bluuebunny/crossref_metadata_2025 huggingface dataset:
Regional microstructural alteration of the corpus callosum in preclinical Alzheimer’s disease
Authors: Jeon So Yeon , Yi Dahyun , Byun Min Soo , Lee Jun Ho , Lee Younghwa , Ahn Hyejin , Joung Haejung , Jung Gijung , Lee Jun‐Young , Kim Yu Kyeong , Kang Koung Mi , Sohn Chul‐Ho , Lee Dong Young
Published: December 2020

Background

While previous studies consistently reported regional microstructural changes of the cerebral white matter (WM) in Alzheimer’s disease (AD) dementia and mild cognitive impairment (MCI), little information is available for such changes in the preclinical stage of AD. We first aimed to investigate regional microstructural alteration of the WM in cognitively normal (CN) older adults with amyloid‐beta (Aβ) deposition. We also tried to develop a prediction model for Aβ positivity in CN using information on WM microstructural alteration and clinical variables that can be easily obtained in memory clinics.

Method

Seventy‐five CN older adults from the Korean Brain Aging Study for the Early diagnosis and prediction of Alzheimer’s disease (KBASE) cohort were included in the analyses. All Participants underwent comprehensive clinical and neuropsychological assessment, T1 MRI, diffusion tensor imaging (DTI), and [11C]PiB‐PET. All CN subjects were divided into Aβ positive (CN+) and negative (CN‐) based on the level of cerebral Aβ retention on [11C]PiB‐PET. Multivariate stepwise logistic regression analyses were conducted to develop Aβ positivity prediction models.

Result

When compared to CN‐, CN+ showed high mean diffusivity (MD) value of the genu of the corpus callosum (CC_genu) (F(1,73) = 6.357, p = 0.014, Figure 1). The area under the curve (AUC) of the receiver operating characteristics curve for the Aβ positivity prediction model only using MD of the CC_genu was 0.653 [confidence interval (CI) = 0.511‐0.794]. Model with MD of the CC_genu, age, and word list recall and constructional recall test scores were finally selected. The AUC of the final model was 0.851 [CI = 0.765‐0.937] (Figure 2).

Conclusion

The findings indicate that microstructural alteration of the CC_genu occurs even in the stage of preclinical AD. When taken together with episodic memory scores commonly available in clinical practice, information about such regional WM microstructural alteration can be used to screen preclinical AD.
Exploring the role of Amerindian genetic ancestry and ApoEε4 gene on Alzheimer disease in the Peruvian population
Authors: Cornejo‐Olivas Mario R. , Rajabli Farid , Veliz‐Otani Diego M. , Whitehead Patrice L. , Hofmann Natalia K. , Hamilton‐Nelson Kara L. , Illanes‐Manrique Maryenela , Milla‐Neyra Karina , Marca Victoria , Sarapura‐Castro Elison , Rivera‐Valdivia Andrea , Mejía Koni Katerin , Adams Larry D. , Mena Pedro Ramon , Vance Jeffery M. , Isasi Rosario , Cuccaro Michael L. , Beecham Gary W. , Meza‐Vega Maria , Castro‐Suarez Sheila , Custodio Nilton , Montesinos Rosa , Mazzetti Pilar , Pericak‐Vance Margaret A
Published: December 2020

Background

The ApoEε4 allele is a major risk factor for AD whose effect shows strong racial/ethnic differences. Among the populations ApoE shows the strongest effect in East Asians (EA) (ε3/ε4 odds ratio OR: 3.1–5.6; ε4/ε4 OR: 11.8–33.1) and has a relatively lower effect in non‐Hispanic Whites (NHW) (ε3/ε4 OR: 3.2; ε4/ε4 OR: 14.9). The effect of ApoEε4 in populations with Amerindian (AI) ancestry is unknown. Peruvians with high AI (∼80%) genetic ancestry provide an opportunity to assess the effect of ApoEε4 in AD individuals with AI genetic ancestry. Our aim is to use data from the Peruvian population to assess the role of AI genetic ancestry and the ApoE gene on AD.

Method

Genotyping including both ApoE and Illumina GSA array was performed in 147 Peruvians (54 AD cases and 93 cognitively intact (CI) controls). PC‐AiR and model‐based ADMIXTURE approach inferred population structure. To assess local ancestry, phasing using SHAPEIT (with 1kGP reference) was followed by RFMix (HGDP reference panels). Association between affection status and ApoEε4 dose was analyzed using logistic regression, adjusting for age, gender, PC1‐3.

Result

Admixture analysis showed that Peruvians have a substantial AI (62%) ancestral component (31% European, 4% African and 3% EA genetic ancestry). AD individuals have higher frequency of ApoEε4 allele than CI individuals (7.4% vs 3.7%, respectively, p‐value = 3e‐4). Logistic regression analysis showed ApoEε4 dose significantly associated with AD in Peruvians (OR = 4.92, CI: 2.07‐12.83, p = 6e‐4). The average of the local ancestry proportions around the ApoE were close to the average global ancestry proportions (AI:56%, EU:37% and AF:7%).

