posterior areas (k = 302, 300, Z = 3.93, 3.62), and working memory to volume in left temporal, parietal, and frontal cortices (k = 21‐88, Z = 3.28‐3.67). Attention to visual stimuli was associated with GMV of cerebellar (k = 20‐281, Z = 3.36‐3.59) and parieto‐occipital regions (k = 20‐76, Z = 3.28‐4.17), and attention to auditory stimuli mainly with prefrontal regions (k = 113, 49, Z = 3.96, 3.53). Interestingly, slower reactions to complex stimuli were related to higher GMV in occipital gyri (k = 28, Z = 3.56).

Conclusion

Our results suggest that EF and attention in people with aMCI are related to integrity of regions beyond those normally implicated in memory decline (e.g. the hippocampus). As investigation into aMCI is crucial for preventing disease progression, our findings should be further investigated by studies with a control group of healthy older adults.
Development of harmonized and co‐calibrated scores for memory, executive functioning, language, and visuospatial in the AIBL Study, ADNI, and NACC datasets
Authors: Crane Paul K. , Trittschuh Emily H. , Mez Jesse B. , Saykin Andrew J. , Sanders R. Elizabeth , Gibbons Laura E , Lee Michael L. , Scollard Phoebe , Choi Seo‐Eun , Rainey‐Smith Stephanie , Chooi Cheyenne K , Gavett Brandon E , Maruff Paul , Ames David , Culhane Jessica E. , Gauthreaux Kathryn , Chan Kwun Chuen Gary , Biber Sarah , Stephens Kari , Kukull Walter A. , Dumitrescu Logan , Hohman Timothy J. , Mukherjee Shubhabrata ,   Alzheimer’s Disease Neuroimaging Initiative
Published: December 2022

Background

The Australian Imaging, Biomarkers and Lifestyle (AIBL) Study is a prospective study collecting extensive cognitive, clinical, fluid, and imaging biomarkers data from older adults living in Australia. Integration of outcomes between large prospective studies of AD will provide greater precision in models of AD brain‐behavior relationships, so it is important to align composite scores for cognitive domains between such studies.

Methods

Detailed methods for AIBL, the Alzheimer’s Disease Neuroimaging Initiative (ADNI) and the National Alzheimer’s Coordinating Center (NACC) have been published. Briefly, AIBL participants had cognition assessed with an extensive neuropsychological test battery alongside health and biomarker assessments at entry and each 18‐months thereafter. Granular‐level cognitive data were obtained and an expert panel of two neuropsychologists and a behavioral neurologist categorized each element as assessing memory, executive functioning, language, visuospatial, or none of these, exactly as we have done previously. We also identified elements we had previously calibrated from other studies; after careful quality control and confirmation these served as anchors enabling co‐calibration. We used confirmatory factor analysis bi‐factor models to calibrate the AIBL battery with other studies. We used those calibrations to obtain co‐calibrated scores for all AIBL participants at every study visit. Here we show descriptive statistics for baseline visits, separately by diagnosis (normal cognition, mild cognitive impairment (MCI), dementia) for two enrollment waves for AIBL as well as for each phase of ADNI and across the Uniform Data Set (UDS) 1 & 2 (UDS1/2) and UDS3 time periods for NACC.

Results

Box plots for memory, executive functioning, language, and visuospatial for people with normal cognition are in Figure 1, MCI in Figure 2, and dementia in Figure 3. These figures show there is substantial cognitive variation across waves within these disease stage groups and across studies.

Conclusion

Co‐calibrated neuropsychological domain scores provide a common metric for integrating cognitive data across studies. Co‐calibrated scores aggregated across large prospective AD studies such as AIBL, ADNI, and NACC provide a foundation for large‐scale models of the development of AD and can serve as phenotypes for genetics studies. Co‐calibrated scores are available from AIBL, ADNI, and from NACC.
Health behaviors and advanced planning in cognitively unimpaired older adults following amyloid PET disclosure: Preliminary findings from the Wisconsin Registry for Alzheimer’s Prevention
Authors: Clark Lindsay R. , Erickson Claire M , Basche Kristin E , Chin Nathaniel A. , Johnson Sterling C.
Published: December 2022

Background

As biomarker testing becomes more widely available, people will have opportunities to learn their Alzheimer’s disease (AD) biomarker results. We developed an AD biomarker disclosure protocol to return results to research participants interested in learning this risk‐related information (Figure 1). This analysis assesses the effectiveness of a post‐disclosure dementia risk‐reduction counseling session and investigates health and advanced planning behaviors following amyloid PET disclosure.

