bluuebunny/crossref_metadata_2025 huggingface dataset:
Water exchange across blood‐brain barrier is associated with CSF amyloid‐42 level in healthy older adults
Authors: Gold Brian T , Shao Xingfeng , Wang Danny JJ
Published: December 2020

Background

The purpose of this study was to identify the association between a neuroimaging measure of brain water permeability and Alzheimer’s biomarkers in healthy older adults.

Method

Thirty‐nine older adults (20 female, age=72.7±5.3 yrs) without neurological disease underwent MRI on a Siemens 3T Prisma Fit system (Erlangen, Germany) using a 64‐channel head coil. The MR pulse sequence was a diffusion prepared 3D GRASE pCASL that has been detailed previously. The CSF samples were collected by lumbar draw within 6 months of MRI scan and quantification of CSF levels of A42, tau, and p‐tau was performed. Standard neuropsychological (NP) testing was performed on 37 of the participants to evaluate the cognitive performance. CBF/ATT/kw maps were normalized into the MNI space, and regional analysis was performed on the whole brain and in the frontal/temporal/parietal lobe, and subcortical regions including hippocampus, parahippocampal gyrus, anterior/posterior cingulate cortex (ACC/PCC), precuneus, caudate and putamen. Separate linear regression analyses were run with regional kw, CBF or ATT values as the independent variable and either CSF values or NP scores as the dependent variable and age and gender as covariates.

Result

Significant associations were found between A42 and kw in the whole brain (beta=0.43, t=3.2, p=0.012) and frontal lobe (beta=0.43, 2.7=, p=0.013), after controlling for age and sex. The associations between kw and A42 were also significant in the precuneus (beta=0.46, t=3.1, p= 0.004), parietal (beta=0.56, t=3.9, p < 0.001) and temporal lobe (beta=0.42, t=2.6, p = 0.015. No significant association was found between kw and CSF tau or p‐tau levels. A significant positive correlation was found between digit symbol substitution test (DSST) and kw in frontal lobe (beta=0.38, t=2.3, p=0.028).

Conclusion

The significant associations between kw and CSF A42 level and digit symbol in healthy older adult brains suggests kw may serve as an early imaging marker of AD.
Hydrogen sulfide alleviates lipopolysaccharide‐induced memory impairment, neurodegeneration and neuroinflammation in Swiss albino mice
Authors: Kshirsagar Viplav Vitthal , Thingore Chetan , Juvekar Archana
Published: December 2020

Background

Alzheimer’s disease (AD) is a major neurodegenerative disorder characterized by Aβ‐plaque deposition, formation of neurofibrillary tangles, neuroinflammation, and neurodegeneration. Although not the initiator of the disease, neuroinflammation has been known to play a pivotal role in the pathogenesis of AD. Neuroinflammation was induced by systemic lipopolysaccharide (LPS), which expresses a cascade of enzymes leading to tau hyperphosphorylation and deposition of β‐amyloid plaques, ultimately leading to cell apoptosis. Hydrogen sulfide (H2S) has been reported to have anti‐inflammatory and neuroprotective activity, though the exact mechanism for its effect has not been explored. Thus, Sodium hydrosulfide (NaHS), a known H2S donor, was used to determine the mechanism of its neuroprotective activity in LPS‐induced apoptosis and neuroinflammation in mice.

Method

NaHS (2.5, 5, and 10 mg/kg i.p.) was administered to Swiss albino mice for 28 days. From 15th day, LPS (0.25mg/kg i.p.) was administered for 7 days along with NaHS. Memory impairment was evaluated by using Morris Water Maze (MWM) task and Y‐maze task. At the end of the experiment, animals were euthanized and brain tissue homogenates were used for evaluating biochemical parameters. Brain tissue homogenates were evaluated for anti‐apoptotic (c‐Jun and Caspase‐3), anti‐inflammatory (TNF‐α and IL‐6), antioxidant [Glutathione (GSH), superoxide dismutase (SOD) and lipid peroxidation (LPO)], and Acetylcholinesterase (AChE) activities.

Result

LPS administration significantly increased neurodegeneration and caused cognitive impairment in mice. NaHS lead to improved basal memory retention in MWM and Y‐maze tasks. Treatment with NaHS attenuated LPO which was induced by LPS. NaHS normalized the decreased levels of GSH in LPS treated groups. However, NaHS administration failed to significantly prevent increase in AChE activity. The activity of superoxide dismutase was significantly increased in NaHS + LPS treated groups. LPS upregulated c‐Jun and Caspase‐3 levels and NaHS prevented it. Increase in the expression of proinflammatory cytokines (TNF‐α and IL‐6) were significantly alleviated by NaHS treatment.

Conclusion

H2S treatment significantly attenuates LPS‐induced oxidative stress, memory deficit, neurodegeneration, and neuroinflammation. The results indicate that H2S is effective in providing protection against neurodegeneration and H2S containing hybrids can be explored further for their potential clinical use as prophylactic and symptomatic therapy in AD.
A case of progressive multifocal leukoencephalopathy with HIV positivity
Authors: Yu Yingxin
Published: December 2020

Background

We report a case of progressive multifocal leukoencephalopathy with HIV positive. We analyzed her epidemiology, clinical manifestation, neuroimaging and laboratory test.

