bluuebunny/crossref_metadata_2025 huggingface dataset:
Visual mental imagery in mild cognitive impairment: A pilot study
Authors: Vita Antonella Di , D'Antonio Fabrizia , Boccia Maddalena , Lisi Stefania , Savino Chiara Di , Piccardi Laura , Guariglia Cecilia , Lena Carlo
Published: December 2020

Background

Visual Mental Imagery (VMI), the ability of seeing with the mind eyes, has shown to be related with autobiographical memory deficits inAlzheimer's disease (AD) (El Haj et al., 2019). Hippocampus, affected by AD neuropathology since early stages, plays a pivotal contribution to the recollection of previous memories in service of VMI; however, little is known about VMI in Mild Cognitive Impairment (MCI). Basing on the current model of VMI and findings that the various processes and contents of VMI decline differently in physiological ageing (Piccardi et al. 2015), we investigated whether VMI is involved by MCI analyzing which processes and specific contents are compromised to evaluate the possible role of deficit in VMI as early neuropsychological marker of dementia.

Method

Twelve amnestic‐MCI patients (mean age = 75.42, SD = 5.68; mean education=10.92, SD=4.17) and eleven healthy controls (HC) (mean age = 71.09, DS = 8.40; mean education = 13.18, SD = 4.64), matched for Age and Education, were enrolled. VMI was extensively assessed in all patients and controls by means of 1) an adapted version of The Complete Visual Mental Imagery Battery (CVMIB; Palermo et al., 2016), including tasks evaluating the generation, maintenance, inspection and transformation of different types of visual mental images (i.e. objects, buildings and faces), and 2) the O’Clock test (Grossi et al.,1994) that allows to disentangle the possible role of perceptive difficulties in the VMI task’s performance.

Result

Parametric and non‐parametric analyses revealed that MCI performed worse than HC in all CVMIB’s tasks except transformation (i.e. Mental Rotation and Folding tasks) and for the generation of VMI of faces. VMI deficits seem not attributable to perceptual difficulties due to the absence of deficits in the Perceptive task of the O’Clock Test (see Figure 1).

Conclusion

Present preliminary results suggest that VMI is impaired since the early phase of cognitive decline and an extensive assessment of VMI, taking into account the different components and contents of VMI, may be used to better characterize MCI neuropsychological profile as well as early neuropsychological marker of dementia.
Evaluation of genetic risk for Alzheimer’s disease in the Hong Kong Chinese population
Authors: Zhou Xiaopu , Chen Yu , Lai Nicole Chit Hang , Li Yuen Tung , Kwok Timothy C.Y. , Mok Vincent C.T. , Zhang Yulin , Ma Shuangshuang , Liu Saijuan , Chen Yuewen , Tong Estella Pui‐Sze , Ip Fanny C.F. , Mok Kin Y. , Hardy John , Fu Amy K.Y. , Ip Nancy Y.
Published: December 2020

Background

Alzheimer’s disease (AD) is a leading cause of mortality in the elderly. Although genome‐wide association studies (GWASs) have identified dozens of genetic risk factors in the Caucasian population, their associations with AD in the Chinese population have not been thoroughly investigated.

Method

A TaqMan‐based single‐nucleotide polymorphism genotyping assay was implemented to evaluate Caucasian GWAS risk variants in a Hong Kong Chinese AD cohort (n = 732). Logistic regression analysis was performed to examine the associations between these risk variants and AD, adjusting for age and gender.

Result

Several Caucasian AD candidate loci including SORL1(rs11218343) and ABCA7(rs4147929) were associated with AD in the Hong Kong Chinese AD cohort.

Conclusion

Known Caucasian AD GWAS candidates can contribute to AD risk in the Chinese population. This suggests that AD pathogenesis might share general mechanisms in both Asian and Caucasian populations.
Proximity to parental age at onset exacerbates amyloid burden while mental conditions exacerbate neural loss during midlife
Authors: Arenaza‐Urquijo Eider M , Salvadó Gemma , Operto Greg , Minguillón Carolina , Sánchez‐Benavides Gonzalo , Crous‐Bou Marta , Grau‐Rivera Oriol , Sala‐Vila Aleix , Falcon Carles , Suárez‐Calvet Marc , Zetterberg Henrik , Blennow Kaj , Gispert Juan Domingo , Molinuevo Jose Luis ,   ALFA Study
Published: December 2020

Background

The identification of the earliest biomarker changes and modifiable factors to be targeted in early interventions is crucial for Alzheimer’s disease (AD) prevention. The objective were (1) to evaluate the hypothesis that proximity to parental age at onset (AAO) in sporadic AD is associated with greater AD and neural injury biomarker alterations during midlife and (2) to assess the role of non‐modifiable and modifiable factors on AD and neural injury biomarkers.

Method

A total of 291 cognitively unimpaired (CU) participants with family history (FH) of sporadic AD (aged 49‐73) from the ALFA study. [18F]Flutemetamol‐PET SUVRs, CSF Aβ42/40 and p‐tau were used as AD biomarkers. Hippocampal volumes and CSF t‐tau were used as neural injury biomarkers (Elecsys® immunoassays, Roche diagnostic). Mental and vascular health proxies were calculated. We ran multiple regression models to assess the effect of proximity to parental AAO and its interaction with age on AD and neural injury biomarkers. We also evaluated the effects of FH load (number of parents affected), sex, APOE‐Ɛ4, education, vascular and mental health.

