bluuebunny/crossref_metadata_2025 huggingface dataset:
ACSS2 and the metabolic‐epigenetic axis in Alzheimer’s disease
Authors: Egervari Gabor , Berger Shelley L.
Published: December 2020

Background

We examine the contribution of the metabolic‐epigenetic regulatory axis1to protective histone acetylation in the brain, which is impaired in Alzheimer’s disease (AD). ACSS2 (acetyl‐CoA synthetase 2) is a key metabolic enzyme that is chromatin‐bound in neurons2. ACSS2 is recruited to specific promoters and maintains a local pool of acetyl‐CoA that fuels histone acetylation and drives the expression of key neuronal genes that regulate learning and memory.

Method

We characterize the genomic distribution of neuronal histone acetylation and ACSS2 in post‐mortem human brains from young, old and AD subjects. We also assess dynamic changes in chromatin localization and function of neuronal ACSS2 in mouse models of AD that rely on intra‐cerebral injection of human pathological AD‐tau in non‐transgenic mice3. To further establish the role of ACSS2 in AD etiology, we perform AD‐tau injections in mice lacking or overexpressing ACSS2 and assess consequent changes in AD neuropathology and phenotype.

Result

We showed that ACSS2 is required for brain histone acetylation as well as learning and memory in vivo
4. Intriguingly, we recently showed that loss of protective histone acetylation potentially underlies AD and related dementia in humans5. In post‐mortem human brains from young, old and AD subjects, we found that while normal aging is characterized by increased neuronal histone acetylation, this enrichment is lost in AD. We thus hypothesize that impaired function of ACSS2 could underlie the loss of protective histone acetylation in AD and consequent neuropathological and cognitive impairments. We anticipate that chromatin‐bound ACSS2 is lost during the development of AD and that this loss underlies subsequent changes in histone acetylation, chromatin accessibility and transcription of key neuronal genes required for learning and memory. We expect a more severe disease phenotype in ACSS2 knock‐out mice while ACSS2 overexpression might have a protective effect.

Conclusion

Overall, we expect this study to be of significant interest to the field as positive results could establish ACSS2 as a key neuroprotective metabolic enzyme and a potential new therapeutic target for humans suffering from AD. Acknowledgements: G.E. is supported by the Alzheimer’s Association Research Fellowship (AARF‐19‐618159).
Does verbal fluency test administration order impact performance?
Authors: Dominguez Antonella Yael , Aragón Irina , Sanjurjo Natalia Sierra , O´Neill Santiago
Published: December 2020

Background

Verbal Fluency Tests measure the ability to produce words in a given time. Semantic fluency (SF) is related to the production of words within a category and phonological fluency (PF) with words that start with the same letter1. These tests are frequently used in the standard neuropsychological evaluation. Age, education2,3 and the order of administration4,5 can affect the performance. This study aims to evaluate the impact in the order of administration on verbal fluences performance in spanish.

Method

Cross‐sectional analytical study.52 healthy adults participated in this study. Participants were divided into two groups (G1 and G2) matched by age (M 64.48 DS 9.37), education (M 13.21 SD 4.65), gender (F: 31 M: 17) and estimated CI level based on years of education and their performance on a word accentuation test (WAT‐R)6. In G1 it was applied first SF and later PF. In G2 the order of presentation was inverted. T test and Pearson correlations were calculated in SPSS statistical program.

Result

Two outliers were found in G1. Taking out outliers and their matches, no significant effect in the order of application was observed when comparing both groups in the SF (t= 888 p = .379) and PF (t = ‐1.510 p = .138). When analyzing whether the order of fluencies administration varied the performance in G1 and G2, no differences were found for gender but a correlation with education was observed (SF: r = .30 p = .037; PF: r = .60 p <.001) and age (SF: r = .40 p = .005; PF r = .32 p = .027). When making a more detailed analysis of the groups, significant effect was observed for the years of education and FP (p = .002): the group with less than 7 years of schooling differed from groups from 8 to 12 (p =. 012) and more than 12 years of schooling (p =. 003).

Conclusion

The results suggest that the performance in verbal fluences of older adults may be influenced by normal aging and years of education. This must be taken into account when choosing standards and interpreting the results of neuropsychological tests.
Assessment of naming by auditory confrontation in adults
Authors: Aragón Irina , Dominguez Antonella Yael , Sanjurjo Natalia Sierra , O´Neill Santiago , Rojas Galeno
Published: December 2020

Background

One of the most frequent symptoms in normal aging and in some neurodegenerative diseases is the difficulty to find words. Naming assessment is fundamental in a standard neuropsychological assessment. Even though visual difficulties have a high prevalence in older adults, visual confrontation tests have been utilized as the gold standard to detect the word finding impairment. In the Auditory Naming Test (ANT) different descriptions of objects are presented orally, and the patient should name the object described. Although there have not been published norms for adults for this test so far, the ANT has shown to be more sensitive than visual naming tests in mixed etiology dementia. The aim of this study was to analyze the ANT performance in older adults and generate normative data in Argentinian population (Spanish first language speakers).

Method

Cross‐sectional descriptive‐observational study. The participants were assessed with Spanish adaptation of ANT and Beck Depression Inventory. SPSS program was used and Pearson correlations, ANOVA, means and standard deviations were calculated.

