bluuebunny/crossref_metadata_2025 huggingface dataset:
Different abnormalities of electroencephalographic (EEG) markers in quiet wakefulness are related to visual hallucinations in patients with Parkinson’s and Lewy body diseases
Authors: Babiloni Claudio , Lopez Susanna , Pascarelli Maria Teresa , Lizio Roberta , Noce Giuseppe , Ferri Raffaele , Soricelli Andrea , Nobili Flavio Mariano , Arnaldi Dario , Famà Francesco , Orzi Francesco , Buttinelli Carla , Giubilei Franco , Salvetti Marco , Cipollini Virginia , Bonanni Laura , Franciotti Raffaella , Onofrj Marco , Fuhr Peter , Gschwandtner Ute , Ransmayr Gerhard , Aarsland Dag , Parnetti Lucilla , Farotti Lucia , Marizzoni Moira , D'Antonio Fabrizia , de Lena Carlo , Güntekin Bahar , Hanoğlu Lutfu , Yener Görsev , Emek‐Savas Derya Durusu , Triggiani Antonio Ivano , Taylor John‐Paul , McKeith Ian , Stocchi Fabrizio , Vacca Laura , Hampel Harald , Frisoni Giovanni B , De Pandis Maria Francesca , Del Percio Claudio
Published: December 2020

Background

Parkinson’s disease (PD) is the second‐most common neurodegenerative disorder that affects 2–3% of the population ≥ 65 years of age and may belong to cognitive deficits and dementia in 50% of cases. Disease with Lewy Bodies (DLB) is emerging as another important cause of dementia in pathological aging. PD and DLB are both due to intra‐neuronal Lewy bodies and are characterized not only by motor dysfunctions but also cognitive and/or psychiatric symptoms. An open issue is the extent to which these diseases are distinct entities. In this respect, here we compared cortical sources of resting state eyes‐closed electroencephalographic (rsEEG) rhythms in PD and DLB patients as a function of global cognitive status.

Method

Clinical and rsEEG rhythms in demographic matched PD (N = 93), DLB (N = 46), Alzheimer’s disease dementia (AD, N= 70) and healthy elderly (Nold, N = 60) subjects were available from an international archive. Pathological groups were matched as cognitive status. Individual alpha frequency peak was used to determine the delta, theta, alpha1, alpha2, and alpha3 frequency band ranges. Fixed beta1, beta2, and gamma bands were considered. The eLORETA freeware estimated rsEEG cortical sources.

Result

Compared to the Nold subjects, the AD, DLB, and PD patients showed higher widespread delta source activities and lower posterior alpha source activities. Specifically, posterior alpha source activities were more abnormal in the AD than the DLB and PD groups, while widespread delta source activities were more abnormal in the PD and DLB than the AD group. As main novel results, in relation to the DLB and PD patients with low cognitive deficits and the control groups (Nold, AD), those with high cognitive deficits were characterized by higher parietoccipital delta source activities (DLB, Figure 1) and widespread alpha sources activities (PD, Figure 2).

Conclusion

These novel results suggest that in DLB and PD patients resting in the quiet wakefulness, abnormalities in cortical neural synchronization at delta and alpha frequencies are differently related to cognitive status despite the essence of alpha‐synucleinopathy.
Influence of cerebral glucose metabolic rate on cognitive function in Alzheimer's subjects
Authors: Edison Paul , Femminella Grazia Daniela , Livingston Nicholas R , Raza Sanara , Nowell Joseph , Carver Stefan , Holmes Clive , Blunt Eleanor G , Lawrence Robert M , McFarlane Brady , Tadros George , Ritchie Craig W , Ridha Basil H , Bannister Carol , Walker Zuzana , Archer Hilary , Coulthard Elizabeth , Underwood Ben , Prasanna Aparna , Koranteng Paul , Karim Salman , Junaid Kehinde , McGuinness Bernadette , Nilforooshan Ramin , Macharouthu Ajayverma , Donaldson Andrew , Thacker Simon , Russell Gregor , Malik Naghma , Mate Vandana , Knight Lucy , Kshemendran Sajeev , Harrison John E , Brooks David J , Passmore Anthony Peter , Ballard Clive
Published: December 2020

Background

18F‐fluorodeoxyglucose‐positron emission tomography (FDG‐PET) measures regional cerebral glucose metabolism –which is a biomarker of neuronal function in Alzheimer’s disease (AD) Neuropsychological measures such as the Alzheimer’s Disease Assessment Scale – Cognitive Subscale (ADAS‐Cog) – a measure of memory, language and praxis has been used as an outcome measure in AD clinical trials. ADAS‐Cog‐12 attempts to overcome such limitations, by including an additional delayed word recall measure. The objective of this study was to compare baseline ADAS‐Cog‐12 scores with cerebral glucose metabolic rate measured with FDG‐PET with arterial input in subjects who have undergone baseline scans for the Evaluation of Liraglutide in treatment of Alzheimer’s disease (ELAD) study.

Method

107 subjects diagnosed with AD underwent baseline FDG‐PET scans with continuous online blood sampling along with discrete sampling for radioactivity and plasma glucose. They also underwent detailed neurological and neuropsychological testing including ADAS‐Cog. FDG PET was analysed using spectral analysis with arterial input and following regions were sampled : hippocampus, medial temporal lobe, temporal, anterior cingulate, posterior cingulate, frontal, parietal and occipital cortices. ADAS‐Cog scores were calculated for all the subjects.

Result

Pearson’s product‐moment correlation showed that ADAS‐Cog scores (at 0.01 level) negatively correlated with all FDG‐PET ROIs derived from spectral analysis (‐0.36≤|r|≤‐0.54). Greatest correlations occurred between ADAS‐Cog and the temporal cortex (‐0.54), parietal cortex (‐0.51) and frontal lobe (‐0.51).

