bluuebunny/crossref_metadata_2025 huggingface dataset:
NeuroEPO in mild‐to‐moderate Alzheimer’s disease
Authors: Pérez Leslie , Sosa Saily , Bringas Giosmany , López Danay , Valenzuela Carmen , Peñalver Ana Ivis , Dalmau Evelio , Rodríguez Teresita , Urrutia Nelky
Published: December 2020

Background

NeuroEPO, is a nasal pharmaceutical solution of recombinant human erythropoietin with low sialic acid.

Methods

Phase II/III, prospective, double‐blind, randomized, placebo‐controlled, multicenter with adaptive design clinical trial involving patients with mild‐to‐moderate Alzheimer’s. NeuroEPO or placebo, with doses 0.5 or 1.0 mg 3 times a week for 48 weeks was administered by nasal route. The primary outcome measure was a score on the 11‐item cognitive subscale of the Alzheimer’s disease Assessment Scale (ADAS‐cog11, with scores ranging from 0 to 70 and higher scores indicating greater impairment). Secondary outcome measures were: % annual change of hippocampus volume by magnetic resonance imaging (MRI) studies, neuropsychological scales and adverse events. An interim analysis was made according to the criteria as established in the protocol.

Results

Per‐protocol‐analysis, 69 patients finished one year of treatment. 49% of the patients showed improvement, 9% remained stable and 42% got worse, according to the ADAScog11 score. Regarding the hippocampus % annual change, 48 patients were analyzed. 58% of those patients remained stable and 42% witnessed a decline in the hippocampus volume compared with the % annual change of patients with AD (∼4.4%). No serious adverse events related with NeuroEPO were reported.

Conclusions

NeuroEPO improve clinical outcomes in patients with Alzheimer’s disease with good security profile. Therefore, it could be useful in the treatment of this kind of patients.
Empirically defining preclinical Alzheimer’s disease in the era of biomarkers
Authors: Kiselica Andrew M. , Kaser Alyssa , Benge Jared
Published: December 2020

Background

The National Institute on Aging and Alzheimer’s Association released a research framework defining an Alzheimer’s Continuum (AC) based on the presence of at least one b‐amyloid biomarker, independent of clinical symptoms. Staging of the AC will occur along 6 levels of severity. Stages 3‐6 map onto current conceptualizations of mild cognitive impairment and mild, moderate, and severe dementia. However, stages 1 and 2 are preclinical stages, which are less well characterized. These early stages are defined by three criteria: subjective cognitive complaints, transitional declines on cognitive testing, and neurobehavioral symptoms. The goals of the current study were to 1) examine base rates of these criteria among groups of individuals defined as amyloid positive (A+) and amyloid negative (A‐); 2) evaluate inter‐rater agreement for subjective cognitive complaints and neurobehavioral symptoms; and 3) assess the impact of different diagnostic standards on rates of classification into AC stages 1 and 2.

Method

Analyses were completed on a subsample of cognitively normal participants from the Uniform Data Set, categorized as A+ (n = 101) or A‐ (n = 447).

Result

Overall rates of subjective cognitive complaints (A+: 34.90%, A‐: 29.90%;
χ
2
= 3.33, p = .068) and neurobehavioral symptoms (A+: 22.40%, A‐: 22.40%;
χ
2
= 0.00, p = .990) did not significantly differ across amyloid groups. Inter‐observer agreement was fair for subjective cognitive complaints (k = .24) and fair‐to‐moderate for neurobehavioral symptoms (k ranged from .34 to .53). Multivariate base rate analysis revealed that subtly low cognitive scores were more common in amyloid positive than amyloid negative individuals (e.g., the base rate of two scores £9th percentile was 38.00% for A+ individuals but only 24.90% for A‐ patients,
χ
2
= 6.98, p = .008). The rates of classification into AC stage 1 versus 2 depended on the number of criteria required for stage 2: 57.40% versus 42.60% (one criterion), 28.70% versus 71.30% (two criteria), and 6.90% versus 93.10% (all three criteria).

Conclusion

Implementing a two criteria standard may be preferred to provide a balance between false negatives and false positives. Directions for future research are discussed.
Correlated levels of cerebrospinal fluid pathogenic proteins in drug‐naïve Parkinson's disease
Authors: Ono Kenjiro , Murakami Hidetomo , El‐Agnaf Omar M.A. , Tokuda Takahiko , Ohmichi Takuma , Miki Ayako , Ohashi Hideaki , Owan Yoshiyuki , Saito Yu , Yano Satoshi , Tsukie Tamao , Ikeuchi Takeshi
Published: December 2020

Background

Toxic oligomeric α‐synuclein (αS; O‐αS) has been suggested to play a central role in the pathogenesis of Lewy body diseases such as Parkinson's disease (PD). Cerebrospinal fluid (CSF) levels of αS, O‐αS, total and phosphorylated tau, and amyloid β 1‐42 (Aβ1‐42) are thought to reflect the pathophysiology or clinical symptoms in PD. In this study, we examined correlations of the CSF levels of these proteins with the clinical symptoms, and with each other in drug‐naïve patients with PD.

Method

Twenty‐seven drug‐naïve patients with PD were included. Motor and cognitive functions were assessed using the Unified Parkinson's Disease Rating Scale (UPDRS), Montreal Cognitive Assessment (MoCA), and Neurobehavioral Cognitive Status Examination (COGNISTAT). CSF levels of total αS, O‐αS, Aβ1‐42, total tau and tau phosphorylated at threonine 181 (P‐tau181p) were measured. CSF levels of these proteins were compared with clinical assessments from the UPDRS, MoCA and COGNISTAT using Spearman correlation analysis. Spearman correlation coefficients among CSF protein levels were also evaluated.