Result

115 adults (79 women, mean age: 66.57 SD: 10.36, mean education: 13,86 SD: 5.04) without concomitant pathologies that potentially affect cognition participated were assessed (table 1). There were no differences in performance according to sex. A negative correlation with age was found (r ‐.289, p = .002). A positive correlation was found with education (r .308, p = .001). A later analysis revealed that this correlation only occurs in the group of 50‐59 years (r .605, p < .001) and 60‐69 years (r .405, p = .022).

Conclusion

In the present study, the performance in the ANT of older adults was analyzed and normative data were generated. Age and education influence the performance of this test.
Subcortical atrophy in dementia with Lewy bodies
Authors: Philippi Nathalie , Noblet Vincent , Botzung Anne , Blanc Frédéric
Published: December 2020

Background

Dementia with Lewy bodies (DLB) is typically associated to less pronounced cortical atrophy than Alzheimer’s disease (AD). However, our clinical experience suggests that DLB patients have a prominent subcortical atrophy, contrasting with overall preserved neocortical and hippocampal regions. Therefore, the objective of the present study was to test the existence of a subcortical atrophy in DLB patients as compared to AD patients and normal controls. We hypothesized that patients with DLB would have larger ventricular volumes than AD patients and controls, at least when considering the ventricular volume relatively to the global cortical volume.

Method

We included 55 DLB patients (30 mild to moderate [d‐DLB], 25 prodromal [pro‐DLB]), and compared their cerebral volumes to those of 51 AD patients (31 mild to moderate [d‐AD], 20 prodromal [pro‐AD]), matched for age, educational level and MMSE scores, and to those of 17 healthy control subjects (CS), matched for age and educational level. Total ventricular volume (TVV) volumes were extracted using freesurfer. We also examine the ratio of the TVV against the total cortical volume (Cortex). We included Total intracranial volume and age as nuisance covariates.

Result

We found that both d‐DLB group(p = 0.003) and pro‐DLB group (p = 0.006) had significantly higher TVV compared to the CS. Compared to the AD patients, TVV was significantly higher in the d‐DLB group vs. the d‐AD group (p = 0.03), though, only at the level of a trend in the pro‐DLB group vs. pro‐AD group (p = 0.055). As for the TVV/Cortex ratio, a significant difference was found for the DLB groups compared to both CS (d‐DLB: p = 0.002; pro‐DLB: p = 0.004) and AD groups (d‐DLB vs. d‐AD: p = 0.03; pro‐DLB vs. pro‐AD: p = 0.04).

Conclusion

DLB patients have higher ventricular volumes compared to healthy controls and AD patients, reflecting a larger subcortical atrophy. This was more particularly the case when considering the ventricular volume relatively to the global cortical volume, which suggests it could serve as a potential biomarker for the differential diagnosis between DLB and AD patients, even at the prodromal stage.
Cytokine profile in cerebrospinal fluid of elderly individuals is modulated by three‐month exercise intervention, in parallel with improvements of physical fitness and cognitive functions
Authors: Ukropcova Barbara , Tomkova Maria , Kovanicova Zuzana , Schon Martin , Slobodova Lucia , Straka Igor , Nemec Michal , Kosutzka Zuzana , Matejicka Peter , Turcani Peter , Sedliak Milan , Valkovic Peter , Ukropec Jozef
Published: December 2020

Background

Physical inactivity accelerates ageing‐associated cognitive decline while regular physical exercise improves neurocognitive health, in parallel with improvements of physical fitness and whole‐body metabolism. However, the knowledge on putative bioactive molecules, mediators of exercise benefits in human brain is still very limited. Our aim was to evaluate effects of the aerobic‐strength training intervention on the spectrum of chemokines/cytokines in the cerebrospinal fluid (CSF) of elderly individuals.

Method

The CSF from the subgroup of ten elderly individuals (1M/9F; controls/MCI patients 4/6; age = 65.7 ± 3.9yrs; BMI = 25.8 ± 3.5 kg/m2), who underwent 3‐month supervised aerobic‐strength training (3 × 1 h/week), was obtained by the atraumatic lumbar puncture technique before and after training intervention. Levels of 174 chemokines/cytokines were measured with the aid of the cytokine array (RayBiotech). Body weight and composition (Dual‐energy x‐ray absorptiometry/DEXA), BMI, physical fitness (VO2max, Rockport walk test) and cognitive functions (Addenbrooke's Cognitive Examination/ACE‐R, Trail making test A/TMT‐A, computerized cognitive test Cogstate) were assessed.

Result

Aerobic‐strength training improved aerobic fitness (VO2max, p = 0.03), cognitive functions (ACE‐R score, p = 0.0033; TMT‐A time score, p = 0.027; Learning/working memory, p = 0.016; Visual learning, p = 0.03) and reduced gynoid fat mass (p = 0.01). Three‐month supervised aerobic‐strength training intervention significantly modulated 5 out of 174 examined cytokines in CSF of the elderly individuals. Levels of 2 cytokines were increased by +11.7% and +11.3%, respectively (both p < 0.05), and another three cytokines displayed reduced levels >5% (p < 0.05 for all) in response to training. All distinctly regulated cytokines have previously been shown to be involved in the regulation of neuroinflammation, blood‐brain‐barrier integrity, and neuroprotection.