Conclusion

In this study, ADAS‐Cog‐12 scores correlated well with the cerebral glucose metabolism, suggesting cerebral glucose metabolism could be used as a surrogate marker for cognitive function in Alzheimer’s disease intervention studies, and is a sensitive maker for neuronal function.
Association of white matter hyperintensities with sub‐threshold amyloid accumulation
Authors: Moscoso Alexis , Rey‐Bretal David , Silva‐Rodríguez Jesús , Grothe Michel , Schöll Michael , Aguiar Pablo
Published: December 2020

Background

Previous studies investigating the relationship between amyloid‐β (Aβ) pathology and white matter lesions have led to inconsistent results. A potential explanation for these disparities is the cross‐sectional design of most of these studies, which might have increased the confounding effect of vascular pathology. Here, we used a longitudinal design to investigate whether white matter lesion burden is associated with faster rates of longitudinal Aβ accumulation among cognitively normal older adults without PET‐evidenced Aβ pathology.

Method

One hundred fifty‐nine cognitively normal participants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) who were Aβ‐negative at baseline were examined. All the participants had a T1 and FLAIR MRI scan at baseline, as well as baseline and at least one follow‐up [18F]florbetapir PET scans acquired in 2‐year intervals for up to 8 years. The Geometric Transfer Matrix method was used to correct for partial volume effects, including those coming from spill‐in counts from the white matter. A previously defined cortical summary region including frontal, parietal, cingulate, and temporal cortices was used to assess global amyloid burden. Standardized Uptake Value Ratios (SUVR) were computed using the cerebellar gray matter as reference region. The association between global and regional white matter hypertense (WMH) burden, and Aβ accumulation was assessed using linear mixed models adjusted by demographics and baseline SUVR.

Result

Partial volume correction increased the measured annual rate of change of cortical SUVR (+2.4%) compared to non‐corrected data (+0.5%). There were no significant correlations between baseline WMH and baseline subthreshold cortical SUVR. In the longitudinal analysis, increased baseline cortical SUVR and increased baseline burden of global (p = 0.006), frontal (p = 0.006), and parietal WMH (p = 0.003) were associated with faster amyloid accumulation (Fig.1). WMH‐related Aβ accumulation occurred in parietal, frontal, and, to a lesser extent, cingulate cortices. These results remained unchanged after a sensitivity analysis excluding participants with the highest cortical SUVRs.

Conclusion

We demonstrate that a specific spatial distribution of WMH is predictive of future Aβ accumulation among cognitively normal elderly without PET‐detectable Aβ pathology. These findings add to recent studies pointing to a direct relationship between WMH and Aβ pathology in early Alzheimer’s Disease.
Tau deletion enhances neurogenesis in adult MAPT‐/‐ mice
Authors: Criado‐Marrero Marangelie , Sabbagh Jonathan J. , Blair Laura J.
Published: December 2020

Background

Tau is the major microtubule associated protein (MAPT) that, under normal conditions, supports neuronal microtubule’s stability. However, pathological tau self‐aggregates and disrupts microtubules function contributing to common hallmarks in neurodegenerative diseases like Alzheimer's disease (AD) and frontotemporal dementia (FTD). Besides dementia, tau pathology has been associated with the progressive development of behavioral symptoms because it affects brain regions in the limbic system and there are comorbid symptoms of depression with AD. However, it is not known if this is a direct consequence of neuropathological changes or a response to the psychological burden of dementia.

Methods

The current study investigated the effect of tau deletion in depressive‐like behavior and neurogenesis using the Mapt
‐/‐ mouse model, which contains a targeted deletion of tau gene. We used behavioral (forced swim, tail suspension, learned helplessness) tests and molecular (cell culture, immunohistochemistry and proteomic mass spectrometry) tools to evaluate tau‐induced changes.

Results

At 6‐months of age, we found that both female and male Mapt
‐/‐ mice are resistant to depressive behaviors. Unlike depressed patients, the hypothalamic pituitary adrenal axis was not affected in Mapt‐/‐ mice suggesting that the glucocorticoid signaling is not responsible for conferring protection from depression in these mice. Since depression has also been linked to deficient adult neurogenesis, we measured neurogenesis in the hippocampal dentate gyrus and subventricular zone using 5‐bromo‐2‐deoxyuridine (BrdU) labeling. We found that tau deletion promotes long‐lasting effects in hippocampal neurogenesis as observed at 14‐months‐old mice. Induction of proteins involved in neurogenesis was observed in limbic areas including the hippocampus, frontal cortex and amygdala of the Mapt
‐/‐ mice.

Conclusion

All together, these findings suggest that tau may have a role in the depressive symptoms observed in many neurodegenerative diseases and identify tau as a potential molecular target for treating depression.
Metabolic risk factors, but not vascular lesions and β‐amyloid, are associated with functional connectivity across the Alzheimer’s disease spectrum
Authors: Köbe Theresa , Gaubert Malo , Lange Catharina , Garnier‐Crussard Antoine , Bougacha Salma , Gonneaud Julie , de Flores Robin , Landeau Brigitte , De la Sayette Vincent , Chetelat Gael , Wirth Miranka
Published: December 2020

Background

Alzheimer’s disease (AD) is a multifactorial disease, characterized not only by pathological protein aggregation (Ab and tau), but also by early vascular dysfunctions and functional connectivity alterations (Iturria‐Medina 2016; van der Kant 2019). The study objective was to investigate the association between different markers of vascular health as well as brain β‐amyloid burden and brain network functional connectivity across the AD spectrum.

