bluuebunny/crossref_metadata_2025 huggingface dataset:
Association between race/ethnicity and neuroimaging biomarkers in middle‐ and older‐aged adults
Authors: Turney Indira C , Lao Patrick J , Rentería Miguel Arce , Laing Krystal K , Beato Juliet M , Chesebro Anthony G , Amarante Erica , Igwe Kay C , Schupf Nicole , Mayeux Richard , Manly Jennifer J , Brickman Adam M
Published: December 2020

Background

Alzheimer’s disease and related disorders (ADRD) disproportionately affect African American, Hispanic, and American Indian older adults. Previous studies report racial/ethnic differences in markers of aging and neurodegeneration, but results are inconsistent due to small, non‐representative samples. We hypothesized that accelerated aging would manifest as a stronger negative relationship between age and MRI biomarkers among community‐dwelling racial/ethnic minorities compared with non‐Hispanic Whites.

Method

ADRD‐related neuroimaging measures of composite cortical thickness (CT) in AD signature regions and white matter hyperintensity (WMH) volume were assessed in White (n=274), Black (n=451), and Hispanic (n=663) participants from community‐based, intergenerational studies of cognitive aging and dementia. WHICAP participants are Medicare‐eligible participants aged 65 and older. The Offspring cohort includes middle‐aged children of the WHICAP study participants (of the 1482 participants, 1209 families were represented). We examined the association of cohort age and race/ethnicity with each imaging marker, after adjusting for sex/gender and family relatedness, and tested interactions between cohort age and race/ethnicity in separate models.

Result

WHICAP participants were 75±6.5 years old and Offspring participants were 55±10.5 years old at time of MRI. As expected, WHICAP participants had lower CT in AD signature regions than Offspring (β=‐.06,95%CI:‐.05,‐.08). Compared with Whites, Blacks and Hispanics had lower CT in AD signature regions, but an interaction between cohort age and race/ethnicity revealed that older Blacks had disproportionately thinner CT in AD signature regions (β=‐.05,95%CI:‐.01,‐.10). Offspring participants had lower WMH volume than WHICAP participants (β=‐1.4,95%CI:‐2.1,‐.58). Blacks had more WMH burden overall (β=1.04,95%CI:.13,2.0), but there were no interactions between race/ethnicity and cohort age on WMH burden.

Conclusion

Among diverse, community‐based participants, there are disparities in markers of brain atrophy in both cohorts but this effect is intensified with age, where older Blacks show disproportionately greater brain atrophy compared with other groups. Disparities in small vessel cerebrovascular disease are apparent in middle‐age and late‐life, but this effect is similar across age‐groups. Results suggest that racial/ethnic disparities in markers of brain aging and disease are apparent even in middle‐age and, in the case of neurodegeneration, may amplify with increasing age. These differences may be due to accelerated aging secondary to sociocultural factors and experiences.
Forecasts for numbers of people living with dementia to 2050 and estimates for impact of smoking cessation: A modelling study in four European countries
Authors: Ahmadi‐Abhari Sara , Bandosz Piotr , Shipley Martin J , Whittaker Hannah , Middleton Lefkos T , Kivipelto Miia , Brunner Eric , Kivimaki Mika
Published: December 2020

Background

Forecasting dementia prevalence and the impact of preventive lifestyle interventions, requires accounting for the reduced risk of dementia and cardiovascular disease (CVD) and the concurrent increase in life‐expectancy and growing population susceptible to dementia. We aimed to forecast prevalence of dementia in Sweden, Spain, France and Poland in 2020 and 2050 assuming calendar trends in mortality rates and incidence of dementia and CVD continue the trajectories observed over the past two decades, and to estimate change in this number if elimination of cigarette‐smoking was successful.

Method

We developed a Monte‐Carlo Markov model with data derived from official statistics for population numbers and mortality rates and the Survey for Health, Ageing and Retirement in Europe for baseline prevalence estimates and transition probabilities. All input parameters were age‐ and sex‐specific and were projected to the future based on observed calendar trends. Relative risks of CVD, dementia, and mortality for smoking, obtained from meta‐analyses of published studies, were used to modify transition probabilities proportionate to the change in population attributable risk fractions if smoking is eliminated by 2025.

Result

Life‐expectancy at age 50 in Sweden was estimated at 31.1 years in 2020, increasing to 35.3 by 2050 if observed trajectories continue, and at 36.1 if smoking elimination was successful (Figure). Corresponding figures were 32.6, 41.7, and 44.0 years respectively for Spain; 32.5, 38.7, and 40.7 for France; and 30.3, 37.8, and 39.9 for Poland. Estimated numbers of people living with dementia in 2020 and 2050, and estimated numbers by 2050 if smoking was eliminated were 147,000 (age‐standardized prevalence 4.2%), 223,000 (4.1%) and 239,000 (4.2%) respectively in Sweden (Table); 1,090,000 (6.8%), 2,913,000 (6.4%) and 3,194,000 (6.6%) in Spain; 998,000 (4.8%), 2,128,000 (4.3%) and 2,400,000 (4.2%) in France; and 623,000 (3.9%), 1,254,000 (3.5%) and 1,442,000 (3.5%) in Poland.

