bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of APOE4 on Alzheimer’s disease, Lewy body disease, cerebral amyloid deposition and cognitive dysfunction
Authors: Jung Jin Ho , Jeong Seong Ho , Jeon Seun , Baik Kyoungwon , Lee Yang Hyun , Chung Seok Jong , Yoo Han Soo , Sohn Young H. , Lee Phil Hyu , Ye Byoung Seok
Published: December 2020

Background

We investigated the effects of apolipoprotein E e4 allele (APOE4) on the risk of Alzheimer’s disease (AD) and/or Lewy body disease (LBD), cerebral amyloid deposition, and cognitive dysfunction.

Method

We consecutively recruited 131 control subjects and 208 (110 non‐demented and 98 demented) patients with AD and/or LBD. Patients were categorized into typical AD (pure AD and Lewy body variant of AD), typical LBD (pure LBD and LBD with amyloid deposition), and typical AD with LBD based on clinical features and biomarker evidence from 18F‐Florbetaben (FBB) positron emission tomography (PET) and dopamine transporter PET. Logistic regression analysis was performed to investigate whether APOE4 increased the risk for each disease. General linear models (GLMs) were performed to investigate the independent and interaction effects of APOE4, typical AD and typical LBD on cerebral FBB deposition, cross‐sectional cognition and the rate of longitudinal cognitive decline.

Result

APOE4 increased the risk of pure AD, AD with DLB, Lewy body variant of AD, and DLB with amyloid deposition, but did not increase the risk of pure LBD. In overall participants, APOE4 increased the risk of typical AD, but not typical LBD. APOE4, typical AD and typical LBD were positively associated with occipital FBB deposition; typical LBD was associated with higher occipital FBB deposition in the absence of typical AD; and APOE4 was associated with higher occipital FBB deposition in the presence of typical LBD. In GLMs for cross‐sectional cognition, APOE4 was associated with lower scores in verbal memory tests and higher clinical dementia rating sum of boxes (CDR‐SOB); it was associated with higher CDR‐SOB in the presence of typical LBD and lower scores in verbal memory tests in the presence of typical AD. APOE4 had no significant effects on the rates of longitudinal cognitive changes.

Conclusion

APOE4 is associated with increased risks of AD and amyloid deposition but not with LBD. APOE4 and typical LBD are independently and synergistically associated with occipital amyloid deposition. APOE4 interacts with typical AD on poor memory function and interacts with typical LBD on higher CDR‐SOB cross‐sectionally, but did not have significant effects on longitudinal cognitive decline.
From systems biology to precision medicine: Leveraging heterogeneity
Authors: Saykin Andrew J.
Published: December 2020

Background

Knowledge regarding cognitive decline in older adults with Alzheimer’s disease and related disorders (AD/ADRD) has accumulated rapidly but has not yielded disease modifying therapies or prevention. Clinical and biological heterogeneity are key challenges for identification of viable therapeutic targets. Some degree of mixed pathology is typical and it seems increasingly unlikely that targeting amyloid beta or tau alone will arrest AD progression. A precision medicine approach leveraging heterogeneity to tailor therapeutic strategies to an individual’s biological and phenotypic profile may prove more effective.

Method

Data and analytic approaches are growing rapidly, e.g., the ADNI cohort includes over 2000 individuals at various stages along the AD continuum followed longitudinally with various combinations of cognitive assessment, multi‐modal MRI, PET (FDG, amyloid & tau) as well as biosample collection for genomics, proteomics and metabolomics assays. Other clinic‐ and community‐ based cohort studies are also collecting rich high dimensional data sets of various types. Genomic data is accumulating on an unprecedented scale with the NIA AD initiatives anticipating the availability of 50,000 complete human genomes for analysis in the coming years. In parallel, human brain bank derived neuropathology and –omics data and model systems for AD are being developed, validated and leveraged for therapeutic development. Multi‐scale analytic strategies are needed to identify informative and actionable features from such large and high‐dimensional data sets.

Results

Evidence demonstrating that AD is biologically “complex,” involving multiple risk genes and biological pathways, and lifestyle factors leading to gene by environment interactions will be reviewed. One promising approach to addressing biological complexity is development of polygenic risk scores (PRS), which aggregates small susceptibility and protective effects from various genes and pathways into a composite measure. Second generation PRS are endophenotype‐specific targeting genetic influences on A/T/N, vascular, inflammatory and other AD related pathways.

Conclusion

Mapping between phenotypic and biological heterogeneity remains a work in progress. The current NIA‐AA research framework emphasizes biomarker‐based classification, which is important for properly targeted clinical trials. We hypothesize that a systems approach incorporating polygenic profiling across disease dimensions may provide a basis for tailored therapeutics during the earliest stages of disease.
Imaging genomics in the ENIGMA Consortium
Authors: Thompson Paul M
Published: December 2020

Background

We offer an update on recent work by the ENIGMA Consortium, CHARGE Consortium, and UK Biobank ‐ and a worldwide alliance of over 1,400 scientists ‐ to understand how human genetic and epigenetic variation affect biomarkers of brain aging and Alzheimer's disease (AD).

