bluuebunny/crossref_metadata_2025 huggingface dataset:
Using imputation to harmonize longitudinal measures of cognition across two large cohorts: AIBL and ADNI
Authors: Shishegar Rosita , Cox Timothy , Rolls David , Dore Vincent , Lamb Fiona , Robertson Joanne S , Laws Simon M , Porter Tenielle , Maruff Paul T , Savage Greg , Rowe Christopher C , Masters Colin L , Weiner Michael W. , Villemagne Victor LL , Burnham Samantha C ,   the Alzheimer’s Disease Neuroimaging Initiative,   the AIBL research Group
Published: December 2020

Background

To ensure the generalisability of findings and consider more nuanced hypotheses, larger sample sizes are required. Combining data from different but similar study cohorts is one solution. However, the disparity of these datasets, e.g. using differing tests to assess specific cognitive domains, makes this a non‐trivial task. Here, we propose a harmonisation solution using imputation strategies1,2 for cognitive memory performance in AIBL3 and ADNI4.

Method

AIBL participants (N=1813 [1180 NC, 297 MCI and 328 AD; aged 72.52±7.72; 777 males]) and ADNI participants (N=1945 [756 NC, 820 MCI, 369 AD; aged 73.92±7.23; 1028 males]) were included in this study. Scores for tests administered in one cohort but not the other were imputed in the cohort for which they were missing (with the RAVLT5 being used in ADNI and the CVLT‐II6 in AIBL). Non‐parametric multivariate imputation using random forests (missForest)7 was employed to impute the ‘missing’ data and test scores across both cohorts from the full neuropsychological testing batteries, and age, gender, years of education and APOE‐ɛ48 status were used to inform the models. The discriminatory power of the actual and imputed scores to differentiate between NC, MCI & AD was assessed. To further validate the method, data for Logical Memory II (LMII; administered in both cohorts) was simulated as missing in each cohort, respectively, and the correlation between the actual and imputed LMII test scores was assessed.

Result

Similarly, high levels of significant discrimination (p<.001) between clinical classifications were observed for the actual and the imputed scores of the CVLT‐II and RAVLT (Figure 1). Comparing the imputed LMII test scores which were simulated as missing to the actual LMII scores resulted in correlation coefficients of ≥90%.

Conclusion

The need to combine large datasets will increase as we aim to improve the generalisability of findings and test more complex hypotheses. The results here suggest it is possible to use data imputation, capitalising on underlying structures and relationships, to impute specific tests scores in a cohort for which that test what not administered. In turn, providing a practical solution for data harmonization across large, cross‐sectional and longitudinal datasets. References: 1doi:10.1038/srep21689.2doi:10.1002/sim.5894.3doi:10.1017/S1041610209009405.4doi:10.1212/WNL.0b013e3181cb3e25. 5doi:10.1002/1097‐4679(199311)49:6<883::AID‐JCLP2270490616>3.0.CO;2‐66doi:10.1076/clin.14.4.526.7204. 7doi:10.1093/bioinformatics/btr597.8doi:10.1212/wnl.43.8.1467.
Evolution of the core clinical features of dementia with Lewy bodies
Authors: Choudhury Parichita , Radford Jonathan Graff , Wurtz Lincoln , Aakre Jeremiah A. , Brushaber Danielle , Jones David T. , Knopman David S. , Kantarci Kejal , Savica Rodolfo , Graff‐Radford Neill R. , Drubach Daniel A. , Fields Julie A. , Machulda Mary M. , Pedraza Otto , Forsberg Leah K. , Allen Laura A. , Miyagawa Toji , St. Louis Erik K. , Silber Michael H. , Kremers Walter K. , Petersen Ronald C. , Boeve Bradley F. , Ferman Tanis J.
Published: December 2020

Background

Dementia with Lewy Bodies (DLB) is the second most common cause of degenerative dementia but the evolution of the core clinical features of DLB has not been clearly defined. The objective of this study was to identify the temporal relationship between each core feature from the estimated onset of cognitive symptoms.

Method

Participants include 485 patients with probable DLB who were evaluated at the Mayo Clinic Alzheimer Disease Research Center with neurologic and neurocognitive assessment. Each core clinical feature was compared using Kaplan‐Meier (KM) curves with the sentinel event representing age at which each core feature developed, or time from estimated cognitive onset.

Result

The sample was disproportionately male (76%). Patients were followed longitudinally, with 84% followed until death. Mean MMSE at the last evaluation was 18.3 ± 7.8. KM curves for age of onset and cumulative incidence for DLB core features as time from cognitive onset are provided. REM‐sleep behavior disorder (RBD) developed earliest and in 77% of our sample with a median KM survival estimate of 69 years (95% CI: 67.6–70.8). RBD was present in greater than 50% of patients at cognitive symptom onset. The median KM survival estimate for cognitive symptom onset was 70.2 years (95% CI: 69.3‐71.0). Parkinsonism developed in 89% with a median KM survival estimate of 73.7 years (95% CI: 72.7‐74.7). 76% had fluctuations with a similar median KM survival estimate of 74.6 years (95% CI: 73.7‐75.8). Visual hallucinations (VH) were present in 70% emerging at a median KM survival estimate of 80.2 years (95% CI: 79.5‐ 81.3). Cumulative incidence estimates for median time from cognitive onset to parkinsonism, fluctuations and VH were 2 years (95% CI: 2.0‐2.5), 2.3 years (95% CI: 2.0‐3.2) and 4.3 years (95% CI: 4.0‐4.8 years), respectively.