Conclusion

Our results showed that the risk for AD from ApoEε4 in Peruvians is higher than we have observed in NHW populations. Given the high admixture of AI in the Peruvian population, it suggests that the AI local ancestry is contributing to a strong risk for AD in ApoEε4 carriers. This would align with the current believed migration pattern of AI from East Asia, where ApoEε4 carriers have the highest ApoEε4 risk for AD. Further ascertainment is ongoing to identify additional AI ApoEε4 carriers to directly ascertain risk.
Effects of the novel FTD‐ALS gene CYLD on cell death mechanisms
Authors: Dobson‐Stone Carol , Lee Albert , Chung Roger S. , Hallupp Marianne , Boccanfuso Lauren , Oyston Lisa J. , Kwok John B.
Published: December 2020

Background

Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are clinically and pathologically overlapping disorders with shared genetic causes. We previously identified a disease locus on chromosome 16p12.1‐16q12.2 for a large European Australian family with FTD‐ALS [Dobson‐Stone et al 2013, Acta Neuropathol 125:523‐533]. We have recently identified the p.M719V substitution in CYLD as the causal mutation at this locus. CYLD is a lysine‐63 deubiquitinase and CYLDM719V shows significantly increased deubiquitinase activity [Dobson‐Stone et al, Brain, accepted Dec 2019]. We sought to determine what biological pathways are affected by the presence of this mutation.

Method

We performed label‐free mass spectrometry quantitative proteomic analysis of HEK293 lysates overexpressing wild‐type (CYLDwt), FTD‐ALS mutant CYLDM719V or deubiquitinase‐inactive mutant CYLDD681G. We used Ingenuity Pathway Analysis to predict dysregulated biological pathways. We examined necroptosis in L929 cells overexpressing CYLDwt and CYLDM719V, measuring cell viability (ATP production) and cell death (membrane permeabilisation).

Result

276 proteins exhibited significantly altered expression when CYLDM719V was overexpressed, relative to CYLDwt. Pathway analysis predicted activation of apoptosis with CYLDM719V. This is likely related to deubiquitinase activity, as CYLDD681G was predicted to have the opposite effect. We are working to validate these findings by immunoblot and co‐immunoprecipitation analyses. CYLD has recently been identified as a mediator of another cell death pathway, necroptosis. We found a small but significant effect of CYLDM719V on cell viability after treatment with necroptosis inducer Z‐VAD‐FMK in L929 cells at 0.2 μM (8.8% decrease relative to control, Student’s t test p = 0.006), 2 μM (26.1% decrease, p = 0.0003) and 20 μM (38.6% decrease, p = 0.00005). CYLDwt showed significant effects only at higher doses (0.2 μM: 1.1% decrease, p = 0.396; 2 μM: 10.8% decrease, p = 0.049; 20 μM: 32.5% decrease, p = 0.0001).

Conclusion

Our study indicates that CYLDM719V may act in part by inappropriate activation of apoptosis and/or necroptosis, possibly via sensitising CYLD’s response to death stimuli. It remains to be seen which of these mechanisms is critical to CYLD’s effects on neurodegeneration in FTD and ALS, although our data lend support to the emerging research showing necroptosis as a plausible therapeutic target for ALS.
Reduced transcallosal inhibition in Alzheimer’s disease compared to healthy controls
Authors: Agrawal Adesh Kumar , Mehta Urvakhsh M. , Naik Shalini S. , Thanki Milind Vijay , Mitra Sayantanava , Varghese Mathew
Published: December 2020

Background

In Alzheimer’s disease (AD), structural changes in the corpus callosum are known to precede clinical signs. Transcranial magnetic stimulation (TMS) can be used to study functional integrity of the corpus callosum through ipsilateral silent period (iSP). We examined iSP duration between patients with mild cognitive impairment (MCI)/AD and healthy controls.

Method

15 patients of AD (n = 10) and MCI (n = 5), and 15 healthy controls were recruited. All subjects completed clinical (Clinical Dementia Rating Scale, Instrumental Activities of Daily Living Scale for Elderly, Everyday Abilities scale for India, & Neuropsychiatric Inventory) and cognitive (Hindi Mental Status Examination, attention, working memory and semantic verbal memory) evaluations. Twenty single TMS pulses (suprathreshold pulse delivered to right motor cortex with the ipsilateral/right hand maintained in 20% of its maximal contraction) and twenty paired pulses (subthreshold priming pulse delivered 3ms before suprathreshold test pulse over left motor cortex) were delivered to assess inter‐cortical inhibition (iSP) and intra‐cortical inhibition (ICI) respectively.

Result

iSP duration was significantly reduced (df = 27; t = ‐2.76; p‐0.01)) in the clinical group as compared to healthy controls. However, there were no significant differences in ICI. There was no significant association between iSP and clinical or cognitive performance.

Conclusion

The presence of inter‐cortical rather than intra‐cortical inhibition deficits in AD supports the hypothesis of corpus callosum dysfunction in AD. A lack of association between iSP and severity indices suggest this measure may be examined as an early marker of AD.
Cerebrovascular disease influences hippocampal subfield atrophy in mild cognitive impairment
Authors: Wong Fennie , Yatawara Chathuri , Low Audrey , Wong Benjamin , Kandiah Nagaendran
Published: December 2020

Background

Distinguishing between pure AD and AD with concomitant CVD is challenging due to overlapping pathogenesis such as cerebral accumulation of amyloid‐β (Aβ) plaques and neurofibrillary tangles. In recent years, hippocampal subfield volumes have been recommended over other neuroimaging markers of AD due to its functionally distinct nature and higher accuracy. However to date, patterns of hippocampal subfield atrophy in prodromal AD with and without concomitant CVD remain largely unexplored. This study investigates the associations and differences in hippocampal subfield volumes in mild cognitive impairment (MCI) with significant/non‐significant cerebrovascular disease (MCI+/‐CVD).

Method

176 MCI subjects (mean age=65.56 years, SD=8.77) underwent neuropsychological assessments and magnetic resonance imaging. White matter hyperintensities were quantified using modified Fazekas ratings. Subjects with Fazekas ratings of ≥ 8 were categorised as MCI+CVD. Demographics, brain volumetric measurements for grey and white matter volumes, periventricular and deep white matter hyperintensities and hippocampal subfields were examined in MCI+/‐CVD. Multiple linear regressions were conducted for MCI+CVD to examine predictions of hippocampal subfield volumes on cognitive performance.