Conclusion

Substantial increases in numbers with dementia by 2050 emphasize the importance of planning public health policies that meet the growing health‐ and social‐care needs of dementia patients in the next three‐decades. Although smoking cessation increases dementia‐free life‐years, it is unlikely to halt the increase in the numbers of dementia patients that result from concurrent increases in life‐expectancy.
Potentially inappropriate medications that impact cognition are common in older adults with Alzheimer’s disease or related dementias, driven by antipsychotics
Authors: Vickers Lauren , Martinez Ashley I , Wallem Alexandra M , Moga Daniela C
Published: December 2020

Background

Older adults with dementia are particularly vulnerable to adverse effects of potentially inappropriate medication (PIM) use. The Beers Criteria identifies PIMs, including antipsychotics, benzodiazepines (BZD), and non‐benzodiazepine benzodiazepine receptor agonist hypnotics (Z drugs) that are linked to cognitive impairment or decline (“Cog‐PIMs”). This study investigated the difference in Cog‐PIM use as reported for patients with and without Alzheimer’s disease or related dementias (ADRD) in a nationally representative sample of the United States population.

Methods

We conducted a cross‐sectional study using the 2016 National Ambulatory Medical Care Survey. The analysis included non‐perioperative office‐based visits for patients ≥ 65 years old. Visit characteristics were compared between those with and without ADRD using descriptive statistics, and adjusted logistic regression was used to identify predictors of Cog‐PIM use.

Results

Of the 218,182,131 outpatient visits, 2.2% were for patients with ADRD (N=4,651,563). Approximately twice as many visits with Cog‐PIM reports were among those with ADRD compared to those without (22.9 vs 10.7%), after adjusting for known confounders, ADRD was not a significant predictor of Cog‐PIM report (OR [95% CI] 1.2 [0.4‐3.3]). This is likely because there were no differences between groups in report of BZDs (8.7 vs 8.8%) and Z drugs (2.2 vs 1.9%). The most striking difference in Cog‐PIM report between those with and without ADRD occurred with antipsychotics, which were noted in 15.5% vs 0.8% of visits; the most common included quetiapine (40.0%), haloperidol (26.2%), and olanzapine (20.3%). After adjusting for potential confounders, ADRD was a significant predictor of antipsychotic report (aOR [95% CI] 34.9 [8.7‐141.1]). Hispanic ethnicity and report of >5 medications were also significantly associated with antipsychotic use (4.3 [1.4‐13.4] and 6.3 [1.9‐20.7] respectively).

Conclusion

In a nationally representative sample, Cog‐PIM use was reported in nearly one‐quarter of visits for patients with ADRD, driven by report of an antipsychotic. Presence of ADRD was a significant predictor of visits reporting an antipsychotic, and both traditional and atypical antipsychotics were highly prevalent. Given that these medications are not recommended for older adults and that they may negatively impact cognition, future work should investigate points of intervention to reduce Cog‐PIM use (specifically antipsychotics) in the ADRD population.
Peripheral neurofilament light (NFL) chain level predicts the two‐year outcome of amnestic mild cognitive impairment in Chinese Han population
Authors: Zhao Qianhua , Ding Ding
Published: December 2020

Background

Biomarkers that could track disease onset and progression in patients with mild cognitive impairment (MCI). We investigate whether peripheral neurofilament light (NfL) concentration is associated with clinical outcome in a MCI cohort.

Method

A cohort of 401 patients with aMCI underwent annually longitudinal clinical follow‐up and neuropsychological testing. Plasma level of NFL, Abeta40, Abeta42, total Tau were assessed using an ultrasensitive immunoassay on the Single molecule array (Simoa) platform.

Result

Plasma markers samples were analyzed for Tau, Abeta 40/42 and NFL; data assessed as predictors of conversions from MCI to dementia. Among all the patients, 258 finished two‐year annually follow‐up. Of which, 80 (31.0%) converted to dementia, 129 (50.0%) remained to be MCI , 49 (19.0%) reversed to cognitively normal. Plasma NFL levels were elevated in conversion group compared to non‐conversion group. Elevated plasma NFL showed strong association with the cognitive decline, after adjusting for age, sex, and comorbid diseases. Plasma Abeta40/42 ratio also showed a trend to discriminate converter out of MCI patients, but didn’t reach statistical significance.

Conclusion

Elevated baseline plasma NFL level was associated with greater rate of cognitive decline in MCI patients, and with the conversion from MCI to dementia in Chinese population.
A novel P75‐neurotrophin receptor antagonist, EVT901, reduces neuroinflammation in the TGFAD344 rat model of Alzheimer’s disease
Authors: Kang Min Su , Singleton Thomas A , Aliaga Arturo Aliaga , Massarweh Gassan , Gauthier Serge , Soucy Jean‐Paul , Kostikov Alexey , Rosa‐Neto Pedro
Published: December 2020

Background

p75‐neurotrophin receptor (p75NTR) plays an important role in cell death in adults and has been associated with age‐related basal forebrain degeneration and in Alzheimer’s disease (AD). A recent study demonstrated the reduced pro‐inflammatory response and improvement of the functional outcome by blocking p75NTR following traumatic brain injury. Here, we aimed to test whether a novel p75NTR antagonist, EVT901, reduces neuroinflammation caused by AD pathology in the TgFAD344 rat model (Tg). We hypothesized that chronic administration of EVT901 will reduce the neuroinflammation caused by amyloidosis and hyperphosphorylated tau in the AD rat model.