Result

CSF levels of αS were negatively correlated with UPDRS part III (motor score) (p < 0.05) and bradykinesia (p < 0.01), and positively correlated with COGNISTAT subtest of judgement (p < 0.01) and CSF levels of Aβ1‐42 (p < 0.001), total tau (p < 0.001) and P‐tau181p (p < 0.01). Lower CSF levels of Aβ1‐42, total tau and P‐tau181p were significantly related to worsening of some motor and/or cognitive functions. The CSF level of O‐αS showed no correlation with any motor and cognitive assessments or with CSF levels of the other proteins.

Conclusion

CSF levels of αS are correlated with some clinical symptoms and CSF levels of other pathogenic proteins in drug‐naïve PD patients. These correlations suggest a central role for interaction and aggregation of αS with Aβ1‐42, tau, and phosphorylated tau in the pathogenesis of PD. Although O‐αS has been shown to have neurotoxic effects, CSF levels do not reflect clinical symptoms or levels of other proteins in cross‐sectional assessment.
Atrophy patterns of hippocampal subfields in T2DM patients with cognitive impairment
Authors: Xu Yun , Zhao Hui , Li Mengchun
Published: December 2020

Background

To identify the volume changes of hippocampus subfields in T2DM patients with cognitive impairment and to determine whether these atrophy patterns in hippocampal subfields are associated with different cognitive domain functional impairment.

Method

A total of 117 individuals were recruited, including T2DM patients with cognitive impairment (T2DM‐CI) (n=34), T2DM patients without cognitive impairment (T2DM‐nonCI) (n=36) and normal controls (NC) (n=47). Hippocampal and subfield volumes were assessed using structural magnetic resonance (MR) scans Structural MR images were processed by the FreeSurfer 6.0 image analysis. Then, further correlation analyses were used to estimate the relationship between the cognitive domain and hippocampal subfield volume.

Result

The total hippocampal volume was smaller in the T2DM patient groups, especially in the T2DM‐CI group, than in the NC group. Regarding the hippocampal subfields, among the three groups, the volumes of the left subiculum, presubiculum, and fimbria and the right CA1 and molecular layer HP were significantly decreased in the T2DM‐CI group (all P values <0.05/12). Partial correlation analyses showed that the volumes of the left subiculum, left fimbria and left presubiculum were most strongly related to executive function. The right hippocampal CA1 volume was significantly correlated with memory (P values <0.05). The levels of blood glucose had no relationship with cognitive function

Conclusion

Our results indicated that atrophy was heterogeneous across the hippocampal subregions of T2DM patients with cognitive impairment. Among these subregions, the smaller volumes of the left subiculum, left fimbria and left presubiculum were significantly associated with lower executive function, the atrophy of the right CA1 seemed to be related to memory impairment.
A randomized control trial of activity scheduling to reduce the impact of the caring role on older adults with dementia
Authors: Ho‐yin Lai Frank
Published: December 2020

Background

Participating in meaningful activities is important to an individual’s wellbeing. Activity scheduling enables older adults with dementia and their spouse caregivers to structure their activities consistently in the directions they value.

Method

This was a 12‐week single‐blinded randomized control trial using a parallel group experimental design study. Community‐dwelling older adults with mild to moderate dementia and their spouses received the community health education program during the first two‐weeks. Then the participants were randomly assigned to one of the two groups for the following 10 weeks. In the control group, participants received 10 weekly education sessions on dementia care education. In the experimental group, participants received the same dementia care education program plus activity scheduling offered by occupational therapists with the intervention focused on scheduling events that are pleasant and improving communication.

Result

From August 2018 to August 2019, 50 couples completed the intervention. The activity scheduling showed improvements with respect to alleviating the impact of the caregiving role, reducing the behavioural and psychological symptoms of dementia, decreasing the caring demand and generally improving the quality of life. A significant difference between the two groups was shown regarding the impact of the caring role, and the alleviation of disruption and depression behavior, with an effect size of .61 (95% CI = .39‐.67), .45 (95% CI = .35‐.71) and .50 (95% CI = .35‐.71) respectively. The differences between the groups indicated the experimental group showed an improvement over time in alleviating the role of caring, with Cohen’s d = .64 (95% CI : .38 to .78), and alleviating disruption and depression behavior, with an effect size of .45 (95% CI = .38‐.52) and .50 (95% CI = .43‐.59) respectively. Moreover, the number of caring hours needed, dropping from 6.98 to 5.98 hours in the experimental group.

Conclusion

Activity Scheduling is straightforward to administer and personalized in nature. There were significant reductions in caregiving demand. Through proper coaching and regular facilitation, AS can help caregivers create pleasant events in their daily living and quality of life of people receiving care can be much enhanced.
VADEC program: Cognitive impairment (CI) assessment in Spain
Authors: Palomo María Sagrario Manzano , Maiztegui Covadonga Fernandez , Vila Eduardo Martinez
Published: December 2020

Background

Analyze the controversies in diagnosis and neuropsychological approach of patients with CI. Achieve a consensus of Good Clinical Practice Guidelines (GCPG) that stablish which cognitive tests are suitable.

