bluuebunny/crossref_metadata_2025 huggingface dataset:
Chitosan nanoparticles alleviate Alzheimer’s disease in zebrafish by adopting a dual strategy
Authors: Saleem Suraiya
Published: December 2020

Background

Alzheimer’s disease (AD) is a progressive neurodegenerative disease. It is the most prevalent form of dementia in the world affecting almost 47 million people worldwide. The main pathological hallmark of AD is progressive memory loss. Zebrafish possess 70% similarity with the human genome. Zebrafish have been used extensively in developmental biology and molecular genetics. Zebrafish are being widely used as a predominant model for studying neurodegenerative diseases. In this current study, we have attempted to establish Aβ induced model of AD in Zebrafish. Validation of this model is done by behavioral analysis.

Method

The various assays performed to test memory were spatial memory testing, preference for light and dark environments and their ability to recognize novel objects from the previous objects. SEM, TEM, FTIR, AFM and particle size analysis were performed to validate the nanoparticles thus formed. Amyloid beta was injected mid ventrally into the zebrafish brain, which were previously given Chrysin by oral gavage.

Result

The various assays performed are spatial memory testing, preference for light and dark environments and their ability to recognize novel objects, which revealed the drastic changes in the behavior of Aβ injected fishes. Further validation of the Aβ model was done using immunohistochemical (IHC) staining of brain sections of Aβ injected fish, which confirmed the presence of Aβ with Aβ antibody. The present study establishes a model of AD in zebrafish which will be useful for therapeutic drug intervention in future. Chitosan nanoparticles loaded with the naturally occurring flavonoid, chrysin, were synthesized. The nanoparticles were validated on the basis of their physical and chemical properties. It was also observed that the chrysin loaded chitosan nanoparticles led to protection and restoration of synapses of the amyloid beta treated zebrafish. Chitosan also possessed the ability to disintegrate the amyloid plaques in vivo.

Conclusion

This study provides insight into the dual strategy by which Chrysin‐ Chitosan nanoparticles alleviate Alzheimer’s like condition. This dual strategy adopted by the Chrysin‐ Chitosan nanoparticles therefore holds potential to serve as a therapeutic strategy to treat AD.
Amyloid‐β CSF/PET discordance vs tau load 5 years later: It takes two to tangle
Authors: Reimand Juhan , Collij Lyduine , Scheltens Philip , Bouwman Femke H. , Ossenkoppele Rik ,   and the Alzheimer's Disease Neuroimaging Initiative
Published: December 2020

Background

Amyloid‐β pathology assessed in vivo using CSF and PET results in discordance (CSF+/PET‐ or CSF‐/PET+) in 10‐20% of cases. An amyloid‐β CSF+/PET‐ profile has been proposed to mark the pathological beginnings of amyloid‐β accumulation (Palmqvist et al., 2016), providing a powerful model to study the interplay between amyloid‐β and tau at the earliest stages of Alzheimer’s disease.

Methods

We included 730 participants without dementia (282 cognitively normal, 448 MCI) from the Alzheimer’s Disease Neuroimaging Initiative database with available baseline [18F]florbetapir PET and CSF Aβ42 within one year. Established cut‐offs were used to determine amyloid‐β CSF/PET status. We used linear mixed modelling to study the association between amyloid‐β CSF/PET status and tau pathology measured in CSF and cognitive performance (both available at baseline) or by using [18F]flortaucipir tau‐PET (performed 5.2±1.2 years later). Using Kaplan‐Meier estimates and Cox regression, we investigated the association between amyloid‐β CSF/PET status and progression of syndromic diagnosis. Additionally, we calculated the proportion of CSF+/PET‐ participants who during follow‐up (i) progressed to amyloid‐β CSF+/PET+, and/or (ii) became tau‐positive based on [18F]flortaucipir PET.

Results

Mean age of the participants was 73±7 years, 52% were male and mean MMSE was 28.4±1.6. (Table 1). Amyloid‐β CSF+/PET+ (N=318) participants had elevated CSF (p)tau levels and worse cognitive performance at baseline, while CSF+/PET‐ (N=80) participants were overall similar to the CSF‐/PET‐ (N=306) group (Figure 1). Five years after baseline, [18F]flortaucipir PET uptake in the CSF+/PET‐ group (1.20±0.13) did not differ from CSF‐/PET‐ (1.18±0.08, p=0.69), but was substantially lower than CSF+/PET+ (1.48±0.44, p<0.001). Progression of syndromic diagnosis occurred less often in amyloid‐β CSF+/PET‐ (14%, hazard ratio [HR]=0.22[0.12,0.41], p<0.001), CSF‐/PET+ (8%, HR=0.10[0.02,0.41], p=0.001) and CSF‐/PET‐ (10%, HR=0.16[0.11,0.24], p<0.001) participants, compared to the CSF+/PET+ (44%) group (Figure 2). Of the CSF+/PET‐ subjects, 21/64 (33%) progressed to amyloid‐β CSF+/PET+, whereas only one (3%, difference p<0.05) became tau‐positive based on [18F]flortaucipir PET.

Conclusions

Sufficient amyloid‐β load detectable by both CSF and PET is required before substantial tau deposition emerges. Compared to participants with abnormal amyloid‐β levels on PET and CSF, the discordant CSF/PET groups have a distinctly better prognosis.
How prepared are the EU‐5 countries’ health systems to deliver a disease‐modifying treatment for Alzheimer’s?
Authors: Mattke Soeren , Wang Mo , Ullrich Andreas
Published: December 2020

Background

Prior research suggests that health systems are unprepared for a potential disease‐modifying treatment (DMT) for Alzheimer’s disease and projected substantial delays in access. We analyzed whether and to what degree changes to institutional arrangements (e.g., policies, incentives and regulations) could improve capacity and readiness in five countries.