Conclusion

In this DLB cohort, RBD was most likely to precede cognitive onset. The evolution of the other core features after cognitive onset was parkinsonism and fluctuations and then VH. While VH occur about 4 years after cognitive symptom onset, parkinsonism and fluctuations occur within the first 2 years.
Reduced density of noradrenergic fibers without prominent neuron loss or tau pathology in the locus coeruleus in APP knock‐in mouse models of Aβ amyloidosis
Authors: Iijima Koichi M. , Sakakibara Yasufumi , Ibaraki Kyoko , Takei Kimi , Saito Takashi , Saido Takaomi C. , Sekiya Michiko
Published: December 2020

Background

Locus coeruleus (LC) is a nucleus containing the cell bodies of noradrenergic neurons in the brain, and is one of the earliest regions affected by Alzheimer’s disease (AD). Norepinephrine (NE) is critical for cognitive functions as well as anti‐inflammatory and neuroprotective properties, both of which are implicated in AD. LC neurons are among the first to display tau pathology and that significant loss of forebrain noradrenergic projections is evident at prodromal stage of AD, suggesting that abnormality in LC‐NE system initiates the disease pathogenesis. However, mechanisms underlying neurodegeneration in LC‐NE system remain elusive. We have previously reported that AppNL‐G‐F/NL‐G‐F
mice, which harbor three familial AD mutations (Swedish, Beyreuther/Iberian, and Arctic) exhibited cognitive deficits and severe neuroinflammation accompanied by massive amyloid‐β (Aβ) pathology. In this study, we asked whether and how LC‐NE system is altered in AppNL‐G‐F/NL‐G‐F
mice.

Method

To ask whether AppNL‐G‐F/NL‐G‐F
mice exhibit noradrenergic degeneration, we compared the density of norepinephrine transporter (NET)‐positive fibers in the cortex and hippocampus as well as the number of dopamine β‐hydroxylase (DBH)‐positive neurons in the LC between AppNL‐G‐F/NL‐G‐F
and wild‐type (WT) C57BL/6J mice at 24 months of age. We also examined whether tau pathology occurs in the LC‐NE system in these mice.

Result

Histochemical analyses revealed that 24‐month‐old AppNL‐G‐F/NL‐G‐F
mice exhibited significant decreases in the density of NET‐positive fibers in the prefrontal and entorhinal cortices and the hippocampal CA1, the regions associated with learning and memory, compared to WT mice. In contrast, AppNL‐G‐F/NL‐G‐F
mice did not display loss of DBH‐positive neurons in the LC even at 24 months of age. Furthermore, AppNL‐G‐F/NL‐G‐F
mice did not develop prominent tau pathology either in the nerve terminals or in the cell bodies of LC neurons.

Conclusion

This study demonstrates that Aβ pathology is sufficient to reduce the density of noradrenergic fibers independent of neuron loss and tau pathology in the LC. These results also suggest that age‐dependent accumulation of Aβ in the cortex or tau in the LC may additively and independently damage LC neurons from the nerve terminals or from the cell bodies, respectively.
Prioritizing potential diagnostic biomarkers of Alzheimer’s disease by investigating gene expression data: A network‐based approach
Authors: Chand Yamini , Sao Prachi , Singh Shivani , Chandra Niharika , Das Surojeet , Singh Sachidanand
Published: December 2020

Background

Alzheimer’s Disease (AD) is a progressive neurodegenerative disorder. The identification of differentially expressed genes (DEGs) across affected brain regions can provide new insights into the mechanisms of AD.

Method

Our study aims to identify potential biomarkers of AD across brain regions using gene expression and network‐based approaches. The gene expression data were downloaded from Gene Expression Omnibus (GEO) for the series GSE5281. The series comprises expression data from 6 brain regions Entorhinal Cortex (EC), Hippocampus (HIP), Middle temporal gyrus (MTG), Posterior cingulate cortex (PC), Superior frontal gyrus (SFG) and visual cortex (VCX). Differentially expressed genes (DEGs) were identified using GeneSpring GX 12.6.1 software. A protein‐protein interaction network (PPIN) was constructed from high throughput experiments using Biosogenet. A subnetwork comprising common DEGs and their first neighbors was extracted from the complex PPIN, and the network centralities, including degree and betweenness, were calculated using NetworkAnalyzer plugin in Cytoscape 3.7.1.

Result

Our results identified 4748 non‐redundant DEGs, of which 1493 and 3255 constitute the up and down‐regulated genes, respectively. A total of 124 common DEGs were identified across more than four brain regions. The subnetwork comprised 5723 and 140625 nodes and edges, respectively. Topological analysis of the subnetwork identified 474/148 Hub/Bottleneck genes and 146 Hub‐Bottleneck genes. Two HB genes EGFR and FYN and two H genes NOTCH2NL and SRRM2 were identified as up‐regulated across four brain regions. Six HB genes CUL3, COPS5, HSP90AB1, YWHAZ, YWHAB, and CDC42, and two H genes SNCA, TUBA4A were identified down‐regulated across five brain regions. Furthermore, four HB genes UBC, CUL1, C1QBP, and UBQLN1 and 10 H genes TUBB, GAPDH, SSX2IP, AP2M1, PSMA1, SKP1, TERF2IP, ATP5A1, CCT7, and NDUFA4 are found to be down‐regulated across four brain‐region. Of these, SNCA, GAPDH, UBQLN1 were known to be associated with AD.

Conclusion

The identification of AD biomarkers across different brain regions integrating differential gene expression study and network‐based approach may provide new insights into the mechanisms of AD.
The association between aldehyde dehydrogenase gene (ALDH2) polymorphism and cognitive impairment among Chinese oldest old
Authors: Jin Xurui , Long Tingxi , Chen Huashuai , Zeng Yi , Yan Lijing
Published: December 2020

Background

Aldehyde dehydrogenase 2 (ALDH2) is one of the aldehyde dehydrogenase isoforms responding for 3,4‐dihydroxyphenylglycolaldehyde metabolism and a common mutation in ALDH2 (rs671 AG or AA) causes the activity of ALDH2 to be reduced which was associated with Asian flush and series of cancers. Recent study suggested that carrying rs671 A allele and high intaking of alcohol will jointly increase the risk of Alzheimer disease in mice. Accordingly, we investigated the association between the ALDH2 RS671 genotype and cognitive impairment among Chinese oldest old.