Conclusion

Supervised 3‐month aerobic‐strength training improved aerobic physical fitness and cognitive functions in the elderly. The distinct modulation of chemokines and cytokines in cerebrospinal fluid in response to training intervention could indicate a role of these bioactive molecules in the exercise‐induced adaptive response in human brain. Funding: APVV 15/0253, VEGA 2/0107/18, SAS‐MOST JRP 2018/10.
Probing amyloid beta dynamics in the brain using distinct strains of the neurotropic parasite Toxoplasma gondii
Authors: McGovern Kathryn E. , Cabral Carla M. , Koshy Anita A.
Published: December 2020

Background

Data suggest that amyloid beta (Aβ), produced by processing of the amyloid precursor protein, is a major initiator of Alzheimer's disease (AD) and a highly conserved anti‐microbial peptide. To gain new insights into Aβ modulation, we sought to harness the power of the coevolution between the neurotropic parasite Toxoplasma gondii and the mammalian brain. Prior studies attributed Toxoplasma‐associated protection against Aβ to increases in anti‐inflammatory cytokines (TGF‐β and IL‐10) and infiltrating phagocytic monocytes. These studies only used one Toxoplasma strain making it difficult to determine if the noted changes were associated with Aβ protection or simply infection.

Method

To address this limitation, we infected an AD mouse model with each of the genetically distinct, canonical strains of Toxoplasma (type I, type II, or type III) and assessed plaque burden, immune cell infiltration, and cytokine levels in the brain. We also assessed Aβ’s role in coordinating the immune response against the parasite by acting as a chemokine for infiltrating immune cells. Additionally, Aβ’s action against the parasite itself was assessed.

Result

We found that only type II infection was protective against Aβ deposition. Both strains elicited increased numbers of CNS T cells and myeloid lineage cells as well as elevated pro‐inflammatory cytokines, but neither group showed a >2‐fold elevation of TGF‐β or IL‐10 at the protein level. In addition to providing protection, we have gone on to show that type II infection can reduce amyloid plaque burden in mice that already exhibited plaque deposition. We also determined that infiltrating macrophages in the type II inflammatory environment are most efficient at clearing Aβ.

Conclusion

These data suggest that we can now use our identification of protective (type II) and nonprotective (type III) Toxoplasma strains to determine what parasite and host factors are linked to decreased Aβ burden rather than simply with infection. Current work is focused on defining the point at which amyloid clearance peaks, phenotyping the immune cell infiltrates that contribute to clearance, at which point excess Aβ is beneficial to the host, and whether the parasite may actively subvert the antimicrobial actions of Aβ.
Hypertension‐related white matter pattern in patients with mild cognitive impairment: A fixel‐based analysis
Authors: Tsai Chih‐Chien , Chen Yi‐Chun , Chen Yao‐Liang , Cheng Jur‐Shan , Lin Sung‐Han , Wang Jiun‐Jie
Published: December 2020

Background

Hypertension, which might contribute the white matter hyperintensities (Alber et al., 2019), is related to a higher risk of mild cognitive impairment (MCI) (Reitz et al., 2007). Studies used diffusion tensor imaging to reveal white matter lesions. In this cross‐sectional study, we used fixel‐based analysis to investigate the influence of hypertension for white matter differences in patients with MCI.

Method

The study protocol complied with the tenets of the Declaration of Helsinki and was approved by the Institutional Review Board. 80 patients with MCI (39 men and 41 girls; mean age: 68.33±7.92 years; 41 patients with hypertension), and 55 healthy control (HC, 30 boys and 25 girls; mean age: 62.02±6.99 years; 14 participants with hypertension) were recruited. MRI was performed with a 3T MR750 scanner (GE Medical Systems, Milwaukee, WI). Diffusion‐weighted images were acquired using a spin‐echo echo‐planar‐imaging sequence with TR/TE/ = 4000 ms/103.5 ms, with along 64 non‐collinear directions using b‐values of 0 and 1000 s/mm2. FBA was performed by MRtrix3 (https://github.com/MRtrix3/mrtrix3) following the recommended procedures (Raffelt et al., 2017). Fixel‐based metric, which included fiber density (FD), fiber bundle cross‐section (FC), and FDC (multiplying FD and FC) was calculated. Statistical analyses of the image were performed with the code fixelcfestat in MRtrix3 with A FWE‐corrected p < 0.05 (Nichols and Holmes, 2002).

Result

The white matter difference between HC and patients with MCI with /without hypertension was performed by the comparisons of FBA metrics. In the status without hypertension, patients with MCI reduced in FC and FDC predominantly in the posterior limb and retrolenticular part of internal capsule, superior and posterior corona radiate, when compared with HC. In the status with hypertension, patients with MCI reduced in FC and FDC predominantly in the superior cerebellar peduncle, posterior limb and retrolenticular part of internal capsule, and posterior corona radiate, when compared with HC.

Conclusion

This study provided a thorough fixel‐based metrics of white matter differences in patients with MCI and HC with new evidence of FD, FC, and FDC, which helped to clarify the pathological changes influenced by hypertension for specific white matter regions.
AAV vectors to study the functional consequences of neuronal and astrocytic tau pathology using in vivo 2‐photon imaging
Authors: Vogels Thomas , Vargova Greta , Majerova Petra , Hromadka Tomas
Published: December 2020

Background

Tau pathology is a defining histopathological feature of Alzheimer’s disease (AD) and primary tauopathies such as progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). Whereas AD is mostly characterized by neuronal tau pathology, primary tauopathies such as PSP and CBD also present with glial tau pathology. How tau pathology affects the activity of distinct neuronal cell types (e.g. interneurons) or glial cells (e.g. astrocytes) is currently unknown. We have developed adeno‐associated virus (AAV)‐based tauopathy models of neuronal and astrocytic tau pathology to study the functional consequences of tau pathology using in vivo 2‐photon imaging.