Method

For 10 years, ENIGMA, CHARGE, and (more recently) the UK Biobank have screened the genomes and neuroimaging data from over 50,000 persons worldwide, as well as epigenome‐wide methylation data, to ask: (1) which common and rare genetic variants affect the brain throughout life? (2) which variants affect brain aging and biomarkers of AD ‐ such as hippocampal volume, longitudinal brain atrophy rates over time, and white matter hyperintensities? (3) how do AD risk variants, in APOE and elsewhere, affect brain biomarkers from youth to old age? For 10 years, we harmonized analyses of worldwide anaotmical MRI, diffusion MRI, rsFMRI, and EEG markers across over 200 cohorts, to examine how genome‐wide genomic variation and epigenetic variants affect structural and functional biomarkers of aging and AD.

Result

GWAS in over 51,662 persons revealed over 200 common genetic variants affecting cortical architecture; of 255 nominally significant loci (P ≤ 5 × 10−8); 199 survived multiple testing correction (P ≤ 8.3 × 10−10; 187 surface area; 12 thickness). Variation in cortical and hippocampal structure is genetically correlated with cognitive function, AD, Parkinson’s disease, insomnia, major depression and ADHD. ENIGMA's Plasticity Working Group analyzed longitudinal MRI data of 10,163 persons aged 4 to 99 years, and discovered 5 genome‐wide significant loci and 15 genes influencing brain change rates at different times throughout life, and an age‐dependent effect of the APOE haplotype on brain structure. These age‐dependent influences of common genetic variants implicate immunological and metabolic processes. Epigenome‐wide screens revealed additional loci where methylation levels robustly associate with hippocampal volume in cohorts worldwide.

Conclusion

Common genetic variants affect rates of brain change, hippocampal and regional cortical measures, throughout life; coordinated analyses of harmonized data are revealing the timing of genetic and epigenetic drivers of brain aging, and the first catalogs of common variants that associate with longitudinal markers of brain aging.
Does oxaloacetate preserve mitochondrial function in the aged brain?
Authors: Gupte Raeesa , Keselman Paul L. , Christian Sarah K. , Hu Jinxiang , Swerdlow Russell H. , Harris Janna L.
Published: December 2020

Background

Age is the main risk factor for many neurodegenerative disorders including Alzheimer’s disease (AD). One hallmark of brain aging is mitochondrial impairment resulting in bioenergetic dysfunction. Therefore, limiting age‐related decline in mitochondrial function may be an attractive therapeutic strategy to mitigate the risk of AD. Oxaloacetate (OAA) is a metabolic intermediate in the TCA cycle, gluconeogenesis, and amino acid biosynthesis. Treatment with OAA has been shown to enhance neuronal bioenergetics, neurogenesis, and mitochondrial biogenesis in young adult mice, but its effects in aged subjects are unknown. We sought to determine whether OAA treatment in aged rats can alter brain metabolism and mitochondrial function.

Method

In aged male F344 rats (20‐22 months) we used in vivo proton magnetic resonance spectroscopy (1H‐MRS) to obtain baseline neurometabolic readings from two regions of interest: Ctx+ (cortex and subcortical tissue) and Hipp (hippocampus and dorsal striatum). We then treated rats with 1 g/kg/day i.p. OAA (n=14) or vehicle (n=14) for 7 days, followed by post‐treatment 1H‐MRS scans. On day 8 we used an Oxygraph‐2k to compare brain mitochondrial respiration in the OAA vs. vehicle‐treated groups.

Result

OAA treatment significantly increased levels of N‐acetylaspartate, glutamate, aspartate, phosphocreatine, lactate, alanine, and ascorbate in a region‐dependent manner. No significant differences were observed in mitochondrial respiratory flux between the OAA and vehicle‐treated groups.

Conclusion

After 1 week of treatment with OAA, aged rats showed changes in brain metabolites linked with bioenergetic function but did not show significant differences in the kinetics or capacity of brain mitochondrial respiration. These findings diverge from previously reported effects of OAA in younger adult mice, highlighting the critical importance of testing novel AD therapies across a range of ages.
MRI decline pattern in early onset MCI due to Alzheimer’s disease
Authors: Contador José , Sala‐Llonch Roser , Pérez‐Millan Agnés , Balasa Mircea , Borrego‐Écija Sergi , Sanchez‐Valle Raquel , Lladó Albert ,   Alzheimer’s Disease Neuroimaging Initiative
Published: December 2020

Background

Structural neuroimaging longitudinal studies in Alzheimer’s disease (AD) have consistently defined a “cortical signature” of gray matter loss. Apparently, early‐onset AD (EOAD) has a greater density of amyloid, a more generalized atrophy and a more aggressive evolution than late‐onset AD (LOAD). We hypothesize EOAD would show pronounced longitudinal cortical atrophy, especially in associative areas like precuneus and in addition to temporal lobe loss.

Methods

We investigate longitudinal 3T‐MRI structural data from the Alzheimer’s disease Neuroimaging Initiative (ADNI) 2 cohort. We included patients aged ≤65 years with a baseline mild cognitive impairment (MCI) diagnosis. According to AD biomarkers at baseline, patients were divided into MCI due to AD with high likelihood (MCI‐AD) and MCI unlikely due to AD (MCI‐nonAD). We downloaded the summary of longitudinal measures for volume and cortical thickness. We used linear mixed effects in SPSS25 with data at baseline and month 24 to compare atrophy progression between groups. We focused on “AD's cortical signature”, including entorhinal, inferior temporal, middle temporal, inferior parietal, fusiform areas, and also precuneus and posterior cingulate. In addition, we studied volume of hippocampus (HpV) and total subcortical supratentorial (SSupratV). We tested for group by time interactions and significance level was set at p<0.05, FDR corrected.