Result

MCI+CVD (N=39) performed worse than MCI‐CVD in all neuropsychological assessments. MCI+CVD had significantly smaller volumes in the hippocampal tail (p=.042), subiculum (p=.015), CA1 (p=.023), molecular layer (p=.009) and fimbria (p=.025). MCI+CVD had significant associations between hippocampal subfield volumes and cognitive performance: hippocampal tail with global cognition (p=.049) and visuospatial skills (p=.004); subiculum with global cognition (p=.026) and episodic memory (p=.001), molecular layer with global cognition (p=.049) and episodic memory (p=.010) and fimbria with episodic memory (p=.038).

Conclusion

MCI+CVD has significantly greater hippocampal subfield atrophy, with atrophy of the hippocampal tail, subiculum, molecular layer and fimbria correlating to poorer performance in global cognition, visuospatial skills and episodic memory. The findings of this study may guide future research in investigating longitudinal changes in hippocampal atrophy in MCI+/‐CVD and the corresponding implications on cognitive performance.
Adherence to a Mediterranean diet is associated with better cognitive performance many years later in the PRIME cohort
Authors: McGrattan Andrea , Mcevoy Claire T , Woodside Jayne V , Linden Gerry , Passmore Anthony Peter , Holmes Clive , Patterson Christopher , Teeling Jessica , McGuinness Bernadette
Published: December 2020

Background

Greater adherence to a Mediterranean Diet (MD) has been associated with reduced cognitive decline and dementia risk. The Prospective Epidemiological Study of Myocardial Infarction (PRIME) recruited 10,600 European male participants between 1991 and 1993 aged 50‐59 years. The aim of this study was to examine the association between adherence to a MD (at baseline) and subsequent cognitive performance.

Method

Dietary data was collected via a short, self‐administered 16‐item Food Frequency Questionnaire; an adapted version of the traditional MD Score was also developed (aMDSR) and median values of intake for each MD component were used as the cut‐off point to calculate the aMDSM. In 2017, follow‐up cognitive assessments using the Addenbrooke’s Cognitive Examination – Revised (ACER) commenced within the Belfast cohort (n=405).

Result

For aMDSM, those in the Low MD category scored lower on all cognitive tests compared to the High MD category, with significant differences reported for ACE‐R (p = 0.001), ACE‐R sub domain of memory (p = 0.038), fluency (p = 0.001) and visuospatial skills (p = 0.030). For participants with a ACE‐R score below 88, suggestive of cognitive impairment, there were 19.3% in the Low MD category and 7.2% in the High MD category (p = 0.004). There were 7.4% in the Low MD category and 2.7% in the High MD category who obtained an ACE‐R score below 82, indicative of probable dementia, with no statistically significant difference between categories (p=0.09). In an adjusted model for age, education and cardiovascular risk factors, this significant difference was maintained, with those in the High MD category being 56% less likely to have an ACE‐R score of <88/100 (OR 0.442, 95% CI 0.241‐0.810, p=0.008) compared to those in the Low MD category. For participants with a ACE‐R score below 82, indicative of probable dementia, there were 7.4% in the Low MD category and 2.7% in the High MD category with no statistically significant difference between categories (OR 0.661, 95%CI 0.269‐1.621, p=0.37) .

Conclusion

In the PRIME Belfast cohort, higher adherence to a MD was associated with better cognitive performances 26 years later in some but not all analyses.
APOE4 packs a punch in women: Sex‐specific vulnerability for tau and neuroinflammation
Authors: Wang Yi‐Ting , Kang Min Su , Therriault Joseph , Pascoal Tharick A. , Lussier Firoza Z , Savard Melissa , Benedet Andréa Lessa , Tissot Cecile , Arias Jaime Fernandez , Gauthier Serge , Rosa‐Neto Pedro
Published: December 2020

Background

The role that sex plays in Alzheimer’s disease (AD) has long been the subject of intense investigation. Considerable amount of literatures showed a disproportionally high prevalence of AD in women. Moreover, sex differences were observed in disease manifestation, rates of cognitive decline, cerebral atrophy, as well as the response to treatments, suggesting that sex serves as a crucial factor in the disease heterogeneity. APOE is the strongest genetic risk factor for sporadic AD, with the ε4 allele conferring increased risk. It was found that female ε4 carriers show stronger risk for clinical AD. Other studies showed that female ε4 carriers have higher p‐tau levels in cerebrospinal fluid and show worse memories than male ε4 carriers. Despite evidence supports APOE has a stronger association among women compared with men, limited work has evaluated the effects of ApoE4 on AD core neuropathology including amyloid, tau and microglial activation in a sex‐specific manner.

Method

This was a cross‐sectional study in APOE ε4 carriers with AD (n=31), MCI (n=23), cognitively normal controls (n=47) and young healthy controls (n=9) from the TRIAD study at McGill University Research Centre for Studies in Aging, Canada. Cerebral amyloid load, tau neurofibrillary tangles and microglia activation were assessed using positron emission tomography (PET) radiopharmaceuticals [18F]AZD4694 ([18F]NAV4694), [18F]MK6240 and [11C]PBR28 respectively.

Result

No significant difference was found in age, education and MMSE score between male and female subjects. Female ε4 carriers showed significant higher tau burden in hippocampus (P<0.01), entorhinal cortex (P<0.05) and parahippocampal cortex (P<0.05) compared to male ε4 carriers. A sex‐specific vulnerability for tau and neuroinflammation was observed. More specifically, in amyloid‐positive female ε4 carriers, higher tau burden was found to be strongly associated with worse cognitive function assessed by Mini‐Mental State Examination (MMSE). In addition, an positive correlation between amyloid load and microglial activation level was also identified in female APOE ε4 carriers.