Method

We present AAV vectors expressing human truncated tau (amino acids 151‐391/4R) and red fluorophore mCherry in equal ratio under the neuronal human synapsin promotor (AAV‐hSyn‐htTau) or the astrocytic GFAP promotor (AAV‐GFAP‐htTau). AAVs expressing only mCherry under the same promotors were used as controls. AAVs were injected into the hippocampus of wild‐type mice for histological, biochemical, and behavioral characterization.

AAV‐hSyn‐htTau was injected intracerebroventricularly in PV‐Cre mice to study the effects of tau pathology on pyramidal neurons or interneurons using in vivo 2‐photon calcium imaging. AAV‐GFAP‐htTau was injected into the cortex of wild‐type or CX3CR1‐YFP mice to study the effects of astrocytic tau pathology on neuronal activity or microglia using in vivo imaging, respectively.

Result

AAV‐hSyn‐htTau and AAV‐GFAP‐htTau both induced widespread expression of mCherry and hyperphosphorylated tau in neurons or astrocytes, respectively. Only the neuronal model induced abundant sarkosyl insoluble tau and methoxy‐XO4+ aggregated tau. In vivo 2‐photon calcium imaging of cortical neurons revealed increased spiking activity in truncated tau‐expressing PV+ interneurons, but not in pyramidal cells, suggesting that tau‐mediated alteration of interneuron activity is an early pathological event. No cognitive impairments were detected at early timepoints.

Astrocytic tau pathology led to inflammatory changes of blood vessels, such as upregulation of adhesion molecules VCAM1 and ICAM1. No changes in cognition or neuronal spiking activity were detected at the examined timepoints. Analysis of microglial morphology and motility is currently ongoing.

Conclusion

AAV‐based tauopathy models are attractive tools to study the consequences of neuronal and glial tau pathology in vivo. Funding: VEGA 2/0135/18 and SyDAD (Horizon 2020, 676144)
Physical activity and sleep are each independently associated with brain function during an inhibitory task: Cross‐sectional results from the monitor‐OA study
Authors: Falck Ryan S , Hsu Chun Liang , Li Linda C , Liu‐Ambrose Teresa
Published: December 2020

Background

There is a growing body of evidence that sleep and physical activity (PA) are critical for the maintenance of brain functions that decline with age. However, few studies have examined how these lifestyle factors are independently associated with brain function. To this end, we investigated the associations of objectively‐measured PA and sleep with patterns of activation in the brain during an executive performance task using baseline data from a randomized controlled trial (RCT).

Methods

At baseline, we measured PA and sleep for 7 days using the SenseWear Mini in 61 participants. A subset of the RCT participants (n= 29) underwent a 3T MRI scan, during which we examined brain activation patterns using the Go/No‐Go executive performance task. We contrasted brain activation patterns during the GO and NOGO conditions (i.e., NOGO – Go) of accurate trials. We then performed three separate models (each controlling for age, sex, and education) wherein we examined the associations of brain activation during an inhibitory task with: 1) PA; 2) sleep duration; and 3) sleep efficiency (i.e., ratio of time spent sleeping to time spent trying to sleep). Significant clusters were corrected for multiple comparisons (p< 0.05) to determine region‐specific activation patterns.

Results

Table 1 describes our participants at baseline. Participants had a mean age of 61 years (SD= 9 years), and 79% were female. We determined that greater PA was associated with greater blood‐oxygen‐level dependent (BOLD) signal activity in the insular cortex (Figure 1A). Longer sleep duration was associated with increased BOLD signal activity in the precuneus, lingual gyrus, and lateral occipital cortex (Figure 1B). However, we did not find that sleep efficiency was associated with greater BOLD signal activity in any brain region.

Conclusions

PA and sleep duration are each associated with greater brain activation in regions which are 1) associated with executive performance; and 2) susceptible to age‐associated decline. However, sleep efficiency does not appear to be related to brain activity patterns associated with executive functions.
The impact of amyloid‐beta positivity with 18F‐florbetaben PET on neuropsychological aspects in Parkinson’s disease dementia
Authors: Na Seunghee , Jeong Hyeonseok S , Chung Yong‐An , Song In‐Uk
Published: December 2020

Background

The neuropathology of Parkinson’s disease dementia (PDD) is heterogenous, and the impact of each pathophysiology and their synergistic effects are not fully understood. The aim of this study was to evaluate the frequency of Alzheimer’s disease using 18F‐florbetaben PET imaging and the impact of co‐existence with Alzheimer’s disease on neuropsychological aspects in patients with PDD.

Method

A total of 23 patients with PDD participated in the study. All participants underwent 18F‐florbetaben PET and completed a standardized neuropsychological battery and assessment of motor symptoms. The results of cognitive tests, neuropsychiatric symptoms, and motor symptoms were analyzed between the positive and negative 18F‐florbetaben PET groups.

Result

Four patients (17.4%) showed significant amyloid burden. Patients with amyloid‐beta showed poorer performance in executive function and more severe neuropsychiatric symptoms than those without amyloid‐beta. Motor symptoms assessed by UPDRS part III and the modified H&Y Scale were not different between the two groups.