Results

We included 22 MCI‐AD and 26 MCI‐nonAD patients. MMSE mean score was lower in MCI‐AD [Table1]. MCI‐AD had significant lower baseline Cth in precuneus, middle temporal and entorhinal and lower HpV. At group by time interactions, MCI‐AD showed significant greater CTh atrophy in middle temporal, enthorhinal and posterior cingulate, and higher volume decrease in HpV and SSupratV than MCI‐nonAD [Figure1]. Notably, the rest of areas studied were not significantly different at baseline or at group by time effects.

Conclusion

Compared to MCI‐nonAD, MCI‐AD showed greater decline in only some of the areas previously defined as the cortical AD signature and in hippocampal volume and global subcortical volume. The study could be biased by the small sample size, by the age being close to LOAD and by no stratification by clinical symptoms. Further analyses are needed to understand AD atrophy progression pattern in relation to age at onset.
Oral administration of Byrophyllum pinnatum flavonoid ameliorates cognitive impairment via modulating cortical neurochemicals and oxidative stress in aluminum chloride‐induced Alzheimer’s disease‐like condition in wistar rats
Authors: Ogidigo Joyce Oloaigbe
Published: December 2020

Background

Aluminum, a potent neurotoxicant is a major risk factor involved in the perturbation of neurochemicals leading to the development and progression of Alzheimer’s disease. Byrophyllum pinnatum is widely distributed in Southern Nigeria and used locally for the treatment of various ailments including neurological disorders. This study was aimed to access the neuro restorative potential of B. pinnatum flavonoids (BPF) in aluminum chloride (AlCl3)‐induced AD‐like condition in Wistar rats

Methods

B. pinnatum flavonoids were characterized using FTIR and ultra‐high‐performance Liquid chromatography coupled with a mass spectrometry UPLC‐MS/MS. Thirty (30) male adult Wistar rats were used in this study and divided into five groups (n=6). Symptoms mimicking AD were induced in rats by administering 150mg/kg b.w of AlCl3 orally for 21 days. After the induction, animals were divided into five groups (n=6) and treated with BPF (50 and 100 mg/kg body weight) and 3 mg/kg of Rivastigmine for another 21 days. Neuro behavioral activities were assessed using Morris water maze tasks. Acetyl‐cholinesterase (AChE), BACE‐1 and oxidative stress markers were assessed following standard protocols. Semi‐quantitative reverse transcriptase‐PCR (RT‐PCR) was used to access the expression patterns of AChE and BACE‐1 mRNA in the cortex of rats.

Results

Characterization of BPF revealed the presence of flavonols and flavone as the major constituents. Furthermore, AlCl3 overload caused behavioral alterations and showed impaired cognitive function similar to AD alongside increased brain cortical AChE activity, MDA level and decrease in antioxidant enzymes. In addition, AlCl3 induction caused the up‐regulation of AChE and BACE‐1 mRNA expressions in the cortex of rats. Conversely, oral administration of BPF (50 and 100 mg/kg body weight) significantly ameliorated cognitive deficits, restored oxidant‐antioxidant balance and modulated neurochemical markers, as evidenced by the improvement in brain function. Besides, BPF contributed towards the down‐regulation of AlCl3‐increased AChE and BACE‐1 mRNA expressions in the cortex.

Conclusion

The current work demonstrates the therapeutic potential of B. pinnatum and suggests that it can ameliorate cognitive impairment caused by AlCl3 through reverting oxidative stress, restoring neurochemical function.
Mild to moderate levels of anxiety in a healthy population cohort are related to face recognition with negative emotions and white matter integrity
Authors: Chen Pin‐Yu , Chen Chang‐Le , Hsu Yung‐Chin , Tseng Hui‐Ming , Can Cam , Tseng Wen‐Yih Isaac
Published: December 2020

Background

The face recognition tasks were applied to test the healthy population cohort with mild to moderate levels of anxiety and they underwent MRI scans to evaluate their brains' white matter integrity.

Method

MAP‐MRI analysis applied to estimate diffusion indexes Generalised Fractional Anisotropy (GFA) of segmented white matter tracts in a healthy (N=174) population‐based sample (mean MMSE 28.39) from the Cambridge Centre for Ageing and Neuroscience (Cam‐CAN) data including normal adults ages 18‐88 to examine microstructural properties of specific association fiber tracts involved in face recognition processing. Half sample (n=88) had anxiety symptoms ( Hospital Anxiety Scale 9.7) and half sample (n=88) were matched with age and sex and without anxiety symptoms. Two kinds of behavioral face tests to white matter measures including three pairs of association tracts, namely inferior fronto‐occipital fasciculus (IFOF), inferior longitudinal fasciculus (ILF) and uncinated fasciculus (UF). The two kinds of behavioral face tests applied were Benton Test of Facial Recognition which assesses the ability to match pictures of unfamiliar faces with variation of head orientation and lighting, and face recognition test of emotion assessing recognition of positive emotion (happiness), negative emotions (angry, disgust, fear, and sad) and surprise emotion. Paired sample t test were applied to compare the two groups' HAS, behavioral tests, and GFA of white matter tracts.

