bluuebunny/crossref_metadata_2025 huggingface dataset:
Change in retinal layer thickness and vascular parameters in preclinical Alzheimer’s disease: A 2‐year longitudinal study
Authors: Bruinenberg Annelies E. , van de Kreeke Aleid , Verbraak Frank , Bouwman Femke H. , Yaqub Maqsood , Van Berckel Bart N.M. , Tomassen Jori , den Braber Anouk , Visser Pieter Jelle
Published: December 2020

Background

The past year, the retina has received increasing attention as a possible biomarker for (preclinical) Alzheimer’s disease (AD). Though cross‐sectional differences where inconsistently replicated in literature, longitudinal change over time of retinal layer thickness and/or retinal vascular parameters (RVPs) may differ between preclinical AD and controls.

Method

149 cognitively healthy monozygotic twins aged ≥60 were included from the EMIF‐AD PreclinAD study.1 Participants were classified as preclinical AD (Aβ+) based on a positive [18F]flutemetamol PET image and as controls (Aβ‐) on a negative flutemetamol PET image. As a continuous measure of Aβ aggregation we used the [18F]flutemetamol PET binding potential (BP
ND). At baseline and follow‐up, after a mean of 22 months (range 15 – 32 months), the total and individual inner retinal layer thickness in the macular region (ETDRS ring), the peripapillary retinal nerve fiber layer thickness and 7 RVPs were measured on optical coherence tomography (OCT) and fundus images. OCT measurements could be analyzed in 145 participants and fundus images in 114 participants. Ocular measurements were compared between Aβ+ and Aβ‐ participants and related to the BP
ND.

Result

There were no differences in change over time in any of the measured retinal layer thicknesses between pre‐clinical AD patients (n=16) and controls (n=129) (see figure 1). We did, however, find a positive association between BP
ND values and an increase in the inner plexiform layer (IPL) thickness in the inner perifoveal ETDRS ring (CI: 0.575 – 2.841, p=0.003). Although arteriolar caliber, venular caliber and tortuosity of arteries all showed a significant decrease over time in the total group, no differences were found between Aβ+ (n=13) en Aβ‐ participants (n=111, table 1), nor did these RVP changes show a relation to BP
ND value at baseline.

Conclusion

The use of OCT measurements and RVPs as a longitudinal screening method for preclinical AD seems limited, but IPL changes may serve as a starting point for future research. Reference: (1) Konijnenberg E, Carter SF, Ten Kate M, den Braber A, Tomassen J, Amadi C, et al. The EMIF‐AD PreclinAD study: study design and baseline cohort overview. Alzheimers Res Ther. 2018;10(1):75.
Delirium READI:(Researching Efficient Approaches for Delirium Identification): Clinician experiences and perspectives when screening for delirium in persons with dementia
Authors: Fick Donna Marie , Boltz Marie , Husser Erica , Ngo Long H , Shrestha Priyanka , Inouye Sharon K , Marcantonio Edward R
Published: December 2020

Background

Less than half of all delirium in persons with dementia is identified. By 2050, 14 million older persons in the United States will have dementia. These individuals are more likely to be hospitalized than those without dementia, and more than 50% will experience delirium during hospitalization. Previous work suggests that delirium may accelerate the clinical course and trajectory of cognitive decline, and is associated with worse outcomes and suffering. Despite this evidence, we know little about clinician experience with screening and management of delirium superimposed on dementia (DSD). Therefore, we interviewed hospital‐based clinicians to inform implementation of hospital‐wide systematic delirium identification, including clinician knowledge and experience with DSD.

Method

We conducted in‐depth qualitative interviews in person and over the phone as part of a larger mixed methods study of N=934 (535 older adults and 399 clinicians) that tested a two‐step process for delirium identification using the Ultra‐brief two item delirium screen (UB‐2) and 3D‐CAM. We report on the qualitative analysis of 14 interviews with 6 physicians, 4 registered nurses and 4 nursing assistants who had screened for DSD in the larger study at two hospital study sites. Data were analyzed using coding and thematic analysis (Creswell, 2016). Interviews ranged in length from 14 to 47 minutes.

Result

Although clinicians valued the quick tools to detect delirium, they described skepticism and challenges in evaluating DSD. One physician noted, "Many times I think healthcare providers, whether it's a doctor, a nurse, whatever, we just chalk up behavior in the hospital, "Oh, they're demented. They have dementia. You expect this [confusion]... People who are confused, they get up and they fall. Preliminary themes identified were: skepticism, bias and low expectations, stage of dementia as important, fluctuation and repeated screening, role of family in screening, nonverbal communication and cues, and knowing the person.

Conclusion

Our study suggests that clinicians lack knowledge and confidence in assessing for and managing DSD. Clinicians may still consider DSD to be “normal” in hospitalized patients with dementia. Future implementation studies should also address attitudes and knowledge regarding delirium assessment, management and prevention in DSD.
Associations of automatically segmented enlarged perivascular spaces with neuropathology and cognitive decline in a community cohort of older adults
Authors: Petit Carles Javierre , Tamhane Ashish A. , Evia Arnold M. , Makkinejad Nazanin , Agam Gady , Bennett David A. , Schneider Julie A. , Arfanakis Konstantinos
Published: December 2020

Background

Enlarged perivascular spaces (EPVS) have been linked to increased risk of stroke, lower cognitive function, and vascular dementia. However, neuropathologic correlates of EPVS, and their contributions to cognition, are unclear. In this work, a deep‐learning algorithm for automatic segmentation of EPVS was developed, and allowed full quantification of EPVS in the whole brain and regionally. Then, neuropathologic correlates of EPVS and contributions of EPVS to cognition were analyzed within each region in a large community‐based cohort of older adults.