Conclusion

Amyloid PET scan of a patient with PDD can effectively reflect co‐existing Alzheimer’s disease pathology. Amyloid PET scan might be able to help physicians of PDD patients showing rapid progression or severe cognitive/behavioral features.
Biobank innovations for chronic cerebrovascular disease with Alzheimer's disease study (BICWALZS)
Authors: Son Sang Joon , Park Bumhee , Roh Hyung Woong , Kim Narae , Jo Yong Hyuk , Lee Eunyoung , Lee Kyoungmin , Lee Haelim , Ha Jae Ho , Lee Kang Soo , Kim Eun‐Joo , Seo Sang Won , Choi Seong H. , Hong Chang Hyung
Published: December 2020

Background

Biobank Innovations for chronic Cerebrovascular disease With ALZheimer’s disease Study (BICWALZS) aimed to recruit 650 individuals, aged from 40 to 90 years, to investigate how chronic cerebrovascular contribute to the brain changes or brain pathologies related to the Alzheimer’s disease (AD) process.

Method

All participants received comprehensive clinical and neuropsychological evaluations, multi‐modal brain imaging, including magnetic resonance imaging (MRI), magnetic resonance angiography, Flutemetamol positron emission tomography (PET), blood and genetic marker analyses at baseline, and a subset of participants underwent actigraphy monitoring and fibroblast sampling. Participants are to be followed annually with brief clinical assessments, and some subjects with amyloid or subcortical ischemia are evaluated biannually with the full assessment, including neuropsychological, MRI and laboratory tests.

Results

In total, 543 individuals had volunteered for this study. Among them, 345 individuals with mild cognitive impairment (MCI), 44 individuals with subcortical vascular dementia(SVaD) and 154 individuals with AD dementia (ADD)–were enrolled at baseline.

Conclusion

The BICWALZS cohort is a prospective, longitudinal cohort study that recruited participants with a wide age range and a wide distribution of cognitive status (MCI, SVaD and ADD) and it has several strengths in its design and methodologies. Details of the recruitment, study methodology, and baseline sample characteristics are described in this paper.
Understanding the MCI elderly people’s sense of well‐being through “Legacy Art Work”: A comparative study of Southeast China and Taiwan
Authors: Lin Wan‐Yu
Published: December 2020

Objective

The purpose of the research is to understand the influence of “Legacy Art Work” on the mild cognitive impairment (MCI) elderly people in cross‐Straits areas, and to discuss why these elderly people’s sense of well‐being can be improved by participating in the activity, through analyses of their feelings, life experiences and sentiment after their participation.

Methods

“Legacy Art Work” was programming initiated by Elder Share the Arts (ESTA, USA) and qualified by the official announcement as Prevention and Delayed Dementia Care Plan (PDD Care Plan, Taiwan), which believes that expressive art work can produce a happiness and stability in its participants. Through coordinated designed activities to multi artistic materials, one can enhance physical activation and attain inner peace. The research applies qualitative research method and semi‐structured interview with six elderly people, four volunteer workers and four family members in two different daycare centers associated with hospitals in both Southeast China and Taiwan.

Results

The researcher concludes as follows: I. Regarding the experiences and feelings of the elderly people while being in the activity, the elderly people who partake in the activity are significantly encouraged and willing to express more. II. Concerning the elderly people’s daily interaction with others after partaking in the activity, they become joyful and be inspired by the peers in the program of the activity. III. As for the influence of the activity on the sense of well‐being of the elderly people, the elderly people gain the sense of achievement and support from the society by their earnest commitment in the activity, and in return gratefully feedback to others.

Conclusions

These MCI elderly people’s sense of well‐being can be improved by participating through “Legacy Art Work”. Furthermore, the researchers will plan to practice the program in the Long Term Care institutions and communities in China in the near future.
Intracranial stenosis predicts cognitive decline in a memory clinic cohort
Authors: Lim Mervyn Jun Rui , Tan Chuen Seng , Gyanwali Bibek , Chen Christopher , Hilal Saima
Published: December 2020

Background

Intracranial stenosis (ICS) is associated with cognitive impairment and dementia. It is suggested that ICS significantly increases the risk of progression from mild cognitive impairment to dementia. However, data examining the effects of ICS on cognitive decline are lacking. Thus, we aimed to investigate the effect of ICS on cognitive scores over a period of three years in a memory clinic cohort.

Methods

Participants were recruited from the National University Hospital memory clinic in Singapore. Data was collected using a standardized questionnaire, physical examination and 3T MRI at baseline. ICS was defined as arterial narrowing that exceeded 50% of the luminal diameter in any of the intracranial vessels. Cognitive functioning was measured at baseline and annually for 3 years using the mini‐mental state examination, Montreal cognitive assessment (MoCA), and a detailed neuropsychological test battery that has been locally validated.

Results

311 participants attended all three follow up visits. The mean age was 71.8 ± 7.8 years and 138 (44.4%) of participants were male. A total of 54 (17.4%) participants had intracranial stenosis. ICS modified the positive association between cognitive scores of two consecutive visits. Compared to persons with no ICS, persons with ICS showed a significant difference in association in MoCA (β [Yes]: 0.84 [95%CI: 0.79 ‐ 0.90] vs. β [No]: 0.91 [95%CI: 0.87 ‐ 0.95], p‐value = 0.007), global cognition (β [Yes]: 0.93 [95%CI: 0.88 ‐ 0.99] vs. β [No]: 1.00 [95%CI: 0.95 ‐ 1.04], p‐value = 0.037), executive function (β [Yes]: 0.85 [95%CI: 0.79 ‐ 0.90] vs. β [No]: 0.78 [95%CI: 0.74 ‐ 0.82], p‐value = 0.014), and memory (β [Yes]: 0.92 [95%CI: 0.87 ‐ 0.97] vs. β [No]: 0.98 [0.95 ‐ 1.00], p‐value = 0.016). These results remained significant after controlling for other risk factors and imaging markers.