Method

VADEC program is based on Delphi Methodology in order to reach to a consensus about diagnostic criteria and cognitive assessment scales more suitable in CI, and its relationship with epidemiologic and diagnostic guidelines or bibliographic sources published. The specific questionnaire was completed by neurologists specialized in dementia in Spain. It was proposed many items or questions (1‐9 scores), and decide the median value, the confidence degree and the group consensus achieved.

Result

The program was developed from 1st June to 31th July 2017. 130 neurologists were involved (21 years of clinical practice) in public system (90.8%). About 38.67 % of patients had CI, 41.15% moderate and 20.18% severe. There was a consensus of using Petersen criteria to define MCI as a syndrome. MMSE is considered the most useful tool, followed by Clock Drawing test (CDT), Friedman or MOCA test. It´s necessary to have more information, over all in DSM‐V, and the convenience of elaborating a GCPG which harmonized MCI criteria.

Conclusion

There was a great consensus about using MMSE or MEC test. There was a wide consensus about the utility of MoCA, CDT and Friedman test. These results express the necessity of GCPG in CI about the use of cognitive test in Spain.
Application of transcranial direct current stimulation (tDCS) to enhance attention, visuo‐motor coordination and executive function in older adults with mild cognitive impairment
Authors: Ho‐yin Lai Frank
Published: December 2020

Background

Extensive research had shown executive dysfunction in people with cognitive impairment is associated with functional abnormalities in prefrontal regions such as the right inferior frontal gyrus (Right IFG) or the left dorsal lateral pre‐frontal cortex (Left DLPFC). Relevant studies suggest that transcranial direct current stimulation (tDCS) may be a useful therapeutic tool in enhancing attention, visuo‐motor coordination and working memory performance.

Method

This study aimed at investigating the effect of tDCS stimulation over left DLPFC or right IFG on attention, inhibition and working memory in people with mild cognitive impairment (MCI) and healthy older adult controls (HC). Recruited participants, aged from 65 to 80 years, included mild cognitive impairment and healthy control older adults. They were randomly divided into experimental and control arms. In experimental arm, participants were randomized to receive either anodal or sham tDCS over the Right iFG or Left DLPFC. tDCS will be administrated in a 2 mA anodal tDCS or sham stimulation to the Left DLPFC or Right IFG for 20 min. Each participant will undergo the performance‐based measure of executive function (The Chinese Multiple Errands Test, Chinese MET) before and immediately after the stimulation. During the anodal or sham tDCS stimulation, subjects will perform three neuropsychological tests: Trail Making Task (TMT), Stroop Test (ST) and N‐back Task (NBT).

Result

16 MCI and 16 healthy control, aged 65‐80 years were recruited. Linear mixed model analysis using group (HC vs. MCI), stimulation (anodal vs. sham) and region (Left DLPFC vs. Right IFG) as factors were performed. There was significant improvement in TMT, NBT in the group that received the anodal stimulation to Left DLPFC with an effect size of .73 (95% CI = .59‐.82) and .76 (95% CI = .65‐.81) respectively. Moreover, significant improvement noted in ST when participants received anodal stimulation to Right IFG with effect size of .71 (95% CI = .58‐.83).

Conclusion

tDCS showed to be an useful tool in enhancing attention, visuo‐motor coordination and working memory performance in older adults with MCI. These pilot findings can be further confirmed by collection of a large sample size as in this on‐going study.
Human rights in the context of dementia
Authors: Flavin Theresa M
Published: December 2020

Background

At Present, when a diagnosis of dementia is suspected or delivered, the initial advice to the person involved is ‘get your affairs in order’. One is urged to sign over all decision making to a ‘power of attorney’ at the earliest opportunity. While this may be convenient for medical legal professionals and even family members, any potential for hope, utility or self determination for the individual is eliminated. Research has shown that when a person has appropriate support in the decision making process, that decisions, big, small, lifestyle, financial as well as those relating to daily activities can be continued well into the progression of the disease. Resources are available to educate legal, medical and care professionals as well as families and caregivers on how to do this well, however the stigma persists at the highest level that when dementia is even suspected, that capacity has to be demonstrated to make even the simplest choices. This is a very direct violation of the fundamental human right of self determination, yet as a society we have not taken any meaningful steps to address the gaps in the community understanding of what capacity means from day to day in the context of dementia, how we can support someone to maintain their dignity, self esteem and self determination as long as humanly possible. I intend to speak from lived experience to how it feels to have capacity questioned at all times, in the medical and legal context, how it feels to be urged to ‘get onto the sunset cruise’ and never look back. I also intend to speak to the lived experience of having support with decision making, and the potential for enormous changes in the outcomes when a person with dementia is not only given ‘permission’ to have support in making decisions but is afforded such support as a human right and an entitlement. There is much room for improvement, and i remain optimistic that we can do much much better in the future if we work with people living with dementia instead of for or instead of us!
Allele specific targeting of APOE‐E4 expression: The novel CRISRP/CAS9‐based platform for precision therapy for Alzheimer’s disease
Authors: Kantor Boris , Moncalvo Malik , Ilich Ekaterina , Rittiner Joseph , Dong Wendy , Asmus Natalie , Falek Carmel , Yu Young Jun , Gu Jeffrey , Tringali Dominic , Chiba‐Falek Ornit
Published: December 2020

Background

APOEe4 is well‐established genetic risk factor for late onset Alzheimer’s disease (LOAD). It has been demonstrated that DNA methylation plays an important role in controlling the levels of APOEe4 expression. Furthermore, the differential methylation levels were reported between disease‐ and naïve‐ individuals. It also has been shown that reduction of APOEe4 levels may alleviate LOAD pathology. Here we aimed to develop a novel approach for specific and accurate modulation of APOEe4 gene expression.