Result

Proximity to parental AAO was associated with β‐amyloid, but not with neural injury biomarkers, and interacted with sex and age, showing women and older participants increased β‐amyloid (see Fig1). FH load and APOE‐Ɛ4 showed independent contributions to β‐amyloid load. Education, vascular and mental health proxies were not associated with AD biomarkers. However, lower mental health proxies were associated with decreased hippocampal volumes with age (see Fig1).

Conclusion

Proximity to parental AAO may offer a timeline for detection of incipient β‐amyloid changes in women. In risk‐enriched middle‐aged cohorts, mental health may be a target for early interventions.
Sex differences in the relation of mixed TDP‐43 and AD pathologies to risk of dementia and cognitive decline
Authors: Barnes Lisa L. , Yu Lei , Kapasi Alifiya , Lamar Melissa , Bennett David A. , Schneider Julie A.
Published: December 2020

Background

It is well‐established that TDP‐43 pathology (also known as LATE) is commonly observed in the brains of older persons, is often mixed with AD pathology, and increases the risk of impairment in episodic memory and Alzheimer’s dementia. It is not known whether there are sex differences in the relation of mixed TDP‐43 and AD pathology with Alzheimer’s dementia and decline in memory.

Method

We included 1,406 autopsied participants who initially enrolled without dementia from three ongoing epidemiologic longitudinal clinical‐pathologic studies of aging: Religious Orders Study, Rush Memory and Aging Project, and Minority Aging Research Study. Participants underwent annual clinical evaluations for diagnosis of Alzheimer’s dementia, including the administration of seven cognitive tests to create summary measures of episodic memory. Systematic uniform neuropathologic examination quantified TDP‐43, AD, and other age‐related pathologies. Persons were categorized into 4 groups; those with no AD or TDP, ‘pure’ TDP, ‘pure’ AD, and mixed AD/TDP. We conducted mixed effects and logistic regression models controlling for age at death, sex, race, and education with cognitive decline and dementia as outcomes, respectively.

Results

In fully adjusted models that controlled for demographics and other age‐related pathologies, compared to older persons without AD or TDP‐43 pathology, those having either or both pathologies had faster decline in episodic memory. Further, there was a sex difference such that the association of mixed AD/TDP‐43 on episodic memory decline was stronger in women than in men (b = 0.040, SE = 0.018, p = 0.022). Similarly, compared to those with no AD or TDP, having ‘pure’ TDP (OR = 3.261), ‘pure’ AD (OR = 4.176), or mixed AD/TDP‐43 (OR = 10.342) increased the odds of dementia (all p’s <0.001). However, “pure” TDP‐43 pathology increased the odds of dementia more strongly in men than in women (OR = 1.392, 95% CI: 0.555, 0.012), in fully adjusted models.

Conclusion

The results suggest sex differences in the effects of mixed AD/TDP‐43 pathology and ‘pure’ TDP pathology on risk of Alzheimer’s dementia and decline in episodic memory. These effects are independent of demographics and other age‐related pathologies.
Genetic risk prediction of late‐onset Alzheimer’s disease based on tissue‐specific transcriptomic analysis and polygenic risk scores
Authors: Jung Sang‐Hyuk , Nho Kwangsik , Kim Dokyoon , Won Hong‐Hee ,   Alzheimer’s Disease Neuroimaging Initiative
Published: December 2020

Background

Large‐scale genome‐wide association studies (GWAS) have identified more than 25 genomic regions related to Alzheimer’s disease (AD). Recent studies showed polygenic risk score (PRS) could be used to identify individuals at high risk of AD. Despite this success, prediction and early intervention of AD still remain challenging. In this study, we constructed prediction models for AD with clinical features, PRS, and tissue‐specifically predicted gene expression levels, and evaluated prediction performance.

Method

We used whole‐genome sequencing data of 446 European participants (207 AD cases and 239 cognitively normal controls) from the Alzheimer’s disease Neuroimaging Initiative (ADNI), and performed quality control of genotyped data using PLINK (Table 1). PRS was derived based on a large‐scale GWAS summary statistics (Lambert et al. 2013) using PRS‐CS. We selected genes significantly associated with AD in brain using MetaXcan and the GWAS summary statistics. For these genes, we predicted gene expression levels in 13 brain regions for our study participants by using PrediXcan and GTEx V7. Then, we built a set of different prediction models that incorporated clinical features, PRS, and transcriptomic features using the Random Forest algorithm for the comparison. We evaluated prediction performance in 10‐fold cross‐validation.

Result

An AD prediction model using only demographic information and APOE ε4 status yielded an AUC of 0.726 (±0.055). As shown in Table 2, the inclusion of PRS significantly improved the prediction performance with an AUC of 0.758 (±0.0489). In addition, the inclusion of PRS and transcriptomic features produced much higher performance with an AUC of 0.794 (±0.061). Furthermore, the top 10 overlapping genes in 13 brain regions used in the prediction model were known AD susceptibility genes (Table 3).

Conclusion

Our study has improved the performance of existing AD genetic risk prediction models by incorporating tissue‐specific transcriptomic factors and PRS, suggesting that tissue‐specific transcriptomic factors and conventional PRS may be partly independent and complementary, so that both are important genetic risk predictors for the classification of AD. In particular, predicted brain expression factors could further provide an indication of tissue‐specific regulatory effects in AD.
Chaperone imbalance drives tau pathogenesis
Authors: Criado‐Marrero Marangelie , Blair Laura J. , Gebru Niat , Blazier Danielle , Baker Jeremy D.
Published: December 2020

Background

The microtubule associated protein tau pathologically aggregates in neurons, a central component of ∼15 neurodegenerative diseases termed tauopathies, which include Alzheimer’s and Parkinson’s disease. Our work has demonstrated that age‐ and disease‐related changes to the cellular chaperone repertoire likely contribute to the abnormal buildup of tau. Recently, we have found that two Hsp90 co‐chaperones, the 52kDa FK506‐binding protein (FKBP52) and the activator of 90 kDa heat shock protein ATPase homolog 1 (Aha1), promote tau aggregation in vitro and in the brains of tau transgenic mice. This led us to hypothesize that imbalances in these chaperones may trigger tau misfolding in the aging brain.