Method

We used a genetic sub‐study of the Chinese Longitudinal Healthy Longevity Survey including 1949 participant aged over 90 years old. Mini‐Mental State Examination (MMSE) score was used to ascertain cognitive impairment at baseline, defined as MMSE score less than 18 out of 30. RS671 genotype was further categorized as non‐carrier (GG) and carriers (AG or AA). Multivariable logistics regression models were applied to examine the association between RS671 genotype and cognitive impairment.

Result

Among the participants, 76.2% were women and 36.0% were RS671 carriers, with a mean age of 100.7 (SD 3.29) years. The mean MMSE score was 16.4 (SD: 10.6) and 49.3% of the participants had cognitive impairment. Carrying RS671 mutation was associated with 26.1% higher odds (95% CI: 0.7%‐58.0%) of cognitive impairment. Significant interaction between RS671 genotype and fruit consumption (P=0.045) was observed. Carrying RS671 mutation was significantly associated with higher odds of cognitive impairment among those with low fruits consumption (OR=1.58, 95% CI 1.01‐2.51), but the significance was not significant in the group with high fruits consumption.

Conclusion

In the Chinese oldest old, carrying ALDH2 RS671 mutation was associated with higher odds of cognitive impairment, and the association between RS671 genotype and cognitive impairment is more pronounced in those with low fruit consumption. No interaction between alcohol consumption and RS671 genotype was observed.
Alterations in the bone microarchitecture in Psen1 L166P KI mice depicting pathogenesis of Alzheimer’s disease
Authors: Suryadevara Vidyani , Krehbiel Connor J , Monte Willis S
Published: December 2020

Background

An accelerated bone loss (osteoporosis) has also been reported in the early stages of Alzheimer’s disease, as seen by the reduction in bone mineral density in these patients, compared to healthy individuals. In the present study, we investigated knock‐in mice with a Psen1 mutation(L166P) and a human APP Tg+(Psen1 L166P KI). These mice develop brain amyloid pathology by six months of age, evidenced by amyloid deposition in the cerebral cortex; the role of PSEN1 L166P on bone has not previously been reported.

Method

Psen1 L166P KI and strain‐matched wildtype control mice were analyzed by Dual Energy X‐ray Absorptiometry(DEXA) to determine whole‐body mineral density and bone mineral content in vivo over time. The left femur and L5 vertebra were isolated and analyzed by micro‐CT(SkyScan 1172) to quantify cortical and trabecular microarchitecture.

Result

DEXA analysis of Psen1 L166P KI mice identified a reduction in whole‐body mineral density and bone mineral content in females(p<0.05), but not male, mice compared to age‐ and gender‐matched wildtype control mice at 12 months of age. Cortical bone loss identified by micro‐CT analysis of the femur included a significant reduction in total cross‐sectional area, cortical area, cortical thickness, periosteal thickness, and minimum moment of inertia(p<0.05). Trabecular bone loss identified in female PSen1 KI femurs was evidenced by a reduction in trabecular thickness(p<0.05). In contrast, male PSEN1KI femurs had significantly reduced bone volume fraction, tissue mineral density, and trabecular number compared to male wildtype mice.

Conclusion

Female Psen1 L166P KI mice exhibit a loss in the trabecular and cortical structure in a sex‐dependent manner. These findings indicate that a Psen1 L166P mutation may alter bone morphology via direct crosstalk with the brain (possibly through Aβ deposition) or by endogenous PSEN1 in bone cells. Furthermore, recent studies have reported that Psen1 deletion results in skeletal abnormalities, consistent with PSEN1’s role in bone cells. These studies suggest a concurrence of amyloid pathology and changes in bone metabolism that may parallel the accelerated bone loss reported in human AD. They also indicate that the bone pathology in AD may be a biomarker to consider in the early detection and progression of AD patients.
APOE ε4 genotype, lifestyle profiles, and cognitive function among Chinese oldest old
Authors: Jin Xurui , He Wanying , Gong Enying , Yin Ruoyu , Ji John Sihan , Li Yaxi , Chen Huashuai , Zeng Yi , Yan Lijing
Published: December 2020

Background

APOE ε4 is the single most important genetic risk factor for cognitive impairment and Alzheimer disease. While its interaction with lifestyle profile on cognition has been controversial and a recent study indicated that healthy lifestyle profiles only showed its benefits among APOE ε4 non‐carriers among those elderly aged over 65 years old. Accordingly, we examined the association between the APOE genotype and cognitive impairment and its interaction with lifestyle profiles among Chinese oldest old (aged over 80 years old).

Method

APOE ε4 is the single most important genetic risk factor for cognitive impairment and Alzheimer disease. While its interaction with lifestyle profile on cognition has been controversial and a recent study indicated that healthy lifestyle profiles only showed its benefits among APOE ε4 non‐carriers among those elderly aged over 65 years old. Accordingly, we examined the association between the APOE genotype and cognitive impairment and its interaction with lifestyle profiles among Chinese oldest old (aged over 80 years old).

Result

Among the 6,160 participants, 57.6% were women and 17.5% were APOE ε4 carriers, with a mean age of 90.1 (SD 7.2) years. The mean MMSE score was 23.3 (SD: 0.4) and 18.2% of the participants had cognitive impairment at baseline. Carrying APOE e4 allele was associated with 22% higher odds (95% CI: 1.02‐1.46) of cognitive impairment. Compared with those with unhealthy lifestyle score, participants with healthy lifestyle score were associated with a 38% (95% CI: 23% ‐ 50%) lower odds of cognitive impairment. No significant interaction between APOE genotype and lifestyle profiles was observed. The association between lifestyle profiles and cognitive function did not vary by APOE genotype.