Method

Cognitively unimpaired older adults enrolled in the Wisconsin Registry for Alzheimer’s Prevention (WRAP) were recruited into the Amyloid Disclosure Study which provides education, amyloid PET results, and dementia risk‐reduction counseling. Participants rated their progress on a brain health goal set at the risk‐reduction visit and rated satisfaction and usefulness of this visit at follow‐up. Participants completed measures of health behaviors and planning at pre‐ and post‐disclosure (1 month, 7 months) visits. Linear mixed‐effects regression (LME) and t‐tests were used to assess outcomes over time and compare responses for amyloid elevated and non‐elevated participants.

Result

Amyloid elevated (30%) and non‐elevated (70%) participants were similar in demographics and health/planning behaviors at baseline (n = 63; age = 71.3±4.5; 67% women; Table 1). 82% of participants recommended the risk‐reduction visits (Table 2). Goal attainment measures indicated 85% of participants made at least some progress on their brain health goal (55% met or exceeded goal at 7 month follow‐up; Table 3). Results from LME models demonstrated no main effects of time, biomarker result, or the interaction of time x biomarker result on health behavior or planning measures (Table 4). No differences in health behaviors or planning were observed between elevated and non‐elevated participants at follow‐up (p’s ≥ .05).

Conclusion

Preliminary analyses indicate that health behavior or advanced planning do not differ between participants receiving elevated or non‐elevated amyloid PET results at one or seven months following disclosure. However, participants endorse usefulness and satisfaction with a post‐disclosure dementia risk‐reduction visit, and a majority make progress on their personal brain health goal. As participants continue to enroll and complete follow‐up assessments, we plan to update results with a larger dataset and provide future directions regarding more personalized assessments of brain health and planning outcomes.
Longitudinal Qualitative Analysis of the Role and Perspective of the Care Partner During and Four Weeks Following Disclosure of Amyloid PET Scan Results
Authors: Kim Jeong Eun , Cheng Rebekah , Tamres Lisa K , Lingler Jennifer H
Published: December 2022

Background

Amyloid PET scans allow for the visualization of amyloid plaque in the brain, which, in the context of mild cognitive impairment (MCI), signal heightened risk for progression to Alzheimer’s dementia (AD). Disclosure of such results can profoundly impact patients as well as their family care partners. The purpose of this study was to examine the role and perspectives of family care partners during and after the return of amyloid PET results.

Method

We used qualitative description to analyze transcripts of audio‐recorded results disclosure sessions and 4‐week follow‐up interviews of participants with MCI and their care partners who were randomized to the disclosure arm of the Return of Amyloid Imaging Scan Results (RAISR) trial. Focusing on care partners (n = 36), we conducted line by line coding and thematic analysis with the goals of 1) categorizing the frequency and nature of the questions raised by care partners during the open‐ended segment of the disclosure sessions, and 2) describing care partners’ perceptions of their loved one’s results in the month following disclosure.

Result

At disclosure, 13 families received positive for amyloid, and 21 received negative scan results. Care partners of those learning of amyloid positivity asked approximately twice as many questions as those receiving negative results (averaging 5.6 vs. 2.8 questions per session). Seven themes were identified in the questions: study logistics, AD/AD care, result clarification, next steps given result, outside resources, requests for scan images, and “other.” The vast majority of questions fell under AD/AD care (n = 47), followed by questions about study logistics (n = 24). The overarching theme of the week 4 interviews was a general sense of acceptance of the scan results. However, instances of inadequate comprehension of the scans’ implications were noted, particularly among partners of amyloid negative patients, some of whom interpreted the result to mean that their loved one’s MCI was nonprogressive.