Method

Two parallel longitudinal studies were conducted to characterize the progression of amyloidosis and neuroinflammation in TgFAD344 rat models (WT = 15 & Tg = 22) and the effect of EVT901 on neuroinflammation (Tg = 6). In the first study, animals underwent 60‐minute dynamic PET scans using [18F]AZD4694 for amyloid‐beta and [11C]PBR28 for neuroinflammation at 15 and 22 months. During the intervention study, animals received 1 mg/kg of EVT901 for 7 days via tail vein injection at 22 months. These animals also underwent [11C]PBR28 PET one day before and after the intervention. The 1 mg/ml drug was prepared in a 10% PEG‐400/90% saline solution. All PET images were matched to the respective MRI and normalized to the average template. [18F]AZD4694 BPND and [11C]PBR28 BPND were quantified based on the SRTM method using pons and midbrain as a reference region, respectively.

Result

The first study demonstrated a significant increase in [18F]AZD4694 and [11C]PBR28 uptake in both the hippocampus and neocortex in Tg compared to WT at baseline and follow‐up. TgFAD344 rats showed a longitudinal increase in [18F]AZD4694 and [11C]PBR28 binding in similar regions. Our second study demonstrated a significant reduction in [11C]PBR28 binding following the intervention in the hippocampus and parietotemporal cortex.

Conclusion

This study demonstrated the amyloid pathology and neuroinflammation in the TgFAD344 rat model is captured by [18F]AZD4694 and [11C]PBR28 in vivo. Furthermore, a novel p75NTR antagonist, EVT901, reduces the neuroinflammation induced by AD pathophysiology. Blocking p75NTR can be considered a novel therapeutic target to reduce neuroinflammation in AD.
Neurocognitive mechanisms of spatial pattern separation in older adults with and without subclinical memory impairment
Authors: Márquez Freddie , Larson Myra S , Smith Anna , Miranda Blake A , McMillan Liv , Sathishkumar Mithra , Yassa Michael A.
Published: December 2020

Background

Decline in episodic memory is a hallmark feature of Alzheimer’s disease (AD). Episodic memories can be operationalized as detailed conjunctions of items and their spatiotemporal context. Our past work has uncovered deficits in pattern separation of similar object memories in nondemented older adults. However, separation of similar spatial locations was only slightly impaired in this population. We hypothesized that these deficits may be more readily observable in individuals with subclinical memory impairment (assessed by verbal list recall). We also sought to determine the neural mechanisms by which spatial pattern separation deficits may manifest in older adults, focusing on the posterior parietal network which is involved in spatial processing and implicated in AD.

Methods

Two cohorts were included in this analysis. The first is a group of older adults with subclinical memory impairment (aged impaired – AI, age range: 61‐91; mean MMSE: 28.3 ± 1.50; mean RAVLT delayed recall: 9.66 ± 4.05). The second is a group of non‐demented older adults without memory impairment (aged unimpaired – AU; age range: 61‐86; mean MMSE: 28.1 ± 1.59; RAVLT delayed recall: 11.4 ± 3.01). Participants underwent whole brain high‐resolution resting state functional magnetic resonance imaging (1.5 × 1.5 × 2 mm resolution). They were also administered a battery of neuropsychological tests including tests of object and spatial pattern separation. We used performance on the RAVLT as the outcome predicted by performance on the discrimination tests. Specifically, we used delayed recall (DR), retroactive interference (RI), and percent forgetting (PF).

Results

Behaviorally, spatial, but not item, pattern separation performance predicted RAVLT DR, RI and PF scores in the AI group, but not the AU group. Functional connectivity analyses revealed that the connectivity of regions involved in spatial processing was significantly related to spatial pattern separation performance in the AI group, but not the AU group.

Conclusion

These results validate the neurobiological basis of spatial pattern separation and suggest that such tasks can be used to detect early stages of AD, which has important implications for future diagnostics and treatment approaches.
Physical performance and cognition in an ethnically diverse cohort of oldest‐old individuals: The LifeAfter90 study
Authors: Whitmer Rachel A , Kawas Claudia H , Gilsanz Paola , Glymour M Maria , Mungas Dan M , DeCarli Charles , Mayeda Elizabeth Rose , Peterson Rachel , George Kristen M , Corrada Maria MM
Published: December 2020

Background

In prior studies of oldest‐old, poor physical performance is associated with cognitive impairment and risk of incident dementia, though this was in highly educated Caucasians. There is limited data on physical performance in diverse cohorts of oldest‐old. Identification of how physical performance is emblematic of frailty, health, and underlying pathology in representative populations is essential. Here we examine the cross‐sectional association between physical performance and cognitive function among the first 610 participants enrolled in LifeAfter90, an ongoing multiethnic oldest‐old cohort.

Method

LifeAfter90 participants are long‐time members of the Kaiser Permanente Northern California Health Care System without a dementia diagnosis in their medical record at the time of recruitment. Evaluations are every six months and include a neuropsychological tests with the Spanish and English Neuropsychological Assessment Scales (SENAS) and physical performance measures (4‐meter walk and hand grip). The SENAS assesses domains of episodic memory, semantic memory, and executive function. 4‐meter walk was measured twice and averaged, handgrip was measured 3 times in the dominant hand and averaged. Using linear regression, we studied the cross‐sectional associations between the two physical performance measures and SENAS cognitive domains across racial/ethnic groups adjusted for age, gender and education.

Result

At baseline, participants were on average 92.6 years of age, 62% were women, 45% had a college education, and 68% were racial/ethnic minorities (Table 1). Overall, those with better grip strength and shorter walk time had better cognitive scores overall, and across all three domains. However, when stratifying by race these associations were not ubiquitous across all groups (Table 2). Namely, physical performance was only associated with executive function in Whites (Table 2); while physical performance was consistently associated with all three domains in Black, Latino, and Asian oldest‐old individuals.