Conclusion

We provide striking evidence that female is more vulnerable for the effects of APOE ε4 on tau and neuroinflammation, suggesting APOE may modulate AD pathology in a sex‐specific manner, particularly in the presence of amyloidosis.
Comparison of two analytical platforms for blood‐based surrogate biomarkers of amyloid pathology
Authors: De Meyer Steffi , Schaeverbeke Jolien , Gille Benjamin , Verberk Inge M.W. , Luckett Emma Susanne , Thijssen Elisabeth H. , Gabel Silvy , Mauroo Kimberley , Bruffaerts Rose , Stoops Erik , Vanderstichele Hugo Marcel , Teunissen Charlotte E. , Vandenberghe Rik , Poesen Koen
Published: December 2020

Background

Formation of amyloid plaques and fibrillary tau tangles in brain are key pathological hallmarks in Alzheimer’s disease (AD). Surrogate biomarkers of these hallmarks have been established in CSF. However, a less invasive sample source would simplify the recruitment and the follow‐up of response in clinical trials targeting the pathological hallmarks in AD. We assessed the performances of two analytical platforms for plasma beta‐amyloid (Aβ) species and total tau (t‐tau) as surrogates of amyloid‐PET status.

Methods

Plasma Aβ1‐42 and Aβ1‐40 were quantified in cognitively healthy controls (n=160, age[mean]=69, 46% female) and amnestic MCI (aMCI) patients (n=41, age[mean]=71, 43% female) by i) the Simoa Amyblood platform (Amsterdam UMC and ADx NeuroSciences) and ii) an ELISA platform (Euroimmun, Lubeck, Germany) employing identical antibody pairs. Plasma t‐tau was quantified with a prototype ELISA (ADx NeuroSciences). The same biomarkers were also measured in CSF (ELISA [Euroimmun]). Controls underwent [18F]‐flutemetamol PET and aMCI patients received [18F]‐florbetaben PET (SUVRcomp cut‐off for amyloid positivity=1.38 and 1.29, respectively). Spearman correlations between CSF and plasma biomarkers were calculated and the performance of plasma biomarkers to identify amyloid PET positivity was determined through ROC analysis. Bonferroni correction adjusted for multiple comparisons.

Results

For ELISA, the strongest correlations were found among amyloid biomarker ratios between plasma and CSF within the aMCI cohort (r=0.6561‐0.8123, p<0.0023); most of these correlations were also present in controls, albeit weaker (r=0.4308‐0.5498, p<0.0078). Using Amyblood, correlations were weaker than for ELISA, most not surviving Bonferroni correction (Table 1). All plasma biomarker ratios could differentiate between amyloid‐PET positive and amyloid‐PET negative subjects in both cohorts (AUC[range]=0.719‐0.876, p<0.0001). Plasma t‐tau identified amyloid positivity only in the aMCI cohort (AUC[range]=0.818, p<0.0001), while plasma Aβ1‐42 could do so only in controls (AUC[range]=0.676‐0.679, p<0.0027). Within the aMCI cohort, Aβ1‐42/Aβ1‐40 performed better than Aβ1‐42 when measured with Amyblood (p=0.0064). No differences in performances were observed between platforms for any biomarker (p>0.543) (Table2). Logistic regression analysis including age, gender and APOEε4 as covariates did not significantly improve performances.

Conclusion

Measuring amyloid species with blood‐based immunoassays renders good performance to assess amyloid PET status, especially in aMCI. To this end, Amyblood did not outperform ELISA.
BIN1 rs744373 SNP is associated with increased mean diffusivity in non‐demented elderly
Authors: Rubinski Anna , Franzmeier Nicolai , Neitzel Julia , Ewers Michael
Published: December 2020

Background

The rs744373 SNP in the bridging integrator‐1 gene (BIN1) is the second most important risk factor of sporadic Alzheimer’s disease (AD) after ApoE genotype. We have recently shown that the BIN1 SNP is associated with higher tau deposition in the brain (Franzmeier et al. Nat Commun 2019). Recent findings indicate that BIN1 protein is highly expressed in the white matter (WM) in the brain. Although WM alterations are common in AD and may contribute to dementia symptoms, it is unclear whether BIN1 risk allele is associated with lower WM integrity. To address this research gap, we tested whether BIN1 rs744373 is associated with WM alterations in non‐demented elderly, independently of amyloid PET.

Methods

We included diffusion tensor imaging (DTI) data, 18‐F AV45 amyloid PET, and AV1451 tau PET from 61 individuals including cognitively normal controls (CN, n=35) and individuals with mild cognitive impaired (MCI, n=26) from ADNI. 14 CN and 15 MCI individuals were BIN1 rs744373 SNP carriers. Global mean diffusivity (MD) and global fractional anisotropy (FA) were mapped within the white matter. In linear voxel‐based regression analyses, we tested the BIN1 rs744373 genotype effect on MD (primary outcome) and FA values, controlled for age, gender, education, diagnosis and global amyloid PET. We further assessed the voxel‐level group differences in MD (BIN1 rs744373 carriers vs. non‐carriers) using TBSS. Tau PET was assessed in projection areas of major fiber tracts.