Method

Desk research and expert interviews in France, Germany, Italy, Spain, and the U.K. focusing on planning for and coverage of memory services, ability of providers to adapt to a surge in demand and provider capabilities along the patient journey from diagnosis to treatment.

Result

No country has a government‐led plan to prepare for the advent of a DMT or advance planning to budget for the expected increase spending. Spain and the U.K. have expert‐led initiatives to inform the policy dialog. Screening for cognitive decline is not recommended or covered in any of the countries. While all cover initial evaluation of memory complaints in primary care settings, it is often not performed because of limited knowledge, lack of tools and fatalistic attitude.

Patients with suspected cognitive decline have access to specialist memory services in all five countries, led by geriatric psychiatrists (Germany and U.K.) or neurologists (France, Italy and Spain). Scale and scope vary substantially within and across countries, with only France and the U.K. attempting to standardize services. Only Italy and Spain cover biomarker testing based on PET scans or CSF tests for routine care. Memory services operate at capacity in all countries with wait times of at least two months, and limited flexibility to scale up due to low numbers of dementia specialists, lack of budget and complex planning processes. Psychiatry‐led services tend to be less prepared for the medicalized requirements of a DMT delivery.

Conclusion

Institutional preparedness and funding for a DMT needs to be improved in all five countries, particularly by strengthening primary care with training and tools, such as simple cognitive tests and blood‐based tests for Alzheimer’s biomarkers, as workforce and budget constraints limit the ability to scale up specialist services. Such improvements would also improve access to and quality of memory care in the absence of a DMT.
Comparison of 18F‐Flortaucipir visual assessment, SUVR quantification and CSF pTau for defining T‐status in the AT(N) framework
Authors: Provost Karine , Iaccarino Leonardo , Soleimani‐Meigooni David N. , Lesman‐Segev Orit H. , Joie Renaud , Mattsson Niklas , Hansson Oskar , Eichenlaub Udo , Edwards Lauren , Strom Amelia , Pham Julie Q. , Mellinger Taylor J. , Janabi Mustafa , Baker Suzanne L. , Jagust William J. , Rabinovici Gil D. ,   ADNI
Published: December 2020

Background

Tau‐PET is included in the AT(N) research framework to define T‐status. However, no consensus exists as to how to classify patients as T+ or T‐ with this modality. We aim to compare T‐status derived from 18F‐Flortaucipir (FTP) PET visual assessment, 18F‐FTP SUVR quantification, and CSF pTau.

Methods

278 subjects who underwent 18F‐FTP PET and CSF analysis within 1 year were included from UCSF and ADNI. The cohort consisted of a continuum from cognitively normal controls (CN) to Alzheimer’s disease dementia (AD), and non‐Alzheimer’s disorders (clinical diagnoses, Table 1). T‐status was derived from: (1) 18F‐FTP consensus between two readers performing blinded visual assessment based on a priori criteria (Figure 1, inter‐rater k=0.68, 95%CI 0.59‐0.76; Provost et al, HAI Conference, 2020); (2) 18F‐FTP SUVR quantification of from a temporal meta‐ROI using a previously validated threshold (SUVR >1.27, Ossenkoppele et al. 2018); (3) Elecsys® Phospho‐Tau (181P) CSF (Roche Diagnostics) applying a ROC‐based threshold derived from an external ADNI cohort comparing amyloid‐positive AD vs. healthy controls (pTau >24.5 pg/mL).

Results

T+ was assigned in a higher proportion of AD, MCI and amyloid‐positive CN with 18F‐FTP visual assessment compared to 18F‐FTP SUVR and CSF pTau (Table 2). However, visual ratings also yielded the highest proportion of T+ in amyloid‐negative CN and MCI. Contrasting amyloid‐positive AD/MCI with other groups, sensitivity was highest for 18F‐FTP visual assessment, while specificity was highest for 18F‐FTP SUVR (Table 3). In a subset of patients with autopsy (n=11), T‐status derived from 18F‐FTP visual assessment had an accuracy of 100%, compared to 82% for SUVR quantification and 64% for CSF pTau. Overall agreement between the 3 classification criteria ranged from 68% to 76% in the whole cohort (Figure 2) and was highest in patients with AD (94%). Patients with concordant T‐status across all three modalities were significantly younger, had higher CSF pTau, higher 18F‐FTP SUVR (Figure 3), and were more likely to be amyloid positive.

Conclusions

Concordance of T‐status derived from 18F‐FTP visual assessment, SUVR quantification and CSF pTau varies across disease stage, being highest in AD. 18F‐FTP visual assessment offers highest sensitivity, while SUVR threshold maximizes specificity.
Determining the role of lactate metabolism on age‐dependent memory decline and neurodegeneration in Drosophila melanogaster
Authors: Frame Ariel K. , Simon Anne F. , Cumming Robert C.
Published: December 2020

Background

Although lactate has traditionally been considered a waste product, recent discoveries show lactate plays many beneficial roles in the brain. Astrocyte generated lactate can function as a fuel for neurons to enable long‐term memory. However, elevated lactate has been detected within the brain and cerebrospinal fluid of Alzheimer’s disease patients; a finding associated with hastened memory impairment. Whether perturbed lactate levels contribute to age‐related memory impairment is unknown. This study uses the fruit fly Drosophila melanogaster to elucidate the role of lactate metabolism in cognition during aging.