Method

To test this, we overexpressed Aha1, FKBP52, or control protein using adeno‐associated virus serotype 9 (AAV9) bilaterally injected into the hippocampus of 10‐month‐old wild‐type mice (n = 6/AAV). After 7 months of expression, we collected brain tissues to determine the effects on tau accumulation.

Result

We have found that high levels of these chaperones can promote abnormal tau phosphorylation and aggregation, but that the species of tau that was affected was different depending on which chaperone what expressed. While we did see an overall increase in silver‐positive staining, we did not detect any true tau tangles in the brains of these mice.

Conclusion

Based on these studies, we would expect that with enough time, or in the presence of human tau, high levels of these pro‐aggregation chaperones may be sufficient to drive tau pathogenesis. Overall, these findings demonstrate that imbalances in specific chaperones may have a significant impact on the tau in the aging brain.
Amyloid pathology, but not vascular pathology, is associated with risk of incident dementia in non‐demented memory clinic participants
Authors: Haan Renée , Bos Isabelle , Leeuwis Anna E. , Ebenau Jarith L. , van den Bosch Karlijn A. , Barkhof Frederik , Van Berckel Bart N.M. , Teunissen Charlotte E. , Scheltens Philip , Visser Pieter Jelle , van Der Flier Wiesje
Published: December 2020

Background

Cerebral accumulation of amyloid contributes to cognitive decline and progression to dementia. Also vascular pathologies have been suggested to contribute to dementia. We investigated the putative additional effects of vascular and amyloid pathology in patients with subjective cognitive decline (SCD) and mild cognitive impairment (MCI).

Method

We included patients with SCD (n=294; age 62±6, 40%F, MMSE 27±2) or MCI (n=266; age 66±7, 34%F, MMSE 27±2) from the Amsterdam Dementia Cohort (ADC), with available baseline amyloid status (by CSF or PET), available MRI and longitudinal follow‐up (>1 year). Patients were defined as amyloid positive (A+) when either CSF Aβ 1‐42 or amyloid‐PET scan was abnormal. Vascular positive (V+) was defined as having at least one abnormal vascular MRI marker (Fazekas score 2 or 3, microbleeds ≥1 or lacunar infarcts ≥1). We used Cox proportional hazard models to analyze progression to dementia with sex and age as covariates, firstly analyzing A+ and V+ separately, followed by both simultaneously. In addition, we analyzed the effect of each vascular component separately. All analyses were stratified for baseline clinical diagnosis (SCD, MCI).

Result

At baseline 59 (20%) SCD patients were A+ and 75 (26%) V+, 142 (54%) MCI participants A+ and 124 (47%) V+. At follow‐up (3.0 ± 1.9yrs), 21 (7%) SCD and 92 (35%) MCI developed dementia (Table 1). In both SCD and MCI, amyloid pathology was associated with increased risk of dementia (SCD: HR[95%CI]=4.8[2.5‐9.0]; MCI: 1.7[1.2‐2.5]), while the presence of vascular pathology was not (SCD1.5[0.8‐2.7]; MCI: 0.9[0.6‐1.2]). When we entered both determinants simultaneously in one model, associations remained largely similar. There was no interaction between amyloid and vascular pathology (SCD: HR=0.7, CI95%=0.2‐2.6; MCI: HR=0.89, CI95%=0.4‐1.78). When analyzing the three vascular components separately, we found a trend association of microbleeds with incident dementia in SCD, but not in MCI (SCD: HR[95%CI]=2.3[0.96‐5.4]; MCI: 0.8 [0.5‐1.3]).

Conclusion

In this memory clinic cohort of patients with SCD and MCI, we found that – although amyloid pathology and vascular pathology were equally prevalent – only amyloid pathology was associated with incident dementia.
Grey zone amyloid burden heralds future memory decline: The SCIENCe Project
Authors: Ebenau Jarith L. , Verfaillie Sander C.J. , van den Bosch Karlijn A. , Timmers Tessa , Wesselman Linda M.P. , van Leeuwenstijn Mardou , Barkhof Frederik , Prins Niels D. , Scheltens Philip , van Der Flier Wiesje , Van Berckel Bart N.M.
Published: December 2020

Background

We aimed to compare different thresholds for amyloid‐beta pathology and their associations with memory decline, and to investigate the clinical significance of ‘grey zone’ amyloid‐beta burden in cognitively normal individuals.

Method

We included 162 cognitively normal participants with subjective cognitive decline (SCD) from the SCIENCe cohort (64±8yr, 38%F, MMSE 29±1). Each underwent a 70‐minutes dynamic [18F]florbetapir PET, T1‐weighted MRI and longitudinal neuropsychological assessment (n=149≥2 visits). PET scans were classified as positive/negative for amyloid pathology by visual assessment (VA). We calculated a mean binding potential (BPND) and mean standardized uptake value ratio (SUVr50‐70) for a composite region of interest (orbitofrontal, temporal, anterior/posterior cingulate, precuneus). Using Gaussian mixture modelling and k‐means clustering (2 clusters: 90% of low cluster, 10% of high cluster), we derived 3 thresholds for amyloid positivity (A+) based on both BPND and SUVr. We compared associations with memory decline for each threshold using linear mixed models (LMM). To investigate whether grey zone amyloid burden is clinically meaningful, we divided the sample into quantiles, and additionally predefined a grey zone using K‐means thresholds (K‐low/K‐grey/K‐high).