Results

BIN1 rs744373‐carriage was associated with elevated global white matter MD values (p=0.003, Figure 1), independent of global Aβ PET SUVR, and regional MD predominantly located within the left superior/inferior longitudinal fasciculus, left/right uncinate fasciculus and left inferior fronto‐occipital fasciculus (Figure 2). No significant effect on FA was observed. When stratified by diagnosis, associations between BIN1 rs744373 and elevated global MD were significant in the MCI subgroup (p=0.01). Mediation analyses of the effect of BIN1 on white matter via tau PET in connected areas will be discussed.

Conclusion

BIN1 rs744373 risk allele is associated with white matter alterations in MCI independent of Aβ, suggesting that BIN1 SNP may enhance the risk of microstructural white matter impairment and thus contribute to dementia symptoms.
Using the Framingham Cardiovascular Disease Risk Score to predict cognitive performance in cognitively normal non‐hispanic whites and Mexican American elders
Authors: Vintimilla Raul , Balasubramanian Kishore , Hall James R. , Johnson Leigh Ann , O'Bryant Sid
Published: December 2020

Background

Prevalence of cardiovascular disease risk factors (CVRFs) is higher among Mexican Americans (MAs) that non‐Hispanic Whites (NHWs), placing this population at a higher risk of cognitive decline. The purpose of this study was to examine the relationship between the Framingham Cardiovascular Disease 10‐years risk score (FCVDRS) and cognitive performance among MAs and NHWs. This study extends the limited literature about FCVDRS and cognition among MAs.

Method

We studied 518 cognitively normal participants (92 NHWs and 426 MAs) from an epidemiological study of aging. Gender, age, hypertension treatment status, systolic blood pressure (SBP) level, smoking status, diabetes mellitus diagnosis (DM), HDL, and total cholesterol levels were used to calculate the FCVDRS for each individual. A linear regression was conducted to examine the association of FCVDRS with MMSE, logical memory I and II, Trails B, FAS, and digit span scores. A one‐way ANOVA was used to analyze the relationship of FCVDRS categories (low < 10, moderate 10 – 20, high > 20), and test scores, along with Tukey post hoc tests to elucidate the magnitude of differences between the groups. Education was entered as a covariate in the model.

Result

MAs had a higher prevalence of DM, higher SBP, and lower HDL values. Linear regression model was significant only for executive function in MAs , F(1,352) = 7.86, p = 0.005. One ‐way ANOVA showed a significant difference for Trails B, F(2,351) = 5.21, p = 0.006, and MMSE, F(2,414) = 3.00, p = 0.005 among MAs. In both cases, post hoc test indicated that MMSE and Trails B mean scores were lower in the high risk group when compared to the low risk group. No significant trends were seen in the Non‐Hispanic White subset.

Conclusion

Our data has shown that FCVDRS can be used to predict performance on measures of global cognition and executive function in MAs. Although more work has to be done to further understand the predictive power of FCVDRS, there is promise in using this model to develop early intervention programs targeted to MAs.
Development of the mobile cognitive app performance platform for detection of AD‐related cognitive change
Authors: Mechanic‐Hamilton Dawn , Lydon Sean , Halberstadter Kimberly , Lane Jacqueline , Das Sandhitsu R. , Wolk David A.
Published: December 2020

Background

This pilot study investigates the psychometric properties of a mobile app‐based memory task, the mobile cognitive app performance platform (mCAPP), to detect memory changes associated with preclinical Alzheimer’s Disease (AD). A mobile, reliable, valid, short, and engaging cognitive assessment is necessary for early detection and tracking change in individuals at risk for AD.

Method

Participants included 30 older adults (60% female; age=70.9±4.1, years of education=16±2.5; 73% Caucasian) with normal cognition who are enrolled in the Penn ADRC cohort. The mCAPP memory task includes learning and then matching hidden card pairs and incorporates increasing memory load, pattern separation features (lure vs. non‐lure), and spatial memory (moving target cards). Participants completed the NACC UDS3 neuropsychological battery and additional cognitive measures, within six months of the mCAPP testing and twenty participants completed a high‐resolution structural MRI scan.

Result

Almost all participants found the difficulty level of the mCAPP game to be “just right” (92%), 65% reported they enjoyed the game and 43% reported they would play it for fun. Higher average number of guesses at higher memory load levels was correlated with lower story learning and memory, digit span, trail making test (TMT) B and olfactory performance (p<0.05). Higher average duration of time on the higher memory load levels was correlated with worse performance on digit span, animal naming, TMT A and B, and olfaction (p<0.05). The number of guesses and duration of time on lure vs. non‐lure trials was significantly different, with more guesses and more time required for the lure trials (requires pattern separation) at higher memory load levels [Guesses: 8 card, t(29)=5.6,p<0.001; 12 cards, t(29)=4.5,p<0.001; Duration: 8 cards, t(29)=6.9,p<0.001; 12 cards, t(29)=5.9,p<0.001]. At some higher memory load levels, longer duration of time on trials correlated with smaller mean thickness of the parahippocampal cortex (p<0.05).

Conclusion

In this study, we show feasibility, validity, and utility of multiple memory components of the mCAPP memory task for use in detecting subtle cognitive differences associated with preclinical AD. Future work will include examination of the relationship of mCAPP variables with molecular biomarkers, at‐home and burst testing, and development of additional measures in other domains of cognition.
Regional differences of amyloid PET SUVR induced by spatial smoothing and the role of reference region
Authors: Palombit Alessandro , Manber Richard , Joules Richard , Wolz Robin
Published: December 2020

Background

Spatial smoothing can be applied to imaging data from Amyloid PET (Ab‐PET) scans in clinical trials with the aim of decreasing the noise level and improve tissue delineation to the ultimate extent of easing the structural registration process. In this study, we quantify regional differences of Ab‐PET attributable to post‐reconstruction spatial smoothing.