Conclusion

APOE genotype and lifestyle profiles were associated with cognitive function among Chinese oldest old, respectively and healthier lifestyle is associated with lower odds of cognitive impairment regardless of APOE genotype.
Anticholinergic burden among participants in Alzheimer’s clinical trials
Authors: Kennedy Richard E. , Fowler Mackenzie E. , Cutter Gary R. , Schneider Lon
Published: December 2020

Background

Medications with anticholinergic properties are known to adversely affect cognition with acute administration, and have been associated with increased dementia incidence. Such drugs are taken by a substantial number of older adults despite guidelines recommending that their use be avoided in this population. The extent to which participants in AD clinical trials use medications with anticholinergic properties, and their effect on trial outcomes, is currently unknown.

Methods

We used a metadatabase of 18 ADCS studies and ADNI to examine total anticholinergic burden. We included 15 studies for a total of 4,002 subjects with AD. We calculated the total anticholinergic burden for each participant using the Anticholinergic Burden Scale.4 For the 10 studies with longitudinal data on the ADAS‐cog, we estimated the annual rate of decline using linear mixed effects models with adjustment for age and education, and compared rates of decline using random effects meta‐analysis.

Results

Across the 15 studies, the mean total ACB score was 1.63 (SD 2.13). Approximately 25% of participants had a clinically relevant anticholinergic burden, defined as a total ACB score 3. Meta‐analysis showed the rate of decline for participants with total ACB 3 was 1.2 points/year greater than the rate for participants with total ACB < 3 (Figure).

Conclusions

Use of medications with anticholinergic properties is common among participants in AD clinical trials. High levels of anticholinergic burden are associated with greater rates of cognitive decline, and may offset benefits of cholinesterase inhibitors or experimental interventions. Reducing unnecessary use of medications with anticholinergic properties among AD trial participants is needed, and trials should consider stratifying by anticholinergic burden to reduce potential confounding in analyses.
LDL cholesterol may have protective properties for brain health in older age: Do we need to re‐think current guidelines?
Authors: Kuszewski Julia C , Zaw Jay Jay Thaung , Wong Rachel HX , Howe Peter RC
Published: December 2020

Background

Elevated low‐density lipoprotein (LDL) cholesterol is a major contributor to cardiovascular diseases (CVD), which are associated with accelerated cognitive decline. However, recent studies suggest LDL cholesterol to be protective against cognitive decline in the very elderly (>85 years). We investigated associations between serum LDL cholesterol, cerebrovascular function and cognition in community‐dwelling adults aged 50‐80 years, testing for differences between mid‐life (50‐64 years) and older age (65‐80 years).

Method

Our cross‐sectional analysis used baseline assessments from 236 older adults (78% female, age: 65±0.5 years, BMI: 28.2±0.3 kg/m2, LDL: 3.7±0.1 mmol/L) participating in two intervention trials investigating effects of vasoactive nutrients on cognition, cerebrovascular function and cardiometabolic biomarkers. None were taking statin medication. Assessments included a battery of 10 neuropsychological tests, transcranial Doppler ultrasound to measure cerebral blood flow velocity (BFV) and cerebrovascular resistance index (CVRi), clinic blood pressure and a fasted venous blood sample to measure serum cholesterol.

Result

LDL cholesterol correlated with Framingham CVD risk in mid‐life (R=0.360, P<0.001), but not in older adults (R=‐0.124, P=0.174). In adults aged >65 years (n=122), higher LDL cholesterol correlated with higher mean BFV (R=0.255, P=0.009), lower CVRi (R=‐0.266, P=0.006) and higher overall cognitive performance (R=0.228, P=0.011). The latter two were inversely correlated (R=‐0.154, P=0.024, age adjusted).

Conclusion

LDL cholesterol appears to have a positive association with cerebrovascular and cognitive functions in advanced age; hence, pharmacologically reducing LDL cholesterol to <2mmol/L as currently recommended might not be beneficial for this age group. Further research is warranted to establish optimal LDL cholesterol levels in the elderly.
Directed graph‐based longitudinal model for spatiotemporal dynamics of amyloid, tau, and neurodegeneration in the Alzheimer’s disease spectrum
Authors: Lee Wha Jin , Cho Hanna , Shin Jeong‐Hyeon , Lyoo Chul Hyoung , Seong Joon‐Kyung
Published: December 2020

Background

β amyloid deposition, pathological tau, and neurodegeneration are regarded as critical biomarkers to biologically define Alzheimer’s disease (AD) in living people. Development of tracers for positron emission tomography (PET) enables extracellular amyloid plaques and intraneuronal neurofibrillary tangles to be detected in vivo. Identifying in vivo spatiotemporal dynamics of those three biomarkers could be a key to understand the disease progression in Alzheimer’s continuum.

Methods

We recruited 74 healthy controls, 61 amnestic mild cognitive impairment patients, and 38 AD patients with T1‐weighted magnetic resonance image (MRI) and two PET scans ([18F]Flortaucipir for tau and [18F]Florbetaben for Aβ) with about two‐year follow‐up data. Longitudinal W‐scores were calculated from standardized uptake value ratios (SUVRs) for two PET data and cortical thicknesses for MRI data. All participants were aligned in the order of standardized baseline tau SUVRs using the frequency‐based tau spreading model. Partial correlations (PC) were then computed between every regional pair of baseline and follow‐up data for each biomarker within a time window involving a part of participants. Directed graphs were constructed based on the PCs for each biomarker by moving the time window through the temporal participant‐orders.

Results

Amyloid seemed to follow the Thal stage. With the early window most connections existed within neocortex, and the connections moved to allocortex. Tau also seemed to follow the Braak stage showing the connections advanced from entorhinal regions to neocortex as the subject window moves to late order. However, temporal domain of amyloid and tau connections within the same area were distinct each other. Especially for tau, we found that the network hubs varied temporarily and diameters of the temporal graphs seemed to increase substantially as the hub moves out of the medial temporal lobe. Neurodegeneration showed similar trends to tau with later temporal domain.