Method

The enzyme lactate dehydrogenase (dLdh), which facilitates the interconversion between lactate and pyruvate, was genetically manipulated in glia and neurons of Drosophila melanogaster. Transgenic flies were tested for changes in lifespan, memory, climbing ability, neurodegeneration as well as dLdh and lactate levels in the brain. Tests in transgenic flies were performed at ages ranging from young (7 days) to old (28 days). Memory was assessed using the courtship conditioning paradigm, of which only male flies can be tested.

Results

Lactate and dLdh protein levels were correspondingly elevated or lowered in transgenic flies with increased or decreased dLdh expression respectively. Transgenic flies with either increased or decreased dLdh expression exhibited reduction in lifespan and neurodegeneration at old age. These detrimental effects were present whether dLdh expression was altered in either neurons or glia, yet only neuronal dLdh upregulation caused deficits in climbing ability. Young transgenic flies with altered dLdh expression in either neurons or glia all exhibited memory similar to control. Interestingly, only flies with increased glial‐derived dLdh expression had an impact; memory was impaired at middle age then recovered at old age.

Conclusion

Prolonged perturbation of lactate metabolism results in neurodegeneration and increased rate of health decline in flies. The impact of altered lactate levels on memory appears to be cell type specific and dynamic. Excess glial‐derived lactate only appears detrimental to memory during middle age. However, excess or diminished production of lactate, within neurons or glia, hastens aging and neurodegeneration. Future studies of age‐related diseases, such as Alzheimer’s, should focus on lactate metabolism and metabolic interplay between neurons and glia.
Visual attention as a model for interpretable neuroimage classification in dementia
Authors: Cole James , Wood David , Booth Thomas
Published: December 2020

Background

Deep learning has the potential to aid clinical decision‐making in dementia, by automatically classifying brain images. However, several key limitations currently prohibit clinical adoption: 1) network design must be optimised for 3D neuroimaging; 2) analysis must be computationally feasible; 3) model decisions must be interpretable. Interpretability is particularly crucial, as clinicians need to understand how and why each automated decision is made.

Method

We address these issues using a 3D recurrent visual attention model tailored for neuroimaging: NEURO‐DRAM. The model comprises an agent which, trained by reinforcement learning, learns to navigate through volumetric images, selectively attending to the most informative regions for a given task. We trained and tested NEURO‐DRAM using T1‐weighted MRIs from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) dataset. This entailed n=162 Alzheimer’s Disease (AD) patients and n=160 healthy controls (HCs), split into training (90%) and testing (10%) data. Classification generalisability was evaluated using independent AD patients (n=130) and HCs (n=100) data from the Open Access Series of Imaging Studies (OASIS) dataset. Finally, we assessed the potential to transfer the classification task (i.e., no extra training needed) to discriminate between the baseline MRIs of people with stable or progressive mild cognitive impairment (MCI).

Result

NEURO‐DRAM achieved 98.5% balanced accuracy when classifying AD patients from HCs from ADNI and 99.8% in OASIS, significantly out‐performing a baseline convolutional neural network. When classifying stable versus progressive MCI, accuracy was 77.8%. For each test participant, an individualised trajectory was obtained, depicting the brain regions that were used to make the specific classification (Fig. 1). The regions ‘visualised’ by the model’s trajectories included the hippocampus, parahippocampal gyrus and lateral ventricles. Computation time for training NEURO‐DRAM was substantially faster than the baseline network (10 minutes versus 45 minutes).

Conclusion

Using a data‐driven approach, near‐perfect classification of AD patients from HCs can be achieved. To reach this high level of performance, our model learns to ‘visually’ attend to the areas of the brain radiologically associated with AD. Importantly, the neuroanatomical trajectory for each individual run through the analysis can be visualised, providing an intuitive way to interpret how NEURO‐DRAM has reached a classification decision.
Screening for dementia in Down syndrome using the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE)
Authors: Mattar Guilherme Prado , Haddad Glenda Guerra , Uchida Ricardo Riyoiti , Fonseca Luciana Mascarenhas , Forlenza Orestes Vicente
Published: December 2020

Background

Down syndrome (DS) is genetically associated with Alzheimer´s disease (AD), and the neuropathological features of AD can be found in DS brains since early adulthood. Screening tests are required for the clinical assessment of dementia; however, the presence of intellectual disability at various degrees precludes the use of most of the available cognitive screening tests in this population, and few instruments have so far been validated for this purpose. The aim of the present study was to examine the psychometric properties of the IQCODE for the screening for cognitive/functional decline and dementia in DS.

Method

92 aging adults with DS (mean age 43.45 SD 8.51; 61.0% males) were enrolled for a cross‐sectional assessment by two independent psychiatrists. Inclusion criteria were: diagnosis of DS according to the International Classification of Diseases, tenth edition (ICD‐10); minimum age of 30 years; and having an informant with daily contact with the subject for the past 10 years at least. Participants were assessed by the Cambridge Examination for Mental Disorders of Older People with Down syndrome and others with Intellectual Disability (CAMDEX‐DS) using a validated Brazilian version, and by the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE). The concurrent validity of the IQCODE was analyzed in relation to the gold standard CAMDEX‐DS diagnosis.

Result

Participants were allocated into three diagnostic groups according to the CAMDEX‐DS: 1‐ dementia (N= 13); 2‐ prodromal dementia (N=17); and 3‐ stable cognition (N=62). ROC curve analyses were carried out to determine the diagnostic accuracy of the IQCODE in comparison to CAMDEX‐DS by diagnostic pairs indicated that the IQCODE optimal cut‐off scores for each diagnostic pair were as follows: (a) AD versus stable cognition: 3.14 (AUC=0.993; sensitivity: 100% specificity: 96.8%; (b) AD + prodromal versus stable cognition: 3.11 (AUC=0.975; sensitivity: 93.3%; specificity: 91.9%).