Method

The sample included 131 participants with normal cognition, subjective cognitive decline, mild cognitive impairment and clinical AD from the IMAP cohort (Caen, France). Vascular risk factors comprised mean arterial pressure, body‐mass‐index (BMI), glycemia and HbA1c levels. White matter hyperintensities (WMH) were segmented from FLAIR‐MRI using the “lesion‐segmentation‐tool” (Schmidt, 2017). Brain β‐amyloid burden was measured by the mean of AV45‐SUVR in an AD‐related neocortex mask (LaJoie 2012). Resting‐state functional connectivity (RSFC) was determined within seven predefined functional networks (Schaefer 2018, Verfaillie 2018). Partial correlation analyses were run to assess associations of vascular risk factors, total WMH load and β‐amyloid burden with RSFC. Additionally, we tested for interaction effects with β‐amyloid status in linear regression analyses. All models were age‐ and sex‐adjusted.

Result

Participant characteristics are presented in Figure 1. Across all participants, higher BMI and higher glycemia were associated with lower RSFC within the default‐mode, salience/ventral‐attention, fronto‐parietal and dorsal‐attention networks (Figure 2 and 3). Results remained significant after correction for diagnostic group status. No associations were found between RSFC and total WMH load or β‐amyloid burden (p≥0.05). There were no significant moderation effects by β‐amyloid positivity (p≥0.05).

Conclusion

These findings demonstrate that metabolic‐related vascular risk factors, but not cerebrovascular or β‐amyloid pathologies, are associated with functional connectivity specifically within cognition‐related functional networks. Our study further highlights that connectivity alterations associated with metabolic risk, previously shown in diabetes patients (Musen 2012; Chen 2015), are also present in a non‐diabetic aging and AD cohort. Given that functional connectivity supports reserve capacity, connectivity failure within higher‐order networks may limit resilience against aging and pathological processes.
Characteristics of family carers of people with Down syndrome suffering from Alzheimer’s disease
Authors: Rebillat Anne‐Sophie , Hiance‐Delahaye Anne
Published: December 2020

Background

Caring for people with dementia is highly challenging, and family carers are recognised as being at increased risk of physical and mental ill health. (Pinquart & Sorensen, 2007). People with Down syndrome (DS) face an extremely high risk to develop dementia due to Alzheimer’s disease (AD) (Ballard C et al., 2016). Risk for AD increased from 23% in those aged 50 years to 80% in those aged 65 years and above (McCarron et al, 2017). The management of these patients is particularly complex given the pre‐existing intellectual disability, behaviour and co‐morbidities (Esbensen AJ et al, 2018). Behavioural and psychological symptoms were found to be a major cause for referral (Adams et al, 2008) and caregivers reported difficulty to understand behavioural changes (Iacono T et al., 2014). Caregivers were showed to have misconceptions about AD development in DS and underutilize available resources (Ilacqua et al, 2019) but there is no data concerning family carers in particular.

Method

The aim of this study is to describe family carers of people with DS and AD followed at Lejeune Institute in Paris. Data were collected retrospectively and included family carers of patients with DS and suffering from AD followed at Lejeune Institute in Paris (France) from November 2016 to December 2019.

Result

About 600 patients with DS and aged at least 35 years have had geriatric assessments in our clinic. Around a third have developed AD. A large part of them lived in institutions but with the support of family carers who face the challenge of pathological aging.

Conclusion

It is crucial to take interest in these family caregivers because of the complexity and the burden of diagnosis of AD in DS, which institutional care does not necessarily reduce.
Southern European genetic ancestry shows reduced APOE E4 risk for Alzheimer disease in Caribbean Hispanic population
Authors: Rajabli Farid , Adams Larry D. , Tejada Sergio , Rodriguez Vanessa C. , Mena Pedro Ramon , Prough Michael , Bussies Parker , Feliciano Nereida I. , Silva‐Vergara Concepcion , Contreras Maricarmen , Hamilton‐Nelson Kara L. , Acosta Heriberto , Vance Jeffery M. , Cuccaro Michael L. , Feliciano‐Astacio Briseida E. , Beecham Gary W. , Pericak‐Vance Margaret A.
Published: December 2020

Background

The APOE ε4 allele is a major risk factor for AD whose effect shows strong racial/ethnic differences. Among non‐Hispanic White (NHW) populations APOE shows the strongest effect in Northern European (NEu) (rs429358: OR = 3.32, CI:3.20‐3.45) and has a relatively lower effect in Southern European (SEu; i.e., Iberia, Italy, etc) populations (rs429358: OR = 2.27, CI:2.06–2.50). However, it is not clear if this difference in effect is due to genetic or environmental effects. Hispanic/Latino populations with a large proportion of SEu ancestry provide a unique opportunity to assess both global SEu ancestry (i.e., genome‐wide ancestry) and local SEu ancestry (chromosome/region specific ancestry) in populations with environments distinct from SEu. Our objective is to use data from a Caribbean Hispanic Puerto Rican (CHIPR) population to assess the role of SEu genetic ancestry and the APOE gene on Alzheimer disease (AD) risk.

Method

APOE and genome‐wide genotyping were performed in 412 CHIPR (231 cases, 181 controls). Local ancestry was calculated using SHAPEIT and RFMix. Global ancestry was assessed using GENESIS. Association between affection status and APOE genotype was analyzed using logistic regression models by adjusting for age, gender, and population substructure.

Result

The admixture analysis showed that CHIPR have a substantial SEu ancestral component (∼67%). At the APOE gene, the local ancestry was 68% SEu, 20% African, and 12% Amerindian. Logistic regression model showed a significant association of the APOE ε4 risk allele with AD (CHIPR: OR = 1.9 CI:1.3‐2.8, p‐value = 4.4e‐4).