Conclusion

Family care partners play active roles in eliciting information and clarification during amyloid PET results disclosure. However, our findings regarding care partners of amyloid negative patients affirm that disclosing clinicians should not assume that those who ask fewer questions have an adequate understanding of the information presented.
Moderate‐Severe Traumatic Brain Injury History and Chronic Traumatic Encephalopathy Neuropathology in Brain Donors Exposed to Repetitive Head Impacts
Authors: Culhane Julia E , Abdolmohammadi Bobak , Nair Evan S , Saltiel Nicole , Tripodis Yorghos , Martin Brett M , Palmisano Joseph , Katz Douglas I , Dwyer Brigid , Daneshvar Daniel H , Goldstein Lee E , Dams‐O'Connor Kristen , Kowall Neil W , Stern Robert A , Huber Bertrand R. , Stein Thor D. , Mez Jesse B. , McKee Ann C. , Alosco Michael L
Published: December 2022

Background

Repetitive head impacts (RHI) from American football and other sources are associated with the neurodegenerative tauopathy chronic traumatic encephalopathy (CTE). Moderate‐to‐severe traumatic brain injury (msTBI) has been suggested to be sufficient to precipitate CTE. Yet, this evidence is based on small case series of msTBI and the interplay between msTBI and RHI on CTE risk is unknown. We modeled the associations between msTBI history and years of American football play (proxy for RHI exposure duration) on CTE neuropathology among deceased American football players.

Methods

The sample included 471 deceased male football players from the UNITE brain bank, all 40+ years old. Informants of donors were administered the Ohio State University TBI Identification Method to assess TBI history. Loss of consciousness (LOC) for 30+ minutes defined msTBI. CTE was neuropathologically diagnosed and staged using published criteria. Outcomes included CTE status, CTE severity (low vs high), and cumulative p‐tau burden—summary of semi‐quantitative ratings of p‐tau severity across 11 brain regions (n = 402). Binary or linear regressions tested the association between msTBI and each outcome, controlling for age and years of football. A years of play x msTBI history interaction term was examined.

Results

Tables 1‐2 shows sample characteristics (mean age = 67.89, SD = 12.70; 15.7% Black). Of the sample, 114 (24.2%) had a msTBI history. Years since last TBI with LOC was 37.16 (SD = 18.66) years. 344 (73.0%) had autopsy‐confirmed CTE. There was no association between msTBI and CTE status (OR = 1.38, 95% CI = 0.81,2.33, p = 0.24), CTE severity (OR = 0.77, CI = 0.41,1.44, p = 0.41), or cumulative p‐tau burden (beta = ‐1.03, 95% CI = ‐2.77,0.71, p = 0.25). In contrast, years of football play was associated with CTE status (OR = 1.15, 95% CI = 1.10,1.21, p<0.01), CTE severity (OR = 1.14, 95% CI = 1.08,1.21, p<0.01), and cumulative p‐tau burden (beta = 0.44, 95% CI = 0.32,0.56, p<0.01). There were no years of play x msTBI interaction effects (ps>0.05).

Conclusions

msTBI history was not associated with CTE neuropathology, nor did it modify the effect of years of football play on CTE status and severity. These findings argue against msTBI as a contributor to CTE in the setting of RHI. Examination of age at msTBI and msTBI frequency, as well as non‐CTE neuropathological correlates of msTBI are next steps.
Regional white matter hyperintensities in posterior cortical atrophy and logopenic progressive aphasia
Authors: Pham Nha Trang Thu , Radford Jonathan Graff , Machulda Mary M. , Spychalla Anthony J. , Schwarz Christopher G. , Senjem Matthew L. , Lowe Val J. , Vemuri Prashanthi , Jack Clifford R. , Josephs Keith A , Whitwell Jennifer L
Published: December 2022

Background

White matter hyperintensities (WMH) are markers of cerebral small vessel disease and have been associated with higher risk of typical amnestic Alzheimer’s disease (AD), however, little is known about the role of WMHs in atypical variants of AD. This study aimed to determine the frequency and distribution of WMH in two atypical variants of AD: logopenic progressive aphasia (LPA) and posterior cortical atrophy (PCA), and determine whether WMH are associated with demographic and clinical outcomes in these cohorts.