Conclusion

ICS modified the positive association between cognitive scores of two consecutive visits where the association becomes less pronounced among persons with ICS for MoCA, global cognition and memory, but more pronounced for executive function. This suggests that ICS may be a useful indicator of vascular brain damage and may warrant consideration of anti‐atherosclerotic treatment in clinical trials.
Activation of oxidative stress is associated with Aβ accumulation induced by chronic sleep restriction in rats
Authors: Zhao Beiyu , Qu Qiumin
Published: December 2020

Background

Alzheimer’s disease (AD) is the most common age‐associated neurodegenerative disease featured by progressive learning and memory deficit, and Aβ was identified as playing a key role in the process of AD. Increasing evidence suggested an association between sleep deprivation and AD. Our recent study found that chronic sleep restriction (CSR) caused cognitive impairment and Aβ accumulation in rats, but the underlining mechanism was unclear.

Method

Healthy male Sprague‐Dawley (SD) rats (10 months old) in this study were randomly separated into two groups, CSR group and control group. Rats in CSR group were put in sleep deprivation drums for 20 hours a day for 7 days, 14 days or 21 days. reactive oxygen species (ROS) was detected by chemical fluorometric method, malondialdehyde (MDA) was tested by TBA, and WST‐1 was used to detect superoxide dismutase (SOD) levels.

Result

In CSR‐rats, ROS and MDA significantly increased in hippocampus and cortex (p<0.05), while SOD declined (p<0.05). Furthermore, ROS and MDA were positively correlated with Aβ in hippocampus (ROS: r=0.7677, p=0.0002; MDA: r=0.8032, p<0.0001) and cortex (ROS: r=0.6555, p=0.0031; MDA: r=0.8024, p<0.0001), and SOD was negatively correlated with brain Aβ (hippocampus: r=‐0.7366, p=0.0004; cortex: r=‐0.5657, p=0.0144). The oxidative stress levels were negatively correlated with LRP1 (hippocampus: r=‐0.6384, p=0.0044; cortex: r=‐0.4739, p=0.0469) and positively correlated with RAGE (hippocampus: r=0.8272, p<0.0001; cortex: r=0.7130, p=0.0009). In peripheral plasma, MDA significantly increased after CSR (p<0.05), and was negatively correlated with sLRP1 (r=‐0.6804, p=0.0019) and sRAGE (r=‐0.8425, p<0.0001). SOD showed the opposite tendency (sLRP1: r=0.9194, p<0.0001; sRAGE: r=0.6790, p=0.0019).

Conclusion

Oxidative stress in brain and plasma may be involved in the CSR‐induced Aβ accumulation. The underlying mechanism may be associated with disrupted clearance of Aβ.
Evaluating NODDI‐based biomarkers of Alzheimer’s disease
Authors: Reina Julio E Villalon , Nir Talia M , Thomopoulos Sophia I , Salminen Lauren , Jahanshad Neda , Thompson Paul
Published: December 2020

Background

Multi‐compartment (MC) diffusion MRI (dMRI) models are increasingly used to evaluate brain microstructure beyond the classic diffusion tensor model (DTI). The ability to separate the neural tissue into distinct compartments, i.e., intracellular volume fraction (ICVF), extracellular volume fraction (ECVF) and free‐water (FW), offers novel biomarkers for early detection of cognitive decline and Alzheimer’s disease. The most commonly used MC model used is Neurite Orientation Dispersion and Density Imaging (NODDI). Recent evidence shows that the voxel‐wise volume fractions compartment can be wrongly estimated if the same T2 relaxation time is assumed for the gray matter (GM), white matter (WM) and corticospinal fluid (CSF). To more accurately estimate the tissue compartments, here we use a novel method recently proposed by the DMIPY package (https://github.com/AthenaEPI/dmipy), that initially estimates a response function for each brain region (GM, WM and CSF) and uses these to better estimate the ICVF and FW compartments.

Method

We analyzed ADNI‐3 multi‐shell diffusion MRI (dMRI) data to estimate NODDI measures and to assess their ability to predict mild cognitive impairment (MCI). For each measure, we used regularized logistic regression to find cohesive clusters of brain tissue that contribute to correct classification. Data included 34 participants with MCI (mean age: 75.6±7.8yrs, 22M/9F) and 74 cognitively normal individuals (CN; mean age= 74.1±7.1yrs; 25M/39F). Siemens Prisma 3T multi‐shell dMRI data included 13 b0 images, 6 b=500, 48 b=1000, and 60 b=2000 s/mm2 diffusion weighted 32 images (voxel size=2mm, TE=71ms, TR=3300ms, δ=13.6ms, Δ=35ms). We fit three types of NODDI: the classic NODDI model, the NODDI model with a GM tissue response function, and with a WM response function.

Result

The NODDI model with the GM response function increased the accuracy of the logistic regression classification (see Table 1). The highest recall was achieved by the neurite dispersion index (ODI) in all three models.