Conclusion

In this oldest‐old, racially/ethnically diverse cohort, physical performance is associated with better executive function, semantic memory and verbal episodic memory. Markers of frailty and health may have different meaning in diverse populations. Understanding differences in the association between physical performance and cognitive performance is crucial as they could reflect racial/ethnic differences on burden of pathology.
Insulin‐like growth factor‐1 (IGF‐1) is a biomarker of objective cognitive impairment but not subjective cognitive complaint in cerebral palsy
Authors: Ng Ted Kheng Siang , Tagawa Alex , Carollo James , Heyn Patricia C.
Published: December 2020

Background

Cognitive impairments are common in cerebral palsy (CP), however the evidence on the biological underpinnings of these impairments in CP has been scarce. Although insulin‐like growth factor‐1 (IGF‐1) is involved in cognitive deficits, its roles in cognitive functions in CP is unknown. We aimed to examine whether IGF‐1 is a biomarker of objective and self‐reported cognitive functions in CP.

Method

Based on a priori screening criteria, we recruited 72 adults with CP for a cross‐sectional study conducted in an accredited clinical motion analysis laboratory at Children’s Hospital Colorado. Subtests of the Wechsler Adult Intelligence Scale (WAIS) were administered to assess multiple cognitive functions. We used The Patient‐Reported Outcomes Measurement Information System (PROMIS) to measure multiple domains of self‐reported health, including cognitive complaints. Biomarkers were measured by fasting blood tests. All biomarkers measured were log‐transformed to conform to statistical normality.

Result

CP patients recruited had mean age=20 (SD=5.3), Male=47.2% and female=52.8%. Controlling for covariates, IGF‐1 correlated significantly with multiple cognitive domains, including delayed recall and recognition (declarative memory), block design (visual‐spatial and motor skills), and symbol search (processing speed). Furthermore, IGF‐1 correlated significantly with two other biomarkers, IL‐6 and IGF‐BP3, suggesting a network of insulin signaling and inflammatory biomarkers contributing to the objective cognitive impairment in multiple domains in CP patients. No association was found with subjective memory complaint, although IGF‐1 associated significantly with social roles and activities and physical function domains of PROMIS.

Conclusion

In CP patients, IGF‐1 is a useful biomarker for objective cognitive impairment and other self‐reported functions, but not subjective cognitive complaint.
Longitudinal changes in A/T/N imaging biomarkers in early‐onset and late‐onset Alzheimer’s disease
Authors: Baek Min Seok , Cho Hanna , Kim Hankyeol , Lee Jae Hoon , Ryu Young Hoon , Lyoo Chul Hyoung
Published: December 2020

Background

To investigate the effect of onset‐age on the baseline and longitudinal changes in A/T/N imaging biomarkers in the Alzheimer’s disease (AD) spectrum.

Method

71 Aβ‐positive cognitively impaired (CI+) individuals and 67 Aβ‐negative cognitively unimpaired (CU‐) individuals completed longitudinal two PET scans (18F‐florbetaben for Aβ and 18F‐flortaucipir for tau) and magnetic resonance (MR) imaging studies with a mean follow‐up duration of two years. Based on the onset‐age of cognitive impairment, baseline and the annual change in standardized uptake value ratio (SUVR) values and regional volumes were compared between 15 early‐onset (EOCI+, onset < 65 yrs) and 56 late‐onset (LOCI+, onset ≥ 65 yrs) CI+ groups.

Result

Baseline Aβ burden and its accumulation rate were not different between the EOCI+ and LOCI+ groups. When compared to LOCI+, EOCI+ group showed greater baseline tau burden and its accumulation rate in widespread cortical regions except for the medial temporal regions. Baseline volume of the entorhinal cortex was smaller in the LOCI+ group than that in the EOCI+ group, while the volume atrophy rates in the parietal cortex and precuneus were higher in the EOCI+ group although these regions did not survive correcting for region‐wise multiple comparisons.

Conclusion

Early‐onset AD patients have greater tau burden and are more likely to be vulnerable to progressive tau accumulation in the widespread neocortex, and thereby may be more vulnerable to the progressive neurodegeneration than the late‐onset AD.
Rostro‐caudal locus coeruleus integrity differences vary with age and sex using ultra‐high field imaging
Authors: Riphagen Joost M. , van Hooren Roy W.E. , Pagen Linda H.G. , Poser Benedikt A. , Jacobs Heidi I.L.
Published: December 2020

Background

Autopsy studies reported that the locus coeruleus (LC) is one of the initial regions to accumulate tau early in life. With every increase in Braak stage, LC volumes declines with approximately 8%. In addition, animal studies have reported a sexual differentiation of the locus coeruleus (LC), reflecting a higher number of neurons in women. Given the reported sexual dimorphism in subcortical volumes and cortical tau deposition, indicating a higher vulnerability in women, we sought to examine age and sex‐differences along the rostro‐caudal axis of the LC by using dedicated novel structural ultra‐high field imaging methods.

Method

Inclusion: 89 participants 20‐85 yrs (45F/41M,Age females 49(sd19.29), males 51(sd22.2) p=0.65). Imaging was done at 7T, including MP2RAGE anatomical scans and our previously validated MT‐TFL sequence that enables imaging the length of the LC at 0,4mm3. Structural scans were bias‐field corrected and we generated a common template using an iterative diffeomorphic warp estimate with Advanced Normalization Tools (ANTs http://stnava.github.io/ANTs/) and LC templates were constructed by manual tracing the average projection map (RWEvH, Figure 1A). The segmented LC was then projected to each high‐resolution MT‐TFL to extract the voxel‐intensity along the rostro‐caudal length. Linear mixed effects models examined age differences in LC intensity along this axis (age by z‐coordinate) as well as the modulation of sex (age by sex by z‐coordinate), implementing a random slope for position and random intercept for each subject.