Method

The patient was a 36‐year‐old right‐handed man with 4 months of left upper limb numb, 2 months of left limbs weak. 4 months ago, he felt cold on her left upper limb without any reason.3 months agohe suddenly couldn’t recognize his routine home way for several minutes. 2 months ago, he felt dizzy and weak on his left upper limb. He was considered as cervical spondylosis without recover after massage. His brain MRI showed his right frontal and parietal cortex ischemic, right thalamus, corona radiata and callosum ischemic infarction (subacute stage), and posterior angel of bilateral ventricles demyelination. The focus weren’t enhanced on brain enhancement MRI. He got treatment according to cerebral infarction and didn’t relieve. His blood test results showed decreased white cells, red cells and platelet count. His CSF test was normal. His serum NMDA, AQP4 antibody were all negative.1 months ago, he began to have fever and could relieve after cortisone. He couldn’t get better after antiviral therapy according to viral encephalitis. His bilateral vision suddenly got blind. His PET‐CT scan was normal. He didn’t relieve after immune globulin. His nervous system examination showed his cognitive function deceased, left central facial paralysis and left limbs upper motor neuron paralysis. His bilateral light reflex was normal. However both of his eyes couldn’t react on light. His bone marrow aspiration was normal. Finally, he got HIV test and the result was positive. His CSF and urine of JC virus PCR test were 1000000copies/ml and 2000copies/ml.

Result

He was diagnosed as progressive multifocal leukoencephalopathy and HIV infection. 1 month later, he was dead.

Conclusion

The syndromes of this case became worse and worse, but he couldn’t get right diagnose and treatment. His brain MRI image seems like ischemic stroke. The most important HIV test was done at the final stage. This case gave us a lesson and we should keep mind on HIV test.
Brahmi (Bacopa Monnieri) for dementia due to Alzheimer’s disease: Systematic review and meta‐analysis protocol
Authors: Vishnu Venugopalan Y. , Padma Vasantha , Basheer Aneesh , Gupta Anu , Kirubakaran Richard
Published: December 2020

Background

Bacopa Monnieri or Brahmi is a herb belonging to plant family Scrophulariaceae whose medicinal properties have been reported in Indian traditional medicine (Ayurveda) literature for treatment of anxiety, intellect and memory disorders. Even though there is good quality preclinical evidence on utility of Brahmi, peer‐reviewed published data on the use of the Brahmi in Alzheimer’s disease (AD) and MCI‐AD is limited. Most of the research on Brahmi are methodologically weak in design and a systematic review of the existing literature will give us the best available evidence to undertake future research including a multicentre randomised controlled trial comparing Brahmi and Choline‐esterase inhibitors.

Method

Primary objective is to determine the clinical efficacy and safety of Brahmi in people with mild, moderate or severe dementia due to AD and MCI‐AD. Secondary objective is to compare the efficacy and safety of different doses of Brahmi. We will include RCTs and quasi‐RCTs, regardless of publication status or language, that have compared Brahmi with placebo or a choline esterase inhibitor in persons with AD and MCI‐AD, irrespective of any duration of intervention including cross‐over trials. We will include individuals diagnosed with dementia due to AD or MCI‐AD according to ICD‐10, DSM IV/DSM V, NINCDS‐ADRDA or Duboi’s criteria. Brahmi of any formulation and dose given for any duration will be the intervention. Placebo or any Choline esterase inhibitor at standard doses given for AD and MCI‐AD will be the comparator.

Result

The outcomes that will be assessed are 1) Cognitive function (2) Activities of daily living 3) Behavioural disturbance 4) Clinical global impression 4) Quality of life 5) Dependency 6) Death 7) Acceptability of treatment as measured by withdrawal from trial 8) Safety as measured by the incidence of adverse effects leading to withdrawal 9) Safety as measured by the overall incidence of adverse effects. Subgroup analysis include 1) Mild, moderate and severe dementia, and those with MCI‐AD 2)Duration of intervention 3) Different doses of Bacopa

Conclusion

This systematic review and meta‐analysis will bring out the current best available evidence regarding efficacy and safety of Brahmi in treatment of AD and MCI‐AD
Population prevalence of autosomal dominant Alzheimer’s disease: A systematic review
Authors: Potter Richard R , Long Alexandra P , Lichtenstein Maya L
Published: December 2020

Background

Alzheimer's disease is the leading cause of dementia, accounting for >50% of cases. Autosomal dominant Alzheimer's Disease (ADAD) is estimated to account for approximately 1% of AD cases. Current estimates of ADAD prevalence have largely been drawn from subjects already diagnosed with dementia, thus representing a biased sample. This study aimed to perform a systematic review investigating ADAD prevalence through currently available epidemiological studies to determine whether a more accurate estimation of population prevalence can be made.

Method

A systematic review was performed. Medline, Pubmed, Web of Science, and ClinicalKey were used to locate studies pertaining to ADAD prevalence (mutations of PSEN1, PSEN2 and APP). Search terms: (Autosomal Dominant or Familial or Early Onset) and (Alzheimer’s or Dementia) and (Prevalence or Epidemiology). Inclusion criteria: Humans of any age and gender, studies after 1985, and studies available in English from any country. Exclusion criteria: case reports, case series, clinical trials, cohort studies, studies that focused on ApoE or less established genes, and studies that focused on diseases besides Alzheimer’s Disease. Two independent reviewers conducted all levels of screening, data abstraction, and quality appraisal with a third arbitrator to settle discrepancies.