Result

Paired t test results showed hospital Anxiety Scale, mean reaction time (RT) of face recognition test in negative emotion, GFA of left IFOF and left UF were significantly different in two groups. Pearson correlation analysis showed mean RT of face recognition test in negative emotion was significantly negative correlated with GFA of left UF.

Conclusion

Healthy life‐span population cohort with mild to moderate anxiety symptoms spent longer time recognizing faces with negative emotions and white matter integrity of the specific tract UF reflected this characteristic. There was brain‐behavior relationship.
The changing of cognitive function and the influence of learning effect on the results before and after the CSF tap test in patients with normal pressure hydrocephalus
Authors: Liu Caiyan , Li Jie , Huang Xinying , Dong Liling , Mao Chenhui , Hou Bo , Feng Feng , Wei Junji , Cui Liying , Gao Jing ,   PUMCH NPH Research Group
Published: December 2020

Background

The CSF tap test evaluation needs repetitive test of walking ability and cognition. Our study aimed to explore the changes of cognitive function and the influence of learning effect on the results in CSF tap test when evaluating the patients with normal pressure hydrocephalus (NPH).

Method

CSF tap test was carried out in 134 patients with NPH 2013‐2018 in neurology clinic of Peking Union Medical College Hospital. All patients underwent detailed neuropsychological evaluation (MMSE, MOCA, Trail Making test, Digital symbol, Stroop‐c test) and walking ability (10 meter walking test, up and go test), and head MRI examination. Patients who did not complete the four time point evaluations of CSF tap test due to severe dementia or any other reasons were excluded. Nonparametric test was used to test the difference of z‐scores of executive function (including connection test, number sign and shop‐c test) between the baseline and the four time points after CSF tap test. According to the baseline MMSE scores, the subjects were divided into MMSE > = 26 and MMSE < 26 groups. The changes of z‐scores of three executive function tests were observed in the group.

Result

Compared with the baseline, the Z‐score of executive function began to improve at 24 hours and 72 hours, and there was a statistically significant difference (P 0.001 and 0.000, respectively). Within the MMSE > = 26 group, there was a significant improvement in executive function at 24 hours and 72 hours compared with baseline (P <0.05). In the group with MMSE < 26, the executive function Z‐score at 72 hours was significantly improved compared with that at baseline (P = 0.000), while the improvement at 8 hours and 24 hours was not significant.

Conclusion

It was found that the executive function of CSF was improved with different evaluation points. According to the classification of MMSE scores, it was found that patients with different cognitive states had different characteristics of executive function curve, which could not be explained by learning effect.
Functional neuroanatomy of episodic memory in the human brain
Authors: Maass Anne
Published: December 2020

Background

Aβ and tau pathology progress along distinct anatomical networks before they overlap in the course of Alzheimer’s disease. Tau neurofibrillary tangles early and almost universally deposit in lateral parts of the entorhinal cortex (EC) in old age, the major gateway for hippocampal‐neocortical communication. Aβ plaques preferentially accumulate in posterior‐midline and medial frontal regions, where pathologies converge in the transition towards AD.

Method

In the first part of our FRS we will summarize the current knowledge about the functional neuroanatomy of memory, with focus on the entorhinal cortex and its neocortical connectivity. Our knowledge builds on intrinsic functional connectivity data and task‐based fMRI. We will further review our current understanding about the stereotypical accumulation patterns of tau and Aβ pathologies based on recent in vivo PET data in cognitively normal older adults and cogntiviely impaired patients.

Result

The human EC can be functionally subdivided into anterior‐lateral (alEC) and posterior‐medial (pmEC) subregions based on its differential functional connectivity with neocortical streams and hippocampus. The alEC shows preferential connectivity with perirhinal cortex and anterior‐temporal regions, which are highly vulnerable to tau pathology as shown by in vivo PET data. The pmEC shows preferential connectivity with parahippocampal cortex and a posterior‐medial network, regions that show early Aβ PET signal. These two neocortical networks are also differentially involved in the processing of and memory for object/items vs scenes/spatial information. Tau pathology in the entorhinal cortex even in the absence of Aβ plaques relates to memory deficits in cognitively yet unimpaired older adults.

Conclusion

Aβ and tau pathology likely affect different functional brain networks, which might lead to differential memory deficits in the course of Alzheimer’s disease.
Tau, neural function, and episodic memory in the medial temporal lobe
Authors: Berron David
Published: December 2020

Background

The human medial temporal lobe (MTL) is heavily connected with neocortical regions in the posterior‐medial and the anterior‐temporal system. In order to achieve successful memory functioning, those systems have to interact with each other as well as with the hippocampus. At the same time, subregions in the MTL are affected by neurofibrillary tangle (NFT) pathology in aging and Alzheimer's disease (AD) which is strongly associated with memory impairment.

Method

In three different samples of cognitively unimpaired (CU) individuals, we analyzed how tau pathology (measured using Tau PET and CSF pTau levels) was associated with altered resting‐state functional connectivity, task‐related functional activity, MTL subregional atrophy, white matter tract integrity and memory function.