Conclusion

The IQCODE appears to be a suitable tool for the brief screening of cognitive/functional decline in aging DS adults.
Racial comparisons of MRI and PiB PET in acute stroke
Authors: Koenig Lauren N , McCue Lena , Grant Elizabeth A , Massoumzadeh Parinaz , Roe Catherine M , Xiong Chengjie , Moulder Krista L. , Wang Liang , Zazulia Allyson , Kelly Peggy , Dincer Aylin , Zaza Aiad , Morris John C. , Shimony Joshua S , Benzinger Tammie L.S.
Published: December 2020

Background

Stroke and Alzheimer disease share risk factors and often co‐occur, and both have been reported to have a higher prevalence in African‐Americans. However, the interaction of race, stroke, and Alzheimer disease has not been established.

Method

We compared MRI and PiB PET biomarkers of non‐demented participants with and without acute ischemic stroke (total n=243, age 65‐101), with a focus on comparing African‐Americans (n=42 with stroke, n=84 without) to Non‐Hispanic Whites (n=39 with stroke, n=78 without). Our assessment included radiologic reads of the number of large infarcts, small infarcts, microbleeds, and leukoaraiosis; a PET measure of amyloid binding; quantitative measures of hippocampal volume and white matter hyperintensities; and longitudinal Mini Mental State Exam (MMSE) scores. Statistical analysis used logistic regression models to predict each biomarker using race and stroke status, while controlling for age, family history, APOE4, education, sex, and high blood pressure.

Result

PiB PET did not differ significantly by stroke status or by race, with 23.6% of participants being classified as amyloid positive (Figure 1). As expected in stroke, the acute stroke participants were more likely to have large infarcts, small infarcts, microbleeds, and non‐zero Fazekas scores. MMSE showed racial differences at baseline (mean 26.8 for African‐Americans, 27.9 for Non‐Hispanic Whites, p=0.03), but not longitudinally. Overall, African‐Americans were more likely to have microbleeds (32.8% vs 22.6%, p=0.04). Within the stroke group African‐Americans were more likely to have small infarcts (75.6% vs 56.8%, p=0.049). Combined, African‐Americans were also more likely to have more than 5 microbleeds ‐ the cutoff for many Alzheimer clinical trials (15.2% vs 9.6%, p=0.04).

Conclusion

Preclinical Alzheimer disease does not appear to be a risk factor for stroke and did not differ by race in our sample. Standard clinical MRI measures differed by stroke status, but showed few racial differences. The observed lower MMSE scores in African‐Americans has been reported previously and may arise for a variety of reasons. In individuals with stroke, African‐Americans may have more severe pathology as evidenced by greater numbers of small infarcts and microbleeds. African‐Americans may be more likely to be excluded from Alzheimer disease clinical trials due to having 5 or more microbleeds.
Investigating early changes in cognitive ability in the cognitively healthy and early‐stage cognitively impaired older adult populations
Authors: Idowu Mojitola , Parton Andrew , Szameitat Andre
Published: December 2020

Background

Decline in cognitive ability is well understood to occur due to advanced age and pathological impairment. However, not all affected aspects of cognitive ability deteriorate at the same rate (Petersen, RC, et al., 1997; Craik, FI, and Salthouse TA, 2000, 2008, 2011; Salthouse, TA, 2009, 2012).

In this study, we research how executive function abilities (mental processes that regulate and control our cognition) differ between cognitively healthy older adults and individuals living with Mild Cognitive Impairment (MCI) and early‐stage Alzheimer's disease (AD). Assessment was focused on four areas of executive functions dual‐tasking, inhibition, shifting and updating commonly utilised in everyday life (Miyake, A, et al., 2000; Alvarez, JA, and Emory, E, 2006; Suchy, Y, 2009; Baddeley, A., 2012). The aim is to better understand the nature and rate of deterioration as a means to aid in early detection and intervention for both conditions.

Method

We aim to assess approximately 30 cognitively healthy older adults, and a combination of 30 individuals living with MCI and early‐stage AD on four different aspects of executive functions, i.e. dual‐tasking, inhibition, shifting and updating. Two separate tasks will be utilised to measure each EF, dual‐tasking (the Test of Everyday Attention dual‐task telephone search subtest and Psychological Refractory Period paradigm task), inhibition (the Hayling Sentence Completion test and Stroop task), shifting (the Trail Making Test and a task switching test), and updating (the backward digit recall span test and a N‐back task).

Result

Data collection is ongoing.

Conclusion

We predict better cognitive ability will be evident in the healthy older adult group, followed by the MCI and then the early‐stage AD groups. However, we expect dual‐tasking and updating ability to be most severely affected in individuals living with early‐stage AD and then shifting with inhibition showing most preservation.
A specific pattern of memory errors in asymptomatic at‐risk for AD
Authors: Gagliardi Geoffroy Pierre , La Corte Valentina , Epelbaum Stéphane , Houot Marion , Dubois Bruno , Dalla Barba Gianfranco
Published: December 2020

Background

While memory performance is well studied in preclinical Alzheimer's disease (AD), there are relatively few studies concerning memory errors. However, in the clinical and prodromal stages, intrusions are very frequent, and the specific error profile appears to be particularly diacritical compared to other diseases. In this study, we explore whether the specific pattern of errors produced in memory tests can be predicted by AD biomarkers load in asymptomatic individuals at risk for AD.