Method

This work included 287 participants of two longitudinal studies, Rush Memory and Aging Project, and Religious Orders Study (Figure 1). Ex‐vivo T2‐weighted images, and detailed neuropathologic examination by a board‐certified neuropathologist (blinded to all data) were obtained for one brain hemisphere from each participant. A total of 10 neuropathologies were assessed (Figure 2).

The data from 10 participants with varying EPVS severity and manually segmented EPVS were used to train a deep learning model (Figure 3) to automatically segment EPVS in the ex‐vivo MRI data of all participants.

Relative EPVS volume (EPVSrel), meaning EPVS volume normalized by white matter volume, and total number of EPVS (EPVSnum) was calculated for each participant. Similar measurements were made per lobe and basal ganglia (e.g. EPVSnum‐parietal). All measures were square root transformed to reduce skewness.

Result

The deep learning model achieved a mean Dice Similarity Coefficient of 0.655 ± 0.058 (comparison in Figure 4). Whole brain relative EPVS volume and number were associated with gross infarcts (Figure 5). Regional EPVS were associated with gross infarcts in most of the brain, and with cerebral amyloid angiopathy mainly in the occipital and temporal lobes (Figure 5). Relative EPVS volume in the occipital lobe was negatively correlated with semantic memory (‐0.443, p = 0.03) and perceptual speed (‐0.311, p = 0.048) above and beyond what was explained by neuropathologies and demographics.

Conclusion

This investigation provides robust evidence on the neuropathologic correlates of EPVS and the contributions of EPVS on cognition in a large community‐based cohort of older adults. Fully quantitative assessment of EPVS was facilitated by automatic EPVS segmentation using deep learning. EPVS were shown to have associations with gross infarcts and cerebral amyloid angiopathy, and independent contributions on cognition.
Neuropsychiatric index and relationship quality for caregivers of older Mexican Americans
Authors: Cantu Phillip A , Aranda Maria P
Published: December 2020

Background

Informal caregivers play a key role in supporting older Mexican Americans, as they are less likely to enter nursing facilities than other racial/ethnic groups in the U.S, even when faced with high levels of physical and cognitive impairment. The quality of caregiving relationships is directly related to caregiver stress. However, there is little research on the correlates of caregiver assessment of relationship quality. Assessment of caregiver relationship quality is especially important for Mexican American older adult caregivers due to the high prevalence of cognitive impairment and dementia in this population.

Methods

Using data from caregiver supplement of the wave 7 of the Hispanic Established Population for the Epidemiologic Study of Elderly (HEPESE)(n=460) study of very old (Age 85+) Mexican Americans we examine the association of relationship quality with care recipient health, caregiver health, and caregiver finances. Caregiver relationship quality is measured using both positive and negative relationship assessments separately. We use linear regression to examine the correlates of caregiver relationship quality net of caregiver and care recipient demographics, care recipient physical (caregiver‐rated health, ADL and IADL disability) and mental health (caregiver‐rated NPI and care recipient MMSE), caregiver health (caregiver‐rated health and depression) caregiver finances (income and financial burden).

Results

Caregivers who were married to the care recipient reported both less positive and more negative assessments. Male care recipients, married caregivers, and caregiver depression were related to positive but not negative assessments. Both positive and negative assessments were significantly associated with IADL disability and NPI score but not MMSE score.

Conclusions

Relationship quality for Mexican Americans among the very old is related to hands‐on care tasks and not financial strain. Disability status suggests that early changes in functional status are more stressful than more severe disability due to adjustment periods. Married caregivers may report higher relationship quality due to additional support from spouses in caregiving roles. NPI status is the most strongly associated correlate of both positive and negative relationship quality, while MMSE was not significantly related to either. Our results suggest that caregiver assessments of behavioral disturbances are more important to relationship quality than care recipient tested cognitive functioning.
Reduced cortical thickness in World Trade Center responders with cognitive impairment
Authors: Clouston Sean , Deri Yael , Horton Megan , Tang Cheuk , Diminich Erica D , Pellecchia Alison , Carr Melissa , Gandy Samuel , Sano Mary , Bromet Evelyn , Lucchini Roberto , Luft Benjamin
Published: December 2020

Background

Recent reports suggest that World Trade Center (WTC) responders are at increased risk for cognitive impairment (CI). The current study utilized neuroimaging to determine whether WTC responders with CI have reduced cortical thickness (CTX).

Method

WTC responders (N=99) with and without CI, recruited from an epidemiologic study of cognitive aging among WTC responders, participated in a neuroimaging study that included a T1‐MPRAGE protocol. CTX was computed in 34 Desikan‐Killiany atlas regions of interest (ROIs). Regional CTX between CI and non‐CI responders were compared using t‐tests and reported using Cohen’s D, and whole‐brain surface‐based morphometry using threshold‐free cluster analysis. Sensitivity analyses were used to examine possible associations of CTX with symptoms of PTSD and/or severity of WTC exposure. Analyses were adjusted for multiple comparisons using the false discovery rate (FDR = 0.05).