Conclusions

In this study, we suggested the in vivo temporal alterations of interregional affections for amyloid, tau, and neurodegeneration from asymptomatic to clinical AD. All biomarkers exhibited analogous trends to previous researches and the moments of appearances for each biomarker were different. To detect these peculiar spatiotemporal characteristics between biomarkers might be valuable to figure out AD progression.
Novel application of digital dementia phenotyping and risk classification for insurance and longevity risk modeling
Authors: Rao Anitha , Miller Benjamin , Kulman Tanzila , Pinho Paulo , Aggarwal Neelum T
Published: December 2020

Background

As the global prevalence of Alzheimer’s disease and related dementias (ADRD) continues to soar, risk bearing entities in both the public and private insurance and financial services sector will be faced to evaluate and estimate the cost of care, morbidity, and mortality for ADRD patients. Historically, insurance actuaries have evaluated ADRD from a homogenous risk perspective. Risk variability in dementia and multi‐morbid risk is not considered during actuarial insurance risk modeling practices across various types of insurance products including long term care insurance (LTCI), pension longevity risk, life insurance, and health insurance in the public and private sector.

Method

In a multi‐carrier insurance deployment, Neurocern Inc, a neuroinformatics and data analytics company, applied a novel method to collect neurobehavioral and morbidity risk attributes for potential ADRD patients who were applying for LTCI claims benefits. Utilizing Neurocern’s proprietary analytics, risk attributes were collected on each ADRD patient over a 10‐month time frame from carriers that represented over 1 million lives, and approximately more than $50B in claims exposure. Digital dementia phenotypes and risk classifications were developed using Neurocern’s predictive analytics.

Result

A total of 228 patients (F=154, M=74) were assessed and the following cognitive domains were included: memory, visuospatial, behavioral, executive, language, and motor. Additional data such as functional status, claims data, and prescription data was collected on a subset of patients. MMSE and SPMSQ ranged between 1‐30 and 0‐10 respectively. Education level ranged from 8th grade to postgraduate level. Neurocern’s analytics created clustered risk classifications and the cost of care varied significantly between risk classes.

Conclusion

Neurocern’s predictive analytics created a first to market proprietary digital dementia risk classification score for insurance and longevity risk modeling. This research highlights the application of a multivariate ADRD actuarial risk modeling approach in insurance and longevity markets for estimating cost of care, morbidity, and mortality.
Altered cerebral vessel amplitude and oscillation frequencies in Alzheimer’s disease compatible with impaired amyloid clearance
Authors: Grimmer Timo , Kotliar Konstantin , Ortner Marion , Conradi Anna , Hacker Patricia , Hauser Christine , Günthner Roman , Muggenthaler Claudia , Förstl Hans , Diehl‐Schmid Janine , Schmaderer Christoph
Published: December 2020

Background

Retinal vessels are similar to cerebral vessels in their structure and function. Using a non‐invasive in‐vivo technique, we demonstrated previously that retinal vessel response to flicker is more emphasized and delayed in patients with dementia due to Alzheimer’s disease (AD) compared to healthy controls (HC). Increasing evidence suggests that interstitial fluid of gray matter appears to flow outward via paravascular spaces which are located alongside cerebral vessels possibly being passively propulsed by vessels’ pulsatility. Impaired pulsatility resulting in impaired clearance of molecules such as beta‐amyloid may in parts explain amyloid deposition in the brain. Moderate low pulsatility frequencies of around 0.1 Hz have been reported as the driving force for paravascular drainage in mice just recently. We aimed to elucidate whether retinal vessels’ pulsatility in particular at low frequencies (0.05‐0.15 Hz) is changed in AD at the stage of dementia or mild cognitive impairment (MCI).

Methods

Three groups of participants were examined by Dynamic Vessel Analyzer (IMEDOS Systems): 17 patients, 72.0 (62.0 – 79.0) y.o. [median (1st quartile – 3rd quartile)], with mild‐to‐moderate dementia due to probable AD ; 23 patients, 69.0 (61.0 – 71.0) y.o. with MCI due to AD, and 18 anamnestic healthy control subjects 66.5 (61.3 – 66.5) y.o. without cognitive impairment (HC).

Results

Power spectra of the temporal arterial curves differed between the groups. Especially at moderate low frequencies around 0.1 Hz (0.05 – 0.15 Hz) ADD and most MCI arterial oscillations, characterized by the normalized area under the power spectrum, prevailed over HC oscillations. Within the heart frequency range of 0.8 – 0.9 Hz retinal arterial pulsations in MCI and AD groups were significantly more emphasized as in the HC group.

Conclusions

In ADD and MCI power spectra of retinal arterial oscillations seem to shift from very low to moderate low frequencies. Interestingly, the latter frequencies correspond to those reported for lymphatic vessels in humans and those for paravascular drainage in mice. The emphasized retinal arterial pulsation at moderate low frequencies in ADD and MCI group would be compatible with the view of compensatory upregulation of paravascular drainage in AD and strengthen the amyloid clearance hypothesis.
Emerging beta‐amyloid pathology is associated with tau, synaptic, neurodegeneration and gray matter volume differences
Authors: Molinuevo Jose Luis , Milà‐Alomà Marta , Salvadó Gemma , Gispert Juan Domingo , Grau‐Rivera Oriol , Sala‐Vila Aleix , Sánchez‐Benavides Gonzalo , Arenaza‐Urquijo Eider M , González‐de‐Echávarri José Maria , Simon Maryline , Kollmorgen Gwendlyn , Zetterberg Henrik , Blennow Kaj , Suárez‐Calvet Marc ,   ALFA Study
Published: December 2020

Background

New clinical trials, like the A3, are targeting participants with emerging amyloid pathology (between 20‐40 centiloids (CL). The aim of this study is to describe if there are detectable differences in tau, synaptic, inflammatory, neurodegeneration CSF markers and brain structure in participants with emerging amyloid pathology.