Method

Seventy‐five LPA and 39 PCA patients were recruited by the Neurodegenerative Research Group and underwent two‐ dimensional fluid‐attenuated inversion recovery (FLAIR) MRI and Pittsburgh Compound B (PiB) PET. All patients were PiB‐positive. All FLAIR images were segmented using an in‐house software, then were manually edited by a trained imaging analyst. WMH volume was scaled by total intracranial volume to correct for differences in head size. Adjusted WMH burdens were compared between LPA and PCA, and associations were assessed between WMH burden and age, global PiB standard uptake value ratios (SUVRs), and clinical metrics, including tests of general cognitive impairment, executive function, naming, repetition, visuospatial and visuoperceptual function, and parkinsonism. Associations between WMHs and clinical scores were adjusted for age and brain volume to correct for atrophy.

Result

Total WMH burden was similar in PCA and LPA, however, regional differences were identified with PCA having greater subcortical WMH burden in right occipital, parietal, and temporal lobes compared to LPA, and LPA having greater WMH burden in left deep grey and white matter and greater subcortical burden in left parietal lobe compared to PCA. Total WMH burden was greater with older age in both groups but was not related to global PiB SUVR either globally or locally. Greater total WMH was associated with visuoperceptual performance in both cohorts after correcting for atrophy. When assessed regionally, visuoperceptual performance was associated with right subcortical occipital WMH across the cohort.

Conclusion

Regional distribution of WMHs differ across clinical variants of atypical AD and WMHs may impact clinical outcomes, although further work is needed to determine whether they reflect cerebrovascular disease or regionally specific neurodegenerative changes.
Amyloid‐mediated TRAIL DRs activation leads to progressive degeneration of cerebral vascular smooth muscle cells
Authors: Anzovino Amy , Fossati Silvia
Published: December 2022

Background

Vascular accumulation of amyloid beta (Ab) leads to loss of vascular smooth muscle cells (VSMC) in cerebral arteries via unknown mechanisms, promoting cerebral blood flow alterations and contributing to cognitive impairment. Ab species with different lengths or mutated familial variants may have differential effects on VSMC. Ab1‐42, the main pathogenic form of amyloid in the AD brain with the highest propensity to form aggregates, increased apoptosis in brain vascular cells whereas Ab1‐40 was found to be less toxic. By comparison, the familial Ab variant E22Q, induced the most cell death of all the amyloid variants tested. However, there has been little progress in defining the pathways leading to VSMC degeneration in AD and related disorders. The aim of this study was to identify Ab‐mediated cell death mechanisms in VSMC.

Method

Human cerebral VSMC were treated with pre‐oligomerized variants of Ab for 2‐8hrs (acute treatment) and 24‐72hrs (chronic treatment). Analysis of fragmented nucleosomes and visualization of cytochrome c (Cyt. C) expression by immunocytochemistry were used to measure apoptosis. Activation of intrinsic and extrinsic apoptotic pathways were examined by western blot and caspase‐glo assays. The effects of Ab on mitochondrial function were examined using a Seahorse XF96 Analyzer and TMRM fluorescent dye in live cells.

Results

Acute Ab treatment in VSMC up‐regulated tumor necrosis factor‐related apoptosis‐inducing ligand (TRAIL) death receptors DR4 and DR5 with activation of caspase 8 and transient activation of Nuclear Factor k B (NF‐kB). DR4 and DR5 expression remained high with chronic Ab treatment and lead to caspase activation followed by Cyt. C release and apoptosis. 24hrs of Ab treatment also decreased mitochondrial membrane potential and significantly impaired mitochondrial respiration.

Conclusion

Acute exposure of VSMC to Ab causes up‐regulation and activation of DR4/DR5, that, over time, results in mitochondrial dysfunction, caspase activation and apoptosis. Our data suggests that an early and transient activation of NF‐kB may also contribute to the toxic effects of Ab, possibly by inducing pro‐inflammatory pathways in the neurovascular unit.