Result

The low K‐means thresholds (BPND=0.18, SUVr=1.27) were most comparable to VA (specificity 76% and 71%, Table 1). LMM showed that all A+ thresholds had comparable associations with rate of memory decline to VA (range β ‐0.39 − ‐0.48). With increasing quantile‐levels, memory slopes gradually became steeper for both BPND and SUVr. The predefined grey zone (BPND 0.18‐0.27, SUVr 1.27‐1.42) was significantly associated with memory decline for both BPND (β ‐0.29(SE 0.14)) and SUVr (β ‐0.43 (SE 0.14)).

Conclusion

We showed that amyloid positivity thresholds for BPND and SUVr are similar to visual assessment in their association with memory decline. Furthermore, the association between A+ and memory decline is not only driven by individuals with the highest amyloid values, but individuals with grey zone amyloid burden are also at risk of steeper memory decline. Therefore, in case a binary classification is required, we suggest using a relatively low threshold, e.g. BPND 0.18, which includes the grey zone.
Modeling the trajectory of tau deposition in autosomal‐dominant Alzheimer’s disease using the high‐affinity tau tracer [18F]MK6240
Authors: Lussier Firoza Z , Therriault Joseph , Pascoal Tharick A. , Benedet Andréa Lessa , Tissot Cécile , Savard Mélissa , Kang Min Su , Mathotaarachchi Sulantha , Stevenson Jenna , Robb Laura , Rosa‐Neto Pedro
Published: December 2020

Background

Evidence suggests that Alzheimer’s disease (AD) pathology may appear many years prior to the manifestation of clinical symptoms. While autosomal‐dominant AD (ADAD) only accounts for approximately 1% of AD cases, evidence shows it has similar pathophysiological features to sporadic AD. ADAD provides a unique and powerful means to model the pathophysiological cascade of events leading to clinical dementia during this asymptomatic stage, due to the complete penetrance of ADAD genetic mutations and the consistency of age at symptom onset between generations. Objective: To investigate tau deposition in vivo across the course of ADAD in mutation carriers (MC) and noncarriers (NC) using the high‐affinity tau PET tracer [18F]MK6240.

Method

Cross‐sectional data was acquired for 12 MC, 6 of whom were symptomatic, and 11 asymptomatic NC. The majority of participants (91%) were from families with PSEN1 mutations. Estimated years from symptom onset (EYO) was obtained by subtracting the age at symptom onset of a parent or sibling from the participant’s age at assessment. [18F]MK6240 standardized uptake value ratio (SUVR) was calculated 90‐110 minutes post‐injection using inferior cerebellar grey matter as the reference region. Statistical analyses performed included ROI‐based and voxel‐based regressions to examine the association between tau load and EYO in MC and NC.

Result

ROI‐based analyses of [18F]MK6240 SUVR as a function of EYO in mutation carriers revealed strong positive correlations for Braak I‐II, III‐IV, and V‐VI. None of the associations between [18F]MK6240 SUVR and EYO were significant in NC. Voxel‐based analyses showed significant correlation between [18F]MK6240 retention and EYO bilaterally in the entorhinal cortex and in the right posterior cingulate and precuneus in MC, while no associations survived correction for multiple comparisons in NC.

Conclusion

Our results support a common pathophysiological cascade between ADAD and sporadic AD, as tau aggregation appears to follow Braak stages in both cases. Our study suggests that tau pathology appears up to 10 years before the onset of clinical symptoms. The identification of affected individuals using biomarkers early in the course of disease is crucial for better clinical outcomes. These results support the applications of disease‐modifying therapeutic interventions in the preclinical stage of AD.
The COMT rs4680 polymorphism is associated with rate of cognitive decline in older adults with type 2 diabetes
Authors: Manzali Sigalit , Beeri Michal Schnaider , Ravona‐Springer Ramit , Lin HungMo , Liu Xiaoyu , Heymann Anthony , Greenbaum Lior
Published: December 2020

Background

The single nucleotide polymorphism (SNP) rs4680 (Val158Met) in the Catechol‐O‐Methyltransferase (COMT) gene affects dopamine level and has been consistently associated with cognitive functioning; the A allele, encoding Methionine, is linked to better cognition (and higher cortical dopamine levels) and lower risk of dementia than the G allele, encoding Valine. Type 2 diabetes (T2D) older adults have greater cognitive decline and higher dementia risk than non‐T2D persons but the role of COMT in this association has not been examined.

Method

Using data from the Israel Diabetes and Cognitive Decline (IDCD; N=964) study, we examined associations of COMT rs4680 with cognitive decline over a 48‐month period. Approximately every 18 months, participants completed a comprehensive neuropsychological battery of 15 tests transformed into z‐scores and summarized into four cognitive domains: episodic memory, attention/working memory, executive functions and language/semantic categorization. The average of the z‐scores of the four domains defined global cognition. Mixed regression models examined the associations of rs4680 with cognitive decline adjusting for age, sex, education and Jewish origin (Ashkenazi or Sephardi).