Method

Amyloid PET ([18F]‐Flutemetamol, Siemens Biograph 64 mCT PET/CT scanner) and structural MRI were collected in 10 participants (3 AD, 4 MCI). Each Ab‐PET dataset was reconstructed as single saturated image (OSEM, 8 iterations, 21 subsets, PSF+TOF), separately with and without spatial smoothing (3D Gaussian kernel, FWHM = 3mm). Bias field‐corrected and skull‐stripped T1w‐MRI images were segmented with LEAP [Ledig;ISBI;2012] and separately registered to the smoothed/unsmoothed Ab‐PET volumes. Regional SUVR, defined as within‐region average with cerebellar grey matter (GC) or whole cerebellum (WHC) as reference region, was separately calculated for smoothed/unsmoothed Ab‐PET and compared between smoothed/unsmoothed Ab‐PET volumes.

Result

Regional SUVR was found to significantly differ between smoothed/unsmoothed (Wilcoxon signed‐rank test, p < 0.05) with both reference regions. Quantitative SUVR differences (unsmoothed – smoothed) were nonetheless regionally limited (Figure 1A) with a relative difference of ‐0.149% or +0.988% (averaged across regions/subjects) respectively with GC or WHC reference, and very small size effects with Cohen’s d = ‐0.014 (GC) and 0.046 (WHC). A strong rank correlation (Figure 1B) was found between SUVR with different smoothing levels both regarding GC (r = 0.984, p < 0.05) and WHC (r = 0.985, p < 0.05). SUVR relative differences between smoothing levels did not exceed the 5% threshold with GC (WHC similar thus omitted), differences not reaching significance (Figure 2B) if corrected for multiple‐comparisons across regions.

Conclusion

Smoothing‐related regional SUVR differences were found to be below the scan‐rescan physiological level [Tolboom;JNM;2009], suggesting minimal impact on the statistical analyses. Nonetheless, spatial smoothing can improve the PET‐MRI registration robustness by improving Ab‐PET tissue delineation and noise content, an essential feature for automatic processing of large cohorts’ data.
Common and rare variants in Alzheimer’s disease genes are associated with episodic memory in South Asians from the LASI‐DAD study
Authors: Zhao Wei , Smith Jennifer A. , Yu Miao , Moorjani Priya , Ganna Andrea , Dey Aparajit Ballav , Lee Jinkook , Kardia Sharon L.R.
Published: December 2020

Background

Many risk loci for Alzheimer’s disease (AD) have been identified in genome wide association studies (GWAS) conducted primarily in European ancestry (EA). We previously investigated whether SNPs identified in EA were associated with episodic memory in South Asians, and failed to find an association for the majority of SNPs. Due to genetic heterogeneity among different race/ethnic groups, risk SNPs identified in EA GWAS may not be as strongly associated in different ethnicities. Genes, however, have the same function across ethnicities. The goal of this study was to use a gene‐based approach to investigate the association between 39 known risk genes for AD and episodic memory in 937 South Asians from the Diagnostic Assessment of Dementia for the Longitudinal Aging Study of India (LASI‐DAD).

Method

Participants were genotyped using the Illumina Global Screening Array and imputed to 1000G Phase 3v5. We used a gene‐based approach, the sequence kernel association test (SKAT and SKAT‐O), to assess the joint effects of all SNPs simultaneously within each risk gene on two episodic memory scores (total and delayed word recall) after controlling for age, gender, and population structure. We used two weighting schemes: equal weight for all SNPs/variants (beta(1,1)), and upweighting of rare variants (beta(1,25)).

Result

Preliminary analyses showed that 7 genes (APOE, ADAMTS1, RIN3, IQCK, KAT8, HLA‐DRB5, EPHA1) were associated with total learning score and 2 genes (ADAMTS1, CLU) were associated with delayed recall score using the equal SNP/variant weighting approach at a nominal p‐value (p < 0.05). Using the rare variant weighting approach, 5 genes (APOE, ADAMTS1, KAT8, RIN3, HLA‐DRB5) were associated with total learning score and 2 genes (ADAMTS1 and ABCA7) were associated with delayed recall score.

Conclusion

Given that variation in only one gene was associated with both total learning and delayed recall, different biological mechanisms may be involved in these traits. Moreover, the association of the majority of genes was driven by both common and rare variants, whereas only a few associations were driven largely by rare variants. Future work is needed to identify the specific variants that influence episodic memory in South Asians.
Characterization and comparison of memory and affective behavior in common transgenic mouse models of Alzheimer’s disease
Authors: Dong Hongxin , Locci Andrea , Keszycki Rachel M. , Orellana Hector D. , Rodriguez Guadalupe , Fisher Daniel W.
Published: December 2020

Background

Alzheimer’s disease (AD) is a neurodegenerative disorder with cognitive decline, yet over 90% of patients also develop behavioral symptoms during disease progression. While a few studies have identified some aberrant behaviors in transgenic mouse models of AD, rigorous characterization and comparison of AD models for memory and affective behavior has yet to be done.

Methods

We characterized memory and affective behavior in three commonly AD mouse models (5xFAD, APP/PS1, and APPNLGF mice) at 10 months of age. We evaluated working, spatial, and social memory deficits using Y‐maze, novel object recognition (NOR), social recognition, and Morris water maze (MWM). We assayed affective behavior with open field, light‐dark box, social interaction and tail suspension tests. Then, we evaluated the dynamic changes in memory and affective behavior in 5xFAD mice at 6 and 10 months of age.