Method

Here, we took advantage of a newly engineered VRER‐Cas9/gRNA system which specifically and accurately recognized a novel protospacer adjacent motif (PAM) created with SNP‐rs429358 T‐C transition in the APOEe4 gene. The system is based on an all‐in‐one lentiviral vector harboring gRNA/VRER‐dCas9‐DNMT3A. Using this vector, we were able to achieve an efficient enhancement in DNA methylation and the associated reduction in the expression of APOEe4 allele. The system has been validated on the isogeneic APOE‐human induced pluripotent stem cell (hiPSC)‐derived excitatory neurons.

Result

We were able to specifically and efficiently downregulate expression of APOEe4 using isogeneic APOE‐human induced pluripotent stem cell (hiPSC)‐derived excitatory neurons as the experimental model. The reduction in the gene expression was linked to robust and specific DNA methylation.

Conclusion

The developed epigenome‐editing platform highlights the novel approach towards the development of “smart” therapeutics for LOAD.
The use of patient's electronic message history for the automatic preclinical detection of Alzheimer's disease
Authors: Seminck Olga , Hanseeuw Bernard J. , Cougnon Louise‐Amélie , Fairon Cédrick
Published: December 2020

Background

Detecting Alzheimer’s disease (AD) before the onset of symptoms is crucial for the development of effective treatment (1). As biomarkers are costly and/or invasive, there is a need for cost‐efficient and non‐invasive methods that can indicate which individuals need further examination. We present a running project that aims at developing a screening tool applicable to the general population by automatically analyzing the history of electronic messages such as WhatsApp and e‐mails over a period of several years prior to the analysis.

Method

In the first phase of the project (model construction), 30 prodromal or mildly demented AD patients (with biomarkers‐confirmed diagnosis) and 30 clinically normal elderly volunteers are recruited to donate their electronic message histories. Data is gathered and processed according to the General Data Protection Regulation and only sent messages are considered, which are codified to hide personal information. Automatic linguistic analyses are conducted on this data, such as syntactic parsing and lexical analysis and used by machine learning algorithms that establish the evolution of the linguistic abilities of a participant over time. Specifically, we will test how long before AD diagnosis linguistic changes are noticeable versus clinically normal volunteers. In the second phase of the project (model testing), 200 elderly volunteers without AD diagnosis will be recruited to donate their electronic message history and genetically tested for Apolipoprotein E4 (APOE4). We hypothesize that our tool will identify changes in linguistic practices suggestive of preclinical AD more frequently in APOE4 carriers than in non‐carriers.

Result

We are currently collecting and processing data from patients and clinically normal volunteers. We started to run our first linguistic analyses on the data, but we do not have enough participants yet to train a computer model.

Conclusion

If detection of preclinical AD using linguistic markers from electronic message history turns out to be effective, the tool we develop could play an important role in the non‐invasive and cost‐efficient screening of preclinical AD in the elderly population. Specifically, it could facilitate clinical trials in preclinical AD.

Reference

(1) McDade, E. and Bateman, R. J. (2017). Stop Alzheimer’s before it starts. Nature News, 547(7662):153.
Reduced social activities and networks, but not social support, associated with cognitive decline among Chinese elderly
Authors: Fan Zili , LV Xiaozhen
Published: December 2020

Background

The relationship between social connectedness, including social activities, networks and support, and cognitive function remains controversial. The literature about the role of specific social connectedness’ different domains in cognitive function is limited. Our study aimed to examine the associations of social connectedness and its subdomains, with cognitive decline in the Chinese elderly.

Method

We analyzed data from the Chinese Longitudinal Healthy Longevity Survey. A total of 3314 Chinese older adults aged 65 years and over, who completed two waves of cognitive function measurement, were included for analysis. Cognitive decline was defined as an outcome measure in two ways: (1) the absolute change on MMSE score over time, i.e. (baseline MMSE – follow‐up MMSE); (2) the index of “greater cognitive decline”, i.e. ((baseline MMSE – follow‐up MMSE)/baseline MMSE) >0.1.Social connectedness was divided into three subdomains: social activities, social networks and social support. Linear regression models and binary logistic regression analysis were conducted to evaluate the associations of social connectedness and its different domains with cognitive decline, after adjusting for age, sex, education, residence, exercise, drinking, smoking, activities of daily living (ADL), chronic diseases, depressive symptom, and baseline cognitive function. Whether the association between social connectedness and cognitive decline differed by age, education, sex and cognitive function at baseline were also explored.

Result

Among the 3314 participants, the mean age was 80.17 ±9.33years, 49.09% were women, 50.12% of the respondents were illiterate. After 3 years, 768(23.17%) developed greater cognitive decline. Linear regression models and binary logistic regression analysis showed similar results. After controlling for covariates, social connectedness, social activities and social networks were related to slower cognitive decline (social connectedness: OR=0.64, 95%CI: 0.50 ‐ 0.82; social activities: OR=0.81, 95%CI: 0.67 ‐ 0.99; social networks: OR=0.70, 95%CI: 0.57 ‐ 0.87). Social support did not show the significance (OR=0.94, 95%CI: 0.79 ‐ 1.12). The association between social connectedness and cognitive decline was stronger among those with normal cognitive function at baseline and the educated elderly.