Result

In the first sample (n=322 CU), we identified the sequence of MTL subregions being affected by tau accumulation. Tau accumulates early in the perirhinal cortex (Area 35) and was associated with memory function ‐ an effect that was partially mediated by anterior hippocampal atrophy. In the second sample (n=359 CU), we show that while entorhinal/perirhinal cortex functional connectivity with the anterior‐temporal system was predominantly reduced in beta amyloid (Ab) + vs. Ab‐ CU, functional connectivity with the posterior‐medial system was increasingly reduced with increasing levels of pTau in Ab+ CU. Reduced functional connectivity was both related to baseline memory and future cognitive decline, however, not significantly associated with entorhinal thickness or white matter tract integrity. Finally, we show in a third sample (n=22 CU) that increasing levels of pTau are related to increased hippocampal functional activity which are both individually associated with reduced performance in an object memory task.

Conclusion

Taken together, our results from three independent samples suggest that tau pathology affects memory function in early disease stages predominantly via aberrant MTL functional connectivity and activity rather than atrophy or degeneration of white matter tracts.
Memory impairment is a clinical marker of tau pathology in cerebral amyloid angiopathy
Authors: Schoemaker Dorothee , Charidimou Andreas , Zotin Maria Clara Zanon , Raposo Nicolas , Johnson Keith A , Sanchez Justin S , Greenberg Steven M , Viswanathan Anand
Published: December 2020

Background

Cerebral Amyloid Angiopathy (CAA) shows a high comorbidity with Alzheimer’s Disease (AD). Nonetheless, CAA is an independent neuropathological disorder, and over half of CAA cases present without AD‐related tau pathology. Differentiating CAA patients with or without concomitant tau pathology could have important implications for therapeutic approaches. We aimed to determine whether memory impairments in CAA are indicative of underlying tau pathology.

Method

This study included 29 patients fulfilling criteria for mild cognitive impairment (MCI) and probable CAA. Subjects underwent a neuropsychological evaluation, a MRI, and PET scans for in‐vivo estimation of amyloid ([11C]– PiB) and tau ([18F]‐AV‐1451) burden. Structural markers of small vessel disease, total brain volume and hippocampal volume were quantified on MRI images. [11C]‐PiB specific binding was expressed as distribution volume ratios (DVR) and [18F]‐AV‐1451 specific binding as standardized uptake value ratio (SUVR), using the cerebellar cortex as the reference region. CAA subjects were classified as “amnestic” or “non‐amnestic” based on neuropsychological performance. Groups were contrasted on demographic features and quantified MRI markers. Between‐group voxel‐wise comparisons of SUVR [18F]‐AV‐1451 and DVR [11C]‐PiB maps were performed. Mean [18F]‐AV‐1451 SUVR in areas of group differences was extracted for each subject and correlated to memory performance.

Result

In our sample, 14 CAA subjects were classified as “amnestic”, and 15 as “non‐amnestic”. Amnestic and non‐amnestic subjects did not differ in age, education, or sex representation. Groups did not differ on any MRI markers of small vessel disease, nor in total brain volume (p>0.05, for all). However, amnestic subjects showed smaller hippocampal volume (F(1,28)=5.65, p<0.05). Voxel‐wise comparison of DVR [11C]‐PiB maps did not reveal any differences between amnestic and non‐amnestic CAA. Comparison of SUVR [18F]‐AV‐1451 maps revealed significant increase in tau PET binding in several regions for amnestic subjects (Figure 1). Mean tau PET binding in these regions was correlated with memory performance (r=‐0.68, p<0.001), and hippocampal volume (r=‐0.44, p<0.05), after accounting for age.

Conclusion

Amnestic CAA subjects present higher tau PET binding, and smaller hippocampal volume than non‐amnestic CAA. Our results suggest that memory impairments in CAA are related to tau pathology and medial temporal lobe neurodegeneration, consistent with the presence of concomitant AD.
Multilingual text normalization for computer‐based detection of Alzheimer’s disease
Authors: Abiven Frederic , Ratté Sylvie
Published: December 2020

Background

Understanding how Alzheimer’s Disease affects linguistic functions could improve early detection of the disease, since many studies have demonstrated that language alterations can appear at an early stage. In order to measure those functions, we process and analyze transcripts from multiple corpora based on the Cookie‐Theft picture description task. Text normalization plays a big role when it comes to creating a solid dataset from a heterogeneous corpus of patients’ interviews. Current tools for this type of task are limited and tend to be language and context dependant.

Method

This paper presents a simple and efficient method to process textual data in a pipeline architecture, sequencing sub‐problems of cleaning and normalization tasks. Since some of them are language and context dependant, they were made easily configurable, increasing scalability when dealing with new corpora. Then, multiple measures are extracted while cleaning transcripts, as it also contains valuable information, like the number of repetitions or incomplete words removed.

Result

Results show that we are able to improve performance on this time consuming task when working with a multilingual dataset compared to previous studies. In fact, we were able to normalize a French and English Cookie‐Theft corpus easily. Given the great diversity of languages and related structures, this method therefore has certain limitations. Moreover, our findings have shown great potential in cleaning and normalizing measures extracted for detecting Alzheimer’s disease. For instance, the number of retracings removed from transcripts revealed a significant correlation (> 0.5) with the severity of cognitive impairment.