Conclusion

Adding specific response functions for the GM and WM in NODDI improved classification accuracies and recall of MCI subjects. The distribution of the classifying regions was different across the three types of NODDI (Figures 1, 2 and 3).
Relationship between visual alterations and neuropsychiatric symptoms in posterior cortical atrophy
Authors: Lipa‐Pari Karol Melissa , Ibarrola Mariana Longoria , Sosa‐Ortiz Ana Luisa , Acosta‐Castillo Gilberto Isaac
Published: December 2020

Background

Posterior cortical atrophy (PCA) is a cognitive behavioral syndrome characterized by visual and cognitive alterations that is associated with neurodegeneration of the posterior cerebral cortex (occipital, parietal and posterior temporal). 95% of these cases also present neuropsychiatric symptoms (NPS), as anxiety, depression and irritability being the most reported. Due to the early presence of visual disturbances and the dysfunction that they generate, we considered that they could influence the presentation of NPS. The objective of the study was: Describe visual disturbances, neuropsychiatric symptoms and their association in patients with PCA.

Method

Observational, descriptive and cross‐sectional study. Information was obtained from the clinical, neuro‐ophthalmological and neuropsychological evaluation of clinical records of patients with PCA, treated at the Cognitive Aging and Dementia Clinic of the National Institute of Neurology and Neurosurgery (Mexico), from January 2015 to September 2019. Sociodemographic and clinical variables of interest (visual and non‐visual alterations, NPS and baseline clinimetric measures) were analyzed. The association between visual disturbances and NPS was estimated by a bivariate analysis.

Result

The most frequent visual disturbances were difficulty reading (100%) and the visual agnosia (84.6%). The non‐visual acalculia (92.3%) and agraphia (76.9) and the NPS: apathy (76.9%) and irritability (69.2%) All patients had at least one NPS. In the bivariate analysis, a finding with clinical interest was that all patients with prosopagnosia presented anxiety, but only showed a tendency (p=0.06). It was also found that patients with visual agnosia and achromatopsia had less insomnia (p=0.03 and 0.04, respectively)

Conclusion

It was found that the presence of visual agnosia and achromatopsia were associated with the lower presence of insomnia, however, we found no pathophysiological explanation for this relationship. In accordance with our results, an association between prosopagnosia and chronic anxiety has been described, however, in our analysis, this association was marginal, perhaps due to the small number of the sample.
Quantitative neuroimaging of volume loss in persons with Alzheimer’s dementia
Authors: Meysami Somayeh , Raji Cyrus A. , Merrill David A. , Porter Verna R. , Mendez Mario F.
Published: December 2020

Background

Automated brain volumetric software programs are FDA‐cleared for clinical use. However, these programs have not yet been tested in their diagnostic utility, specifically in the clinical setting of AD.

Method

Clinically acquired volumetric MPRAGE brain MRI scans of 79 persons with a clinical diagnosis of AD (age 67.2 ± 11 years) were retrospectively reviewed and then analyzed using Neuroreader, an FDA‐cleared software program. In this sample, 54% were women. The volumes of 45 brain structures were calculated and statistically adjusted for head size, age, and gender. Regional volumes were then compared to a normative database to compute Z‐scores and percentiles for evaluating regionally specific atrophy.

Result

Persons with clinically diagnosed AD demonstrated a pattern of diffuse, global atrophy with a temporal and mesial temporal predilection. Despite exhibiting the greatest magnitude of volume loss, regions such as the hippocampus, amygdala, putamen, ventral diencephalon, left parietal lobe, and temporal lobe were in the 30th‐40th percentile compared to the normative database. These values are higher than the vendor recommended cutoff of 25th percentile for determining abnormally low brain volume.

Conclusion

Data driven quantitative thresholds for volumetrically evaluated brain atrophy on MRI scans do not currently exist in clinical practice. In our study, atrophy in patients with clinically diagnosed AD may be detected with automated brain volumetric software programs. In this study sample, regions demonstrating atrophy were in the 30th‐40th percentile as compared to patients in a healthy normative database. As such, these regions would not have been considered “abnormal” in standard cut‐offs at the 25th percentile. We suggest that regions in the 26th‐40th percentile may therefore be atrophic and future studies with larger samples should further refine these thresholds.
Alzheimer‐associated circular RNA circHOMER1 regulates synaptic gene expression and cognition
Authors: Dube Umber , Harari Oscar , Zimmerman Amber , Hafez Alexander , Brigman Jonathan , Cruchaga Carlos , Mellios Nikolaos , Benitez Bruno A.
Published: December 2020

Background

Circular RNAs (circRNAs) are an unexplored and novel type of non‐coding RNA generated by backsplicing and covalent joining of exons and introns, which are rarely translated into protein. Recent studies have demonstrated that circRNAs are enriched in the brain and differentially altered during aging. However, the mechanism of action of most brain‐expressed circRNAs remains elusive and very little is known about their relevance in neurological disorders. Here, we conducted a circular‐transcriptome‐wide analysis of the differential expression of circRNA in AD cases and their correlation with clinical and neuropathological AD severity measures.