Conclusion

Our findings revealed social connectedness, social activities and social network rather than social support were potentially protective against cognitive decline.
Validation of connected speech as a marker for cognitive change in late‐middle aged African American adults at risk for Alzheimer's disease
Authors: Mueller Kimberly D. , Evans Elizabeth M. , Coley Sheryl L. , Koscik Rebecca L. , Norris Nia , Ramsey Celena M. , Green‐Harris Gina , Gleason Carey E. , Johnson Sterling C.
Published: December 2020

Background

Connected speech‐language (CSL) (linguistic, acoustic, and temporal measures from spoken language) is a promising performance‐based measure of cognition for studies researching Alzheimer’s disease (AD). CSL represents everyday communication and thus may be less influenced by sociocultural factors, but research investigating CSL in underrepresented groups is scarce. Picture description tasks are common for eliciting CSL, typically the Cookie Theft (CT). However, CT is outdated, it does not represent the US’s cultural diversity, and subsequently may not be effective for all groups. Our aims were 1) characterize CSL from late‐middle‐aged African Americans (AA) by sex and APOE; 2) compare AA CSL change vs. standardized language tests across cognitive statuses 3) determine if AA and non‐Hispanic whites (NHW) respond differently to the CT prompt.

Method

CSL measures (Figure 1) were automatically extracted from picture description transcripts from WRAP’s Milwaukee site (AA n=48; NHW n=30). Aims 1 and 3 statistics included t‐tests, chi‐square tests, and ANCOVA. Aim 2 used linear mixed‐effects models in AA with >1‐timepoint (n=30), examining whether longitudinal CSL varied by cognitive status.

Result

Table 1 shows speech metrics and demographics of AA participants by sex. AA and NHW did not differ on most baseline CSL measures including total words spoken (Table 2,3, Figure 2). Changes in CSL (Table 4) and BNT were associated with cognitive status in AA participants, but verbal fluency was not. Literacy was not related to CSL outcomes. CSL had higher effect sizes than BNT (b=.41 vs. .20).

Conclusion

In one of the first studies to characterize prospective CSL from an AD‐risk‐enriched sample of AA adults, we found no sex/APOE carrier status differences in AA CSL, and no differences between AA and NHW on most CSL measures. AA and NHW did not differ in the amount of talking in response to CT. CSL change among cognitively‐declining AAs was similar to that seen previously in a NHW sample. This combined with predominantly weak associations between CSL measures and WRAT‐3 suggest that CSL may reflect a socioculturally unbiased cognitive activity. Future directions include developing an ethnoculturally relevant stimulus picture, analyses with increased time points, sample sizes and AD biomarkers.
Preservation of white matter integrity on DTI 3 years after early menopausal hormone therapies
Authors: Kara Firat , Chen Qin , Reid Robert I. , Schwarz Christopher G. , Tosakulwong Nirubol , Lesnick Timothy G. , Zuk Samantha M. , Lowe Val J. , Fields Julie A. , Gleason Carey E. , Shuster Lynne T. , Bailey Kent R. , Jack Clifford R. , Rocca Walter A. , Miller Virginia M. , Kantarci Kejal
Published: December 2020

Background

The critical‐period theory of menopausal hormone therapy (mHT) suggests that if menopausal hormone therapy begins shortly after menopause, it may have beneficial effects on brain structure and cognitive health. We investigated white matter integrity with diffusion tensor MRI (DTI) 3 years after the end of mHT trial in recently menopausal women who were randomized shortly after menopause.

Method

Participants of this study were enrolled in the Kronos Early Estrogen Prevention Study (aged 42–56 years; 5–36 months past menopause). Participants received the following treatments: 0.45 mg/d oral conjugated equine estrogen (oCEE, n=19); 50 μg/d transdermal 17β‐estradiol (tE2, n=22); or placebo (n=33) for 4 years. Oral progesterone (200 mg/d) was given to hormone therapy groups for 12 days each month. DTI was performed 3 years after the end of 4 years of hormone therapy (n=75), which corresponded to 7 years after randomization. Voxel‐based analysis was performed on DTI to evaluate fractional anisotropy (FA) and mean diffusivity (MD) differences between treatment groups (uncorrected p<0.001).

Result

Voxel based analysis showed higher FA, a measure of white matter integrity, in the superior corona radiata, anterior limb of the internal capsule and splenium of the corpus callosum of participants treated with oCEE compared to placebo (p <0.001, Figure 1A). Furthermore, higher FA was observed in the superior corona radiata, anterior limb of internal capsule and thalamus in participants treated with tE2 compared to placebo (p <0.001, Figure 1B). There were no differences in FA findings between oCEE and tE2 groups, and no MD differences between treatments groups.

Conclusion

A relatively higher FA in a variety of white matter regions in the oCEE and tE2 groups compared to placebo suggest that mHT may have long‐term protective effects on white matter integrity. Previously, we had shown that women in the tE2 group preserved their dorsolateral prefrontal cortex volumes better than the placebo group over 7 years. Our findings suggest that the tracts that connect the dorsolateral prefrontal cortex and the thalamus such as the superior corona radiata and the anterior limb of internal capsule may particularly benefit from mHT.
Lateralizations and enhancers of the loss of function in dementia for olfactory, sensory, and motor domains
Authors: Schonfeld Ethan , Schonfeld Elan , Aman Casey , Gill Navroop , Kim Dami , Rabin Sydney , Shamshuddin Bushraa , Sealey Lloyd , Senno Ricardo Gabriel
Published: December 2020

Background

There exist functional deficits in motor, sensory, and cognitive abilities in dementias (Kluger et al, The Journals of Gerontology: Series B, 1997; Albers et al, Alzheimer’s and Dementia, 2015). In 2010, the National Institute on Aging combined the study of these functions, focusing on clinical manifestations of neurodegeneration of olfactory, sensory, and motor domains as potential clinical markers. Building on these results, we seek to study possible lateralizations in deficit severity to further clinical markers and improve outcomes through functional therapies.