Results

Participants were aged 55.84 years on average, and 47 had CI as determined by clinical mental status examination using the Montreal Cognitive Assessment (MoCA≤20). When compared to unimpaired responders, responders with CI had reduced mean whole‐brain CTX (P = 0.002). Region‐based analyses identified reduced CTX in 21/34 bilateral ROIs (D = ‐0.60) with the largest effects centered in the precentral gyrus (D = ‐0.74, P = 0.007). Surface‐based morphometry revealed that CTX was reduced across large parts of the frontal, temporal, and occipital lobes, all of which remained significant following adjustment for multiple comparisons. While more regions were identified as reduced in responders with both PTSD and CI (18 versus 9 ROIs in responders with PTSD and CI versus CI alone respectively), sensitivity analyses were not able to distinguish CI with PTSD as compared to CI alone.

Conclusions

Results from structural imaging revealed that WTC responders with CI had reduced cortical thickness across multiple brain regions including but not limited to those commonly affected by Alzheimer’s disease. This study represents the first neuroimaging study investigating CTX as an indicator of CI in WTC responders at midlife.
Sex, tau, and cortical thinning in the temporal lobe: Findings from the Harvard Aging Brain Study
Authors: Manning Lyssa K , Properzi Michael J , Scott Matthew R , Hampton Olivia L , Rubinstein Zoe B , Mayblyum Danielle V , Hanseeuw Bernard J , Schultz Aaron P , Rentz Dorene M , Johnson Keith A , Sperling Reisa A , Buckley Rachel F
Published: December 2020

Background

Recent work suggests regional tau burden is proximal to cortical thinning in clinically‐normal older adults. Clinically‐normal older females show higher levels of temporal tau burden than males, but it remains to be seen whether the association between tau pathology and cortical thinning is significantly impacted by biological sex. We hypothesized that females with higher tau burden would show faster cortical thinning than their male counterparts.

Method

123 clinically‐normal older adults from the Harvard Aging Brain Study (clinical dementia rating = 0; age (SD) = 73.6(6.1); female = 58%) underwent cross‐sectional Pittsburgh Compound‐B (PiB)‐PET, Flortaucipir (FTP)‐PET and longitudinal MRI (2.95 years; range = 1.3‐5.3 years post‐tau scan). FTP‐PET was introduced after onset of the study, so the first FTP‐PET scan was used as ‘baseline’. We selected temporal tau ROIs based on our previous results (HABS & ADNI) showing sex differences in tau signal (e.g. entorhinal, inferior temporal, fusiform, middle temporal). We conducted iterative linear mixed models examining the interaction of sex*time*tauROI on cortical thinning across 34 ROIs, covarying for baseline age*time. To assess the impact of PiB on this relationship, we also examined PiB+ and PiB− groups separately (based on HABS PiB DVR cut‐off = 1.186).

Result

Females with higher inferior temporal tau burden showed significantly faster cortical thinning than males in the entorhinal cortex only, t = −2.40, p = 0.02 (see Figure 1). This result was significant in the PiB+ group (n = 33: t = −2.28, p = 0.03), but not PiB− (n = 90: t = −1.60, p = 0.11), suggesting this relationship was driven by a sex effect in PiB+ individuals (see Figure 2). We also found a similar association using fusiform tau (p = 0.03).

Conclusion

In the context of high inferior temporal tau burden, females exhibit significantly faster entorhinal cortical thinning than males. This result suggests that sex may moderate the effect of tau burden on cortical thinning, and for a given level of tau burden, females may be more susceptible to cortical atrophy in temporal lobe structures. We did not adjust for multiple comparisons, so replication is required in another cohort. This relationship between tau pathology and entorhinal neurodegeneration in females provides further insight into how sex‐related cortical structural vulnerability may correspond to pathology over time.
Clinical and neurodegenerative features associated with amyloid‐β‐negative medial temporal tau deposition as measured by multimodal PET imaging
Authors: Grothe Michel J. , Moscoso Alexis , Schöll Michael
Published: December 2020

Background

The combined accumulation of amyloid‐beta (Aβ) plaques and tau neurofibrillary tangles is the defining feature for Alzheimer’s disease (AD) pathology. However, tau can also accumulate in the medial temporal lobe in the absence of Aβ pathology, a neuropathological condition termed primary age‐related tauopathy (PART) that can result in amnestic impairments similar to early stage AD. Here we aimed to describe clinical and neurodegenerative characteristics of older amnestic individuals with Aβ‐negative medial temporal tau deposition as revealed by in‐vivo PET imaging.

Method

In the ADNI cohort we identified a total of 174 older individuals with amnestic deficits (155 amnestic mild cognitive impairment (aMCI), 19 mild AD‐type dementia (ADD)), who had tau‐sensitive ([18F]flortaucipir) and Aβ‐sensitive ([18F]florbetapir or [18F]florbetaben) PET acquisitions, as well as structural MRI and [18F]FDG‐PET scans. Presence/absence of Aβ and tau pathology was determined by applying sensitive cutoffs to Aβ‐PET‐derived centiloid values (>12 centiloids) and entorhinal flortaucipir SUVR (inferior cerebellum reference; >1.175 SUVR, corresponding to the highest value observed in Aβ‐negative healthy controls below 65y (N=13, 56‐63y)). Clinical, genetic, and neuroimaging data of patients with Aβ‐negative tau deposition (A‐/T+, N=19, 17/2 aMCI/ADD) was contrasted to A+/T+ (N=81, 65/16 aMCI/ADD) and A‐/T‐ patients (N=38, 37/1 aMCI/ADD) as well as to A‐/T‐ healthy controls (N=40).