Results

The search identified 2,047 titles; 650 duplicates were discarded. From the remaining 1397 titles, 147 abstracts were identified for further review. Based on predetermined criteria, 19 studies were fully reviewed and included in the study. Prevalence ranged from 0.00‐71.54%. 10 studies took samples from clinic populations, 6 specifically from a community of people diagnosed with dementia, and 3 took samples in a unique manner. 9 of the 19 studies targeted only early‐onset AD. None of the studies performed a true population prevalence without enriching or limiting the sample.

Conclusion

There is large variability in prevalence estimates of ADAD in the literature, which appears related to sample selection and methodological differences. Understanding how these prevalence estimates were obtained is important, since it informs us that, to our knowledge, a true population prevalence of ADAD does not currently exist. To develop a more accurate population prevalence of ADAD, future studies may benefit from less biased genetic screening of a population.
Reduced awareness of cognitive decline is associated with brain amyloid load in asymptomatic elderly individuals at risk for AD: A longitudinal study
Authors: Cacciamani Federica , Sambati Luisa , Houot Marion , Habert Marie‐Odile , Dubois Bruno , Epelbaum Stéphane
Published: December 2020

Background

It has recently been proposed that the awareness of cognitive decline (ACD) may already be slightly reduced in the preclinical phase of AD, in the presence of subtle cognitive changes. This is a recent field of research, and the few studies available do not allow to appreciate the actual evolution of ACD in the pre‐dementia phases of AD. The present study describes the longitudinal trajectory of an index of ACD (ACDI) over 3 years in a cohort of cognitively‐normal elderly, its association to AD biomarkers, as well as its impact on cognitive scores’ evolution.

Method

314 elderly memory complainers, as just as many study‐partners, were followed‐up for 3 years. Brain glucose metabolism and amyloid load were assessed at baseline; screening cognitive tests were performed every 6 months, and a comprehensive neuropsychological evaluation every 12 months. The ACDI was based on the subject‐informant discrepancy on a questionnaire evaluating the subject’s cognitive decline. We performed a Latent Class Linear Mixed Model (LCLMM) to identify different trends of evolution of the ACDI over time, and Generalized Linear Mixed Models to analyse the impact of the baseline ACDI on the evolution of cognitive scores.

Result

The LCLMM identified three classes of subjects sharing similar longitudinal trajectories of the ACDI. Most subjects (76.8%) have accurate ACD (Class 2), and have been considered as the reference group. 18.95% of subjects showed heightened ACD (“worried‐well” individuals). They were comparable to subjects with accurate ACD in terms of AD biomarkers. 4.25% of the sample showing low ACD had higher amyloid burden than the reference group, and were mostly men. The GLMM found no overall effect of baseline ACDI on the evolution of the cognitive scores.

Conclusion

The study of ACD in AD, its evolution and correlates is a topic of growing interest, as it is, notably, a piece of the larger understanding of the pre‐dementia phases of AD. This can be useful for a timely diagnosis of AD, and for the selection of populations to be included in clinical trials.
Cognitive performance and complex functionality in a population with mild cognitive impairment and vascular damage
Authors: Guajardo Maria Elena , Söderlund Maria Elvira , Pagotto Vanina , Schapira Marcelo , Seinhart Daniel Bernardo , Labos Edith
Published: December 2020

Background

Small vessel disease is a frequent cause of vascular damage, observed on magnetic resonance imaging and increased with age.(Pantoni, Poggesi & Inzitari,2007) One scale to assess vascular damage that correlates with cognitive measures is Fazekas scale.(Fazekas, Chawluk, et.al. 1987). Vascular damage can have an impact on cognitive and functional performance.

Method

Cross‐sectional study with prospective recruitment of patients 65 years or more, evaluated in the Geriatric Section, Italian Buenos Aires Hospital. Patients with MCI and brain MRI were included. All subjects were evaluated with a complete neurocognitive battery, and functional scales (complex activities of daily living: EFE). Patients were divided in 3 categories of vascular brain damage according to the MRI in Fazekas (F) group: 0‐1, 2 and 3. Bivariate analysis and multivariable analysis was performed. Odds ratio (OR) and confidence intervals 95% (CI) were informed.

Result

346 patients were included, women 71.7%, mean age: 77.9 (ds 6.1). Fazekas (F) categories: F0‐1: 229 (66.2%), F 2: 79 (22.8 %) y F 3: 38 (11.0 %). Patients with hippocampus atrophy (HA)119 (46.1%).There were no differences in the presence of comorbidities between the 3 categories of Fazekas. Patients with F3 were older (table1). In cognitive profile, patients with F3 showed greater impairment in executive functions and episodic memory than patients with F2 and F0‐1 (table2); in functional profile, patients with F3 showed greater impairment in complex functionality than patients with F2 and F 0‐1 (table 2). Fazekas categories were an independent factor associated with the impairment of the EFE (F3 OR 2.53 CI1.05‐6.11 p= 0.039 ) (Figure 1) and with the free memory delayed recall impairment (F3 OR: 2.84 CI 1.09‐7.43 p= 0.033) (Figure 2)

Conclusion

The results obtained show a functional cognitive profile in patients with MCI and its associations with vascular damage. Severe vascular damage was independently associated with: 1) the deterioration of complex activities of daily living as a manifestation of executive impairment and 2) the deterioration of free memory delayed recall by compromise executive control processes that is critical for to maintain, code and retrieve long time memories.
Deep multilayer brain proteomics identifies molecular networks and Netrin‐1 accumulation in Alzheimer’s disease progression
Authors: Bai Bing , Wang Xusheng , Li Yuxin , Chen Ping‐Chung , Yarbro Jay M. , Beach Thomas G. , Peng Junmin
Published: December 2020

Background

Alzheimer’s disease (AD) displays a long asymptomatic stage prior to development of dementia. Identification of molecular alterations during AD progression would provide insight into temporal alterations associated with AD.