Method

CSF Aß42, Aß40, t‐tau, p‐tau, neurogranin, GFAP, IL‐6, YKL‐40, sTREM2, NfL, S100B and α‐synuclein were measured with Elecsys® CSF assays and the Roche NeuroToolKit robust prototype assays in 303 cognitively unimpaired participants of the ALFA+ cohort. Participants also underwent APOE genotyping, structural MRI, as well as [18F]flutemetamol PET. Emerging amyloid pathology was defined in two different ways for checking results consistency: (1) Participants with less than 40 CL and a positive Aß42/40 ratio to be compared with those having less than 20 CL and a negative ratio (amyloid‐negative) and those with more than 40 CL and a positive ratio (amyloid‐positive). (2) Participants having between 20‐40 CL to be compared with those having less than 20 CL (amyloid‐negative) and more than 40 (amyloid‐positive). All CSF biomarker levels were compared between the emerging amyloid and its corresponding amyloid‐negative and ‐positive groups. SPM12 was used to seek for differences in gray matter volumes (GMv) among groups, after accounting for age, sex, APOE, education.

Result

89 and 16 participants fulfilled emergent amyloid criteria 1 and 2 respectively (demographics Table 1). Compared to the amyloid‐negative group, significantly increased levels of CSF p‐tau, t‐tau, neurogranin, and NfL could already be observed in the emerging amyloid group (both definitions, Figure 1a), whereas the remaining biomarkers only demonstrated increased abnormality in the amyloid‐positive group. Subjects with emerging amyloid pathology compared with the amyloid‐negative ones had greater GMv in the angular, supramarginal, fusiform, anterior temporal and medial frontal pole (Figure 1b). The association of the GMv differences and its interactions with the different biomarkers will also be presented.

Conclusion

These results provide evidence that multiple biological pathways, such as tau, synaptic and neurodegenerative, are already altered in participants with emergent amyloid pathology, which also have greater gray matter volumes. Therefore, intervening very early in the Alzheimer’s continuum may be a priority.
Cerebrospinal fluid levels of SNAP‐25 and SYT1 in Alzheimer’s and Parkinson’s disease
Authors: Brinkmalm Ann , Larsson Victoria , Janelidze Shorena , Zetterberg Henrik , Blennow Kaj , Hansson Oskar
Published: December 2020

Background

Disease‐related synaptic pathologies are common in neurodegenerative diseases, e.g. Alzheimer’s disease (AD), and Parkinson’s disease (PD). In AD, synapse loss appears to occur earlier in the disease process than the plaques or tangles and is more strongly correlated with cognitive decline. Recently it has become possible to study synaptic loss by quantifying synaptic proteins directly in cerebrospinal fluid (CSF). Increased CSF levels of the postsynaptic protein Neurogranin (Ng) in patients with AD or mild cognitive impairment have been shown in several studies. Interestingly, increased CSF Ng levels have not been observed in PD and other neurodegenerative diseases. Significantly elevated CSF levels of the presynaptic proteins GAP‐43, SNAP‐25, and synaptotagmin‐1 (SYT1) have also been found in patients with AD and MCI compared with controls. However, these studies need to be independently replicated in larger and more diverse cohorts, including other neurodegenerative diseases.

Method

We measured the CSF levels of SNAP‐25 and SYT1 in the prospective Swedish BioFINDER study, which included 1282 subjects, of which 553 were Ab‐negative controls, 195 Ab‐positive controls, 110 Ab‐negative cases with MCI, 137 Ab‐positive cases with MCI, 152 cases with AD with dementia and 135 cases with PD.

Result

SNAP‐25 concentration in CSF was increased in AD patients with dementia compared with Ab‐negative controls and MCI patients (p<0.0001), but also compared with Ab‐positive controls. Further, the levels were also increased in Ab‐positive controls and Ab‐positive MCI patients compared with Ab‐negative controls (p<0.0001). In PD, there was a non‐significant trend to decreased levels compared to controls. SYT1 in CSF was increased in AD patients compared with Ab‐negative controls and MCI patients (p<0.0001). The levels were also increased in Ab‐positive controls (p<0.0001) and Ab‐positive cases with MCI compared with Ab‐negative controls (p <0.05). The levels were decreased in PD compared with controls (p <0.05). Group comparison of SNAP‐25 and SYT1 levels. (*p <= 0.05, ****: p <= 0.0001) are shown in figures.

Conclusion

CSF SNAP‐25 and SYT1 concentrations increase already during the preclinical stages of AD, and SNAP‐25 was further increased in AD dementia. In PD, the levels were decreased, especially for SYT1.
Differential involvement of limbic and paralimbic cortex in episodic memory processing in cognitive aging and neurodegeneration
Authors: Schaeverbeke Jolien , Gabel Silvy , Meersmans Karen , Adamczuk Katarzyna , Van Laere Koen , Dupont Patrick , Vandenberghe Rik
Published: December 2020

Background

A key component of cognitive aging is episodic memory decline. Here we examined to which degree structural integrity of (para)limbic cortex and amyloid load contribute to normal episodic memory variation in subjects between 50 and 80 years old using mediation analysis. The main hypothesis was that the effect of age on episodic memory would be mediated through hippocampal volume.