Result

A‐/T+ patients had a markedly lower proportion of APOE‐ε4 carriers (16%) compared to A+/T+ (69%, p<0.001), and a higher proportion of APOE‐ε2 carriers (42%) compared to A+/T+ (1%, p<0.001) and A‐/T‐ (15%, p=0.04). A‐/T+ patients had comparable memory and executive deficits compared to A‐/T‐, but were less impaired than A+/T+, even when excluding ADD patients. In brain‐wide neuroimaging analyses, tau deposition in A‐/T+ was mainly restricted to the medial/inferior temporal lobe and related limbic structures (Fig‐1). These areas also showed marked hypometabolism, but only subtle gray matter atrophy. By contrast, A+/T+ patients showed a widespread neocortical tau distribution, as well as marked neurodegeneration on both FDG‐PET and structural MRI. A‐/T‐ patients did not show significant neuroimaging abnormalities.

Conclusion

Aβ‐negative tau deposition as evidenced by PET associates with distinct clinical, genetic, and neurodegenerative features that resemble that of neuropathologically‐defined PART and may allow to study this condition in‐vivo.
Is Type 2 diabetes mellitus associated with an increased pathological burden in clinically and pathologically diagnosed Alzheimer's dementia?
Authors: Sadrolashrafi Kaviyon , Miller Justin B. , Decourt Boris , Adem Abdu , Sabbagh Marwan N.
Published: December 2020

Background

Epidemiological evidence suggests that Alzheimer’s disease (AD) and Type‐2 Diabetes Mellitus (T2DM) share pathophysiological processes. T2DM causes central insulin resistance, which generates a hypoglycemic microenvironment in the brain. The oxidative stress established as a result leads to mitochondrial dysfunction, inflammation, advanced glycation end‐product (AGE) production, insulin receptor signaling pathway impairment, and insulin‐degrading enzyme (IDE) inhibition. These widespread repercussions catalyze amyloid‐β (Aβ) plaque and neurofibrillary tangle (NFT) formation. Here, we hypothesize that T2DM is associated with an increased AD pathological burden in clinically‐ and pathologically‐diagnosed AD.

Method

All data were obtained from the Uniform Data Set (UDS) v3, the Neuropathology Data Set, and the Researcher’s Data Dictionary‐Genetic Data from the NIA funded National Alzheimer’s Coordinating Center (NACC). The data was compiled by NACC in a dataset querying, the following keywords: “Alzheimer’s disease”, “Type 2 diabetes mellitus”, “Thal phase (A score)”, “Braak neurofibrillary stage (B score)”, “Neuritic plaque score (C score)”, and “Alzheimer's disease neuropathology change (ABC score)”. The dataset relies on autopsy‐confirmed data in clinically‐diagnosed AD patients who were assessed for diabetes type in form A5 or D2 during at least one visit. In our analysis, there were 271 AD cases with T2DM and 8,431 cases without. Differences in scores were explored using one‐way ANOVA. Effect sizes were calculated using sample means and standard deviations (Cohen’s d).

Result

The differences in pathology staging between AD‐confirmed individuals with T2DM and those without were statistically significant, with effects ranging from medium (d = ‐0.34; r = ‐0.17) to large (d = 0.53 and 0.51; r = 0.25). The presence of recent or active T2DM was associated with a higher Thal phase of amyloid plaques (μdiff = 1.89) as well as a higher NIA‐AA Alzheimer’s disease neuropathologic change, ADNC (μdiff = 1.57). The presence of T2DM was also correlated to a lower Braak stage for neurofibrillary degeneration (μdiff = ‐0.30).

Conclusion

These findings suggest that there is more amyloid burden in individuals with AD and T2DM than AD without T2DM. Our results indicate that individuals with T2DM have significantly higher amounts of plaques by Thal stage, as well as higher ABC scores.
Eigen analysis on ultrafast FMRI data shows altered dynamic functional connectivity in MCI individuals
Authors: Park Sung Min , Rane Swati
Published: December 2020

Background

Resting state functional connectivity (rsFC) is a powerful tool to detect brain dysfunction. Recent studies show that resting state networks are not static, but dynamic and alter connectivity in seconds. The use of simultaneous multislice imaging technology allows sub‐second fMRI acquisitions in ADNI3. We leverage eigenanalysis to compare brain connectivity states and their temporal dynamicity between cognitive normal older adults (NC) and MCI participants.

Method

We analyzed 105 ADNI subjects (50 MCI [22M], age = 74 ± 8 and 55 NC [35M], age = 75 ± 8) with T1 and BOLD fMRI acquisition (TR = 600 ms). Processing included motion correction, detrending, despiking, physiological noise correction and registration to standard space. We performed harmonization using ComBat to minimize site‐related variability. We employed a sliding window approach followed by eigenanalysis1 to extract spatially independent connectivity states between regions derived from 4 networks (see Table 1). For each connectivity state, we identified whether the timecourse was different between NC and MCI subjects and created a final difference network comparing the brain state between the two groups.

Result

Figure 1 shows the 10 brain connectivity states, spanning 32 regions and 4 networks, identified using eigennetwork analysis. Figure 2 shows the timecourse for each of the connectivity states. Finally, Figure 3 shows the difference network for the MCI group with and without harmonization. Harmonization appears to have a considerable effect on the connectivity state pattern. We then compared the harmonized difference network to within‐site difference networks. RMSE was smaller for the harmonized network than that of the unharmonized network.