Method

AD stage‐associated molecular networks were characterized by mass spectrometry in 90 frontal cortical tissue samples in five groups, including controls with low/high amyloid plaque and tau tangle pathology (LPC and HPC, respectively), cases with high Aβ pathology and slight mild cognitive impairment (MCI), late‐stage AD with high plaque/tangle pathology, and samples with progressive supranuclear palsy (PSP). We additionally performed whole proteome comparisons between human AD and the 5XFAD and Tau P301S mouse models. Protein targets implicated as altered by AD progression in the proteomic analyses were validated by affinity assays and immunostaining in human tissue and mouse models.

Results

AD stage‐associated molecular networks were characterized by profiling 14,513 proteins and 34,173 phosphosites in human brain with mass spectrometry, highlighting 173 protein alterations in 17 pathways. In total 16,128 proteins in 5xFAD and wild‐type mouse cortex were profiled, and share 97, 89, and 169 protein alterations with HPC, MCI, and AD, respectively, whereas Tau P301S mice share less than 15 protein alterations with each group. Neither mouse model shares more than 15 non‐tau phosphopeptide alterations with each AD sub‐group, although Tau P301S shares up to 78 phospho‐Tau peptides with human AD. During validation of proteins implicated in the proteome characterization, Netrin‐1 levels were found to increase in AD stage progression by immunoblotting but was not augmented in any other neurodegenerative disease cases tested. Additionally, affinity assays demonstrated a direct Aβ‐Netrin‐1 interaction, and immunostaining demonstrated Netrin‐1 and amyloid plaque colocalization in human AD and 5X‐FAD brain tissues, but not in Tau P301S.

Conclusion

Our proteomic analyses reveal altered proteins in AD and related mouse models. Human‐mouse comparisons suggest 5xFAD mice resemble symptomatic AD and that Tau P301S mice reproduce only AD‐related Tau phosphorylation. Netrin‐1 accumulates in AD, shows direct Aβ binding, and colocalizes with amyloid plaques in human AD and mouse 5XFAD brain tissue, and may be vital to AD pathogenesis. These results provide novel insights into AD‐associated proteins and pathways.
Volumetric multispectral optoacoustic tomography of beta‐amyloid deposits in whole mouse brain
Authors: Ni Ruiqing , Dean‐Ben Xose Luis , Rudin Markus , Shi Gloria , Chen Zhenyue , Mu Linjing , Nitsch Roger M. , Razansky Daniel , Klohs Jan
Published: December 2020

Background

The abnormal deposition of fibrillar beta‐amyloid deposits in the brain is one of the major histopathological hallmarks of Alzheimer’s disease. Currently 3D imaging using positron emission tomography for plaque visualization is of a limited resolution (1 mm) in relation to the size of mouse brain in widely used AD models.

Method

We developed a novel high‐resolution non‐invasive volumetric multi‐spectral optoacoustic tomography (vMSOT) of 100 mm resolution using amyloid probe AOI987 to visualize amyloid‐beta distribution in arcAβ and APP/PS1 transgenic mouse models of cerebral amyloidosis. Immunohistochemical staining was performed with AOI987, anti‐Aβ antibody 6E10 and fibrillar amyloid conformation antibody OC on mouse brain sections.

Result

In vivo vMSOT detects higher Aβ load in the cortex, hippocampus and thalamus of arcAβ mice, and in the cortex of APP/PS1 mice compared to non‐transgenic littermates, corresponding with immunohistochemical staining results in mouse brain sections. Confocal microscopy showed co‐localization of AOI987, 6E10 and OC to parenchymal and cerebral amyloid angiopathy in brain tissue sections from arcAb and APP/PS1 mice, thus verifying the specificity of the vMSOT amyloid imaging approach.

Conclusion

We demonstrate a new high‐resolution in vivo 3D amyloid imaging platform across the murine brain in animal models of AD pathology, which facilitates mechanistic studies and the monitoring of putative treatments targeting Aβ.
Verbal and non‐verbal auditory comprehension tests in early diagnosis of Alzheimer's disease
Authors: Fang Ting , Wu Zhong ting , Xiao Jun , Ye Fang
Published: December 2020

Background

The purposes of this study are to correlate auditory comprehension impairment with AD early development and to evaluate the verbal and non‐verbal auditory comprehension tests for early diagnosis of AD.

Method

The 24 healthy controls (HC), 30 amnestic mild cognitive impairment (aMCI) and 27 mild AD (mAD) patients were recruited. The verbal (yes‐or‐no question, listening identification and oral instruction) and non‐verbal (sound categorization, emotion judgment, beat judgement, sound naming) auditory comprehension tests were adapted to evaluate the diagnostic ability of auditory comprehension. The receiver operating characteristic curves were used to analyze the diagnostic values.