Method

318 cognitively normal older adults from the INSIGHT‐PreAD cohort were studied. We present here the data for a three‐year follow‐up. Errors were recorded in two types of memory tests, a verbal test (i.e., FCSRT) and a visual test (i.e., DMS48). Given the distribution of the data, we used Zero‐Inflated Generalized Linear Mixed‐effects Models (ZIGLMMs). Concerning verbal intrusions, two types of patterns were studied, either their context of occurrence (free vs. cued recall) or the type of error (semantically related or not). For visual false recognitions we studied the type of error (i.e. Paired, Abstract or Unique).

Result

Participants produced significantly more semantically related intrusions regardless of the level of brain amyloidosis. Regarding context, participants with higher amyloid produced significantly more intrusions in free recall situations. However, there is no effect of the SUVr on those occurring in cued recall. For false recognitions, the level of brain amyloidosis significantly increases the frequency of unrelated errors (semantically and graphically). All together, the SUVr value efficiently predict a specific error pattern.

Conclusion

This study demonstrates that a specific pattern of memory errors can occur even at early stages of AD evolution. Regarding verbal tests, our results show that asymptomatic at‐risk participants tend to exhibit errors in free recall situations, which can be related to an early executive retrieval dysfunction. In visual modality, the results suggest an abolition of familiarity, associated with the internal temporal regions, which are precociously affected in AD. Our results show that a specific error profile is associated with increased brain amyloidosis in cognitively normal elderly participants.
Do depressive symptoms at time of diagnosis affect the course of dementia over one year?
Authors: Edwards Devin A. , Kirk Andrew , O'Connell Megan E. , Karunanayake Chandima P. , Panyavin Ivan , Morgan Debra G.
Published: December 2020

Background

Depressive symptomatology has long been associated with dementia. The exact form of this association (e.g. whether depression is a risk factor and/or a prodrome) is uncertain. While much research has gone into confirming this link, there has been little investigation into the effects of depression on dementia progression after diagnosis. The aim of this study is to investigate the relationship between depressive symptomatology at dementia diagnosis and cognitive and behavioural decline over a one year period as represented by clinical evaluations.

Methods

In 375 rural and remote patients who had been diagnosed with mild cognitive impairment (MCI), Alzheimer’s disease (AD), or non‐AD dementia, the Center for Epidemiological Studies Depression Scale (CES‐D) was completed at first visit to assess depressive symptomatology. The same cohort was evaluated for cognitive and behavioural decline through the completion of five clinical tests performed at first visit and at a one year follow up. Cognitive decline was assessed using the Mini Mental Status Examination (MMSE), Clinical Dementia Rating Scale (CDR), and two subsets of the Neuropsychiatric Inventory (NPI‐S and NPI‐D). Functional decline was assessed using the Functional Activities Questionnaire (FAQ). Correlations were examined between CES‐D score and change in cognitive and functional scores over one year in the subgroups of Patients with all types of dementia or mild cognitive impairment (ATD, N=375 ), Alzheimer’s type dementia (N=187), and Mild Cognitive Impairment (=74).

Results

No significant correlations were observed between cognitive or functional decline and baseline depressive symptomatology.

Conclusion

Severity of depressive symptomatology at the time of diagnosis does not predict severity of cognitive or functional decline at one year in patients with dementia or mild cognitive impairment.
Genetic and environmental influences on semantic verbal fluency across midlife and later life
Authors: Gustavson Daniel E. , Panizzon Matthew S. , Kremen William S. , Reynolds Chandra A. , Nygaard Marianne , Wod Mette , Catts Vibeke S. , Lee Teresa , Gatz Margaret , Franz Carol E. ,   IGEMS Consortium
Published: December 2020

Background

Despite the relevance of semantic fluency measures to risk for dementia and psychiatric disorders, little is known about their genetic and environmental architecture in mid‐to‐late life. Existing studies in community samples of middle‐aged or older adults have yielded a wide range of heritability estimates for semantic fluency (20% to 77%). Some inconsistency may be due to measures available, but genetic variance on semantic fluency may also differ as a function of age, education, or other variables that varied across these studies.

Method

Participants represent 21,684 middle‐aged and older adult twins (M = 60.84 years, SD = 11.21; Range 40‐89) from six studies from three countries participating in the Interplay of Genes and Environment across Multiple Studies (IGEMS) consortium, representing three countries (Australia, Denmark, and the United States). All subjects completed the same measure of semantic fluency (naming animals in 60 seconds). Education was based on the International standard classification of education (ISCED).

Result

Results revealed small‐to‐moderate phenotypic associations with age (b = ‐.182, p < .001), age‐squared (b = ‐.005, p < .001) and education (b = 1.18, p < .001), with education more strongly positively associated with fluency performance in females than males. Heritability decreased with age, ranging from a2 = .58 to a2 = .40 in 40 versus 89‐year‐olds respectively. Genetic variance increased as education increased and nonshared environmental variance decreased with higher education, but the modification of heritability by education was only observed in males.