Results

All three AD mouse lines demonstrated deficits in working, spatial and social memory compared to WT mice. However, 5XFAD and APPNLGF mice showed more severe working and social memory deficits compared to APP/PS1 mice. In the open field, 5xFAD but not APPNLGF and APP/PS1 mice showed a reduction in the time spent and the number of entries in the center of the arena. In the light/dark box test, both 5xFAD and APPNLGF but not APP/PS1 mice entered land spent less time in the light compartment. Similarly, 5xFAD and APPNLGF mice demonstrated reduced time spent and number of entries around the conspecific in the social interaction test. Finally, 5xFAD and APPNLGF but not APP/PS1 mice had increased immobility in the tail‐suspension test. Interestingly, changes in the affective behavior but not memory deficits were found in 5XFAD mice at 6 months of age, and some of these behavioral alterations worsened at 10 months of age.

Conclusions

Although 10‐month‐old 5xFAD, APPNLGF, and APP/PS1 mice displayed working, spatial and social memory deficits, only 5xFAD and APPNLGF showed robust anxiety‐ and depressive‐like behaviors at this time point. Importantly, the 5xFAD mice displayed significant deficits in affective behavior but not memory impairment at an early time‐point, suggesting that the AD‐pathology may drive changes in affective behavior before more overt memory deficits.
Targeting of misfolded, pathogenic TDP‐43 with rationally designed antibodies
Authors: Cashman Neil R. , Louadi Sarah , Zhao Beibei , Roman Andrei , Gibbs Ebrima , Dijkstra Anke A. , Plotkin Steven S. , Kaplan Johanne
Published: December 2020

Background

Misfolded, aggregated TDP‐43 has been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS), frontotemporal lobar dementia (FTLD) and limbic‐predominant age‐related TDP‐43 encephalopathy (LATE) through direct toxicity, loss of function of normal TDP‐43, induction of misfolding of other neuronal proteins, and prion‐like, cell‐to‐cell propagation of disease. We sought to generate antibodies selectively targeting the misfolded, pathogenic form of TDP‐43 while sparing physiological forms of TDP‐43 important for normal cell function.

Method

Mice and rabbits were immunized with an unfolded N‐terminal domain (NTD) linear epitope predicted to become exposed in cytosolically mislocalized, aggregated TDP‐43 but otherwise buried in natively folded TDP‐43. Selectivity of polyclonal antibody (pAb) for misfolded NTD was confirmed by studies with denaturing and native gel electrophoresis followed by immunoblotting. Monoclonal antibody (mAb) affinity for the immunizing peptide was measured by surface plasmon resonance (SPR). mAb selectivity for pathogenic, aggregated TDP43 was assessed by immunocytochemistry (ICC) of HEK293FT cells transfected with mutant TDP‐43 lacking a functional nuclear localization signal (DNLS) or upon arsenite stress, and by immunohistochemistry (IHC) on patient samples. The ability of mAbs to inhibit cell‐to‐cell transmission of DNLS TDP‐43 was evaluated in cell culture.

Result

Affinity‐purified pAb from immunized animals displayed reactivity with recombinant NTD under denaturing but not native conditions, indicating selectivity for unfolded NTD. mAb clones displayed pM affinity for the NTD epitope by SPR. ICC showed mAb reactivity with cytoplasmic aggregates of DNLS‐TDP‐43 but not wild‐type nuclear TDP‐43. Antibodies also did not recognize TDP‐43 in physiological stress granules in HEK‐293FT cells. IHC of ALS and FTLD CNS sections, but not normal control, confirmed selective immunoreactivity of mAbs with pathogenic TDP‐43. In cell culture, mAbs inhibited transmission of misfolding TDP‐43 from the conditioned medium of donor HEK293FT cells transfected with DNLS‐TDP‐43 to naïve recipient cells.

Conclusion

Immunization with an NTD epitope of misfolded TDP‐43 gave rise to mAbs selective for pathogenic vs physiologically important forms of TDP‐43. The mAbs were capable of inhibiting cell‐to‐cell propagation of misfolding TDP43 in vitro. Such antibodies may have value against extracellular transmission of misfolding TDP‐43 or as pathogenic TDP43‐specific intrabodies expressed intracellularly.
Gait is associated with age and dementia assessments among individuals with Down syndrome
Authors: Van Pelt Kathryn L.
Published: December 2020

Background

Down Syndrome (DS), caused by triplication of chromosome 21, is associated with the development of Alzheimer's disease (AD) neuropathology by age 40 years. However, clinical signs of dementia may not develop until up to decades after neuropathology. Neuroimaging studies indicate that the striatum and frontal lobes accumulate beta‐amyloid early in AD progression. Given these regions are involved in motor and cognitive function, we hypothesized that gait would be associated with changes in cognition and prodromal dementia.

Method

Twenty‐nine participants (n = 16 male) with DS were recruited into the gait study. The average age of participants was 36 (range: 25‐59). The GaitRite mat was used to spatial and temporal gait measures while participants walked at their self‐selected pace or when completing a dual‐task. The dual‐task was counting aloud, starting from a random integer between 1‐10. Participants also completed the Severe Impairment Battery (SIB) and Brief Praxis Test (BPT) to measure cognitive impairment. Linear mixed models evaluated the relationship between age, condition, and gait metrics. Linear regression was used to assess the relationship between gait and cognition metrics.

Result

With increasing age, gait velocity slowed within the counting condition, but not the self‐paced condition (t(180.29) = 2.69; p = 0.008; Figure 1A). There was a trend for step length to shorten with increasing age across all conditions (t(29.01) = ‐1.81; p = 0.08; Figure 1B). Participants’ base stance was wider with increasing age during the counting condition, but not the self‐paced condition (t(179.70) = ‐2.03; p = 0.04; Figure 1C). Faster normalized velocity was associated with better cognition as measured by the SIB (t = 2.99; p = 0.004; Figure 2A) and BPT (t = 2.02; p < 0.05; Figure 2B) across both self‐paced and counting conditions.