Result

We found an age‐related quadratic gradient of the voxel intensity, in which lower voxels intensities were observed in the central section, not rostral or caudal section, in older individuals (Figure 1B; df1480, t=2.91,p= 0.0036). This gradient is sex dependent and shows that this effect is driven by lower intensities in older males compared to females in the central LC (df 1476, t=2.20, p=0.0274, Figure 1C).

Conclusion

We demonstrated a male vulnerability for lower medial LC structural properties. The medial LC is one of the regions initially affected by tau. Other studies reported a female vulnerability to tau. Further analyses including hormonal and biomarker data will help to elucidate the biological underpinnings of the sex‐differences in Alzheimer’s disease processes.
Association of ventricular size on executive function and attention is modified by Apolipoprotein E and moderated by pulse pressure in Alzheimer's disease
Authors: Sapkota Shraddha , McFall G. Peggy , Dixon Roger A. , Masellis Mario , Black Sandra E.
Published: December 2020

Background

Genetic, structural imaging, and vascular risk factors are key determinants of cognitive differences in Alzheimer’s disease (AD). We investigated synergistic associations between three risk factors from each domain on cognition in AD. We focused on (1) whether structural imaging predicts cognitive performance, (2) and is differentially represented by genetic risk and (3) further moderated by vascular risk. Specifically, whether ventricular enlargement predicts EF and attention and whether this is differentially represented by Apolipoprotein E(APOE) and further moderated by pulse pressure (PP).

Methods

We used AD patients (n=321; mean age=71.6(9.6) years; %female=53) from the Sunnybrook Dementia Study (SDS). First, we performed a confirmatory factor analysis to build EF and attention latent factors using five standardized cognitive tests (EF:Wisconsin card sorting test, digit symbol substitution, phonemic fluency, attention:forward and backward digit span). Second, we tested whether ventricular size predicts EF and attention performance at baseline. Third, we tested an APOE effect modification where a different relationship is observed for ventricular size on EF and attention in context of APOE stratification. Fourth, we tested whether PP moderates any effect modification by APOE risk on ventricular size and EF and attention. PP was calculated using systolic minus diastolic blood pressure and divided into low and high groups using the mean PP.

Results

The best fitting model was observed with a two factor EF and attention model (χ2(df)= 4.059(4),p=0.3981; RMSEA (90% CI)=0.007(0.000‐0.085); CFI=1.000; SRMR= 0.023). Increase in ventricular size predicted lower EF (β=‐10.743, SE=4.538, p=0.018) and attention (β=‐13.342, SE=4.762, p=0.005) performance only in the APOE ɛ4+ risk group. This APOE effect modification was further moderated by PP where only APOE ɛ4+ risk carriers with low PP had poorer EF (β=‐16.553, SE=6.002, p=0.006) and attention (β=‐17.054, SE=6.225, p=0.006) performance with higher ventricular size.

Conclusions

EF and attention risk associated with ventricular enlargement was only present in AD patients carrying the APOE ɛ4 allelic risk and further magnified in adults with low PP. Genetic risk stratification in combination with structural imaging and modifiable vascular risk factors may identify AD patients at magnified risk for accelerated decline with potential opportunities for novelinterventions and precision medicine.
The Spanish and english NIH Toolbox in autosomal dominant Alzheimer’s disease: A preliminary report
Authors: Montoya Lucy , Mora Livier , Barrera Lillibeth , Ringman John M.
Published: December 2020

Background

Autosomal dominant Alzheimer’s disease (ADAD), in which the future development of AD can be reliably predicted, allows one to sensitively exam cognitive changes occurring in the earliest stages of the disease. The NIH Toolbox (NIHTB) is a standardized battery that comprehensively assesses multiple aspects of neurological function. In the current study we applied the English and Spanish versions of the cognitive and motor tests from the NIHTB to persons with and at‐risk for ADAD to assess its sensitivity to detecting changes occurring in this form of the disease.

Method

We performed the cognitive, motor, and olfactory tests in the NIHTB in 22 persons with or at‐risk for inheriting ADAD mutations. T‐tests were performed comparing raw scores for non‐carriers to asymptomatic carriers (CDR = 0), mildly affected carriers (CDR = 0.5), and mildly demented carriers (CDR = 1). P values less than 0.05 were considered significant.

Result

Half of the participants were evaluated in Spanish. Three persons were asymptomatic carriers, 4 carriers had CDR scores of 0.5, 6 carriers had CDR scores of 1, and 9 were non‐carriers. No differences favoring non‐carriers over asymptomatic carriers were found. Mildly affected carriers (CDR = 0.5) performed worse on the picture sequence memory tests (p values < 0.02) and the olfactory identification test (5.8 vs. 7.4, p = 0.02). Carriers with CDR scores of 1.0 performed more poorly on the list sorting test (7 vs. 16.9, p = 0.02), the picture sequence memory test (p’s < 0.007), the dimensional change card test (14.2 vs. 29.6, p = 0.01), the fluid cognition composite score (82 vs. 108, p = 0.02), the odor identification test (6 vs. 7.4, p < 0.05) and walked more slowly on the 4 meter gait test (5.0 vs. 4.2, p = 0.033).