Conclusion

We found that the effect of the APOE ε4 risk allele in CHIPR with the high SEu ancestral background (∼67%) is similar to the effect observed in Southern European populations, despite having a distinct environment. Our results support the hypothesis that SEu genetic ancestry modulates the risk of APOE in CHIPRs. This suggests that subcontinental ancestry could also play an important role in modulating the risk for other known AD candidate. Studying the sub‐continental (NEu and SEu) ethnic disparity in the genetics of AD, provides critical information to advance the development of novel therapeutic measures.
LRP1 mediates tau endocytosis in a process that is modulated by apolipoprotein E
Authors: Cooper Joanna M. , Migliorini Mary , Arai Allison L. , Muratoglu Selen C. , Hyman Bradley T. , Strickland Dudley K.
Published: December 2020

Background

Cognitive decline in Alzheimer’s disease correlates with the spreading of neurofibrillary tangles consisting of aggregated forms of tau from the entorhinal cortex to synaptically connected brain regions. It is unclear how tau aggregation propagates across the brain but may involve trans‐synaptic transfer of tau between neurons or uptake of extracellular tau that is constitutively secreted from neurons. Specific receptors involved in these processes have remained elusive, and here we investigate the hypothesis that the LDL receptor‐related protein 1 (LRP1) functions as an endocytic receptor for tau.

Method

We employed 125I‐labeled tau to quantify its cellular uptake, confocal microscopy to examine its colocalization with LRP1, and surface plasmon resonance to assess direct binding of tau and phosphorylated forms of tau to LRP1.

Result

Our results reveal that monomeric tau binds LRP1 with high affinity, while curiously, phosphorylated forms of tau bind LRP1 with much lower affinity. The studies confirm that LRP1 internalization is attenuated the LRP1 antagonist RAP and is reduced by 70% in LRP1‐deficient cells. Confocal microscopy reveals that internalized tau colocalizes with LRP1 in endocytic vesicles. Most of the LRP1‐mediated uptake of tau leads to its lysosomal degradation. We also demonstrate that apolipoprotein E (ApoE) inhibits LRP1‐mediated tau internalization, with the ApoE4 isoform being a more potent inhibitor than other ApoE isoforms. Our studies in LRP1‐deficient cell lines confirm that a RAP‐insensitive second internalization mechanism occurs for tau, suggesting the existence of an LRP1‐independent receptor‐mediated process for tau uptake.

Conclusion

LRP1 functions as an endocytic receptor for tau, mediating the uptake of monomeric forms of tau resulting in its degradation. The ability of ApoE4 to modulate LRP1‐mediated uptake of tau may disrupt the normal physiological process of tau catabolism, leading to tau uptake by other mechanisms causing the spreading of neurofibrillary tangles and exacerbating the progression of tau‐mediated cognitive loss.
Serum neurofilament light and whole brain volume associate with machine‐learning derived brain‐predicted age in the British 1946 birth cohort
Authors: Wagen Aaron , Coath William , Keuss Sarah E , Buchanan Sarah M , Storey Mathew , Lu Kirsty , Pavisic Ivanna M , James Sarah‐Naomi , Street Rebecca E , Parker Thomas D , Lane Christopher A , Keshavan Ashvini , Murray‐Smith Heidi , Cash David M , Malone Ian B , Wong Andrew , Henley Susie , Crutch Sebastian J , Wellington Henrietta , Heslegrave Amanda J , Zetterberg Henrik , Fox Nick C , Richards Marcus , Cole James , Schott Jonathan M
Published: December 2020

Background

Age is the biggest risk factor for dementia, yet human brains do not age uniformly. The British 1946 birth cohort, the world’s longest continuously running birth cohort, provides a unique opportunity to assess these variations in biological ageing. So‐called ‘brain age’ is a biomarker of brain ageing, derived from machine‐learning analysis trained on a large sample of healthy brains (N=2001). Brain age has previously been related to cognitive ageing, physiological ageing and mortality risk (DOI: 10.1038/mp.2017.62), supporting the validity of this approach for assessing biological ageing.

Method

502 participants in the Insight 46 study, all born during one week in 1946, completed baseline cognitive and neuroimaging assessments at age 69‐71. 468 underwent combined 18florbetapir PET‐MRI scans, from which amyloid status (positive/negative), whole brain volume (WBV), total intracranial volume (TIV) and hippocampal volumes (HV) were derived. The T1‐weighted sequence was passed through the Brain‐age algorithm (https://github.com/james‐cole/brainageR), deriving brain predicted‐age (BPA) and brain‐predicted age difference (brain‐PAD; BPA minus chronological age). Serum neurofilament light (NFL) concentration was measured via Simoa immunoassay. A Preclinical Alzheimer’s Cognitive Composite Score (PACC) was calculated as a mean of z‐scores of the Mini‐mental state exam (MMSE), logical memory delayed recall, digit symbol substitution score and the Face‐Name test. Life course metrics (childhood cognitive scores, education level and Framingham Risk scores) were obtained from previous cohort assessments. Multivariate regression models were used to investigate whether life course metrics predict BPA, as well as whether NFL levels, brain volumes, or cognitive scores correlated with BPA, adjusting for chronological age.

Result

There was a significant difference between the 229 females assessed (mean BPA 65.2 years) compared with the 239 males assessed (mean BPA 70.7). BPA was independently associated with serum NFL concentration (p = 0.071) and inversely with whole brain volume (p < 0.001). Life course factors did not predict brain age.