Result

Participants were on average 71.6 (SD 4.6) years old; 42% women; 13.2 (3.5) years of education. Compared to carriers of rs4680 GG genotype (N=249, 25.8%), carriers of the A allele (AA genotype [N = 216, 22.4% ]+ AG genotype [N = 499, 51.8% ]) had faster rates of decline in global cognition (estimate= ‐0.004; p=0.03), executive functions (estimate= ‐ 0.009 ; p= 0.01) and episodic memory (estimate= ‐0.007 ; p=0.04), but not in attention/working memory nor language. For language, there was a main effect with significantly and consistent better function among the GG genotype carriers over time (estimate= ‐0.50; p=0.001). Additionally adjusting for numerous cardiovascular and T2D‐related risk factors and T2D medications did not alter the results.

Conclusion

Our finding suggests that among T2D elderly, COMT SNP rs4680 affects cognitive decline over time. In contrast to the anticipated direction, A allele carriers had poorer cognitive outcomes. There is evidence indicating that the GG genotype protects against onset of T2D and hyperglycemia; our results suggest a more global protective effect of this genotype against T2D and its complications, including cognitive impairment.
Hippocampal volume and shape features in superagers
Authors: Cobia Derin , Paxton Holly , Sridhar Jaiashre , Makowski‐Woidan Beth , Engelmeyer Janessa , Weintraub Sandra , Mesulam Marsel , Rogalski Emily J
Published: December 2020

Background

Interest in factors contributing to superior cognitive aging has increased in recent years with the study of “SuperAgers” – individuals over age 80 with episodic memory performance similar to average middle‐aged adults. Given hippocampal involvement in memory formation, this project aimed to assess the integrity of this structure in the context of “SuperAging.”

Method

Participants included 67 SuperAgers (SA), 28 cognitively average 80+ year‐old cognitively average normal controls (O‐NC) and 25 middle‐aged cognitively average controls (MA‐NC). SA were age >80 with memory performance at or above normative values for individuals 50‐60 years of age and other cognitive scores normal for age. Control groups scored within the average range for age and education on all cognitive domains. Volume and shape of bilateral hippocampi in each participant was estimated using high‐dimensional surface mapping. Comparisons between groups included the use of repeated measure GLM designs.

Result

No significant effect for hippocampal volume by group (SA: left=2006.33, right=2550.02; O‐NC: left=2017.25, right=2537.94; MA‐NC: left=2208.98, right=2589.70; F
117,2=1.453 p=0.23), but a significant hemispheric effect (Right>Left; F
117,1=632.40, p<0.001) and group x hemisphere effect (F
117,2=6.65, p=0.002). Shape models revealed a significant difference among groups in left (F
216,20=9.23, p<0.001) and right (F
216,20=1.81, p=0.02) hippocampal shape. Follow‐up ANOVAs revealed this effect was primarily driven by MA‐NC shape differences (SA vs MA‐NC Left: F
81,10=16.71, p<0.001; Right: F
81,10=3.26, p=0.001). Hippocampal shape did not differ between SA and O‐NC (Left: F
93,10=0.95, p=0.5; Right: F
93,10=1.10, p=0.41), but did significantly differ between O‐NC and MA‐NC in the left hemisphere (F
42,10=12.02, p<0.001), but not the right hemisphere (F
42,10=1.10, p=0.42).

Conclusion

Despite exceptional episodic memory performance, hippocampal integrity does not appear to be a strong discriminating factor in older adults with superior memory function. While no differences in global hippocampal volume between groups emerged, significant shape differences were noted in both SuperAgers and their age similar controls relative to middle‐aged controls. Overall, our findings may represent a phenomenon where memory ability in old age serves more as a function of a diffuse network of cortical structures rather than a single region. Future exploration would include evaluating connectivity of hippocampal‐involved networks that include regions such as medial temporal cortical and diencephalic structures.
The evolution of neuropsychiatric symptoms in atypical variants of Alzheimer’s disease
Authors: Singleton Ellen H. , Rijkers Chrissy , Groot Colin , Papma Janne M. , Gillissen Freek , van Der Flier Wiesje , Scheltens Philip , Pijnenburg Yolande A.L. , Ossenkoppele Rik
Published: December 2020

Background

Neuropsychiatric symptoms (NPS) constitute a pervasive component of Alzheimer’s disease (AD) for patients with a “typical” (i.e. amnestic‐predominant) phenotype. The prevalence and course of NPS is largely unknown in patients with atypical variants of AD and the few conducted studies are clouded by inclusion of Aβ‐negative individuals. Understanding the evolution of NPS in atypical AD is crucial for adequate patient care for individuals with these rare and early‐onset AD phenotypes.

Methods

We included 632 amyloid‐β‐positive subjects from the Amsterdam Dementia Cohort, including 26 behavioral variant AD (bvAD; showing ≥2/6 behavioral variant frontotemporal dementia (bvFTD) criteria), 30 logopenic variant primary progressive aphasia (lvPPA), 75 posterior cortical atrophy (PCA; Table 1). In addition, we included 47 AD patients with isolated predominant amnestic profiles (“amnestic AD”) and 454 amyloid‐β‐positive AD patients without predominant weaknesses on a single domain as “typical AD” reference groups. Linear mixed models were performed to compare baseline and longitudinal change in NPS as measured using Neuropsychiatric Inventory (NPI) scores across groups using general AD as the reference group (average follow‐up NPI assessment: 1.8 years).

Result

At baseline, apathy, appetite changes, disinhibition, aberrant motor behavior, and agitation were most frequent in bvAD patients, showing higher levels than typical AD (Figure 1). Apathy, irritability, anxiety, depression and appetite changes occured most frequently in PCA patients with similar levels as typical AD groups, whereas patients with lvPPA showed lower frequencies on 11/12 NPS compared to typical AD. Linear mixed models showed a significant decrease in total NPI score over time for the bvAD group (β(SE) = ‐0.0067 (0.003), p<.05). No significant changes were found in the other groups (all p>.05, Figure 2).