Conclusion

Thus, this paper contributes to Alzheimer’s disease literature by presenting an efficient tool which allows to speed up the cleaning and normalization process of transcripts. Furthermore, extracted measures from this task could improve results when training for a predictive model in AD detection, since it captures some metrics highly correlated with the patient’s mental health status. Finally, this tool could eventually be used for different types of description tasks since it is not dependant of the context.
Tau‐induced brain atrophy and neuroinflammation accelerated by low‐protein diet and decelerated by selected essential amino acids in a murine model of tauopathies
Authors: Takado Yuhei , Sato Hideaki , Tsukamoto‐Yasui Masako , Minatohara Keiichiro , Takahashi Manami , Urushihata Takuya , Takuwa Hiroyuki , Ono Maiko , Maeda Jun , Sahara Naruhiko , Aoki Ichio , Toyoda Sakiko , Karakawa Sachise , Isokawa Muneki , Kawasaki Noriko , Ueno Satoko , Kanda Mayuka , Nishimura Mai , Suzuki Katsuya , Mitsui Akira , Nagao Kenji , Higuchi Makoto , Kitamura Akihiko
Published: December 2020

Background

Nutritional epidemiology has implicated dietary protein intake in senile dementias. However, mechanistic links of protein and amino acids to age‐related neurodegenerative conditions remain unclear. Here, we tested the hypothesis that dietary intake of protein and amino acids could affect neuronal functions and survival in a mouse model of tauopathies, which develops tau pathologies leading to progressive brain atrophy with aging.

Methods

Non‐transgenic (nTg) and tauopathy model (rTg4510) mice were fed a normal protein diet (NPD) or low protein diet (LPD) from 3 months of age, and brain volume and tau pathologies were measured at 6.5 months of age by MRI and PET, respectively. These imaging assays were also applied to NPD‐ and LPD‐fed mice treated with essential amino acids (EAAs), seven essential amino acids (EAAs), which are primarily composed of leucine, phenylalanine, and lysine with high fluxes into the brain and contain minimum levels of tryptophan, an origin of inflammation‐related kynurenine pathways. Moreover, we performed gene expression profiling of the cortical tissues collected from these mice.

Results

LPD profoundly accelerated the brain atrophy in rTg4510 mice relative to NPD. EAA supplementation to rTg4510 mice markedly suppressed cortical volume reductions in both LPD‐ and NPD‐fed rTg4510. LPD and EAA did not overtly alter PET‐detectable tau depositions uncorrected for atrophy‐induced partial volume effects, raising a possibility of decreased tau burdens in each of surviving neurons to some extent. Gene expression profiling demonstrated neuroinflammatory changes and neuronal dysfunctions in rTg4510 mice, which were worsened by LPD and attenuated by EAAs. Notably, kynurenine levels were elevated by LPD, and this alteration was reversed by EEAs, presumably by competition between EEAs and kynurenine on the entry into the brain.

Conclusion

Our findings highlight the critical roles of specific EEAs in the protection of neurons against tau‐induced toxicity and neuroinflammation.
The apolipoprotein E ε4 allele‐dependent relationship between serum lipid levels and cognitive function: A population‐based cross‐sectional study
Authors: Wei Shan , Gao Ling , Jiang Yu , Shang Suhang , Chen Chen , Dang Liangjun , Wang Jin , Huo Kang , Wang Jingyi , Qu Qiumin
Published: December 2020

Background

Till now, the effect of serum lipid levels on cognitive function is still controversial. The apolipoprotein E ε4 (APOE) allele is the most critical genetic risk factor for Alzheimer’s disease and cognitive impairment. Additionally, APOE ε4 allele has a major impact on lipid metabolism. The aim of this study was to investigate the APOE genotype‐dependent relationship between peripheral serum lipid levels and cognitive impairment.

Method

1273 subjects aged 40‐86 years participated in this cross‐sectional study. Serum lipid levels and the APOE genotype were detected. Mini‐mental state examination was used to diagnose the cognitive impairment or not. Univariate and multivariate analyses were used to analyze the relationships between APOE genotype, serum lipid levels and cognition function.

Result

After controlling for all possible covariates, a significant interaction between low serum high density lipoprotein and the APOE ε4 allele on cognitive impairment (Wald's chi‐square=4.269, df=1, OR=20.094, p=0.039) (Table 1) was found in the total participants. In APOE ε4 carriers, low serum high density lipoprotein was positively associated with cognitive impairment (Wald's chi‐square=8.200, df=1, OR=60.335, p=0.004) (Table 2), and serum high density lipoprotein levels were positively correlated with Mini‐mental state examination score (r=0.217, df=176, p=0.004). There was no significant correlation between serum total cholesterol, low‐density lipoprotein, triglycerides levels and cognitive impairment in either the total participants or APOE ε4 carriers/non‐carriers. (Figure 1).