Method

This IRB approved study performed left/right functional assays of olfactory, sensory, and motor ability. A Peppermint Oil test measured discrete left/right olfactory function; the Von Frey test measured discrete left/right sensory tactile function; a dynamometer was used to measure discrete left/right motor grip strength. The Mini Mental Status Exam was administered; social, medical, and laboratory data were collected (N=84).

Result

While the non‐dementia, right‐handed, population has significantly greater right motor grip strength, the dementia population showed no significant correlation (p=0.127, n=57). Deficit in sensory tactile function worsened on left side (p=0.0387, n=63). Deficit in cranial nerve 1 (CN1) function worsened on left side (p=0.0515, n=37). Enhancers of motor deficit to right side: female (p=0.434, n=32), depression (p=0.455, n=29), MMSE<15 (p=0.382, n=24), and diabetes (p=0.451, n=13). Enhancers of sensory deficit to left side: use of psychotherapeutic agent (p=0.0514, n=47), age≥85 (p=0.070, n=30), MMSE<15 (p=0.0732, n=30), and male (p=0.0826, n=25). Enhancers of CN1 deficit to left side: age<85 (p=0.00262, n=24), medication number>10 (p=0.0725, n=24), and male (p=0.0742, n=15).

Conclusion

The results suggest that in dementia, olfactory and sensory functional deficits lateralize to the left, and motor deficits to the right. Future research should identify enhancers and suppressors of these lateralizations to develop therapies to strengthen at‐risk areas. Furthermore, these lateralized LOF can act as early clinical markers.
Difference of cognitive impairment in ischemic stroke patients based on hemiparesis side at Atma Jaya Hospital, Indonesia, 2014‐2018
Authors: Hamid Gabriella , Wreksoatmodjo Budi Riyanto , Andre Andre
Published: December 2020

Background

Cognitive impairment in stroke patients can decrease their quality of life. The characteristics of cognitive impairment may be different based on the lesion’s location. Objective was to assess the difference of cognitive function in ischemic stroke patients based on hemiparesis side.

Method

A cross‐sectional research on 125 ischemic stroke patients in Atma Jaya Hospital 2014‐2018. Analyzed data includes age, hemiparesis side, MMSE and MoCA‐INA scores. Data was analyzed using univariate and bivariate Mann‐Whitney test.

Result

Patients with left hemiparesis had higher scores in all categories of MMSE and MoCA‐INA than patients with right hemiparesis. In patients aged less than 55 years old, MoCA‐INA results showed that left hemiparesis had a significantly higher language score (p=0,030); but naming, delayed recall, and orientation scores were higher in right hemiparesis. In patients aged more than 55 years old, scores for visuospatial in MMSE and language in MoCA‐INA were higher in right hemiparesis.

Conclusion

Overall scores for MMSE and MoCA‐INA in left hemiparesis were higher than right hemiparesis, although not significant. Language ability measured with MoCA‐INA was significantly higher in left hemiparesis in patients aged less than 55 years old.
Deciphering the mechanistic action of phytoformulation against scopolamine‐induced Alzheimers in rodents
Authors: Rajendran Kayalvizhi , Krishnan Uma Maheswari
Published: December 2020

Background

Brahmi Nei (BN), an Indian traditional phytoformulation composed of eleven plant constituents has been traditionally used for treating various psychiatric disorders, hypertension and cerebral palsy. Some of the key phytoconstituents in this formulation have been explored for their potential role in plaque disruption, crossing the blood‐brain barrier, reversing the cognitive deficit and promoting tau dephosphorylation independently as a mono‐drug. Since Alzheimer’s disease (AD) is a multifactorial disorder affecting various signaling pathways, we hypothesize that BN formulation may be an effective option to treat AD.

Method

The major constituents in BN were identified using LC‐MS/MS technique. The Alzheimer’s model was created using scopolamine hydrobromide in animals through intra‐hippocampal injection at a concentration of 10 µg/µL. After seven days of post‐operative care, treatment was started with three different doses BN1 (0.5 of therapeutic dose, n=5), BN2 (Therapeutic dose, n=5), BN3 (twice the therapeutic dose, n=5) for a period of 28 days. The cognition and spatial learning were assessed using Morris water maze, radial arm maze and elevated plus maze. RT‐PCR, Western blots, biochemical assays analysis were performed to evaluate the therapeutic efficacy of BN against various signaling pathways deregulated in AD. Neuritic plaque deposits were detected using Bielchowsky silver staining while dendritic morphology and spine types were studied using Golgi‐Cox staining.

Result

Our results reveal that BN treatment influences the working memory and hippocampal‐dependent learning pattern in AD‐induced rodents. BN reduced acetylcholine esterase and malondialdehyde concentration in hippocampal tissues. It significantly regulates dephosphorylation of tau, inflammatory pathway and also inhibits the BBB disruption by activating YAP/TAZ. At the cellular level, synaptic degeneration and hippocampal neuronal loss were reversed by BN treatment which also regenerated neurons and increased spine density that is reflected in the superior cognitive improvement displayed by the BN2 and BN3 treated animals in the behavioral studies.