Conclusion

This study assessing the baseline magnitude and longitudinal progression of NPS across amyloid‐positive clinical variants of AD suggests that patients with PCA do not show increased NPS, whereas patients with lvPPA show less NPS than typical AD patients. Despite high baseline levels of NPS in bvAD, NPS decrease over time, corresponding to observations in patients with bvFTD and suggestive of an inverted U‐shape trajectory of NPS in these patients.
A predictive, modeling‐based screening tool to enrich amyloid beta positivity in a cognitively normal sample
Authors: Truelove‐Hill Monica , Erus Guray , Pomponio Raymond , Bashyam Vishnu , Doshi Jimit , Habes Mohamad , Ezzati Ali , Bilgel Murat , Resnick Susan M. , Nasrallah Ilya M. , Wolk David A. , Davatzikos Christos ,   Alzheimer’s Disease Neuroimaging Initiative
Published: December 2020

Background

As β‐amyloid (Aβ) targeted clinical trials have had questionable benefit in treating patients with early symptomatic Alzheimer’s disease, treatment would presumably be most effective if administered during the disease’s preclinical phase. PET scans, while highly sensitive to AD pathology, are less practical for screening a large, cognitively normal population for evidence of preclinical AD. Recruitment methods that produce an Aβ enriched sample before PET data collection would decrease participant burden and potentially lower costs. Here, we develop a simple predictive model using subject demographics, structural MRI, and APOE4 status. Using the model’s estimates of one’s probability of Aβ positivity, we significantly increase the proportion of Aβ+ subjects in a cognitively normal sample.

Method

Data from 875 participants from the Baltimore Longitudinal Study of Aging, Penn Memory Center and the Alzheimer’s Disease Neuroimaging Initiative database were separated into a discovery set including AD, MCI, and cognitively normal participants (n = 673) and a cognitively normal replication set (n = 202). Aβ prediction performance of a logistic regression model was compared across multiple predictor sets. Regression‐based probability values were used to threshold the data, i.e., participants whose values fell below a cutoff were excluded from the thresholded sample. The proportion of Aβ+ individuals between the restricted and complete samples was compared across multiple cutoffs.

Result

Applying a probability cutoff of 0.4 yielded samples with significantly higher proportions of Aβ+ subjects in 3 of the 5 tested models (Table 1). The Lesions model achieved the highest sample enrichment; 40.54% of the thresholded sample were Aβ+, significantly higher than the base rate of 28.22%, χ2 (1) = 8.32, p = .004 (Figure 1). However, there were no significant differences between the enriched sample produced by the Lesions model and those produced by the other significant models, indicating sample enrichment is possible even with different predictors.

Conclusion

Aβ+ probability metrics produced by predictive models provide a novel method of sample enrichment and can be used as an individualized measure of Aβ classification certainty. Fewer PET scans will be necessary to obtain a sufficient Aβ+ sample, reducing burden on participants and researchers and potentially lowering costs.
APOE4 impairs neuron‐astrocyte coupling of fatty acid metabolism
Authors: Qi Guoyuan , Mi Yashi , Shi Xiaojian , Gu Haiwei , Brinton Roberta Diaz , Yin Fei
Published: December 2020

Background

As the strongest genetic risk factor for late‐onset Alzheimer’s disease, the ε4 variant of apolipoprotein E (APOE4) is known to perturb both lipid homeostasis and energy metabolism in brain. However, the mechanistic role of APOE4 in modulating the bioenergetic aspects of lipid species, and its connection with cell‐type‐specific mitochondrial phenotypes are not well understood.

Method

Here, in individual‐ and co‐culture models of primary neurons and astrocytes from humanized APOE3 or APOE4 knockin mice, we describe a loss‐of‐function role of APOE4 in regulating key mechanisms controlling neuron‐astrocyte coupling of lipid metabolism, from neuronal storage of fatty acids (FAs) in lipid droplets (LDs), to the mobilization of neuronal LDs and transport of FAs to astrocytes, and eventually to the energetic degradation of FAs in astrocytes.

Result

Compared to APOE3, APOE4 decreases the sequestering of free fatty acids (FAs) in neuronal lipid droplets (LDs), elevates FA levels and leads to mitochondrial‐ and neuronal dysfunction. These neuronal LDs are eliminated upon astrocyte exposure and FAs are transported to astrocytes together with APOE, with APOE4 in either neurons or astrocytes diminishing the transport efficiency. In APOE4 astrocytes, increased mitochondrial fragmentation underlies a metabolic shift towards enhanced glucose metabolism and reduced FA β‐oxidation, which further elicits astrocytic LD accumulation. Moreover, the lesser capacity in eliminating neuronal lipids and performing β‐oxidation results in compromised ability of APOE4 astrocytes in providing metabolic‐ and synaptic support to neurons.