Conclusion

We demonstrate the use of eigennetwork analysis to determine a dynamic brain connectivity state in MCI that is different than NC. The advantages of this approach are two‐fold: One, all brain regions and resting state networks are considered as a whole instead of studying each network separately. Two, it allows us to study the temporal properties of the networks in addition to their spatial characteristics. This analysis enables us to capture a more accurate depiction of the connectivity of the brain and its dynamic nature.
RPS16 and NOL6 splice region variants are associated with early onset Alzheimer's disease
Authors: Guen Yann Le , Napolioni Valerio , Belloy Michael E. , Eger Sarah J. , Kennedy Gabriel , Morgan Kevin , Greicius Michael D.
Published: December 2020

Background

Common genetic polymorphisms identified by genome wide association explain less than half the genetic variance of Alzheimer’s disease (AD). Rare genetic mutations with larger effect sizes than common variants are expected to contribute to this missing heritability. We developed an extreme phenotype filtering‐based approach to identify rare candidate causal variants.

Method

Figure 1 describes our analysis pipeline. Briefly, we removed AD cases who had a discordant pathology diagnosis, or a known pathogenic mutation, and duplicated individuals (using identity‐by‐descent). We then restricted the analysis to APOE4‐negative cases with age‐at‐onset below 70 and required controls to be cognitively normal over 75. We started with variants present in ADSP whole exome sequencing data to guarantee a minimum number of control subjects for filtering. We restricted our analysis to variants with impact equal to high, moderate, or modifier annotated by Ensembl Variant Effect Predictor. We removed any variants seen in controls over 75 and in less than four early‐onset cases (heuristic threshold). For this case‐filtering step, we limited variant‐count contribution from ADSP extension to two cases because this cohort contains early‐onset pedigrees. We determined the carriers’ ancestral background using SNPWeight and prioritized variants seen in multiple ancestries (assuming that variants increasing AD risk across ancestries are more likely to be causal). UK Biobank was used as a replication cohort for remaining variants (provided that their calls in subjects with both WES data and SNP‐array imputed data demonstrated sufficiently accurate imputation metrics). Variants association with AD diagnosis and AD in siblings was tested, covarying by sex, APOE2 and APOE4 dosages, and the first 10 genetic principal components accounting for population structure. Genes harboring identified variants were tested for differential expression between cases and controls.

Result

Our pipeline identified two variants (Table 1). Table 2 presents the carriers demographics. Table 3 shows the imputation quality and association results in the UK Biobank. Figure 2 emphasizes that NOL6 is upregulated in AD compare to controls across brain regions, while Figure 3 underlines that RPS16 is downregulated.

Conclusion

NOL6 splice region and RPS16 splice donor variants may increase AD risk and should be tested in additional cohorts.
Familial Alzheimer’s disease in Australia
Authors: Bechara Jacob A. , Brooks William S. , Kwok John B. , Halliday Glenda M. , Schofield Peter R.
Published: December 2020

Background

Families with dementia occurring in multiple generations suggest the possibility of inheritance of a single gene disorder. Since the discovery of the Amyloid Precursor Protein gene (APP) Val717Ile London mutation (Goate et al., 1991) and of variants in the Presenilin‐1 and ‐2 (PSEN1 & PSEN2) genes in 1995 (Sherrington et al., 1995), many such families with Alzheimer’s disease (AD) have been able to obtain a genetic diagnosis for their condition. Here we report details of 28 families in Australia and New Zealand who have been found to carry a pathogenic variant in one of these three genes.

Method

Families with young‐onset dementia seeking a genetic diagnosis in Australia were studied according to the following protocol. Family history and clinical characterisation: we enquired about the presence of dementia in siblings, parents and grandparents of the proband. Clinical features of the illness were recorded. We sought consent for DNA studies from living affected individuals: DNA was screened for variants in APP, PSEN1 and PSEN2. Neuropathology: we sought consent for post‐mortem examination of the brain of affected family members for neuropathological characterisation.

Result

Since 1988, at least 28 families in Australia and New Zealand have been found to carry pathogenic AD variants. There were 6 families with variants in APP and 22 with variants in PSEN1. No families have yet been found to carry a pathogenic PSEN2 variant. 24 families have had AD confirmed neuropathologically. Only one proband with a pathogenic variant had no known family history of dementia. This individual carried a PSEN1 Arg278Thr variant and died at 41 of dementia and spastic paraparesis. Brain biopsy showed AD. One parent had died of cancer at 65; the other parent was unaffected on examination at 67 and did not carry the PSEN1 variant.

Conclusion

Family history of young‐onset dementia in at least two generations suggests dominant inheritance and DNA studies may reveal a pathogenic variant. Such variants can occur in individuals without a family history, but we found this to be uncommon.
Olfactory identification deficits are associated with cognitive decline in Chinese older adults: The Taizhou Imaging Study
Authors: Jiang Yanfeng , Tan Ziyi , Zhang Kexun , Zhu Zhen , Wang Yingzhe , Li Peixi , Jin Li , Dong Qiang , Cui Mei , Chen Xingdong
Published: December 2020

Background

Olfaction function has emerged as a potential predictor of cognitive decline and dementia recently. We accessed the association of olfaction and cognitive function in a Chinese cohort.