Conclusion

The results showed a significant association of BPA, a cross‐sectional imaging metric, with a biochemical marker of neuronal damage (NFL) and sex. BPA has utility as an imaging metric that can integrate multiple modalities contributing to biological age, with potential as a predictive biomarker of cognitive decline.
Deep phenotyping of the 5XFAD model: IU/JAX/PITT MODEL‐AD center
Authors: Oblak Adrian L. , Carter Gregory W. , Howell Gareth , Rizzo Stacey J. Sukoff , Sasner Michael , Territo Paul R. , Ash Carl T. , Ingraham Cynthia , Kotredes Kevin P. , Bleckert Adam , Masek Marissa , Patel Neil , Chidambaram Ritesh , Ragan Tim , Lamb Bruce T. ,   MODEL‐AD
Published: December 2020

Background

Alzheimer’s disease (AD) is the most common form of dementia without an effective treatment. Animal models of AD have been valuable tools to understand familial or early onset AD, but to date have not been predictive for translational research. The Model Organism Development and Evaluation for Late‐onset AD (MODEL‐AD) Center is developing, validating, and distributing novel mouse models of late‐onset AD (LOAD) that can be used to develop novel therapeutics. Using the 5XFAD model of early onset AD, we have established pipelines to characterize models across multiple sites using biochemistry, histology, functional assays, in vivo MRI and PET imaging, and Serial Two‐Photon (STP) tomography whole brain imaging.

Methods

At designated time points, animals were subjected to the following assays: Functional ‐ behavioral testing paradigms, and in vivo MRI and PET scanning followed by secondary validation with autoradiography. Biochemistry/Histology ‐ mice were sacrificed, perfused, and tissue harvested, with half of the brain frozen and the other half fixed. On frozen tissue samples we performed bulk RNA‐seq. On fixed tissue samples, we assessed AD relevant changes using the following stains and antibodies: X34 (plaques and NFTs), Lamp1 (dystrophic neurites), Iba1 (microglia). STP Whole Brain Imaging ‐ on additional fixed tissue samples we performed whole brain imaging and regional analysis of Methoxy‐X04 labeled plaques using the TissueCyte® imaging platform.

Results

Combined assessment of the 5XFAD model revealed systematic neurodegenerative changes in the mouse brain. Multiple data sets including histology, biochemistry, RNA‐seq, transcriptomics, in vivo imaging, and STP whole brain analysis show differences throughout disease progression.

Conclusions

We utilized the well characterized 5XFAD model of AD to develop an integrated pipeline for deep phenotyping of novel mouse models of AD. This pipeline combines novel functional and anatomical assays across sites to track the ontology of AD progression, and targeted understanding of the molecular, biochemical and functional progression of AD pathology. Together, this pipeline provides a novel platform for greater understanding of LOAD mouse models and potential therapeutic approaches for AD.
Cerebral small vessel diseases are better associated with ambulatory than office blood pressure measurements
Authors: Melgarejo Jesus D. , Gutierrez Jose , Mena Luis Javier , Lee Joseph H. , Chavez Carlos A. , Calmon Gustavo , Silva Egle , Terwilliger Joseph Douglas , Vanassche Thomas , Verhamme Peter , Staessen Jan , Zhang Zhen‐Yu , Maestre Gladys E.
Published: December 2020

Background

Cerebral small vessel diseases (CSVD) is a forerunner of cognitive decline, vascular dementia, Alzheimer’s disease, and stroke. Which BP index is closest associated with CVSD remains unclear. We aimed this study to examine the association of BP levels, measured by the office and ambulatory BP monitoring (ABPM), with CSVDs, and to determine which BP indexes are better associated with CSVDs.

Method

In the Maracaibo Aging Study, 330 participants (73.3% women; mean age, 58.0 years) underwent ABPM, and magnetic resonance brain imaging to assess white matter hyperintensities (WMH), small artery disease (SAD), and silent brain infarcts (SBI), which were divided into total (SBIt), supratentorial (SBIs), and cortical (SBIc). Statistics included multivariable linear and logistic regression. In models including two BP indexes, we uncorrelated these indexes by regressing one index on the other and by using the residual of one BP index.

Result

The prevalence of SAD, SBIt, SBIs, and SBIc was 5.8%, 11.8%, 10.1%, and 6.1%; respectively. Multivariable models showed that office, 24‐h, daytime, and nighttime systolic BP (SBP) were significantly associated with WMH, SAD, SBIt, SBIs (P<0.05); all diastolic BP (DBP) indexes were related to WMH, but only nighttime DBP was associated to SAD and SBIs (P<0.05). Adjusted for office SBP, the 24‐h, daytime, and nighttime SBP remained significantly associated with WMH (P<0.01), whereas the opposite was for office SBP after adjustment by 24‐h or daytime SBP. With adjustment for office or daytime SBP, the association between SDA and SBIt with 24‐h and nighttime SBP remained significant (P<0.05); nighttime SBP was additionally related to SBIs. Daytime SBP was not associated with CVSD after adjustments by the office, 24‐h, or nighttime SBP. Adjusted for daytime DBP, nighttime DBP were significantly associated with SDA, SBIi, and SBIs (P<0.05).

Conclusion

CSVD was related to 24‐h and nighttime BP. Proper control of the ambulatory BP may reduce the risk for CSVD and associated adverse health outcomes.
Cortical microstructural changes and amyloid beta burden in cognitively normal subjective memory complainers
Authors: Chance Steven A , Torso Mario , Chiesa Patrizia Andrea , Lemercier Pablo , Vergallo Andrea , Lista Simone , Potier Marie‐Claude , Habert Marie‐Odile , Dubois Bruno , Hampel Harald ,   INSIGHT‐preAD Study Group
Published: December 2020

Background

The aim of the present study was to investigate the association between brain amyloid β (Aβ) accumulation and cortical microstructural changes in cognitively normal individuals with subjective memory complaints.