Result

All tests except for yes‐or‐no question presented moderate or higher level of positive correlation in the scores with Mini‐Mental State Examination (MMSE) and Montreal Cognitive Assessment (MOCA), among which sound naming and oral instruction were the best. Statistical analysis identified a significant difference of sound naming and verbal auditory comprehension tests in aMCI group compared with the HC group. In addition, the mAD group exhibited statistically significant difference in sound categorization, sound naming, beat judgement and oral instruction when compared with the other two groups. Oral instruction sound categorization and naming benefited better in early diagnosis than the other subtests.

Conclusion

The impairments of auditory comprehension emerge early in AD, or even aMCI patients, which worsen with the progression of the disease. The tests of sound categorization, sound naming and oral instruction exhibited better discriminative values, which might be beneficial for the early diagnosis of AD.
Mapping the contributing factors of depression in community elders
Authors: Zhao Lei , Yiu Brian , Lam Bonnie Y.K. , Biesbroek J. Matthijs , Luo Yishan , Shi Lin , Mok Vincent C.T. , Wong Adrian
Published: December 2020

Background

The contributing factors of depressive symptoms in elderlies are not known quite well. This study aims to investigate the clinical and neuroimaging risk factors of depression in community elderlies.

Method

Clinical risk factors (Table 1) and MRI scans (including T1‐weighted (T1W), T2‐weighted, FLAIR, diffusion tensor imaging (DTI)) were acquired from 609 stroke‐ and dementia‐free elderlies. T1W images were processed with AccuBrain to quantify volumes of brain anatomical structures (Table 2). White matter hyperintensities (WMHs) were automatically delineated using AccuBrain with manual correction when needed. The generated WMH masks were projected to standard space to calculate regional WMH volumes (Table 2). Other small vessel disease features, including lacunes, cerebral microbleed and enlarged perivascular spaces (EPVS) were visually rated (Table 2). Peak width of skeletonized mean diffusivity (PSMD) was calculated on DTI sequence. These imaging features and clinical variables were used to predict geriatric depression scale (GDS) with support vector regression (SVR). We compared three prediction models here: (1) with clinical variables as predictors, (2) with imaging features as predictors, and (3) with the combination of clinical and imaging features as predictors. Different feature selection methods were attempted. Statistical inference was performed with permutations to investigate the significance of individual contributing factors.

Result

Representative characteristics of the participants were shown in Table 3. For the prediction of GDS, Model 2 with imaging features was inferior to Model 1 with clinical variables (p<0.001), and Model 3 that combined both types of features did no better than Model 1 (p=0.031). In the statistical inference for Model 1 and Model 2, the significant individual risk factors (p<0.01) included clinical variables such as disturbance of gait, hypertension and frequent urine (Table 4), and imaging features such as the WMH volumes within right superior cerebellar peduncle, retrolenticular part of internal capsule and cingulum (Table 5).

Conclusion

Combining clinical variables and MRI‐based features did not achieve better prediction of GDS than using either type of features alone. WMH in specific regions may have more independent contribution to depression than other MRI‐based imaging features. These findings may help to understand the risk factors of depression in community elderlies.
A preclinical model for modulation and characterisation of neuropsychiatric disturbances in Alzheimer’s disease
Authors: Clement Amalie , Wiborg Ove , Stensballe Allan , Asuni Ayodeji A.
Published: December 2020

Background

The events that direct the shift from asymptomatic to symptomatic Alzheimer’s disease (AD) have yet to be fully characterized, however the consensus is that neuropsychiatric disturbances (NPDs) play a significant role in this. Most AD patients (80‐97%) experience at least one NPD at least once during their disease, nevertheless recognizing and treating NPDs remain a major challenge due to the poor understanding of the underlying pathology. Inflammation is thought to contribute to NPD development and ultimately exacerbate AD pathology. In AD, sleep disturbances drive neuroinflammation processes, precede clinical symptoms, and increase the risk of developing AD. Neuroinflammation can also be associated with more server NPDs and is linked to faster cognitive decline and worse prognosis. Contrary to memory and learning, which is reasonably well modelled in transgenic animals, robust preclinical models for NPDs are still lacking. We hypothesis that circadian disruption combined with chronic mild stress can introduce sleep disturbances, alter phenotypic behavior, and exacerbate AD‐related neuropathology in a common mouse model of AD.

Method

We introduced socio‐environmental stress and circadian disruption to APPPS1 and wildtype (WT) littermates, to investigate NPD‐like behavior and changes in the proteome and transcriptome.

Result

This approach altered normal circadian rhythm activity patterns and induced subtle NPD‐like behavior in both WT and APPPS1 mice. Furthermore, these conditions changed normal transcription of clock genes, particularly transcription levels of Cry1, Per1 and Per2 were changed in WT and APPPS1 mice. β‐amyloid plaque load was elevated in prefrontal cortex of APPPS1 mice and we observed changes in the hippocampal proteome of APPPS1 and WT compared to WT and APPPS1 mice under normal conditions.