Conclusion

These data support the coupling of neuron lipid homeostasis, astrocytic FA degradation with cell‐specific mitochondrial function, which is essential to protect neurons from bioenergetic deficits and lipotoxicity. Further, our findings reveal the mechanistic basis of APOE4 in disrupting inter‐cellular FA metabolism in brain that may underlie the exaggerated lipid dyshomeostasis and bioenergetic decline, and increased AD risk for APOE4 carriers.
Brainstem volumetric integrity in preclinical and prodromal Alzheimer’s disease
Authors: Dutt Shubir , Li Yanrong , Mather Mara , Nation Daniel A
Published: December 2020

Background

Autopsy‐based neuropathological studies have suggested the tau pathology observed in Alzheimer’s disease (AD) originates in brainstem nuclei, but no studies to date have quantified brainstem volumes in clinical populations with biomarker‐confirmed mild cognitive impairment (MCI) or dementia due to AD or determined the value of brainstem volumetrics in predicting dementia risk. The present study examined whether MRI‐based brainstem sub‐structural volumes differ between cognitively normal (CN) older adults and those with MCI or dementia due to AD, and whether early preclinical brainstem volumes predict future progression to dementia.

Method

Alzheimer’s Disease Neuroimaging Initiative participants diagnosed as CN (n=822), MCI (n=543), or AD (n=300) underwent baseline T1‐weighted structural MRI scanning with variable clinical follow‐up (6‐120 months). A subset of participants completed baseline fasting lumbar puncture to quantify levels of amyloid‐beta 1‐42 and phospho‐tau. We employed region‐of‐interest and voxel‐based morphometric methods to assess differences between clinically‐diagnosed and biomarker‐defined groups in volumes of the whole brainstem, midbrain, pons, and locus coeruleus. Longitudinal Cox regression analyses determined value of baseline brainstem sub‐structure volumes in predicting progression to a future clinical diagnosis of AD dementia.

Result

Compared with CN individuals, we observed smaller regional volumes in whole brainstem, midbrain, pons, and locus coeruleus regions in patients clinically diagnosed with MCI and AD, and specifically within the midbrain in biomarker‐confirmed cases. Brainstem‐masked voxel‐wise comparisons confirmed volume reduction of a dorsal rostral brainstem region corresponding to the locus coeruleus in MCI and AD relative to CN, as well as in CN who progressed to AD dementia versus those that did not progress to AD dementia. In a preclinical risk analysis, cognitively normal individuals who later progressed to AD dementia exhibited smaller baseline midbrain volumes than individuals who did not develop dementia, and longitudinal analyses indicated smaller midbrain and locus coeruleus volumes conferred greater risk of progression.

Conclusion

Our study indicated that brainstem MRI changes are detectible in preclinical and prodromal populations. Our findings are consistent with the neuropathological observation that AD‐related pathology occurs early in brainstem nuclei and further suggest the clinical relevance of brainstem sub‐structural volumes for preclinical and prodromal AD populations.
Longer and more frequent naps predict incident Alzheimer’s dementia in community‐based older adults
Authors: Li Peng , Gao Lei , Gaba Arlen , Yu Lei , Yaffe Kristine , Buchman Aron S , Bennett David A , Hu Kun , Leng Yue
Published: December 2020

Background

Excessive napping duration has been associated with cognitive decline. The effect of napping frequency is less understood, and little is known about the development of Alzheimer’s disease (AD) associated with napping. We tested whether longer or more frequent naps in the elderly are linked to the development of incident AD.

Method

We studied 1,180 older adults (age: 81.0±7.3 [SD]) in the Rush Memory and Aging Project who have been followed for up to 14 years. Motor activities (i.e., actigraphy; median length: 10 days; range: 2‐14 days) were recorded at baseline to assess napping characteristics objectively. We defined daytime napping episodes as motor activity segments between 10AM and 7PM with continuous zero‐activity for ≥10min but <1h (to avoid off‐wrist periods). Segments that were <5min apart were merged. Alzheimer’s dementia diagnosis was determined using the standard criteria (i.e., the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer’s Disease and Related Disorders Association). Cox proportional hazards models were performed to examine the associations of daily napping duration and frequency with incident AD.

Result

Of 1,180 non‐demented participants at baseline (including 264 with mild cognitive impairment), 277 developed Alzheimer’s dementia within 5.74±3.36 years. On average, participants napped for 38.3±1.0 (SE) min and1.56±0.04 (SE) times per day at baseline. After adjustment for age, sex, and education, every 30‐min increase in daily napping duration was associated with a 20% increase in the risk of incident AD (95% confidence interval [CI]: 9%‐31%; p=0.0002). One more nap per day was associated with a 19% increase in the risk of AD (95% CI: 8%‐30%; p=0.0003). These associations remained after adjustment separately for BMI, depressive symptoms, vascular diseases/risk factors, and other actigraphy‐derived measures including total daily activity, total sleep time, sleep fragmentation, stability and variability of daily activity rhythms.

Conclusion

Longer and more frequent daytime naps are associated with a higher risk of incident AD. Future studies are needed to examine specific underlying mechanisms.
Equivalence of serum and plasma neurofilament light chain levels using highly sensitive automated immunoassay
Authors: Qiu Xiaolei , Lee Stephen , Jackson Jeremiah , Zhao Xingfang , Shields Aileen , Matias Madeleine , Uzgiris Arejas
Published: December 2020

Background

Neurofilament light chain (NfL) in blood is a promising new biomarker for neurogenerative disease1 and clinical progression in presymptomatic Alzheimer disease2. Well established standardization of assays and collection methods are necessary before acceptance for clinical use. Data supporting equivalence of plasma and serum NfL testing are not yet widely published. In this study, we compared three blood collection specimen types, two for plasma and one for serum.

Method

Matched serum, heparin‐treated plasma, and EDTA‐treated plasma from 40 individual donors were acquired. NfL concentration was determined using an automated immunoassay developed at Siemens Healthcare Laboratory, LLC3. Sample equivalence was analyzed with Deming regression.