Conclusion

The BN formulation is an efficient therapeutic option in treating the multiple pathways involved in AD when compared to conventional mono‐drug treatment.
In silico study for neurodegenerative diseases diagnosis: A novel gene panel
Authors: Nguyen Thuy Trang , Vo Tuong Kha , Vo Van Giau
Published: December 2020

Background

Genetic factors are central to the etiology of neurodegeneration, both as monogenic causes of heritable disease and as modifiers of susceptibility to complex, sporadic disorders. Extensive analyses of known the monogenic causes of neurodegenerative diseases by whole‐exome/genome sequencing are technically possible today. We here aimed to compile a comprehensive panel of genes associated with monogenic causes of neurodegenerative diseases (NDs) for use in clinical and research situations.

Method

We systematically searched the publicly available database Online Mendelian Inheritance in Man, and validated the entries against original peer‐reviewed publications in PubMed. First, we selected known pathogenic or putatively pathogenic stroke genes reported in at least one person with the disorders. Then, the diseases phenotype was classified based on each gene into eight subgroups: (1) Alzheimer disease (AD), (2) Parkinson disease (PD), (3) Lewy body dementia (LBD), (4) frontotemporal dementia (FTD), (5) amyotrophic lateral sclerosis (ALS), (6) Huntington disease (HD), (7) prion diseases and other genes related to brain disorders, but without any documented the patient description.

Result

We identified in total 177 genes: 45 associated with AD, 29 associated with PD, 25 associated with LBD, 24 associated with FTD, 23 associated with ALS, 10 associated with HD, 1 may cause prion diseases, and 20 other‐related genes from uncleared brain disorders. We described these 177 genes and the clinical NDs subtype(s) associated with each of them. The resulting gene panel can be used to interpret exome sequencing results regarding monogenic NDs.

Conclusion

The genetic testing panel is applicable to NPs clinical areas and has important implications for family testing.
β‐amyloidopathy in the pathogenesis of age‐related macular degeneration in correlation with Alzheimer’s disease in the aspect of autophagy anomalies
Authors: Ermilov Victor Vladimirovich , Zagrebin Valeriy , Smirnov Alexey Vladimirovich , Markelov Vadim Vladislavovich
Published: December 2020

Background

Recent data of molecular analysis leading to the key role of certain proteins in the etiology and pathogenesis of a group of neurodegenerative diseases (NDD) including age‐related macular degeneration (AMD) gave an impulse to the development of new concepts that allocate separate versions of proteinopathies such as tauopathy, synucleinopathy, amyloidopathy. To study the clinical and morphological features of amyloidogenesis in AMD as a manifestation of the commonality of proteinopathy and β‐amyloidopathy of pathological processes in brain for Alzheimer's disease (AD) and in the eye for AMD, a common fact is described that extra‐ and intracellular stimuli from pathological protein deposits are able to modulate the macroautophagic response, which plays a role in homeostasis of the retinal pigment epithelium (RPE).

Method

111 eyes with morphological signs of “dry” and “wet” forms of AMD and the brain taken from 56 cadavers were examined, using selective methods of amyloid detection.

Result

The amyloid deposits in the patients with AMD were found in 42.3% of cases in all the structural elements of fundus. β‐amyloidopathy was identified in 39% and 80% cases separately in dry and wet form of AMD. The combined accumulation of β‐amyloid in both the eye and the brain was found in 50.6% of cases. β‐amyloid was specific to drusen in eyes with AMD and to senile plaques in brain tissue in the patients with AD. The decrease in RPE nuclei is connected with the process of autophagy.

Conclusion

The authors have demonstrated that the keynote of AMD and AD pathogenesis is β‐amyloidopathy as a manifestation of proteinopathy activated by the amyloid deposits. This view on the problem creates the preconditions for new strategies of treatments, targeting on the pathogenesis of β‐amyloid formation and pathological aggregation, as malfunctioning of autophagy has been related to accelerating aging of RPE cells.
Association between cerebrospinal fluid neurofilament light chain and markers of neurofibrillary pathophysiology: Findings from the Knight Alzheimer Disease Research Center
Authors: Schultz Stephanie A. , Schindler Suzanne E. , Chen Charles , Sutphen Courtney L. , Morris John C. , Fagan Anne M. , Gordon Brian A. , Benzinger Tammie L.S.
Published: December 2020

Background

The objective of this study was to examine the relationship between cerebrospinal fluid (CSF) neurofilament light (NfL) chain levels and established biomarkers of neurofibrillary tangle (NFT) pathophysiology. Secondarily, we assessed the discordance of beta‐amyloid, NFT, and neurodegeneration markers.

Method

236 individuals (207 cognitively normal and 29 cognitively impaired) were selected based on completion of CSF collection and AV1451 and AV45 PET imaging within 1 year, and measurement of CSF NfL, beta‐amyloid‐42, total‐tau, and phosphorylated‐tau181 (p‐tau). Using covariate‐adjusted linear regressions we compared log‐transformed CSF NfL to AV1451 summary SUVRs and CSF p‐tau. Using Gaussian mixture models, we determined positivity thresholds in markers of beta‐amyloid (CSF beta‐amyloid‐42 and AV45), NFT (CSF p‐tau and AV1451), and neurodegeneration (CSF total‐tau and CSF NfL), and assessed discordant results between related biomarkers.