Method

Participants in this study were part of the community‐based Taizhou Imaging Study. At the first wave of cognitive function follow‐up, 770 individuals underwent neuropsychological testing from July 2018 to August 2019, including four cognitive domains‐memory, executive function and attention, visuospatial function, and language. Mini‐Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) were used to assess participants’ global cognition. Among them, 686 participants underwent olfactory identification testing using 12‐item Sniffin’s Sticks test. Dementia and mild cognitive impairment (MCI) were adjudicated by a committee of experts, according to the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM‐IV) and Petersen RC’s criteria, respectively. After data quality control, 684 participants were included in this analysis (Figure 1). Beta regression was used to evaluate the association between olfaction and cognitive function (continuous variables), logistic regression was used to assess the association between olfaction and cognitive status (categorical variable). Potential confounders were adjusted in two models: Model 1 was adjusted for age, sex, and years of education; Model 2 was additionally adjusted for smoking, alcohol consumption, body mass index, exercise, hypertension, diabetes, and hyperlipidemia.

Result

A total of 54 (7.9%) individuals were diagnosed as dementia, 165 (24.1%) individuals were adjudicated as MCI (Table 1). In the fully adjusted Model 2, the associations remained significant (Beta = 0.062 and 0.093, respectively; both P <0.001) (Table 2). Olfactory identification scores were associated with domain‐specific cognitive function scores in Model 2 (visuospatial function: Beta = 0.072, P = 0.003; short delay recall: Beta = 0.120, P <0.001; long delay recall: Beta = 0.057, P = .010; language: Beta = 0.107, P <0.001). Moreover, we found olfactory identification was negatively associated with MCI in Model 2 (odds ration [OR]: 0.88; 95% confidence interval [CI]: 0.81, 0.96) and dementia (OR: 0.76; 95% CI: 0.66, 0.87) (Table 3).

Conclusion

Olfactory identification are associated with both global and domain‐specific cognitive function and could serve as a protector for cognitive decline.
Gait disturbances are associated with increased CSF tau levels in a memory clinic cohort
Authors: Muurling Marijn , Rhodius‐ Meester Hanneke FM , van Gils Mark , Frederiksen Kristian Steen , Bruun Marie , Hasselbalch Steen Gregers , Soininen Hilkka , Herukka Sanna‐Kaisa , Hallikainen Merja , Mattila Jussi , Teunissen Charlotte E. , Visser Pieter Jelle , Scheltens Philip , van Der Flier Wiesje , Lötjönen Jyrki , Pärkkä Juha , de Boer Casper
Published: December 2020

Background

Gait analysis with accelerometers is a relatively inexpensive and easy to use method to potentially support clinical diagnoses of Alzheimer’s Disease and other dementias. It is not clear however, which gait features are most informative and how these measures relate to Alzheimer pathology. In this study, we used in‐depth evaluation of gait in cognitively normal (CN) subjects, Mild Cognitive Impairment (MCI) patients, and dementia patients. We evaluated the associations between dynamics of gait, level of cognitive impairment and CSF biomarkers of Alzheimer’s pathology.

Method

We included CN participants (n=58), MCI patients (n=58) and participants with different types of dementia (n=26) of the multicenter PredictND cohort. Participants performed gait tests in two conditions: a normal walk task and a cognitively complex dual task. Gait was measured using tri‐axial accelerometers attached to the fifth lumbar vertebra (L5). Following principal component analysis, calculated gait features were clustered into four domains: pace, rhythm, time variability and length variability. Associations between gait domains, clinical diagnosis and CSF biomarkers (Aβ42, total tau, pTau) were examined using linear mixed models, included an interaction term with condition (normal and dual walk task) and were corrected for age, sex and center.

Result

Dementia patients showed gait disturbances in the pace domain ((p<0.05), Figure 1, first row), meaning that dementia patients walk slower and with a smaller step length compared to CN and MCI participants. Rhythm disturbances were associated with increased levels of CSF (p)tau in the dual task (Figure 1, third and fourth row). No associations were found with CSF Aβ42 levels in any gait domain (Figure 1, second row).

Conclusion

These findings suggest that gait disturbances increase with level of syndrome diagnosis. Moreover, rhythm disturbances increase with higher levels of CSF total tau and pTau, providing evidence for a direct link with neurodegeneration. These results demonstrate that in‐depth gait analysis with accelerometers might be a potential helpful tool to support clinical diagnosis or can be used as clinical outcome tool in clinical trials.
Proprotein convertase subtilisin/kexin type 9 inhibitor exerts greater efficacy than atorvastatin on ameliorating cognitive impairment in high‐fat diet–induced obesity
Authors: Arunsak Busarin , Pratchayasakul Wasana , Amput Patchareeya , Chattipakorn Kenneth , Tosukhowong Theetouch , Kerdphoo Sasiwan , Jaiwongkam Thidarat , Thonusin Chanisa , Palee Siripong , Chattipakorn Nipon , Chattipakorn Siriporn C.
Published: December 2020

Background

Long‐term consumption of a high‐fat diet (HFD) caused not only obesity with dyslipidemia but also caused brain pathologies which resulted in cognitive impairment. Atorvastatin, a recommended first‐line lipid‐lowering drug, had beneficial effects on metabolic control and mitigated brain pathologies in several models. However, the long‐term use of statin had many side effects which may result in discontinuation of statins for therapeutic treatment. Recently, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor was approved as an effectively therapeutic drug for lowering cholesterol level. PCSK9 inhibitor decreases low‐density lipoprotein receptor (LDLR) degradation, and consequently lowers of LDL levels in the circulation. However, there were only few studies that reported the effect of PCSK9 inhibitor on brain functions. In addition, the comparative effects of atorvastatin and PCSK9 inhibitor on brain functions and cognitive function in HFD‐induced obesity have not been elucidated. We hypothesize that PCSK9 inhibitor has greater effect than atorvastatin on improving brain function and cognitive function in HFD‐induced obesity.