Result

All two way comparisons resulted in strong correlation: NfL concentrations in serum and lithium heparin plasma (slope=1.004, R=0.971), serum and K2EDTA plasma (slope=1.065, R=0.961), and lithium heparin plasma and K2EDTA plasma (slope=1.059, R=0.979).

Conclusion

Individual to individual variability was noted to be higher in plasma than with serum. With a well‐optimized automated immunoassay, NfL concentrations in plasma and serum were equivalent. References: (1) Zetterberg, H., Burnham, S.C. Blood‐based molecular biomarkers for Alzheimer’s disease. Mol Brain 12, 26 (2019) doi:10.1186/s13041‐019‐0448‐1. (2) Preische O, et al, Serum neurofilament dynamics predicts neurodegeneration and clinical progression in presymptomatic Alzheimer's disease, Nat Med. 2019 Feb;25(2):277‐283. doi: 10.1038/s41591‐018‐0304‐3. (3) Plavina, et al, Development of a Sensitive Serum Neurofilament Light Assay on Siemens Routine Immunoassay Platforms, poster presentation, ECTRIMS, 2019.
The state of the science on synchronous video‐conferencing interventions for care partners of persons with dementia
Authors: Tarter Robin R. , Tran Leslie , Lindauer Allison
Published: December 2020

Background

The need for effective clinical interventions to prevent the potentially deleterious health impact of providing unpaid care to friends and family members with Alzheimer’s disease and related dementias (ADRDs) has become increasingly urgent. Synchronous video‐conferencing in which ADRD care partners interact in real time with trained healthcare professionals has emerged as an especially promising method for telehealth interventional research. Here we report on the designs and outcomes of such interventions for care partners of persons with ADRDs.

Method

A scoping review was undertaken following Arksey and O’Malley’s systematic methodological framework. Articles were identified through a comprehensive search of PubMed, PsychINFO, and CINAHL. Inclusion criteria were peer reviewed, data‐based research articles published between 2015 and 2020 reporting results of synchronous video‐conferencing interventions specifically designed to address the needs of care partners of persons with ADRDs. Reviews, scale development, protocols, and case studies were excluded.

Result

Full text screening of 159 articles resulted in the identification of seven articles reporting the results of six independent interventions. Included studies fell into two categories, psychoeducational behavior modification interventions delivered by nursing professionals and facilitated peer support interventions delivered by psychologists and social workers. Interventions varied based on technological mode of delivery, level of interaction among participants and between participants and interventionists, duration and frequency of sessions, and outcomes measured or described. Articles reported evidence of efficacy for decreasing care partner loneliness, depression, burden, and increasing care competence. Feasibility and acceptability of the technological interface varied between interventions, but was high overall.

Conclusion

By comparing and contrasting these 6 synchronous video‐conferencing interventions, we are able support the viability of synchronous video‐conferencing as an effective mode of intervention for care partners of persons with ADRDs, and generate information to inform future research. Despite evidence that care partners need stage‐specific interventions, none of the reviewed studies were tailored to specific dementia stages, and there was a glaring lack of diversity in most study samples. Our results suggest that future research with care partners should not be limited to earth‐bound, face‐to‐face interventions, and that synchronous video‐conferencing has benefits above and beyond other approaches.
Audio‐visual speech perception is associated with cerebral tau deposition on [18F]flortaucipir PET
Authors: Risacher Shannon L. , Herbert Carolyn J. , Vosmeier Aaron , Garrett Makaylah N. , West John D. , Deardorff Rachael , Yates Charles W. , Apostolova Liana G. , Pisoni David B. , Saykin Andrew J.
Published: December 2020

Background

Sensory impairments are associated with dementia and biomarkers of pathology. In a preliminary study, we evaluated whether audio‐visual speech perception, which involves integration of complementary phonetic information from two sensory modalities (vision and hearing), is associated with AD neuropathology on imaging.

Method

14 individuals (2 cognitive normal (CN), 7 subjective cognitive decline (SCD), 4 MCI, and 1 AD) from the Indiana Alzheimer Disease Center and Indiana Memory and Aging Study underwent auditory testing, MRI, amyloid PET with [18F]florbetaben, and tau PET with [18F]flortaucipir. The audiologic testing included a brief pure‐tone hearing screen, followed by CUNY Sentences [1], among other tests. CUNY Sentences are presented using auditory input only (Auditory condition (A)) or using both auditory and visual input (AV using video with sound of an individual saying sentences). Words and sentences correct are scored, as is the difference between word and sentence scores (ΔWdtoSent). Amyloid and tau PET were processed using standard techniques. Mean SUVR from the cortex (amyloid and tau) and lateral temporal lobe (LTL; tau) were extracted. MRI was processed with Freesurfer v6 to extract LTL thickness. Because the CUNY scores were skewed, Spearman correlations were used to assess relations of sentence scores and ΔWdtoSent for both the A and AV conditions with neuroimaging measures of AD pathology (cortical amyloid, LTL and cortical tau, and LTL thickness). Inclusion of age, sex, and ICV where appropriate did not alter the observed results.

Results

Significant associations between AV speech perception for sentences and AV ΔWdtoSent and tau deposition in the LTL and cortex were observed (Figure 1). These results remained significant after the AD participant was removed. Only trend associations were observed for the A condition, which were less robust than in the AV condition. Finally, a trend for a significant association with LTL thickness was observed. No association with amyloid was observed.

Conclusion

Integration of phonetic information from two sensory modalities (vision and hearing) may be a potential a biomarker for tau pathology in patients at risk for AD. Future studies with larger samples and longitudinal follow‐up are needed. Reference: [1] Boothroyd et al. (1988) Ear and Hearing.