Conclusion

Slower velocity, shorter step length, and wider base stance on the dual‐task gait paradigm were associated with increasing age and cognitive impairment. A dual‐task gait may serve as a prodromal indicator of dementia in DS. Earlier dementia detection will facilitate research investigating ADS pathogenesis and subsequently may provide novel targets for preventative research.
Sex‐specific changes in amyloidosis and neuro‐immune modulation in response to alterations in the gut microbiome
Authors: Shaik Shabana M. , Dodiya Hemraj B. , Cao Yajun , Boutej Hajer , Olszewski Monica , Sisodia Sangram S.
Published: December 2020

Background

Microglia, resident macrophages of CNS constantly screen the brain and engage in pathological processes by changing their morphology, expressing various antigens and become phagocytic. This activation causes the release of a wave of chemical mediators that promote the neuroinflammatory milieu. Thus, microglial homeostasis represents a highly plastic multifaceted response, finely tuned by the nature of the stimulus and the molecular repertoire involved. Studies from Sisodia lab have shown that antibiotic (ABX) mediated alterations of the gut microbiome in Thy1‐APPSwe.PS1L166Pmice (APPPS1‐21), resulted in a significant decrease in amyloidosis and altered microglial phenotypes in male mice. To investigate the influence of gut microbiome in modulating microglial function in a sex‐specific manner, we generated transgenic mice that would allow us to assess microglial RNA‐Protein networks and address the molecular mechanisms of CNS immunomodulation.

Method

We generated ‘Thy1‐APP.PS1‐RiboTag’ by crossing APPPS1‐21 mice to RiboTag mice wherein a CD11b promoter drives expression of ribosomal protein L10a (RpL10) that is fused to FLAG/EGFP at the amino‐terminus. Using our established protocol, we altered the microbiome of male and female mice (n=12) by orally gavaging them with ABX from day 14‐21, followed by low dose ABX in drinking water till they are sacrificed (7 wks). Vehicle treated mice were used as controls along with WT‐RiboTag mice. Immunoprecipitation of cortical homogenates with anti‐FLAG was performed to pull‐down actively translated mRNA and proteome in microglia following histopathology.

Result

We evaluated Aβ pathology and found that ABX‐treatment led to reduced amyloidosis in male mice with no significant changes in the female. Analysis of the mRNAs and the newly synthesized peptides resulted in a snapshot of the dynamic translational state of microglial ribosomes. We observed 21 upregulated and 22 downregulated proteins between the WT‐RiboTag and Th1‐APP.PS1‐RiboTag in male mice and 16 upregulated and 70 downregulated in female. Abx treatment resulted in upregulation of 39 and downregulation of 37 proteins in males while the females showed 51 and 9 respectively.

Conclusion

We find marked differences in the mRNA and proteins associated with microglial phenotypes expressed in a sex‐specific manner as a function of changes in the gut microbiome.
Brain and cognitive changes in memory systems vulnerable to Alzheimer’s disease following targeted multiday repetitive transcranial magnetic stimulation applied to healthy young adults
Authors: Phipps Connor J. , Rangel Anthony , Heller Abi M. , Phatak Vaishali S. , Murman Daniel L. , Warren David E.
Published: December 2020

Background

Aging processes — healthy and pathological — contribute to age‐related memory decline, and current treatments offer limited remediation. Targeted non‐invasive brain stimulation (NBS) of memory networks vulnerable to Alzheimer’s disease is a novel approach which can enhance memory in healthy young adults by 20% (Wang et al., 2014). To test generalizability of this finding, we are administering a clinical trial (ClinicalTrials.gov #alz045244) applying targeted NBS to healthy young adults, healthy older adults, and patients with amnestic mild cognitive impairment (aMCI). Here, we report preliminary findings from the trial arm studying healthy young adults.

Method

Our approach replicates methods from Wang et al. (2014). Healthy young adults (N = 16) completed two interventions which combined pre/post‐stimulation brain and cognitive measurement with NBS (treatment or sham for five consecutive days) in the form of repetitive transcranial magnetic stimulation (rTMS). The two interventions were identical except for rTMS parameters. Pre‐/post‐stimulation, brain measures included structural and resting‐state functional MRI data; cognitive measures included cognitive abilities (e.g., hippocampal‐dependent memory). Intervention formats applied rTMS using β‐frequency pulse sequences which alternated 2‐sec. 20 Hz stimulation with 28‐sec. rest for 20 min; the stimulation location was constant (left lateral parietal cortex coactive with a hippocampus‐centered network). Stimulation intensity was tailored to participants’ resting motor threshold (RMT) and varied by condition: treatment, 100% RMT; sham, 10% RMT. Participants completed both conditions in a counterbalanced order.

Result

We successfully mapped hippocampus‐centered functional networks in each participant and localized left lateral parietal targets for rTMS. Furthermore, we observed changes in brain and cognitive measures related to the stimulation condition. Brain measures including resting‐state functional connectivity (RSFC) revealed changes in patterns of RSFC between several areas of the hippocampus‐centered network targeted with rTMS in the treatment condition.

Conclusion

Our ongoing clinical trial measures changes in brain and cognitive variables associated with NBS of a functional brain network supporting memory. The current trial arm focused on healthy young adults, and we found evidence consistent with plasticity in the intrinsic brain network supporting memory. Findings from the remaining arms (older adults, healthy or aMCI) will inform the generalizability of our observations to populations vulnerable to Alzheimer’s disease.