Conclusion

Though we were limited by our small sample size, the NIHTB preliminarily demonstrated utility in detecting deficits in memory and executive function (fluid cognition) and in motor and olfactory abilities in early ADAD. Further studies will better define its utility in detecting early cognitive deficits in AD in both its English and Spanish forms.
Synergistic underpinning of global amyloid and cingulate neuroinflammation underlies tau propagation in Alzheimer’s disease
Authors: Kang Min Su , Ottoy Julie , Savard Mélissa , Mathotaarachchi Sulantha , Pascoal Tharick A. , Chamoun Mira , Stevenson Jenna , Rahmouni Nesrine , Massarweh Gassan , Soucy Jean‐Paul , Gauthier Serge , Rosa‐Neto Pedro
Published: December 2020

Background

Understanding the underling pathophysiology of tau burden and its propagation through Braak stages is imperative in Alzheimer’s disease (AD) and its clinical trial strategy. This multimodal PET study aimed to reveal the Aβ ([18F]AZD4694) and activated microglia ([11C]PBR28) converges to potentiate the NFTs ([18F]MK6240) deposition in AD in Braak stages. We hypothesized that the NFTs deposition driven by Aβ and neuroinflammation leads to cognitive.

Method

A total of 108 participants (70 CN, 25 MCI, and 13 AD) with a high‐affinity binder for TSPO underwent 3 PET scans, MMSE and CDR‐SB. Static [18F]AZD4694, [18F]MK6240, and [11C]PBR28 SUVR images were generated. All PET images were normalized to the ADNI template, used cerebellar grey as a reference region. A total of 35 anatomical based regions including Braak stage 1 – 6 and its combination, 23 anatomical regions, and local‐to‐local interactive region were used to evaluate the important regional effect of amyloid and neuroinflammation on tau. All analyses were corrected for age, sex, education, APOE, and multiple correction using FDR.

Result

We showed a significant synergistic local‐to‐local effect between Aβ and neuroinflammation on NFTs in Precuneus/PCC, basolateral temporal, and medial frontal cortices. Moreover, 3D cross‐regional regressions showed signification interactions between amyloid and neuroinflammation on tau on all Braak stages. Importantly, neuroinflammation in cingulate /precuneus demonstrated the greatest number of interactive effects on tau in the presence of amyloid. Last, global amyloid, cingulate neuroinflammation, and Braak stage 4 tau together led to worse MMSE (p = 0.03) while global amyloid and Braak stage 4 tau together led to worse CDR‐SB (p = 0.003).

Conclusion

This study demonstrated the imperative role of microglia on tau propagation in the presence of amyloid. The microglial activation in the cingulate/precuneus, epicenter of the archetypical brain network, showed the most frequent effect together with global amyloid on tau loads on all Braak stages. Last, all 3 major targets of AD clinical trials led to worse cognitive score compared to its independent effect. This study underscores the local and distal effects of neuroinflammation and amyloid on Braak staging in AD, and shows molecular underpinnings for a promising combination therapy in AD.
Cognitive profile and motor phenotype in Mexican patients with familial early onset Alzheimer disease with the p. Ala431Glu variant of the PSEN1 gene
Authors: Téllez‐Martínez José Alberto , Verson Carmen Alaez , Sosa‐Ortíz Ana Luisa
Published: December 2020

Background

Given the deleterious consequences for patients and families with autosomal dominant AD, it is necessary to identify individuals at risk in preclinical phases, with the objective of include them in clinical intervention trials

Method

We included 11 DNA samples from patients diagnosed with FAD and 9 DNA samples with of patients with EAD, which were analyzed by clinical exome sequencing in Nextera Next Seq equipment. Results are reported on a case‐by‐case basis for genomics, cognitive, neuropsychiatric, motor, and functional evaluations.

Result

We identify 9 carriers of the pathogenic variant p. Ala431Glu of the PSEN1 gene and in 4 of these patients, more than one uncertain significance variant was identified in the ANO5, TYROBP, ALS2, WASHC5, ABCA7, TOMM40, CLU, ATP7B, USH2A genes. In 5 patients we identify another pathogenic variants in PSEN1 gene. Estimated age at onset (AAO) in carriers of A431E variant was 40.6 ± 3.1 years, while in the Non A431E group was 46 ± 11.6. Patients with E431E variant had the worst performance at the beginning and in his last evaluation in all the cognitive tests. The most striking differences were in MMSE (16.3 ± 6.1 and 9.4 ± 6.2 vs 18.1 ± 2.1 and 11.9 ± 4.7) and PHFV tests (4 ± 5.2 and 1.33 ± 2.2 vs 6.1 ± 0.2 and 2.6 ± 2). The most frequent neuropsychiatric symptoms in A431E group was depression, anxiety and irritability, while in the EAD was apathy. Near to 40% of patients A431E has motor symptoms at baseline, and this percentage increased to 80% in the latest evaluation. This group had a high frequency of stiffness, tremor and spastic gait and in EAD the most consistent symptom was postural tremor. The motor‐symptom profile is presented in Figure 1.