Method

180 community‐recruited cognitively intact older adults belonging to the Flemish Prevent Alzheimer's Disease Cohort KU Leuven (F‐PACK) cohort had cognitive test scores within norms as inclusion criterion, genotyping (APOE ε4 and BDNF), MRI and [18F]flutemetamol‐PET. Factor analysis was applied to determine the latent structure in the neuropsychological dataset. The primary factor (variance explained: 23%, Eigenvalue: 2.26) mainly contained episodic memory test scores: Buschke selective reminding (loadings: learning: 0.83, delayed‐recall: 0.96) and Rey Auditory Verbal Learning Test (0.60). Structural T1‐weigthed MRI were processed using voxel‐based morphometry. Hippocampal, entorhinal, perirhinal and parahippocampal volumes were derived by intersecting the modulated gray matter with Brainnetome parcellations. Amyloid load was quantified in a composite neocortical volume on [18F]flutemetamol SUVR with cerebellar grey matter reference. Linear regressions or Mann‐Whitney U tests investigated associations with episodic memory, which were further analyzed with bootstrapped mediation (R‐package ‘lavaan’).

Result

Higher age was negatively related to lower episodic memory scores (β=‐0.066, p<0.001), to lower hippocampal volume (β=‐0.005, p<0.001) and to lower entorhinal cortex volume (β=‐0.003, p<0.001). Lower hippocampal volume (β=3.80, p=0.0004) as well as entorhinal cortex volume (β=3.67, p<0.001) were related to lower episodic memory. There was no significant correlation of amyloid nor a genetic effect regarding age or episodic memory (p>0.12). Hence, we did not include amyloid or genotypes in further analyses. In the mediation analysis, hippocampal volume did not mediate the relation between age and episodic memory (Figure 1A). By contrast, entorhinal cortex volume did mediate the relation between age and episodic memory, however the direct path coefficient was also significant (Figure 1B). No significant indirect effects were found in the path analysis for the perirhinal cortex or parahippocampus (p>0.14).

Conclusion

The effect of age on episodic memory is partly mediated by entorhinal rather than hippocampal volume in cognitive aging.
Localization and protein levels of YKL‐40 in postmortem brain of frontotemporal dementia and Alzheimer’s disease cases
Authors: Hok‐A‐Hin Yanaika S. , Hu William T. , Wouters Dorine , Boonkamp Lynn , Howell J. Christina , Rabano Alberto , Pijnenburg Yolande A.L. , Teunissen Charlotte E. , Hoozemans Jeroen J.M. , Del Campo Marta
Published: December 2020

Background

Levels of the inflammatory protein YKL‐40 (Chitinase 3‐like I) are increased in CSF of patients with Frontotemporal dementia (FTD) and Alzheimer’s disease (AD), suggesting YKL‐40 is a potential CSF biomarker reflecting the ongoing neuroinflammatory process. How YKL‐40 is localized and expressed in the brain in various neurodegenerative diseases is still elusive. In this study, we assessed the presence and levels of YKL‐40 in post‐mortem brain tissue of non‐demented controls and dementia cases with different pathologies (FTD and AD). In addition, we addressed the correlation of YKL‐40 levels between post‐mortem tissue and ante‐mortem CSF.

Method

The presence of YKL‐40 was analyzed in post‐mortem frontal or temporal cortex of non‐demented controls (NDC, total n = 83), FTD patients (n = 90), and AD patients (n = 59) by immunohistochemistry, western blot or ELISA (see Table 1). In a subset of cases where paired ante‐mortem CSF was available, CSF YKL‐40 was also measured by ELISA (n = 9, time interval CSF and post‐mortem collection: 1,4 years).

Result

YKL‐40 appeared to be mainly detected in astrocytes. YKL‐40 levels were similar between FTD or AD and non‐demented controls by either immunohistochemistry, western blot, or ELISA (p>0.05). No correlation between ante‐mortem CSF YKL‐40 and post‐mortem brain YKL‐40 was observed (r = ‐0.49; p>0.05). Interestingly, strong YKL‐40 immunoreactivity was observed in AD cases with an increased presence of cerebral amyloid angiopathy (CAA).

Conclusion

Our data suggest that CSF YKL‐40 changes do not mirror the overall pathological changes affected in FTD or AD. Increased presence of YKL‐40 in AD cases is strongly associated with the presence of CAA and most likely reflects the intense neuroinflammatory response associated with CAA.
Longitudinal changes in [18F]Flutemetamol load in cognitively intact APOE ε4 carriers vs noncarriers: Comparison of three reference regions
Authors: Luckett Emma Susanne , Schaeverbeke Jolien , Adamczuk Katarzyna , Van Laere Koen , Dupont Patrick , Vandenberghe Rik
Published: December 2020

Background

We use the Flemish Prevent AD Cohort KU Leuven (F‐PACK) to determine changes in amyloid load over a longitudinal period, and investigate the influence of APOE ε4 on these changes, comparing three reference regions.

Method

64 cognitively intact healthy F‐PACK participants (baseline age: 68 (55‐80), 30 carriers of APOE ε4) received a static [18F]Flutemetamol‐PET scan at a baseline visit (2010‐2015, acquisition window: 90‐120 minutes), as well as extensive neuropsychological testing (scores within published norms) and structural MRI scan. A follow‐up PET scan has been taken 3.4‐8.6 years after baseline in order to calculate changes in amyloid SUVRcomp in a neocortical composite volume of interest. Either subject‐specific cerebellar grey matter (CGM), or eroded subcortical white matter (ESWM), or pons was used as a reference region. Spearman’s correlation was used to determine the influence of baseline SUVRcomp on follow‐up SUVRcomp. APOE ε4 effects were determined using Wilcoxon matched pairs signed rank tests or Mann‐Whitney U‐tests, for the effects on absolute SUVRcomp and rate of change respectively. Rate of change was defined as absolute change divided by time interval.