Method

A total of 258 individuals (100 males,158 females) from the Investigation of Alzheimer’s Predictors in Subjective Memory Complainers (INSIGHT‐preAD) study [Dubois et al., 2018], were included. The 18F‐florbetapir PET images were used to compute whole brain and regional standard uptake value ratios (SUVr), while T1 structural and diffusion tensor imaging (DTI) scans were analysed to calculate 3 novel cortical grey matter diffusion measures (AngleR, PerpPD and ParlPD) and the mean diffusivity (MD) [McKavanagh et al., 2019]. A linear regression model was used to study the association between the global SUVr value and whole brain cortical diffusion measures, by including the diffusion measure as the dependent variable, and age, sex, APOE genotype and global amyloid SUVr as independent predictors. Partial correlation analysis, controlling for sex, was used to investigate regional associations between SUVr and diffusion values in 6 regions of interest (bilateral anterior cingulate, posterior cingulate, frontal superior orbital, inferior parietal, precuneus, middle temporal cortex). Results were considered statistically significant after false discovery rate correction (FDR <0.05).

Result

Linear regression revealed that whole brain amyloid SUVr values were positively associated with whole brain AngleR (the angle between the principal diffusion direction and the radial minicolumn direction within the cortical grey matter) (β = 0.23, p<0.001). Regional partial correlations indicated significant associations between SUVr and AngleR regional values in left anterior cingulate cortex (r=0.168;p=0.010) and bilateral precuneus (left r=0.173;p=0.005; right r=0.178;p=0.004).

Conclusion

These results showed a significant relationship between Aβ accumulation and cortical architectural change in subjective memory complainers. The regional associations revealed the presence of microstructural changes in key regions commonly affected in the early stage of AD [Palmqvist et al., 2017]. Our novel cortical DTI measures could offer additional information about cortical changes, playing a potential role as index of “neurodegeneration” in the ATN framework [Jack et al., 2018] of Alzheimer’s biomarkers.
Dual disclosure of APOE genotyping and amyloid PET results to cognitively normal older adults: A qualitative analysis
Authors: Lee Athene K.W. , Mandel Nicolas , Popescu Dominique , Williams Randal , Alber Jessica , Thompson Louisa I.
Published: December 2020

Background

Preclinical Alzheimer’s disease (AD) is determined by biomarker risk assessment in cognitively normal individuals. Disclosure of risk is usually required for clinical drug trials targeting specific biomarkers (e.g., beta‐amyloid). More broadly, there is a growing movement towards participant engagement, which has fostered an interest in biomarker disclosure. Apolipoprotein‐E (APOE) genotype disclosure has been well researched, but less is known about dual disclosure of APOE and amyloid PET. Better understanding of how individuals and their families react to AD risk information will help refine the disclosure protocol.

Method

Qualitative interviews were completed with 15 individuals (aged 61‐73) and 10 study partners who received APOE (all e4 carriers) and amyloid PET (5 positive) results as part of clinical trial screening. Interview transcripts were coded for motivation to learn, result comprehension, emotional/behavioral impact, and decision to share results. Analysis aims to characterize APOE vs. PET disclosure experiences between participants and partners.

Result

Motivation included altruism, worries about developing AD, and access to new information and treatment. Amyloid PET was viewed as a natural follow‐up to APOE genotyping or part of a comprehensive risk assessment, not a distinct test. Interestingly, most participants had already decided to learn about APOE and amyloid PET before informing their spouses, and in the case that their spouses disagreed, invited friends as study partners. Participants and partners consistently comprehended APOE as a remote risk factor and amyloid PET as more reflective of imminent AD pathology. However, those with negative PET understood that amyloid levels change over time, questioned how close they were to the threshold, and hoped for a repeat evaluation in the future. Most partners remembered the APOE disclosure more vividly than PET. Participants reported no change in memory complaints or worries about future decline regardless of risk level. Spouses rarely expressed concerns about the participant’s memory, were generally less worried about the results, and none observed memory changes after learning the risk level.

Conclusion

Dual disclosure of APOE and amyloid PET appears to have minimal impact on perception of memory. Participants generally had stronger reactions to amyloid PET, while spouses had more vivid experience with APOE.
Psychological, brain, and hormonal factors associated with caregiver compassion fatigue, burnout, and stress
Authors: Beadle Janelle , Gifford Angela
Published: December 2020

Background

There are approximately 15 million family caregivers providing care to an individual with Alzheimer’s disease or a related dementia (Alzheimer's Association, 2015). Caregivers experience significant amounts of stress due to the challenging nature of providing care to older adults with Alzheimer’s disease and other chronic conditions. These stressors have been linked to dysregulation of hormones which can put caregivers at risk for a variety of diseases and can also negatively impact the brain. The present study (funded by the National Institute of General Medical Sciences) investigates the psychological, hormonal, and neural factors that are associated with compassion fatigue, burnout, and stress in caregivers to older adults with Alzheimer’s disease or other chronic conditions.

Method

The present study will characterize factors associated with greater caregiver compassion fatigue, burnout and stress through three aims: (1) Identify psychological and demographic factors; (2) Assess differences in brain network connectivity; (3) Measure differences in hormonal reactivity in response to emotional situations. The study is currently in the enrollment stage, and we are anticipating approximately 60 subjects by the end of the third year of the study.

Result

Because our study is still on‐going, we will discuss our preliminary results and anticipated outcomes. Pilot results show that caregivers report higher levels of momentary (state) empathy than non‐caregivers across different social contexts. Furthermore, preliminary findings demonstrate variability among caregivers in their cortisol reactivity to others’ suffering is linked to variability in prosocial behavior towards others. Other anticipated outcomes include that trait empathy will be associated with compassion fatigue, and that differences in connectivity between brain networks associated with stress and emotion will be associated with compassion fatigue and burnout.

Conclusion

The results from this study will advance our understanding of key factors associated with compassion fatigue, burnout, and stress in caregivers to older adults with Alzheimer’s disease or other chronic conditions. This study will identify psychological, neural, and hormonal variables that may be useful in the development of interventions to improve caregiver well‐being.