Conclusion

A high frequency of the Jalisco variant is reported in Mexican patients with FAD. This variant is related to early onset of symptoms, rapid progression, as well as a high frequency of motor symptoms. This makes it necessary to consider their identification of this variant as a first step in the diagnostic algorithm of this type of population. The identification of patients carrying this variant requires correct genetic counseling and makes them candidates to enroll in international clinical trials of pharmacological intervention.
Detecting language impairment using ELIEC
Authors: Parsapoor Mahboobeh
Published: December 2020

Background

Machine learning (ML) can detect language impairment. However, it is challenging, if we do not have sufficient language data. To deal with this issue, we suggest using ELiEC or "Emotional Learning‐inspired Ensemble Classifier". It is a new ML algorithms that can learn from a few examples. This paper briefly describes ELiEC (structurally and functionally) and presents preliminary results obtained from employing it on the textual datasets extracted from speech produced by 14 (i.e., five patients and nine healthy control) subjects. We collected the speech samples via a web portal named Talk2Me.

Method

We have developed a language assessment tool combining natural language processing (NLP) techniques and the ELiEC (as an ML tool). NLP techniques extract the total number of word tokens and the total number of unique word types, the total number of sentences, and the total number of syllables. Using the above parameters, we calculate lexical features such as the lexical diversity score, Brunet’s Index (BI), Honore’s Statistic (HS) , Flesch‐Kincaid, and the Flesch Reading‐Ease (FRES) Test readability scores. ELiEC maps linguistic features to patients and healthy controls. In more detail, the ELiEC, which is an ensemble classifier, is developed based on LeDoux’s emotional theory. The theory describes the neural structures underlying the processing of threatening stimuli (see Figure 1) We develop ELiEC by combining classifiers (see Figure 2) according to the interconnections between regions of the brain that are responsible for processing threatening stimuli.

Result

Table 1 compares results obtained from using various ML tools such as Support Vector Machines (SVMs), k nearest neighbor, and ELiEC to distinguish patients and healthy subjects. As observed, ELiEC’s accuracy is 0.87 (+/‐ 0.33). Thus, compared to other ML tools, it can associate language impairment to people with dementia with the highest accuracy and when there is not a sufficient amount of language data from patients.

Conclusion

Our results verified that by utilizing ELiEC, we could develop an accurate MLbased language assessment tool when there is a limitation in recruiting patients. We will improve the ELiEC framework and use it to distinguish people with different types of dementia.
Combining evidence across multiple endpoints with a global statistical test: Comparison of z‐scores versus ranks
Authors: Dickson Samuel P. , Knowlton Newman , Hendrix Suzanne B.
Published: December 2020

Background

Alzheimer’s disease (AD) is a multi‐symptom disease which has cognitive, behavioral, functional and global outcomes. These outcomes are all important measures of disease severity and are driven by the underlying disease process. These symptoms provide multiple, potentially conflicting, answers to the question, “Did the treatment work?”

Method

Outcomes can be combined through standardization of outcomes using ranks or z‐scores. Additionally, the standardization can be performed before calculating change from baseline or after. These four combinations are explored by simulations with no effect, corroborative effects across outcomes, and disparate effects across outcomes (a mix of positive and null effects) to demonstrate the type I error (no effect) and power under various secenarios along with other performance metrics.

Result

All four methods of calculating a GST adequately control type I error. In the absence of ceiling and floor effects, the GST that calculates change from baseline first then combines evidence using z‐scores has the highest power. In the presence of disparate effects, the GST can still be more powerful than any single outcome, though the effect is appropriately attenuated. The GSTs that use ranking outperform z‐score methods in the presence of strong floor or ceiling effects.

Conclusion

A clinical trial with a GST analyzed first can show success as a proof of concept even if the individual outcomes fail to achieve significance, signalling that a development can proceed to later phases. Change from baseline should be calculated first. If there are no ceiling or floor effects, standardization should be performed using z‐scores, otherwise percentiles should be used. GSTs offer a good way to combine outcomes to demonstrate efficacy using fewer subjects.
A comparison of the Montreal Cognitive Assessment and standard cognitive measures in the National Alzheimer’s Coordinating Center and Knight Alzheimer’s Disease Research Center cohorts
Authors: LaRose Megan , Aschenbrenner Andrew J. , Benzinger Tammie L.S. , Gordon Brian A. , Cruchaga Carlos , Morris John C. , Hassenstab Jason
Published: December 2020

Background

The Montreal Cognitive Assessment (MoCA) could be described as a “sampling” of more comprehensive cognitive measures. We investigated the utility of the MoCA in predicting disease progression in the National Alzheimer’s Coordinating Center (NACC) sample in comparison to standard comprehensive cognitive measures collected in the NACC Uniform Dataset 3 (UDS 3). In addition, using the imaging biomarker‐rich cohorts at the Knight Alzheimer Disease Research Center (ADRC), we compared the sensitivity of the MoCA and UDS 3 measures to APOE 4 status, amyloid PET, tau PET, and structural MRI.

Method

Analysis One: In cognitively normal older adults from the NACC cohort (n=6,273, 2.3 +/‐ 0.9 years follow‐up), survival and receiver operating characteristic (ROC) analyses compared the MoCA and UDS 3 measures on their ability to classify disease progression, defined as change in Clinical Dementia Rating (CDR) status from 0 to >0. Analysis Two: In Knight ADRC participants (n = 445), regression models compared the sensitivity of the MoCA and standard cognitive measures to AD biomarkers in all participants and separately in CDR 0s.

Result

Disease progression analyses in the NACC sample resulted in an area under the curve (AUC) estimate for the MoCA of 0.69 for the total score and 0.55‐0.73 for domain scores. For the UDS 3 measures, AUCs ranged from 0.57‐0.73. A cognitive composite similar to a “PACC” yielded an AUC of 0.71. Sensitivity to AD biomarkers including amyloid PET, tau PET, cortical thickness, and APOE 4 status was similar for both the MoCA and UDS 3 measures (all p’s < 0.001). Analyses of CDR 0 participants produced small but significant relationships only with tau PET and cortical thickness (p’s 0.01 – 0.02) for both MoCA and UDS 3 tests.