Result

There was a significant correlation between baseline and follow‐up SUVRcomp for each of the reference regions (CGM: R = 0.69, p = 3.25e‐10; ESWM: R = 0.75, p = 1.14e‐12; pons: R = 0.75, p = 1.29e‐12). There was a significant increase in SUVRcomp at follow‐up, compared to baseline, in APOE ε4 carriers when using only the CGM or pons (CGM W = 118.5, p = 0.02; pons: W = 79, p = 0.003; ESWM: W = 208.5, p = 0.63). No significant differences were found between baseline and follow‐up in non‐carriers, nor in baseline values between carriers and non‐carriers. APOE ε4 carriers had a significantly higher follow‐up amyloid SUVRcomp compared to non‐carriers, only when using the CGM or pons (GCM: U = 658.5, p = 0.05; pons: U = 706.5, p = 0.008; ESWM: U = 586, p = 0.31). Rate of change was also significantly elevated in APOE ε4 carriers versus non‐carriers when using the CGM and pons (GCM: U = 680, p = 0.02; pons: U = 717.5, p = 0.005; ESWM: U = 560, p = 0.51).

Conclusion

Amyloid deposition and rate of change are enhanced by APOE ε4. Cerebellar grey matter and pons are the more suited reference regions to capture early differential effects of the APOE ε4 polymorphism on amyloid accumulation.
Classification of 18F‐flutemetamol scans using machine learning with neuropathology as standard of truth
Authors: Reinartz Mariska , Farrar Gill , Buckley Christopher , Smith Adrian , Thal Dietmar Rudolf , Dupont Patrick , Vandenberghe Rik
Published: December 2020

Background

There is a rising interest in machine learning for classification of images and lesions in medicine. A hurdle is the necessity for enough labeled cases based on an independent standard‐of‐truth. Here we applied linear support vector machine (SVM) to the phase 3 18F‐flutemetamol end‐of‐life study (GE067‐007), where 18F‐flutemetamol PET scans were available in close proximity to the time of autopsy and where brains were characterized in a standardized manner.

Method

As our primary analysis, we trained a leave‐one‐out SVM to discriminate between normal vs abnormal cases based on Bielschowsky silver staining (BSS) (the primary outcome measure of GE067‐007). As a secondary analysis, we also trained a classifier to discriminate between Aβ (Thal) phase 0‐1 vs phase 5. The dataset contained 29 normal and 72 abnormal cases according to BSS SoT and 17 phase 0‐1 and 44 phase 5 cases. To avoid bias, the number of cases was equated between classes (29 per class for BSS and 17 per class for Aβ). Selection of cases per class was performed randomly 50 times.

Result

Compared to the BSS SoT, the classifier had a sensitivity of 84% and a specificity of 90% (accuracy 87%) (Figure 1). Compared to Aβ phase, the sensitivity and specificity was, respectively, 97% and 100% (accuracy 98%). The three discordant BSS SoT normal cases, all had Aβ phase 3 or higher. Overall, highest feature weights were in striatum, middle frontal gyrus, precuneus, middle temporal, and cingulate. When we selected the voxels with the 10% highest amplitudes of feature weights (Figure 2) and re‐ran the analysis against the BSS SoT, performance increased to 95% sensitivity and 98.8% specificity. When we trained the algorithm to distinguish Aβ phase 4 (n=21) or 3 (n=14) from 0‐1, accuracy decreased to 88.8% and 71.9% respectively. In a further analysis, Aβ phase 3 vs 4 classification had an accuracy of 62.4% (95% CI 60.8, 63.9) and for phase 4 vs 5 an accuracy of 60.3% (95% CI 58.4, 62.1).

Conclusion

This study shows that SVM is able to classify 18F‐flutemetamol scans in a binary manner (normal vs abnormal) which closely corresponds to the neuropathology measures.
Effect of sex and physical and cognitive activities on cognitive reserve in a cohort of ethnically diverse, community‐dwelling older adults
Authors: Pa Judy , Aslayan Vahan , Casaletto Kaitlin B , Rentería Miguel Arce , Harrati Amal , Tom Sarah E , Armstrong Nicole , Rajan Kumar B , Gu Yian , Manly Jennifer J , Brickman Adam M , Zahodne Laura B
Published: December 2020

Background

Physical activity and cognitive stimulation may reduce age‐associated cognitive decline, delay dementia onset, and increase cognitive reserve. However, whether the association between these activities and cognitive reserve differs by sex has not been well‐studied. The current study examined interactions between sex and physical or cognitive activities on speed and memory reserve in older adults.

Method

Research participants from the Washington Heights‐Inwood Columbia Aging Project (WHICAP) with normal cognition, mild cognitive impairment, or dementia were included in this study (N=758, age=76.11+6.31, 62% female). Participants were selected based on available measures of 3T brain MRI, physical activity, cognitive activity, and cognition. Speed and memory reserve were calculated as the residuals from regression models partialling out hippocampal volume, total gray matter volume, and white matter hyperintensity volume from speed and memory composite scores, respectively. Physical activity was assessed using the Godin Leisure Time Exercise Questionnaire, converted to metabolic equivalents (METS). Self‐reported cognitive activity (COGACT) was calculated as the sum of three yes/no questions. Sex‐by‐activity (METS or COGACT) interactions and sex‐stratified analyses were conducted using linear regression models. Covariates included age, cohort, education, race/ethnicity, and diagnosis. A secondary analysis considered the effect of APOE4 status based on literature that APOE4 may differentially affect women and men.

Result

Women who reported more physical activity had greater speed reserve, and this effect was not observed for men. Physical activity was not associated with memory reserve. More cognitive activity was associated with greater speed reserve, and this association did not differ by sex. Women, but not men, who reported more cognitive activity had a trend for greater memory reserve. Among women, APOE4 carrier status attenuated relationships between physical activity and speed reserve, and between cognitive activity and speed and memory reserve.

Conclusion

The associations between self‐reported physical and cognitive activities and cognitive reserve are more pronounced in women; although women with APOE4 have less benefit from physical or cognitive activity than women without APOE4. Intervention studies that consider sex and APOE4 status are necessary to understand causal effects of physical and cognitive activities on brain and cognitive health.