Method

Twenty Female Wistar rats were fed with either a normal diet (ND) or HFD for 15 weeks. At week 13, ND rats were given normal saline, and HFD rats were divided into two subgroups to receive either normal saline, atorvastatin (40 mg/kg/day) or PCSK9 inhibitor (4 mg/kg/day) for 3 weeks. At the end of experimental protocol, metabolic parameters, brain function, and cognitive function were determined.

Result

HFD‐fed rats developed obesity, dyslipidemia and insulin resistance. An increase in PCSK9 level, LDLR degradation, oxidative stress, blood brain barrier breakdown, microglial hyperactivation, synaptic dysplasticity, apoptosis, Alzheimer’s‐related proteins production in hippocampus, and cognitive decline were observed in HFD‐fed rats. Atorvastatin and PCSK9 inhibitor equally attenuated Alzheimer’s‐related proteins production and apoptosis in hippocampus of HFD‐fed rats. Interestingly, PCSK9 inhibitor had greater efficacy than atorvastatin on the amelioration of hippocampal oxidative stress level, blood brain barrier breakdown, microglial hyperactivation, synaptic dysplasticity and cognitive decline in HFD‐fed rats. Furthermore, PCSK9 inhibitor, but not atorvastatin, decreased the hippocampal PCSK9 and increased LDLR expression in HFD‐fed rats (p<0.05, Figure 1).

Conclusion

PCSK9 inhibitor exerted greater efficacy than atorvastatin in improving metabolic and brain function in HFD‐induced obesity.
Oligodendroglial alterations in FTD caused by C9orf72 expansion
Authors: Dolcet Sonia Sirisi , Querol‐Vilaseca Marta , Dols‐Icardo Oriol , Pegueroles Jordi , Montal Victor , Muñoz Laia , Torres Soraya , Blesa Rafael , Belbin Olivia , Fortea Juan , Clarimon Jordi , Lleó Alberto
Published: December 2020

Background

The most frequent genetic cause of Frontotemporal Dementia (FTD) and Amyotrophic Lateral Sclerosis (ALS) is the hexanucleotide repeat expansion in the C9orf72 gene. Until now, three different mechanisms have been proposed to explain its pathogenic effects: i) loss of function of the C9orf72 protein, ii) toxic gain of function from sense and antisense C9orf72 repeat RNA, or iii) toxic gain of function from Dipeptide Repeat Proteins. Another important hallmark associated with C9orf72 mutations is the TDP43 accumulation in neurons and glia. As in other neurodegenerative diseases, neuroinflammation is a common feature in FTD; however, the specific role of the innate immune system in FTD associated to specific subtypes of the disease is unknown.

Method

In this study, we investigated changes in the pattern of different glial markers (GFAP, YKL‐40, Iba‐1 and MBP) using immunohistochemistry in the frontal cortex and hippocampus of a cohort of 23 cases diagnosed with C9‐FTD/ALS with TDP43 pathology (C9‐FTD), 8 cases diagnosed with sporadic‐FTD TDP43 (sFTD) and 9 healthy controls (HC). Different in‐house semi‐automated MATLAB algorithms were developed and were used to quantify the immunoreactivity of these different markers.

Result

We found a significant increase of GFAP, YKL‐40 and Iba1 immunoreactivity in C9‐FTD and in the sporadic group compared with a group of healthy controls both in frontal cortex and hippocampus. We also found a decreased of MBP protein immunoreactivity in the group of C9‐FTD samples, both in grey and white matter from the frontal cortex, compared to control and sporadic group of samples. In C9‐FTD group we found a negative correlation between MBP and TDP43.

Conclusion

These results indicate that FTD caused by C9orf72 is associated with myelin loss likely caused by the mutation or its distinct pathology. Understanding these biological processes will help to identify specific pathways associated with this FTLD subtype and help in the development of new therapeutic strategies implicating oligodendroglial cells as a target to reduce the disease progression and improve quality of life of FTD with C9orf72 expansion patients.
Using the Locus Coeruleus as a biomarker in Alzheimer's disease
Authors: Beardmore Rebecca C , Darekar Angela , Holmes Clive , Boche Delphine , Nicoll James AR , Durkin Matthew , Hou Ruihua
Published: December 2020

Background

Neuronal loss and tau aggregation in the Locus Coeruleus (LC) are suggested to be among the earliest pathologies in Alzheimer’s Disease (AD). However this remains to be investigated in vivo. Depletion of cortical noradrenaline (NA) concentration as a result of LC degeneration has proinflammatory effects on microglia and likely contributes to the neuroinflammatory changes observed in animal models of AD. However inflammatory changes within the human LC and the relation to inflammation seen in LC projection areas, e.g. the temporal cortex, has not been investigated.

Method

24 AD participants and 24 age and gender matched cognitively unimpaired subjects underwent a high resolution neuromelanin‐sensitive magnetic resonance imaging (NM‐MRI) scan to enable the LC to be visualised in vivo. A LC contrast ratio was generated by comparing maximum values in the anatomical location of the LC to a reference region in the adjacent pontine tegmentum. Additionally, immunohistochemistry is currently being performed to examine several inflammatory markers in the LC and temporal cortex of 60 human brains at varying stages of disease severity and in relation to the pathology.