Conclusion

Semantic fluency is interwoven with a network of other cognitive abilities and highly relevant to aging/dementia. However, there is much to learn about its genetic and environmental structure and the way these influences vary based on other biological and environmental factors. This is the largest study to examine the genetic and environmental architecture of semantic fluency, and the first to demonstrate that these influences vary based on age, sex, and education. These findings highlight the dynamic interplay of genetic and environmental influences on cognitive function, and highlight the need to examine the genetic underpinnings of cognition using very large samples that can capture these complex associations.
Stimulation of ADAM10 and decrease in plaques by a sleep‐inducing supplement
Authors: Pahan Kalipada
Published: December 2020

Background

One of the pathologic hallmarks of Alzheimer’s disease (AD) is the presence of extracellular amyloid plaques containing Aβ peptides, which originate from the amyloidogenic proteolytic processing of amyloid precursor protein (APP), through the sequential action of β‐ and γ‐secretases. On the other hand, APP can also be cleaved by a non‐amyloidogenic pathway by α‐secretase “a disintegrin and metalloproteinase” 10 (ADAM10), precluding the formation of Aβ peptides. Therefore, delineating drugs and pathways for stimulating non‐amyloidogenic metabolism of APP and lowering plaques is an important area of research. We have seen that oleamide, a sleep‐inducing supplement in human, is present in hippocampal nuclei as a ligand of peroxisome proliferator‐activated receptor alpha (PPARα).

Method

We monitored ADAM10 and ADAM17 in cultured neurons as well as in vivo in the hippocampus of 5xFAD mice by Western blot and immunohistochemistry. Amyloid plaque was monitored in the hippocampus of oleamide‐fed and unfed 5xFAD mice by Western blot and immunostaining. We also recorded cognitive activities by Barnes maze, T maze and novel object recognition test.

Result

This study underlines the importance of oleamide in increasing the expression of ADAM10 in neurons via PPARα. Moreover, the level of oleamide was less in the hippocampus of 5xFAD mice as compared to non‐Tg mice. Oral administration of oleamide increased the level of this molecule in the hippocampus to stimulate ADAM10, reduce plaques and improve memory and learning in 5xFAD mice. However, oral oleamide remained unable to upregulate ADAM10, lower cerebral plaque load and improve cognitive behaviors in 5xFAD mice lacking PPARα.

Conclusion

These results indicate an essential role of PPARα in oleamide‐mediated stimulation of non‐amyloidogenic pathway and suggest that this sleep‐inducing supplement may have therapeutic importance for AD. Supported by Zenith Fellows Award (ZEN‐17‐ 438829) and a grant from NIH (AG050431).
A pilot study on the positive rate of multi‐time point and multiple domain evaluation in cerebrospinal fluid tap test of patients with normal pressure hydrocephalus
Authors: Liu Caiyan , Li Jie , Huang Xinying , Dong Liling , Mao Chenhui , Wei Junji , Hou Bo , Feng Feng , Cui Liying , Gao Jing
Published: December 2020

Background

The CSF tap test evaluation vary a lot in different medical center, which result in the wide range of sensitivity. Our study aimed to explore the effect of multi time point and multiple domain evaluation on the determination of CSF tap test results in patients with normal pressure hydrocephalus.

Method

A total of 150 outpatients with NPH 2013‐2018 from the Department of Neurology of Peking Union Medical College Hospital were enrolled in this study. All patients underwent detailed neuropsychological (MMSE, MOCA, Trail Making Test , Digital Symbol, Stroop‐c test, Grooved pegboard test) and walking ability (10 meter walking test, 5 meter up and go test), and head MRI examination. Patients who did not complete the four time point’s evaluation of CSF tap test to eliminate severe dementia and various reasons. The positive criteria were that the performance of either time or steps in walking test was 20% higher than the baseline level, or both were 10% higher. In the cognitive test, the score of any test is 20% higher than the baseline as a positive criterion. According to this standard, the positive rates of each evaluation test and three evaluation time points were calculated and compared.

Result

The positive rate of 5 meter up and go test on 8 hours, 24 hours and 72 hours after CSF tap test was 40.6%, 42.0%, 48.9%, the positive rate of 10‐meter walking test was 35.8%, 30.9%, 40.7% respectively; the positive rate of Digital Symbol was 23.8%, 38.1%, 42.9% respectively; the positive rate of Trail Making T test was 38.7%, 45%, 57.9%; the positive rates of Stroop‐c performance were 27.0%, 39.3% and 49.1% respectively; the positive rates of Grooved pegboard test on 8 hours, 24 hours and 72 hours after CSF tap test were 25%, 27.9% and 39.7%.

Conclusion

The positive rate of 5 meter up and go test is higher than that of 10 meter walking test, and the positive rate of 24‐hour and 72 hour comprehensive evaluation combined with walk and cognitive evaluation is higher.
Improving the Experience of Dementia and Enhancing Active Life (IDEAL): Investigating the perspectives of people from ethnic minority communities
Authors: van den Heuvel Eleanor , Victor Christina R , Clare Linda
Published: December 2020

Background

People from African Caribbean and South Asian backgrounds come to the attention of memory services at a much later stage in the dementia process than the majority population in the UK, often as a result of a crisis (1,2,3). We aim to discover barriers to service use as well as factors that are important maintaining a good quality of life for people and families affected by dementia.

Method

Twenty‐two semi‐structured interviews were conducted with community leaders, older people with memory problems (with and without a dementia diagnosis) and family caregivers from the target communities. Interviews were audio recorded, transcribed and thematically analysed.

Result

Barriers to service use included acceptance of cognitive decline as normal ageing, stigma associated with metal health, a perceived lack of culturally‐appropriate services and for some communities a profound distrust of UK services and institutions. Important factors for ageing well with memory problems and dementia included the availability of family support, religion and support from the faith community, and recognition of specific dietary and personal care requirements and preferences.