Conclusion

Neither the MoCA nor UDS 3 cognitive measures demonstrated adequate classification of disease progression. Correlations with biomarkers suggests that the MoCA is capable of tracking pathological indicators of AD in individuals with symptomatic disease. However, in cognitively normal participants, both the MoCA and UDS 3 measures were weakly correlated with indicators of neurodegeneration. More sensitive measures or improved assessment methodology is required to reliably detect AD pathology prior to clinical diagnosis.
SINGER (Singapore)
Authors: Chen Christopher
Published: December 2020

Background

The SINGapore GERiatric intervention study to reduce physical frailty and cognitive decline (SINGER) is a pilot study, aiming to evaluate culturally appropriate adaptations of the FINGER interventions, and the feasibility of implementing this protocol in 70 seniors, aged >65 years, with mild‐to‐moderate frailty and/or cognitive impairment over a 6‐month period (Table). The main outcome of this pilot study is the feasibility of and adherence to the multidomain intervention as concerns have been raised particularly for the dietary and cognitive interventions which could require novel and culturally appropriate approaches. We aim to develop scalable digital platforms and build partnerships so as to conduct a larger definitive study in 1200 elderly community dwelling Singaporeans who are at risk for cognitive impairment and dementia. This larger study comparing self‐guided lifestyle management versus a structured multidomain lifestyle intervention will also incorporate neuroimaging and blood biomarkers so as to investigate mechanisms of action.
The association between herpes simplex virus type 1 infection and Alzheimer’s disease
Authors: Wu Donghong , Wang Chuqiao , Pang Peilin , Kong Han , Hao Zixiao , Guo Xuguang
Published: December 2020

Background

There are growing evidences demonstrating the relationship between herpes simplex virus type 1 (HSV‐1) infection and Alzheimer’s disease (AD).

Method

We searched Pubmed, Embase and Cochrane databases for relevant articles. Newcastle‐Ottawa Scale (NOS) was used to evaluate the qualities of these studies. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated using random‐effects models. We also performed subgroup analyses stratified by apolipoprotein ε4 (APOE ε4), NOS score and the method of confirming AD.

Result

A total of 21 studies between 1990 and 2020 were identified. The pooled OR suggested that HSV‐1 infection is a risk factor of AD: pooled OR 1.40 (95% CI: 1.13‐1.75; I2 = 3%, P = 0.42). In the subgroup analyses, the pooled ORs of HSV‐1 infection associated with AD were 0.75 (95% CI: 0.24‐2.37) among the APOE ε4 positive individuals; 0.85 (95% CI: 0.61‐1.17) among the APOE ε4 negative individuals; 1.51 (95% CI: 1.10‐2.06) in the high NOS score studies; 1.23 (95% CI: 0.85‐1.76) in the moderate NOS score studies; 1.47 (95% CI: 1.16‐1.87) in the clinical diagnosis group, 1.20 (95% CI: 0.77‐1.87) in the autopsy group, respectively.

Conclusion

Our systematic review and meta‐analysis suggest that HSV‐1 infection is a risk factor of Alzheimer’s Disease.
Quality comparison of remote vs. in‐person digital speech assessment for dementia
Authors: Robin Jessica , Novikova Jekaterina , Sirotkin Sasha , Yancheva Maria , Kaufman Liam D , Simpson William
Published: December 2020

Background

The COVID‐19 pandemic has brought the need for reliable, remote assessments for clinical trials into sharp focus. Remote, home‐based assessment reduces patient and caregiver burden, enabling more frequent monitoring. There are concerns, however, regarding the quality of in‐clinic vs. remote assessments. In the present study, we compared the quality of verbal responses to a tablet‐based speech assessment in patients with dementia across two settings: in‐person at a clinical research site, and remotely, at home.

Method

The in‐person sample consisted of individuals with Alzheimer’s disease, participating in a clinical trial. The remote sample consisted of individuals with variants of Frontotemporal dementia, participating in a longitudinal observational study. In‐person assessments were conducted at a clinical research site and administered by a trained rater. Remote assessments were conducted in the participant’s home, by a caregiver who had received assessment training and a tablet by mail. 575 in‐person speech samples and 574 remote speech samples were compared. All samples were manually transcribed and tagged for recording anomalies or task compliance issues by trained transcriptionists.

Result

Overall incidence of recording anomalies was low and did not differ significantly (p = 0.63) between in‐person (10.1%; 58/574) and remote (11.1%, 64/575) recordings. Less than 1% of samples in either study were marked as “incomplete task”, “low audio quality” or “noisy background”. Incidences of clinician/caregiver interference were more frequent for remote recordings (1.2% in‐person, 4.5% remote, p = 0.001) and incidences of quiet participants were more frequent for in‐person recordings (4.5% in‐person, 1.0% remote, p < 0.001), though both were relatively rare overall. The mean duration of in‐person samples was significantly longer than remote samples, but mean speech rate did not differ.

Conclusion

This study suggests that remote speech assessments yield recordings of comparable quality to in‐person assessments. We found higher, though still low, rates of caregiver interference for remote assessment, which should be monitored and mitigated in future remote assessment. Remote assessments yielded shorter recordings, but this may be due to the different dementia diagnoses across groups. Future work should compare the same participants across both assessment settings.