Reference

Alzheimer's Association. (2015). 2015 Alzheimer's Disease Facts and Figures.
Cognitive and neurodegenerative profile differences between “mismatch MCI” (A+T‐N+ MCI) And “prodromal AD” (A+T+N+ MCI) increase with time
Authors: McCollum Lauren , Das Sandhitsu R. , Wang Jieqiong , Xie Long , de Flores Robin , Wisse Laura , Xie Sharon X. , Yushkevich Paul , Wolk David A.
Published: December 2020

Background

Per the Amyloid/Tau/Neurodegeneration (A/T/N) framework, beta‐amyloid accumulates during preclinical Alzheimer’s Disease (AD), followed by tau, then neurodegeneration. As AD symptoms are most linked to tau and neurodegeneration, both are expected by the MCI stage of disease. Thus, A+T‐N+ MCI (“mismatch MCI”) is thought to have both AD pathophysiology and non‐AD pathology, with the latter (given absence of tau) driving neurodegeneration and symptoms. We investigate the cognitive and neurodegenerative profile of mismatch MCI compared to “standard” A+T+N+ MCI (“prodromal AD”).

Method

A+ (by CSF) and N+ (by hippocampal volume <90th‐percentile for A+ dementia) MCI patients from ADNI2/GO were grouped by tau status (based on CSF p‐tau): mismatch MCI (T‐; n=44; 34 followed longitudinally) and prodromal AD (T+; n=84; 61 followed longitudinally) (Table 1). Baseline AVLT immediate‐memory first trial, AVLT delayed recall, animal naming (category fluency), and Trails‐B‐minus‐Trails‐A (executive function; log‐transformed) z‐scores were compared. Longitudinal cognition was analyzed using mixed‐effects models. A Kaplan‐Meier analysis compared dementia‐free survival. Whole‐brain voxel‐wise analyses compared cortical thicknesses of each MCI group to A‐ controls. Medial temporal lobe (MTL) subregion volumes, determined using ASHS‐T1 (Xie, 2019) on T1‐weighted MRI, were compared at baseline and longitudinally.

Result

Mismatch MCI had less baseline delayed‐recall impairment (Figure 1), but was similar on other domains. Time*group interaction terms for longitudinal cognition were all significant (p<0.05), indicating slower decline in mismatch MCI (Figure 2). Mismatch MCI had longer dementia‐free survival (Figure 3, p<0.001).Whole‐brain voxel‐wise analyses revealed differential cortical thinning in MCI groups VS controls, with prodromal AD having more extensive atrophy, especially in the MTL (Figure 4). Mismatch MCI had lower mean anterior‐to‐posterior hippocampal volume ratio (p=0.016). While baseline entorhinal cortex, BA35, BA36, and parahippocampal cortex volumes were comparable (both groups had significant atrophy compared to controls), mismatch MCI had slower atrophy in these regions and the hippocampus (Table 2).

Conclusion

Mismatch MCI’s lower anterior‐to‐posterior hippocampal volume suggests possible enrichment in individuals with TDP‐43, a common non‐AD pathology, given previous work suggesting TDP‐43 preferentially affects the anterior hippocampus. Overall, these results support the concept that mismatch MCI and prodromal AD have different underlying pathologic profiles in light of their divergent cognition and neurodegenerative topography.
Omega6/omega3 ethanolamin‐containing plasmalogen (PlsEtn) ratio as a biomarker of Alzheimer's disease progression
Authors: Lorenzi Marco , Fleuriot Lucile , Debayle Delphine , Barelli Helene
Published: December 2020

Background

Single‐cell transcriptomic analysis of AD has revealed that myelination‐related processes are perturbed in brain, suggesting a key role in AD pathophysiology. Oligodendrocytes support neurons and signal transmission in the central nervous system by wrapping axons with myelin, a lipid‐rich membrane structure that depend on fatty acid synthesis and metabolism. Beside galactolipids, the major lipids of myelin are cholesterol and ethanolamin‐containing plasmalogens (PlsEtn). Polyunsaturated fatty acids (PUFA) such as docosahexaenoic acid (DHA, 22:6, omega3), eicosapentaenoic acid (EPA, 20:5, omega3), arachidonic acid (20:4, omega6), and monounsaturated fatty acid oleic acid (18:1, omega9) are the major constituent FA at the sn‐2 position of Pls. Among them, DHA is the most efficient to confer very specific physicochemical properties and membrane fluidity (Pinot et al., 2014).

Method

Our results in lipidomics reveal that brain PUFAs‐Pls levels decrease importantly in cortex T1 and particularly in the frontal white matter (FWM) of AD individuals.

Result

We hypothesized that blood and brain phospholipids deficits could be closely associated with disease progression in AD. This hypothesis is corroborated by our previous results showing statistical association between PUFA‐phospholipids (PC, PE, PS) blood concentrations and brain atrophy and cognition in the ADNI cohort (previous communication at AAIC 2018). In follow‐up analyses, we further demonstrated that blood PUFAs‐PlsEtn deficits specifically related to demyelination present the most significative statistical association between an increase of the ratio omega6/omega3 and the increase of AD severity (high disease stage).

Conclusion

Blood omega6/omega3 PUFAs‐PlsEtn ratio could be a biomarker of the demyelination process observed in AD progression.
Tau formation is associated with microglial activation in more widespread cortical areas than is amyloid deposition
Authors: Leng Fangda , Hinz Rainer , Dani Melanie , Hampshire Adam , Gentleman Steve , Brooks David J , Edison Paul
Published: December 2020

Background

Microglial activation has been found surrounding amyloid plaques and neurofibrillary tangles in brains of Alzheimer’s subjects . In‐vivo imaging using 11C‐PBR28 (a marker of translocator protein over expressed in activated microglia) has demonstrated significant correlation between both amyloid (18F‐Flutematemol PET) and tau deposition (18F‐AV1451 PET). However, it is not clear whether tau or amyloid predominantly influence microglial activation.