Result

In the MRI study, the AD group had a lower LC‐CR compared to controls (p<0.05), which correlated with cognitive impairment. Inflammatory and neuropathological markers in the post‐mortem tissue are currently being quantified.

Conclusion

NM‐MRI may be useful as a biomarker for diagnosis in AD and suggests early degeneration of the LC. Tissue examination will characterise the inflammatory changes observed in patients in order to elucidate the pathological consequences of LC degeneration.
Race and sex differences in midlife changes in cerebral volume and perfusion
Authors: Moonen Justine E. , Nasrallah Ilya M. , Detre John A. , Dolui Sudipto , Erus Guray , Davatzikos Christos , Meirelles Osorio , Bryan R.N. , Launer Lenore J.
Published: December 2020

Background

Cross‐sectional demographic differences in MRI markers of brain health are well established, but less is known about differences in rates of change, particularly in mid‐life. We assessed demographic differences in midlife change of MRI measures of gray matter (GM) volume and perfusion, which are important early markers of late‐life cognitive decline. We also assess the extent to which cardiovascular risk factors explain demographic differences.

Method

Data are from a subsample attending the 25 and 30 year follow‐up MRI exams [n=478] of Coronary Artery Risk Development in Young Adults (CARDIA), a community‐based cohort study at 3 USA‐based centers. Structural 3T MRI was used to quantify total GM as percent of intracranial volume. GM cerebral blood flow (CBF, ml/100gr/min) was measured using pseudo‐continuous arterial spin labeling. To test for interaction between race and sex, multiple linear regression analysis was used entering MRI feature at follow‐up as dependent variable and as independent variables: MRI feature at baseline, center, age, sex, race and the interaction term(race*sex). Next, MRI features at follow‐up were compared amongst groups of race/sex with ANCOVA, adjusting for baseline MRI feature, center, age and additionally for cardiovascular health(CVH) according to the American Heart Association Life’s Simple 7(LS7) metric.

Result

The sample had mean baseline age 50.4(SD 3.5) years, 48.1% male, and 38.3% black. Over the 5‐year follow‐up period, GM volume and CBF significantly declined. Significant interaction between race and sex was observed for GM (P‐interaction=0.0041), such that black men demonstrated a significantly larger volumetric decline than black women, whereas no significant sex differences were observed in whites. Race*sex interaction was also observed for CBF (P‐interaction=0.023), such that men demonstrated a significantly larger decline in perfusion than women in both races, which associations were more pronounced in blacks. Adjustment for LS7‐CVH metric attenuated results slightly but reported associations remained significant.

Conclusion

Our results indicate sex/race specific patterns of midlife decline in cerebral GM volume and in perfusion, which were not fully explained by prevalent cardiovascular risk. Race/sex may be crucial variables in heterogeneity of early cerebral disease, an important marker of late‐life cognitive decline. Additional research is needed to identify the factors driving these associations.
The dynamic interplay between longitudinal subjective and objective cognitive decline along the early AD spectrum in the Harvard Aging Brain Study
Authors: Amariglio Rebecca , Chou Hsiang‐Chin Lori , Buckley Rachel F. , Papp Kathryn V. , Rentz Dorene M. , Johnson Keith A. , Sperling Reisa A.
Published: December 2020

Background

Applying a biomarker‐based definition of Alzheimer’s disease (AD) (Jack et al., 2018) affords characterization of early, disease‐specific symptoms that are subtle, yet dynamic. Our previous work comparing cognitively‐unimpaired individuals with elevated amyloid (Ab+) to non‐elevated (Ab‐), shows increasing subjective cognitive decline, while neuropsychological performance decreases longitudinally. Here, we sought to directly examine longitudinal associations between subjective and objective cognitive decline along the early AD trajectory.

Method

224 cognitively‐unimpaired individuals at baseline from the Harvard Aging Brain Study, a community‐based sample, were followed up to 9 years with annual neuropsychological assessment (PACC) and a participant reported cognitive complaint questionnaire (STIDA). A second cognitive complaint questionnaire (CFI) was introduced several years into the study (mean=3.23 (1.65) years) and was administered to both the participant and a study partner annually thereafter. Ab‐PET using Pittsburgh Compound B was collected closest to the time of CFI. Previously established cut‐offs were used to determine Ab+/‐. Longitudinal trajectories of STIDA, PACC, and CFI (participant and study partner) were examined by Ab status.

Result

Piecewise linear mixed models revealed initially increasing STIDA (0‐3.5years, t=2.17, p = 0.03) that plateaued in the remaining years (3.6‐9.1 years, t = 0.26, p = 0.80) in Ab+. Likewise, increasing STIDA corresponded with decreasing PACC in the first 3 years (r = ‐0.36, p = 0.001), but not in subsequent years (r = 0.11, p = 0.33). When examining cross‐sectional CFI (first collection of CFI) with retrospective PACC (mean= 3.23 years), higher participant CFI (r = ‐0.26, p = 0.03) and study partner CFI (r = ‐0.32, p = 0.006) were associated with steeper PACC decline in Ab+. Finally, comparison of concurrent slopes between longitudinal participant and study partner CFI, revealed a significant divergent pattern (t=‐2.50, p= 0.01), such that study partner CFI increases relative to slightly decreasing participant CFI over time.

Conclusion

Among Ab+ individuals, participant report initially increases and tracks with objective decline. Over time, however, participant report begins to diminish as study partner report continues to increase. Our findings highlight the dynamic nature of subjective report in early AD, which has significant implications for clinically meaningful outcome measures in secondary prevention trials.