Conclusion

Although further characterization of the model is needed, we believe the model presented here can increase our understanding of the circuits responsible for NPD development in AD. This may hold the key to developing better treatments for NPDs and thus improving the quality of life for both AD patients and caregivers.
Mass spectrometry measures of plasma Aβ, tau and P‐tau isoforms’ relationship to amyloid PET, tau PET, and clinical stage of Alzheimer’s disease
Authors: Bateman Randall J. , Barthelemy Nicolas R. , Benzinger Tammie L.S. , Bollinger James G. , Fagan Anne M. , Gordon Brian A. , Hansson Oskar , Holtzman David M. , Horie Kanta , Li Melody , Li Yan , Masters Colin L. , Mawuenyega Kwasi G. , McDade Eric , Morris John C. , Ovod Vitaliy , Sato Chihiro , Schindler Suzanne E. , Weiner Michael W. , Xiong Chengjie
Published: December 2020

Background

Recent advances in understanding the links between amyloid‐beta (Aβ) and specific tau isoforms in brain, cerebrospinal fluid (CSF), and blood indicate that a cascade of events of Alzheimer’s disease (AD) pathophysiology begin with detection of altered CSF and blood Aβ 42/40 ratio, followed by increases in amyloid plaques by Positron Emission Tomography (PET) scan, associated with increased phosphorylation of specific CSF tau isoforms (e.g. p‐tau217 and p‐tau181), before increases in p‐tau205, hypometabolism, and atrophy. Finally, CSF total tau increases before tau aggregation by tau PET and onset of clinical symptoms. The longitudinal tau and Aβ changes which occur in brain and CSF are now being understood in blood, enabling interpretation and understanding of AD progression in much larger and more robust populations.

Method

We compared plasma Aβ 42/40 ratios measured by mass spectrometry to measures of amyloid, tau, and clinical and cognitive status in ADNI, AIBL, Biofinder and the Knight ADRC. In order to improve racial, ethnic, educational, socioeconomic, and comorbid disease diversity, we launched the Study to Evaluate Amyloid in Blood and Imaging Related to Dementia (SEABIRD), a community‐ and clinic‐based study (goal n=1120) to mirror the demographics of the Saint Louis metropolitan area. We mapped the entire blood plasma tau protein with 15 specific regions and analyzed several plasma p‐tau isoforms (e.g. p‐tau217 and p‐tau181) by mass spectrometry and compared with CSF and PET results across two sporadic AD studies.

Result

SEABIRD participants had an initial blood collection and 25% underwent confirmatory amyloid PET. Consistent with ADNI, AIBL, Biofinder and ADRC, we found plasma Aβ 42/40 ratios had high concordance with amyloid PET. In blood plasma tau, we found that some, but not all, plasma p‐tau isoforms had a strong concordance with CSF and PET measures and that p‐tau217 was more concordant for amyloid status compared to p‐tau181. Further, plasma Aβ 42/40 and p‐tau measures identify the stage of disease as measured by PET and CSF measures, Figure 1.

Conclusion

These findings indicate that blood plasma Aβ and p‐tau measures are highly precise biomarkers of brain amyloidosis, tauopathy, and can identify stages of clinical and preclinical AD.
Cleaved Annexin A1 is elevated in neurodegenerative dementia and is associated with pathological burden of amyloid and inflammatory cytokines
Authors: Chua Xin Ying , Chong Joyce R. , Lee Jasinda , Attems Johannes , Aarsland Dag , Francis Paul T. , Lai Mitchell Kim Peng
Published: December 2020

Background

Inflammation is usually terminated by resolution, mediated by pro‐resolving mediators including Annexin A1 (AnxA1) which is known to be involved in granulocyte trafficking as well as efferocytosis of apoptotic neutrophils. Failure in resolution may lead to chronic inflammation, which has been considered a pathological hallmark of neurodegenerative diseases. We investigated the expression levels of AnxA1 in post‐mortem brain tissues and their correlation with pathological burden in dementia.

Method

Protein levels of AnxA1 were measured in post‐mortem parietal cortices (Brodmann area BA40) as well as frontal cortices (BA9) of well characterized Parkinson disease dementia (PDD), dementia with Lewy bodies (DLB), Alzheimer’s disease (AD) patients and healthy controls via immunoblotting. Amyloid and cytokines were quantified via ELISA and Luminex respectively.

Result

In BA40, expression of cleaved (33 kDa) AnxA1 was found to be elevated in DLB and AD as compared to controls. While cleaved AnxA1 (33 kDa) showed an increasing trend in BA9, the increase was not significant. In our cohort of patients with dementia, levels of cleaved AnxA1 was also positively correlated with ratio of soluble amyloid‐β42/40. In addition, as AnxA1 activation has been shown to increase production of anti‐inflammatory markers such as IL10 and IL13. We measured IL10 and IL13 and found positive correlations with AnxA1.

Conclusion

Our results suggest that elevation of AnxA1 in DLB and AD may be a compensatory response to the increased inflammation in neurodegenerative diseases, in an attempt to resolve inflammation. Previous in vitro and in vivo research also revealed elevated AnxA1 in 5XFAD mice models and in vitro AnxA1 treatment reduced pro‐inflammatory and increased anti‐inflammatory cytokines. Our results demonstrate that similar associations are observed in post‐mortem samples and suggest that AnxA1 may play a similar role in humans.
Speech and language disorders as core diagnostic tools for differentiation of neurodegenerative diseases
Authors: Vasenina Elena , Levin Oleg
Published: December 2020

Background

A patient suffering from a neurodegenerative disease may demonstrate various combinations of dysarthria, aphasia, and apraxia. Besides, a speech disorder can be a primary and dominant sign (primary progressive aphasia or apraxia), or can develop secondarily as part of general clinical picture. No unified approach to classification and diagnostics of various speech disorder forms has been developed to date. Aim: to study speech disorders in various forms of neurodegenerative diseases, to assess common structure, clinical‐neuroimaging heterogeneity, and to develop a unified algorithm for differential diagnosis.