Result

CSF NfL was highly associated with CSF p‐tau (p=9.83e‐10), whereas CSF NfL was marginally associated with AV1451 (p=0.006). CSF p‐tau and AV1451 were only moderately correlated (r=0.457). The differences in relationship between tau and NfL markers may be due to effects of age on these three biomarkers of interest. Age was minimally correlated with AV1451 (r=0.326) and moderately correlated with CSF p‐tau and NfL (r=0.410 and 0.512, respectively). Secondarily, we found that our sample was 18.2% discordant between beta‐amyloid markers, 18.7% discordant between NFT markers, and 17.8% discordant between neurodegeneration markers.

Conclusion

The relationship between CSF NfL and NFT pathophysiology differed depending on the NFT biomarker that was considered and may be related to elevations in certain CSF biomarkers as a function of age. Currently, CSF p‐tau and AV1451 are often considered interchangeable measures of NFT pathophysiology. These results suggest more careful consideration and assessment of biomarkers should be taken when choosing markers of beta‐amyloid, NFT, and neurodegeneration.
Association of cognitive health status with happiness, helplessness and hopelessness in different races
Authors: Umucu Emre , Wyman Mary F , Lee Beatrice , Zuelsdorff Megan , Lambrou Nickolas H , Johnson Adrienne L , Bouges Shenikqua , James Taryn T , Salazar Hector , Simó Carola A Ferrer , Carter Fabu P , Asthana Sanjay , Gleason Carey E
Published: December 2020

Background

Cognitive impairments are linked to changes in positive and negative affect. However, it remains unclear whether some dimensions of positive and negative affect are associated with cognitive health status (CHS) and the relationships between pillars of positive and negative affects and CHS function similarly across racial groups. In this study, we tested whether (a) happiness, helplessness, and hopelessness are linked to CHS and (b) if these relationships are similar among blacks and whites.

Methods

Participants were 755 enrollees in the Wisconsin ADRC who had normal cognition, MCI, and dementia at baseline. The majority of participants were female (59.2%) and Caucasian (81.5%). The average age at baseline was 64.23 (SD=10.40).CHS was categorized as cognitively normal, mild cognitive impairment, and dementia. Happiness, helplessness, and hopelessness were measures with three items from the 15‐item Geriatric Depression Scale. For question (a), all races were included in the analyses. For question (b), blacks and whites are subgrouped and all other races were excluded. Chi‐square or Fisher’s Exact tests were conducted to test our research hypotheses.

Results

Chi‐square test results revealed that (a) an association between happiness and CHS, χ
2(2)=6.06, p<.05, (b) an association between helplessness and CHS, χ
2(2)=6.44, p<.05, and (c) an association between hopelessness and CHS, χ
2(2)=14.11,p<.01. The association of happiness with CHS remained significant in blacks (Fisher’s exact=.03), but not in whites, χ
2(2)=1.04, p=.59. The association of helplessness with CHS was not significant for blacks (Fisher’s exact = 1.00), but was significant for whites, χ
2(2)=8.47,p< .05. Finally, the relationship between hopelessness and CHS was not associated in blacks (Fisher’s exact=.19), but was in whites, χ
2(2)=16.31,p<.01.

Conclusion

Race differences in the association of CHS and happiness, helplessness, and hopelessness were found. For blacks, only happiness was significantly associated with CHS, whereas, for whites, CHS was associated with helplessness and hopelessness, but not with happiness. These findings can inform the development of culturally‐tailored interventions to prevent cognitive decline for specific races.
Impact of blood biomarkers on cost and wait time in diagnosing treatment‐eligible patients for Alzheimer’s disease: A simulation study
Authors: Mattke Soeren , Cho Sang Kyo , Bittner Tobias , Hlavka Jakub , Hanson Mark
Published: December 2020

Background

Recent trial results give hope that a disease‐modifying treatment (DMT) for Alzheimer’s disease (AD) might become available, but concerns have been raised that the large number of patients might overwhelm the healthcare system, in particular because of limited capacity of dementia specialists. Blood based biomarker (BBBM) tests for the biologic hallmarks of the disease are a promising tool to improve triaging at the primary care level. We projected their impact on cost and wait times with a simulation model.

Method

We simulate the U.S. population age 50+ over 30 years combining a disease progression model (Cognitively normal to MCI due to AD or due to other causes to dementia) and a system dynamics model for capacity constraints (specialist cognitive testing and confirmatory biomarker testing with PET or CSF). We compare four scenarios for primary care evaluation (1) cognitive screening only (MMSE), (2) BBBM only, (3) MMSE followed by BBBM if positive and (4) BBBM followed by MMSE if positive. Parameter for patient pools, costs and capacity were derived from published data and assumptions.

Result

Using either MMSE or BBBM alone would result in a number of specialist referrals that is projected to continuously exceed capacity from 2020 to 2050. Combining MMSE and BBBM in either order would eliminate wait lists after the first three years. (Figure) The projected number of correctly identified cases (i.e., true positive for MCI due to AD) will increase from ∼480,000 for either MMSE or BBBM alone to ∼600.000 for MMSE and BBBM combined on average each year. Average total cost per year would be an estimated $7.2 billion for MMSE alone, $7.7 billion for BBBM alone, and $6.9 billion for MMSE and BBBM combined, and cost per correctly identified case will decline from ∼$15,000 for MMSE or BBBM alone to∼$11,000 for a combination of MMSE and BBBM.

Conclusion

Combining BBBM with MMSE is projected to increase the efficiency and value of the triage process for eligibility for a DMT at the primary care level, as the addition of a BBBM would reduce wait times for specialist visits and diagnostic yield dramatically without increasing net cost.