Conclusion

Improving the experience of living with dementia for Britain’s ethnic minority communities will depend on educating service providers about community members’needs and aspirations and increasing community awareness of dementia and the help that is available. 1. Botsford, J., Clarke, C.L. and Gibb, C.E. (2012) 'Dementia and relationships: experiences of partners in minority ethnic communities', Journal of Advanced Nursing, 68(10), pp. 2207‐2217. 2. Johl, N., Patterson, T. and Pearson, L. (2016) 'What do we know about the attitudes, experiences and needs of Black and minority ethnic carers of people with dementia in the United Kingdom? A systematic review of empirical research findings', Dementia, 15(4), pp. 721‐742. 3. Mukadam, N., Waugh, A., Cooper, C. and Livingston, G. (2015) 'What would encourage help‐seeking for memory problems among UK‐based South Asians? A qualitative study', BMJ open, 5(9), pp. e007990.
Efficacy of cognitive‐behavioral interventions for caregivers of individuals with a neurocognitive disorder: A systematic review and meta‐analysis
Authors: Verreault Phylicia , Turcotte Valérie , Ouellet Marie‐Christine , Hudon Carol
Published: December 2020

Background

By 2025, 34 millions of people worldwide will be living with Alzheimer's disease or other form of dementia (i.e., neurocognitive disorders). Symptoms of cognitive disorders non‐exclusively include memory deficits and executive deficits, but also functional repercussions in activities of daily living such as doing chores, taking medication and preparing meals. People with neurocognitive disorders often rely on a caregiver to alleviate the impact of their symptoms, but this helps is not without consequences on the caregiver. Indeed, caregivers report subjective burden, depressive symptoms, stress and anxiety, and report a lower quality of life than non‐caregivers. Multiple cognitive‐behavioral therapy (CBT) trials have been conducted to reduce these symptoms, and two meta‐analyses suggest that this method could be beneficial to reduce depressive symptoms. However, no meta‐analysis has been conducted to evaluate the efficacy of this type of intervention on subjective burden.

Method

Eligibility criteria for the individual studies were determined using the PICOS strategy recommended by the PRISMA statement. Articles were selected from PsychNet, MedLine, AgeLine, and ProQuest Dissertation and Theses for the period of 2000 to 2017. Article's selection, data extraction and analysis of bias for individual studies were completed by two independent authors using a consensus procedure when discrepancy occurred. The statistics Q, df, p value and I‐square, and Tau‐square were computed. Standardized effect sizes (Hedge's g) were also computed for all studies.

Result

A total of 20 articles were included in the systematic review. Statistics suggested no significant heterogeneity and a fixed‐effect model was used. Ten studies (N = 200 caregivers) evaluated the efficacy of CBT on subjective burden and the meta‐analysis suggested a significant reduction of subjective burden following CBT. Additionally, 17 studies (N = 437 caregivers) evaluated the efficacy on depressive symptoms and the meta‐analysis revealed a significant reduction following CBT for these caregivers.

Conclusion

CBT for caregivers of individuals with a neurocognitive disorder are beneficial in reducing subjective burden and depressive symptoms, but had no impact on stress, anxiety and quality of life.
Adaptive and maladaptive behaviors of persons diagnosed with mild cognitive impairment
Authors: Gibson Allison , Bardach Shoshana H , Jicha Gregory A
Published: December 2020

Background

Mild cognitive impairment (MCI) can disrupt an individual’s lifestyle. The biopsychosocial model serves as a promising clinical framework to understand the impact of MCI on the individual. Receiving a MCI diagnosis can result in behavioral responses that are either adaptive or maladaptive. Maladaptive behavior refers to types of behaviors that inhibit a person’s ability to adjust to particular situations. For many, an MCI diagnosis leads to maladaptive behaviors, stemming from emotional turmoil and lack of clarity about the future. Developing strategies to circumvent the development of such behaviors could significantly reduce morbidity and mortality in patients with MCI.

Methods

The Aging and Memory Quality of Life (AMQoL) Survey assesses aspects of a biopsychosocial assessment in order to determine the attitudes and behaviors of persons diagnosed with MCI (38 items). The tool was utilized to identify adaptive and maladaptive behaviors. Data were collected on the impact of MCI from 45 individuals diagnosed with MCI and 45 cognitively normal participants serving as control subjects matched for age, gender, and education to distinguish responses to MCI from regular age‐related adaptations (n=90).

Results

Given the categorical nature of the survey, non‐parametric tests were conducted using the Mann‐Whitney u‐test. Subject groups’ mean ranks and p‐values are reported. MCI subjects were less confident, less interested in learning new things and less excited about the future (p‐values 0.027, <0.0001, and 0.016) compared to the cognitively normal respondents. MCI subjects were more likely to want help managing financial affairs (p=0.009) than their cognitively normal counterparts. Subjects scoring high on maladaptive behaviors or MCI were younger, healthier, and scored lower on category fluency, Trailmaking A&B, and Wais digit‐symbol tests (p‐values 0.03, 0.003, 0.008, 0.001, 0.03, 0.04). Further, less than half of individuals with MCI were on medications for cognition.

Conclusion

Analyses of the data demonstrate a significant potential for maladaptive responses to an MCI diagnosis. Developing strategies to circumvent the development of such behaviors could significantly reduce morbidity and mortality. Interventions to counter the negative biopsychosocial effects of MCI diagnosis could improve the quality of life of individuals diagnosed with MCI.
Phospho‐tau217 and phospho‐tau181 in plasma and CSF as biomarkers for Alzheimer’s disease
Authors: Janelidze Shorena , Palmqvist Sebastian , Quiroz Yakeel T. , Lopera Francisco , Stomrud Erik , Su Yi , Chen Yinghua , Serrano Geidy E , Leuzy Antoine , Mattsson Niklas , Strandberg Olof , Smith Ruben , Villegas Andres , Sepulveda Diego , Chai Xiyun , Proctor Nicholas , Zetterberg Henrik , Beach Thomas G. , Blennow Kaj , Reiman Eric M. , Dage Jeffrey L. , Hansson Oskar
Published: December 2020

Background

Cerebrospinal fluid (CSF) p‐tau181 (tau phosphorylated at threonine 181) is an established biomarker of Alzheimer’s disease (AD) reflecting abnormal tau metabolism in the brain. We have recently shown that also plasma p‐tau181 is a promising biomarker for AD (Janelidze et al, Nature Medicine, 2020). We now evaluate whether CSF p‐tau217 or plasma p‐tau217 are even better biomarkers.