Methods

We generated paired‐end 151‐nt, paired‐end, rRNA‐depleted, and RNA sequencing data from frozen parietal cortex tissue from 83 AD patients and 13 controls. We aligned this data to the human reference genome (GRCh38) using STAR and called circRNAs using DCC software. circRNA differential expression (DE) analysis was performed using DESeq2 software. The superior temporal cortex RNA sequencing data from the Mount Sinai Brain Bank (195 individuals) was used as replication cohort. We investigated the association of human cortical circRNA expression with AD case–control status, Clinical dementia rating (CDR) and Braak score.

Results

A total of 3,146 well‐supported circRNAs common to both the discovery and the replication datasets were analyzed. Overall, 164 circRNAs were significantly associated with at least one AD trait in the meta‐analyses. Among them, three circRNAs, circHOMER1, circKCNN2 and circMAN2A1, were significantly associated with CDR score, Braak score and case‐control status. CircHOMER1, a neuronal‐enriched circRNA abundantly expressed in the brain explained 14.3% and 5.8% of the CDR variation in both cohorts. In vivo knockdown of circHomer1 in the mouse frontal cortex alters synaptic gene expression and disrupts cognitive flexibility. Moreover, circHomer1 can bind to an RNA‐binding protein that can increase its synaptic localization. Lastly, ongoing work is aimed at understanding how circHomer1 can affect synaptic gene expression and synaptic transmission.

Conclusion

Multiple circRNAs are differentially expressed in AD brain and are associated with clinical and neuropathological traits. At least one AD‐associated circRNA regulates synaptic gene expression and cognition. circRNAs may yield novel biomarkers or therapeutic targets for AD.
Different effects of metabolic syndrome according to dementia type
Authors: Kim Yeo Jin
Published: December 2020

Background

Metabolic syndrome is a cluster of components that reflect overnutrition, which including hypertension, diabetes, dyslipidemia and obesity. Although metabolic syndrome is a risk factor of cardiovascular disease and type 2 diabetes mellitus, the association between metabolic syndrome and dementia has remained controversial. Using nationwide population cohort data, we investigated the association between metabolic syndrome and dementia in Gangwon province in South Korea.

Method

We analyzed data of Gangwon province for 127,666 individuals aged more than 60 years in the (Korean) National Health Insurance Service (NHIS) cohort who were enrolled between January 1, 2009 and December 31, 2009. Then we investigated the presence of dementia in 2017. We classified type of dementia as Alzheimer’s disease dementia (ADD) and vascular dementia (VD). Dementia including ADD and VD was defined according to criteria in the International Classification of Disease, Tenth Revision, Clinical Modification (ICD‐10‐CM) codes.

Result

Metabolic syndrome was associated with ADD, while it was not associated with VD. Previous stroke was associated with both ADD and VD. Rather than metabolic syndrome, VD was associated with smoking. All five components of metabolic syndrome associated with ADD, independently. However, among components of metabolic syndrome, only high glucose associated with VD. In ADD, it was most relevant when there were three of the five components of metabolic syndrome, while in VD, it was only relevant when there were all five components of metabolic syndrome.

Conclusion

Metabolic syndrome was associated with ADD, while was not associated with VD. VD was associated only with several risk factors that could affect the vascular state rather than metabolic syndrome. We suggested that the effect of metabolic syndrome on dementia would be different depending on the type of dementia.
Decision support models for Alzheimer’s disease and mild cognitive impairment classification based on features extracted from MRI and FDG PET
Authors: Luo Weidong , Ulug Aziz M , Magda Sebastian , Le Linh , Haxton Robert K. , Melton Robert , Miao Yu , Airriess Chris
Published: December 2020

Background

Accurate diagnosis in early Alzheimers’ disease (AD) and Mild Cognitive Impairment (MCI) is critical for patients to start treatments. In AD and MCI patients, there is a high correlation between brain atrophy and metabolism and physical and cognitive impairments. Here we evaluate the performance of machine learning models for identifying AD and MCI subjects based on features extracted from MR and FDG PET imaging.

Method

The ADNI database was used in this study. 201 AD subjects: 80f(58‐88yo), 121m(56‐90yo); 427 MCI subjects: 163f(56‐90yo), 263m(59‐93yo); and 326 NL subjects: 169f(60‐95yo), 157m(66‐91yo) were included. T1‐weighted MRI and matched F18‐FDG PET scans were processed by PETQuant (CorTechs Labs, San Diego, USA). Segmented brain volumes normalized by intracranial volume and corresponding PET ROI SUV ratios (SUVRs) were calculated. Random Forests algorithm was used in creating machine learning models. One‐third of randomly selected data were used for testing while the rest were used for training. The performance of the models and importance of their features were evaluated.

Result

Three models’ performances were evaluated. The first one used both PET SUVRs and MRI‐based volumes, and average model accuracy, recall for identifying AD, MCI and normal were 0.77 and 0.77. The top three features were right isthmus cingulate SUVR, left amygdala volume, and left hippocampus volume. The second model only used MRI, and average accuracy and recall for identifying AD,MCI and normal were 0.77 and 0.76. The top three features were left amygdala volume, left hippocampus volume, and right inferior temporal volume. The third model used PET SUVRs only, and average accuracy and recall were 0.72 and 0.72. The top three features were SUVRs from right isthmus cingulate, left medial‐parietal, and right entorhinal cortex.

Conclusion

These models showed a good classification performance among AD, MCI and normal subjects. The model using MRI and PET showed the best performance and was slightly better than using MRI data alone. The MRI model performed better than using the PET data alone. This suggests MRI volumetric measures provide a better classification power than SUVRs extracted from FDG‐PET images.