Conclusion

APOE ε4 carriers, but not non‐carriers, with lower serum high‐density lipoprotein had a higher prevalence of cognitive impairment and a lower Mini‐mental state examination score. These results suggest that the APOE ε4 allele may affect the relationship between serum lipid levels and cognitive impairment. However, the specific mechanism needs to be further elucidated.
Scoping review of current state of the literature on the impact of music on symptoms of Alzheimer’s disease
Authors: Colverson Aaron
Published: December 2020

Background

Across the globe, researchers, clinicians, and caregivers are continuing to search for solutions to the myriad problems caused by Alzheimer’s disease and related dementias (ADRDs). Music is an area of focus receiving considerable attention for its potential benefits to help manage the effects of neuropsychiatric symptoms upon individuals living with ADRDs. However, attention is lacking on the potential social value of music to positively influence quality of life for both individuals living with dementias and their surrounding communities. This scoping review compiles recent reports on this potential, highlighting the social nature of music and its various uses (e.g. listening, making) to change the often tense and reactive atmosphere surrounding both the individuals living with ADRDs and their surrounding communities into comparatively joyous living environments. Databases used included PubMed, EBSCOhost’s CINAHL and PsychINFO, Cochrane Library (sub‐search conducted using ALOIS, the Specialized Register of the Cochrane Dementia and Cognitive Improvement Group (CDCIG)), ProQuest’s Biological Science Collection, the Journal of Music Therapy and Nordic Journal of Music Therapy, and Google Scholar. After screening for eligibility and inclusion, 26 documents were identified, including review articles, experimental studies, recommendations, pilot studies, conference proceedings, book chapters, and executive summaries. Overall, this review concludes that music can facilitate prosocial engagement between persons living with ADRDs and their surrounding communities, due to a complex interplay of neurobiological mechanisms largely preserved in the ADRD population. More well designed and well controlled empirical studies are necessary to clarify contexts in which music and its various uses may be helpful to improve quality of life for both the individuals suffering from ADRDs and their surrounding communities. Such results would provide further evidence‐based support for the use of music to strengthen both formal and informal patient‐centered care models.
Entorhinal tau is associated with increased hippocampal activation and memory deficits in Alzheimer’s disease
Authors: Richter Nils , Bischof Gerard N. , Dronse Julian , Nellessen Nils , Neumaier Bernd , Langen Karl‐Josef , Drzezga Alexander , Fink Gereon R. , van Eimeren Thilo , Kukolja Juraj , Onur Oezguer A.
Published: December 2020

Background

To date, it remains unclear how the hallmark pathological changes of Alzheimer’s disease (AD), amyloid plaques, and neurofibrillary tangles, affect neuronal activity and, consequently, cognition. In cognitively normal aging, it appears that tau accumulation may drive hippocampal hyperactivity, however, studies investigating this association in AD are sparse.

Method

Patients with mild cognitive impairment (MCI) or mild dementia due to AD (n = 15) underwent positron emission tomography with the tracer [18F]‐AV‐1451, which binds to tau accumulation, and performed a visual item memory task during functional magnetic resonance imaging.

Result

Entorhinal tau accumulation was highly correlated with memory‐related hippocampal activation. Greater tau accumulation and hippocampal activation were negatively correlated with memory performance. Neural activation in other task‐related structures was not correlated with local or global tau accumulation.

Conclusion

Similar to observations in cognitively healthy aging, entorhinal tau accumulation is closely associated with hippocampal hyperactivity and impaired memory performance in MCI and mild dementia. Interestingly, this association is specific for medial temporal lobe structures.
Functional connectivity is associated with tau spreading in dementia with Lewy bodies
Authors: Schumacher Julia , Gunter Jeffrey L. , Przybelski Scott A. , Jones David T. , Graff‐Radford Jonathan , Savica Rodolfo , Schwarz Christopher G. , Senjem Matthew L. , Jack Clifford R. , Lowe Val J , Knopman David S. , Fields Julie A. , Kremers Walter K. , Petersen Ronald C. , Graff‐Radford Neill R. , Ferman Tanis J. , Boeve Bradley F. , Thomas Alan J. , Taylor John‐Paul , Kantarci Kejal
Published: December 2020

Background

Dementia with Lewy bodies (DLB) is neuropathologically defined by the presence of α‐synuclein aggregations, but many DLB cases show significant Alzheimer’s disease (AD) pathology in the form of β‐amyloid and tau. Our first objective was to investigate the effect of AD co‐pathology on functional network failure in DLB. Secondly, we studied how the distribution of tau relates to functional connectivity in DLB.

Method

Twenty‐three DLB, 23 age‐ and sex‐matched AD, and 90 cognitively unimpaired (CU) participants underwent AV1451 tau‐PET, Pittsburgh compound‐B (PiB) PET, and resting state (rs)‐fMRI scans. The rs‐fMRI data were used to calculate the Network Failure Quotient (NFQ), a marker of functional network failure within the default mode network. The NFQ was then correlated with overall cortical tau standardized uptake value ratio (SUVr). The strength of inter‐regional functional connectivity was assessed using the Schaefer100 atlas. Tau‐PET covariance was measured as the correlation in AV1451 SUVr between any two regions across participants. The association between region‐to‐region functional connectivity and tau‐PET covariance was assessed using linear regression. Additionally, we identified the region with highest and the region with lowest tau SUVrs (tau hot‐ and coldspot) and tested whether tau SUVr in all other brain regions was associated with the strength of functional connectivity to these tau hot‐ and coldspots.