Methods

We compared CSF p‐tau217 to CSF p‐tau181 in the Swedish BioFINDER‐1 cohort (n=194). We next evaluated plasma p‐tau217 and plasma p‐tau181 in three cohorts with 1,438 participants: an Arizona‐based neuropathology cohort, including 34 AD and 47 non‐AD participants; the Swedish BioFINDER‐2 cohort, including cognitively unimpaired (n=312) participants, and clinically diagnosed patients with mild cognitive impairment (MCI, n=188), AD dementia (n=126), and other non‐AD neurodegenerative diseases (n=109); a Colombian autosomal‐dominant AD kindred, including 365 PSEN1E280A‐carriers and 257 non‐mutation carriers.

Results

CSF p‐tau217 had stronger correlations with the tau‐PET tracer, and more accurately identified individuals with abnormal tau‐PET scans (AUC=0.93) than CSF P‐tau181. CSF P‐tau217 correlated better than p‐tau181 with CSF and PET measures of neocortical amyloid‐β burden and more accurately distinguished AD dementia from non‐AD neurodegenerative disorders. Antemortem plasma P‐tau217 differentiated individuals with intermediate‐to‐high likelihood of AD according to neuropathology from those without AD (AUC=0.89) and performed significantly better than plasma P‐tau181. Plasma P‐tau217 also differentiated clinical AD dementia from non‐AD neurodegenerative diseases (AUC=0.96) significantly better than plasma P‐tau181, plasma neurofilament light, and established MRI measures, and similar to CSF P‐tau217, CSF P‐tau181, CSF Aβ42/40, and tau‐PET. Increased plasma P‐tau217 was observed already in the pre‐symptomatic stages of AD. In PSEN1 mutation carriers the increase started at age 25, about 20 years prior to estimated onset of MCI. Plasma P‐tau217 correlated with cerebral tau tangle densities in subjects with neuritic plaques (r=0.64). It predicted abnormal tau‐PET scans (AUC=0.95) significantly better than plasma P‐tau181, plasma neurofilament light, CSF P‐tau181 and CSF Aβ42/Aβ40, and similar to CSF P‐tau217.

Conclusions

Plasma and CSF P‐tau217 reflect brain tau burden, increases early in AD, and differentiates AD from other neurodegenerative diseases.
Do deficits in mitochondrial spare respiratory capacity contribute to neuropsychological changes seen in Alzheimer’s disease?
Authors: Bell Simon M. , De Marco Matteo , Barnes Katy , Shaw Pamela , Ferraiuolo Laura , Blackburn Daniel J. , Mortiboys Heather , Venneri Annalena
Published: December 2020

Background

In clinical settings, AD is defined by characteristic deficits in neuropsychological testing supported by amyloid and tau biomarkers and neuroimaging abnormalities. The biological cause of neuropsychological changes is not established. Tau deposition correlates with, but does not fully account for all observed neuropsychological impairments. We have shown mitochondrial spare respiratory capacity (MRSC) is lowered in AD patient fibroblasts. This study investigates if fibroblast mitochondrial functional abnormalities correlate with neuropsychological/neuroimaging changes in AD.

Method

10 AD patient and 10 control fibroblast samples were taken via skin biopsy. Adenosine Triphosphate (ATP) and extracellular lactate were measured using luminescent and fluorescent protocols respectively. Mitochondrial membrane potential (MMP) was measured using tetramethylrhodamine dye. Mitochondrial respiration and glycolytic function were measured using a Seahorse XF Analyzer. In‐depth Neuropsychological profiling, and brain structural MRIs were undertaken on all participants. Correlations were performed between MMP, MRSC and neuropsychological/MRI AD markers.

Result

Reductions in delayed (p<0.0001) and immediate recall (p<0.0001), semantic fluency (p<0.0001), phonemic fluency (p=0.0033) and MMSE (p=0.0009) scores were seen in AD patients. After controlling for age, education and brain reserve; left hippocampal (p=0.001), left parietal (p=0.002), right parietal (p=0.001) and anterior medial prefrontal cortical (p=0.017) gray matter volumes were reduced in AD patients. Fibroblast metabolic markers showed a reduction in MMP (p=0.001), MRSC (p<0.0001), glycolytic reserve(p=0.05), and extracellular lactate (p<0.05) in AD patients. MRSC and MMP correlated significantly with immediate recall ([MRSC, p=0.0041],[MMP, p=0.0115]), delayed recall ([MRSC, p=0.0013],[MMP, p=0.0138]) and semantic memory ([MRSC, p=0.0039],[MMP, p=0.009]) tests. The correlations between MRSC and neuropsychological measures remained after controlling for age, education and brain reserve. No correlations were seen between grey matter volumes and fibroblast metabolism.

Conclusion

This study highlights how in‐depth metabolic analysis of sporadic AD fibroblasts identifies functional abnormalities that correlate with neuropsychological features distinctive to AD. This work may also explain how some of the fundamental biological processes that are affected in Alzheimer’s disease may contribute to the neuropsychological profiles that define the condition.