Methods

11C‐PBR28, 18F‐Flutematemol, 18F‐AV1451 PET scans were performed on clinically diagnosed mild cognitive impairment and Alzheimer’s dementia patients (n=20). 90‐120 minute summed 18F‐Flutematemol, 80‐100 minute summed 18F‐AV1451 and 60‐90 minute summed 11C‐PBR28 images were created. Tracer uptake in cerebellar grey matter was then sampled and individual image was divided by cerebellar uptake. The images were then smoothed with 6mm FWHM and analysed. Multiple regression analysis was performed using by VoxelStats package with 11C‐PBR28 as dependent variable, and 18F‐Flutematemol, 18F‐AV1451 and age as independent variable. Correction for multiple comparison was applied based on random field theory.

Results

In the current model, amyloid deposition was found to contribute to elevated microglial activation in the posterior part of the brain including bilateral temporal, occipital lobe and posterior cingulate. While tau deposition contributed to neuroinflammation in wide‐spread areas covering bilateral frontal, temporal, parietal, occipital lobe and cingulate cortex.

Conclusion

In the current model tau deposition had more unique contribution to microglial activation in MCI and AD cohort, suggesting that tau formation has a stronger association with microglial activation which is independent of amyloid deposition.
A review of factors that contribute to sub‐optimal medication management for older adult with dementia in residential care settings: Nurses’ perspectives
Authors: Agboji Aderonke Oluwatoyin
Published: December 2020

Background

Medication use can play an important role in the health and well‐being of people with dementia in the long‐term care facilities. However, nurses often find the process of managing medicines for this population to be complex and challenging. As a result, various strategies are being employed to facilitate the medication management process including altering or modifying medications, hiding medication in food or drink of residents, and deviation from the ‘rights’ of medication administration (Barnes et al., 2006; Mc Gillicuddy et al., 2017; Mercovich et al., 2014; Qian et al. 2018; Serrano Santos et al., 2016; Thomson et al., 2009; Verrue et al., 2011; Wright, 2002). These practices are associated with increased risk of medication errors (Kartunen et al., 2019). Despite this, factors contributing to these practices are not well understood.

Method

A comprehensive search of CINAHL, Medline, SOCIndex, PubMed, and PsychINFO databases was conducted between November and December 2019. ProQuest Dissertations and Theses and Google Scholar were used to search for gray literature. No date limitation was applied. A modified form of standardized critical appraisal tool known as mixed method appraisal tool (MMAT) was used to assess the quality of the papers (Hong, Gonzalez‐Reyes, & Pluye, 2018). Nvivo was used to extract findings. Data synthesis was done using convergent synthesis approach, more specifically, thematic analysis (Hong et al. 2017).

Result

The search resulted in 806 unique titles for screening. A total of 96 abstracts were screened, after which a full‐text review conducted for 59 articles. After the full‐text review, 12 articles were eligible to be included in the final report. The findings highlighted 2 major factors: individual and system factors

Conclusion

There is need for both individual and system interventions to facilitate safe medication management for residents with dementia.
A preliminary account of ARIA‐E in the ongoing open‐label extension phase of BAN2401‐G000‐201 in subjects with early Alzheimer’s disease
Authors: Swanson Chad J. , Lai Robert Y.K. , Bogoslovsky Tanya , Bradley Heather , Rabe Martin , Zhang Yong , Kramer Lynn D.
Published: December 2020

Background

Amyloid related imaging abnormalities – edema/effusion (ARIA‐E) are a common finding with some anti‐amyloid antibodies. BAN2401 had an ARIA‐E incidence of 9.9% at the top dose of 10 mg/kg biweekly in the 18‐month Phase 2b study BAN2401‐G000‐201. All subjects with ARIA‐E were immediately discontinued per protocol, regardless of radiologic severity or whether symptoms were noted. Here, we assess preliminary ARIA‐E rates for 10 mg/kg biweekly BAN2401 in the ongoing open label extension (OLE), while exploring the ability to dose through ARIA‐E depending on severity and whether symptoms were observed.

Methods

Magnetic resonance imaging (MRI) is conducted to monitor for ARIA‐E at 9wk, 3mo, 6mo, and 12mo over the first 12 months of BAN201 treatment in the OLE. Subjects who experience mild or moderate (severity) radiologic ARIA‐E and are asymptomatic continue dosing per protocol. Dosing is temporarily interrupted in cases of severe (moderate or severe in Japan) and/or symptomatic ARIA‐E and can be resumed up to 2 times upon resolution. Data are based on ongoing reports as of 16 January 2020.

Results

A total of 177 subjects from the core study received at least one dose of BAN2401 in the OLE, with 12 cases of ARIA‐E (2 subjects had ARIA‐E in the core) noted across the various core treatment groups during the extension. A total of 167 subjects underwent 9wk MRI, 159 subjects underwent 3mo MRI, 95 subjects underwent 6mo MRI, and 49 subjects reached 9mo of treatment. Among subjects treated with placebo in the core phase, 4/44 subjects had ARIA‐E to date in the OLE. Most events were identified at 9wk or 3mo MRI, and 11/12 cases are in ApoE4 positives. Subjects have continued with dosing in the presence of ARIA‐E in 6/12 cases (1 questionable, 1 mild, 4 moderate), and 5/6 dose‐interrupted cases have resumed dosing to date. Three (3) of the 12 cases were symptomatic, including symptoms of confusion, headache, visual disturbance. ARIA‐E and symptoms resolved in 2 cases, while one case is ongoing.

Conclusion

Updated OLE data will be presented and compared to reported rates observed and modelled (Hussein et al, 2019) from the core study.