Result

Overall higher cortical tau‐PET uptake correlated with higher NFQ (i.e. greater functional network failure) in DLB who were PiB+ (N=14, ρ=0.60, p=0.02), but not in DLB who were PiB‐ (N=9, ρ=‐0.06, p=0.87). Higher functional connectivity between regions was associated with higher tau covariance in CU, AD, and DLB, independent of PiB status. Higher functional connectivity of a target region to the tau hotspot (i.e. inferior/medial temporal cortex) was related to higher AV1451 SUVRs in the target region whereas higher functional connectivity to the tau coldspot (i.e. sensory‐motor cortex) was related to lower AV1451 SUVr in the target region.

Conclusion

Greater tau burden in DLB patients with β‐amyloid co‐pathology is associated with an AD‐like functional network failure. As previously demonstrated within the AD spectrum, functional connectivity may contribute to the spreading of tau across the brain also in DLB.
Understanding metaphor comprehension in Alzheimer disease: An N400 study
Authors: Dikmen Merve , Karakulak Ece Zeynep , Aygüneş Mehmet , Hanoğlu Lutfu
Published: December 2020

Background

In clinical routine and research, abstract thinking difficulties are often tested by assessing the Alzheimer disease (AD) patient’s ability to understand nonliteral languages. The goal of the present study was to test more specifically the processing of metaphors in AD patients to establish links between clinical observations and measures of brain activity.

Method

Participants: Twelve right‐handed Alzheimer disease (AD) patients and eleven right‐handed healthy volunteers took part in the study. Healthy vounteers were matched with the patients on age and academic level. All of the participants were right‐handed, corrected‐to‐normal vision, and native speakers of Turkish. EEG recording; Brain Vision Analyzer 2.1 Software (Brainproducts, Munich, Germany) was used for EEG data processing. 13 channels EEG active electrodes were placed on a cap (Acticap, Germany) according to the international 10‐20 system (Fp1, Fp2, F3, Fz, F4, C3, Cz, C4, P3, Pz, P4). Electrode impedance was maintained at below 10 kΩ. EEG was amplified and digitized at a sampling frequency of 500 Hz (BrainAmp). The continuous EEG was filtered off‐line with a band pass filter of 0.01‐15 Hz filter. Epochs of interest were selected time‐locked to the target stimulus onset (−200 to 1200 ms) and baseline correction was applied ‐200 to 0 ms. We measured the amplitude of N400 time locked to the onset of critical word, which was also the sentence final‐word.

Result

Repeated measure ANOVA with three repeated variables: 3(electrode site:frontal/central/parietal) 3(electrode laterality: left/middle/right) 4(condition: literal/ conventional/ novel/anormal) and one between variable (group: AS/control) revealed no significant main effect of group, F(1, 21) = 2.596, p > .05. Condition effect was significan F(3,63) = 3.193, p < .05. Moreover, condition type by group interaction was significant F(1,21) = 5.565, p < .05. The pattern of N400 elicited for the only conventional metaphor was different between the two groups.

Conclusion

Large N400 amplitudes for conventional metaphors demonstrated the difficulties in metaphor comprehension in the AD participants as compared to controls. Findings suggest that differences in linguistic information processing cause difficulties in metaphor comprehension in AD. This study was supported financially by the Scientific and Technological Research Council of Turkey (TÜBİTAK; project number: 117S470).
Everyday life priorities and health care preferences of patients living with dementia or cognitive impairment: A systematic review
Authors: Wehrmann Hannah , Raedke Anika , Hoffmann Wolfgang , Michalowsky Bernhard
Published: December 2020

Background

Gaining knowledge about priorities and preferences of people living with dementia (PwD) might help to individualize and to increase the adherence of treatment and care, both could improve patient‐related outcomes. Therefore, the aim of this study was to systematically identify and summarize preferences of PwD or mild cognitive impairment, considering all relevant aspects of healthcare and daily living.

Methods

A systematic review of patient preference studies was conducted to assess needs, priorities, and preferences of PwD or mild cognitive impairment using Pubmed and Science Direct. The inclusion criterion was that preferences were elicited directly by PwD. Of 1,103 studies, only 40 met this inclusion criterion. The ICHOM (International Consortium for Health Outcomes Management) value set for dementia was used to systematize the reported preferences of PwD as follows: (a) clinical status, (b) symptoms, functioning and quality of life, (c) and sustainability.

Results

Twelve studies revealed preferences pertaining to PwDs’ clinical status (a), highlighting that patients prefer to be informed about the diagnosis as early as possible for anticipatory planning of care. Most patients do not want to receive resuscitation, forgoing antibiotics are accepted. In addition, preferences are altruistic: PwD rank being no burden to others higher than being cured. Further, 25 studies reported preferences concerning PwDs’ symptoms, functioning and quality of life (b), demonstrating that PwD are eager to participate in health‐related decisions, especially in decisions about social life and particularly conjointly with their caregivers. Quality of life, patient self‐efficacy and emotional wellbeing were preferred most. Furthermore, institutionalized PwD prefer individualized and person‐centered care, which is commonly missing in nursing homes. Only, three studies elaborated preferences for sustainability (c), revealing that PwD less likely to prefer residential care as compared to persons without dementia.

Conclusion

A multiplicity of studies about patient preferences in dementia was found, that provide useful insights into the patient, which are not always taken into consideration, yet. Future interventional studies should examine whether including these preferences into treatment and care or daily living might improve their outcomes.