Method

1008 patients with neurodegenerative diseases were included in the study by continuous sampling of consultant practice specializing in neurodegenerations: 234 AD, 118 DLB, 62 FTD (behavior and language variants), 366 PD, 22 PSP, 14 CBS, and 292 patients with unspecified and other forms of neurodegenerative pathology. All patients were screened for cortical speech disorders (pure dysarthria was not considered). Patients demonstrating speech and language disorders were tested using the speech disorder assessment test battery we have developed. Structural MRI was performed for all the patients with speech and language disorders to assess ROI.

Result

speech and language disorders were identified in 41% of patients in aggregate group, 78% of AD, 48% of DLB, 31% of PD, 82% of FTD, 64% of PSP, and 96% of CBS patients. Based on the detailed speech assessment battery in aggregate group of all the neurodegenerative diseases 7 subtypes of speech and language disorders were highlighted by means of cluster analysis (Figure 1), principal component method allowed to identify the most significant tests for differentiation of these forms. Aphasia forms and neurodegenerative diseases forms were matched using multinomial logistic regression (Figure 2). We identified the main ROI for all subtypes (Figure 3)

Conclusion

speech disorders in patients with neurodegenerative diseases have a specific structure with clinical‐neuroimaging heterogeneity, which allowed to develop a unified algorithm for differential diagnosis.
Shared genetic etiology underlying Alzheimer’s disease and major depressive disorder
Authors: Chiba‐Falek Ornit , Lutz Michael W , Sprague Daniel , Barrera Julio
Published: December 2020

Background

Patients with late‐onset Alzheimer’s disease (LOAD) frequently manifest comorbid neuropsychiatric symptoms with depression and anxiety being most frequent, and individuals with Major depressive disorder (MDD) have an increased prevalence of LOAD. This suggests shared etiologies and intersecting pathways between LOAD and MDD. Nonetheless, the genetic pleiotropic between LOAD and neuropsychiatric disorders, including MDD, has been understudied.

Methods

We performed pleiotropy analyses by applying a robust new statistical strategy that integrates GWAS summary statistics results for two traits, LOAD and MDD. We used LOAD and MDD GWAS datasets from the International Genomics of Alzheimer’s Project (IGAP) and the Psychiatric Genomics Consortium (PGC), respectively. We complement the study with functional genomic and bioinformatic analyses including, pathway, gene expression and eQTL analyses.

Results

We found a moderate enrichment for SNPs associated with LOAD across increasingly stringent levels of significance with the MDD GWAS association (LOAD|MDD), of maximum 4 and 8‐folds including and excluding the APOE‐region, respectively. Association analysis excluding the APOE‐region identified numerous SNPs corresponding to 40 genes, 9 of which are known LOAD‐risk loci primarily on chromosome 11 regions that contain the SPI1 gene and MS4A genes‐cluster, and others were novel pleiotropic risk‐loci for LOAD conditional with MDD. The most significant associated‐SNPs on chromosome11 overlapped with eQTLs found in whole‐blood and monocytes, suggesting functional role in gene regulation. The reverse conditional association analysis (MDD|LOAD) showed a moderate level, ∼7‐fold, of polygenic overlap, however, no SNP showed significant association. Pathway analyses replicated previously reported LOAD biological pathways related to immune response and regulation of endocytosis.

Conclusion

Here we provide insights into the overlapping genetic signatures underpinning the common phenotypic manifestations and inter‐relationship between LOAD and MDD. The outcomes of this study have several important implications to LOAD genetic architecture including, demonstration of genetic pleiotropy effects between LOAD and MDD, identification of new LOAD loci, validation of LOAD pathways. Furthermore, our data proposes genetic interpretation for the heterogeneity of depression in LOAD. These findings are impactful for the development of actionable targets for novel therapies to treat depression preceding dementia in an effort to delay or ultimately prevent the onset of LOAD.
Hippocampal atrophy is independent of amyloid status 3 years after ischemic stroke
Authors: Brodtmann Amy , Khlif Mohamed Salah , Bird Laura J. , Churilov Leonid , Cumming Toby , Werden Emilio
Published: December 2020

Background

Hippocampal atrophy, long thought to be an imaging signature of Alzheimer’s disease, is seen in a range of neurodegenerative disorders, and in association with vascular risk factors in people without dementia. We examined hippocampal volume (HV) in a group of ischemic stroke patients who participated in an amyloid PET imaging study 3 years after their stroke. Given the complex interactions between normal brain aging, vascular risk factors and brain histopathology, we hypothesized that there would be no association between HV and amyloid status.

Method

The Cognition And Neocortical Volume After Stroke (CANVAS) study is an observational cohort study of 135 patients with ischemic stroke examining brain volume and cognition over 3 years compared to healthy controls. Amyloid 18F‐NAV4694 PET imaging was offered at 3 years as a sub‐study. Only participants with usable MRI scans at 3 years were included. We report centiloids (CLs) not SUVRs for comparison of our results with others using different amyloid PET tracers. CL amyloid status was classified as: CL<15 NEGATIVE; CL 15‐25 UNCERTAIN; CL>25 POSITIVE. In addition, Brain Banking was offered to all CANVAS participants: participants are classified amyloid‐positive with Braak staging>3. We compared HVs between the amyloid‐positive and ‐negative groups and associations between co‐morbidities and vascular risk factors (VRFs) by comparing Charlson Co‐morbidity Indices (CCI) and number of VRF using Multiway ANOVA (anovan, MATLAB 2019b).

Result

One participant was Brain Banked; 34 (27 men) participated in the PET imaging sub‐study. There were no differences in years of education, VRF and CCI between PET and non‐PET participants, although PET participants had larger heads (Fig1). CCI was significantly associated with HV (p<0.0001) but CCI variability was explained by age (collinear). VRFs were not significantly associated with HV. PET participants were significantly older than the 61 (42 men) non‐PET participants (69.6+/‐8.6 vs 64.2+/‐13.5 years; p=0.037). Five participants were amyloid‐positive: Brain Bank participant (Braak Stage 5), 4 PET participants (Fig2). There was no association between amyloid CLs and HV, but amyloid positivity was associated with greater CCI.

Conclusion

In this small study of stroke patients, hippocampal atrophy occurred independently of amyloid pathology and was more associated with age and co‐morbidity.
Identification of subtypes for the behavioral variant of frontotemporal dementia based on the assessment of disinhibition and compulsion
Authors: Godefroy Valérie , Tanguy Delphine , Sezer Idil , Ber Isabelle Le , Bouzigues Arabella , Rametti‐Lacroux Armelle , Carle Guilhem , Azuar Carole , Bendetowicz David , Levy Richard , Batrancourt Bénédicte , Migliaccio Raffaella
Published: December 2020

Background

The behavioral variant of frontotemporal dementia (bvFTD) is characterized by cognitive and behavioral decline due to the progressive brain damage of frontal and temporal regions. We aimed to: 1. identify bvFTD subtypes through the behavioral assessment of social disinhibition and perseveration/compulsion; 2. disentangle the underlying functional and anatomical correlates.

Method

We assessed occurrences of 19 behaviors (derived from current clinical criteria of bvFTD) linked to disinhibition and perseveration/compulsion in a quasi‐ecological setting in 17 bvFTD patients and 16 healthy controls (HC). Subjects also underwent neurocognitive tests and a structural MRI examination. Dimensions extracted through Principal Component Analysis from the behavior variables were compared between patients and HC. A clustering approach applied to behavioral scores allowed to isolate subgroups within the patients. Voxel based morphometry (VBM) was performed to identify specific grey matter atrophy patterns in each subgroup.

Result

We identified two principal behavioral dimensions significantly different between bvFTD and HC. Using scores on these two components (labelled as Compulsion and Disinhibition), we identified two different subgroups of bvFTD patients (bvFTD‐G1 and bvFTD‐G2). BvFTD‐G1, characterized by high Disinhibition, had a small pattern of atrophy, centered on left medial anterior and posterior temporal cortices. BvFTD‐G2, characterized by high Compulsion and cognitive impulsivity, presented a more diffuse and bilateral atrophy pattern largely involving frontotemporal and subcortical regions.

Conclusion

The behavioral assessment of disinhibition and compulsion symptoms allowed the clinical stratification of bvFTD patients into more or less severe stages or forms, and the identification of specific brain circuits associated with disinhibition and compulsion.
Analysis of the relationship between MCI and metabolic syndrome‐related factors in community residents over 50 years old
Authors: Yang Yanrong , LI Zheng , Wang Yan , Pan Gaofeng , Wang Jianghong , FU Liangxiu , Hu Tingting , Gao Jing
Published: December 2020

Background

Current studies had shown that cognitive impairment related to metabolic syndrome, but the relationship between the two has not determined absolutely. Mild Cognitive impairment (MCI) has a high incidence in cognitive impairment and is the early stage of dementia. The analysis of the correlation between MCI and metabolic syndrome related factors can help prevent and cure mild cognitive impairment in the early stag, and reduce the occurrence of dementia and reduce the social burden.

Method

We enrolled 235 cases in community over the age of 50 years. We used the Montreal Cognitive Assessment (MoCA) to assess cognitive function, screening the patients with mild cognitive impairment, and Analyzed the cognitive function and factors associated with metabolic syndrome, such as creatinine (CREA), urea(UA), blood glucose (GLU), low density lipoprotein cholesterol (LDL), very low density lipoprotein cholesterol (VLDL), body mass index (BMI), waist hip ratio (WHR), systolic blood pressure (SBP), diastolic blood pressure(DBP).

Result

The prevalence of mild cognitive impairment was about 79.2%)n=187( among community residents over 50 years old. Comparing to normal cognitive function group and mild cognitive impairment group, the blood glucose and systolic blood pressure showed significant differences( (P<0.05)),and no significant differences in CREA,UA,LDL,VLDL,BMI,WHR,DBP. Compared to normal blood glucose group, the score of executive, calculation and naming in high blood glucose were decreased, and the differences were significant (P<0.05). Compared to normal systolic blood pressure group, the Score of letter fluency in high systolic blood pressure was decreased, and the differences was significant (P<0.05).

Conclusion

The incidence of MCI in community residents over the age of 50 was high, which was closed related to blood glucose and systolic blood pressure. High blood glucose can reduce the patient’s ability of executive, calculation and language, and high systolic blood pressure can reduce letter fluency. Control the metabolic syndrome related factors, can reduce the incidence of mild cognitive impairment, benefit to the life quality of community residents.