bluuebunny/crossref_metadata_2025 huggingface dataset:
Ability of elderly women with cognitive decline in food preparation and related factors
Authors: Eguchi Yoko , Matsuda Yukiko , Matsuoka Teruyuki , Kato Yuka , Ueno Daisuke , Mimura Masaru , Narumoto Jin
Published: December 2020

Background

Food preparation is an instrumental activity of daily living (IADL) affected by even mild cognitive decline. People with cognitive decline may perform some tasks of food preparation if done routinely and with prior proficiency. In Japan, women commonly prepare food owing to the cultural background, but few studies have investigated the impact of dementia in women on food preparation. The aim of the present study was to investigate the relationship between dietary abilities and cognitive and physical decline in the elderly women suspected with dementia.

Method

The subjects were 220 women, aged 65 years or older, who visited a hospital with signs of dementia in the period from February 1, 2017 to April 30, 2019. Information on the social background, ability to prepare food (higher IADL stage indicating worse performance), cognitive function, and physical status (body mass index, nutritional status) was obtained from clinical records.

Result

The mean age of the subjects was 79.6 ± 6.3 years, and 72.6% of them prepared food (including delivery) at least once a day. Regarding the ability of food preparation, 96, 30, 43, 32, and 19 people were in stages 1 (plans, prepares, and serves adequate meals independently), 2, 3, 4 (needs to have meals prepared and served), and unknown, respectively. The total Mini‐Mental State Exam (MMSE) scores for stages 1, 2, 3, and 4 were 23.2 ± 4.1, 20.3 ± 3.5, 19.4 ± 5.1, and 15.9 ± 5.5, respectively. Of the patients in stage 1, 51.0% had cognitive decline. The analysis of variance revealed significant differences in MMSE, Alzheimer’s Disease Assessment Scale scores and serum albumin levels among food preparation stages (F (3, 197) = 23.1; F (3, 194) = 23.18; F (3, 190) = 8.1; p ≤0.001).

Conclusion

Higher food preparation ability is associated with higher cognitive function and better nutritional status. While approximately half of the women with reduced cognitive function sustain their food preparation ability, some women, despite good cognitive function, do not. Therefore, individualized interventions are necessary in food preparation.
Peripapillary retinal nerve fiber layer thickness measured using optical coherence tomography as a marker of Alzheimer's disease
Authors: Wang Xin , Jiao Bin , Liao Xinxin , Liu Hui , Shen Lu
Published: December 2020

Background

Optical coherence tomography (OCT), is an advanced, noninvasive technology that can provide the images of retinal structure, including peripapillary retinal nerve fiber layer (pRNFL), macular retinal thickness (MRT), as well as macular volume (MV). However, whether the retinal structure varied in Alzheimer's disease (AD) patients was still unclear. This study aims to detect the retinal changes of AD patients and explore their correction with severity of disease and classic biomarker.

Method

78 AD patients and 188 HC matched with age and sex were enrolled in this study. The pRNFL thickness, MRT and MV were assessed using OCT. In addition, Aβ42, Aβ40 and tau protein in plasma were detected using Simoa technology.

Result

The results showed that the pRNFL thickness of AD patients was significantly thinner than HC (96.76±10.44 vs 101.4±17.74, p=0.023). Compared with HC, MRT and MV were reduced in AD patients, but the differences were not significant(p>0.05). Furthermore, the pRNFL thickness was significantly negatively correlated with MMSE (r=‐0.362, p=0.005) and disease duration (r=‐0.295, p=0.002); In addition, the pRNFL thickness was positively correlated with t‐tau protein in plasma(r=0.409, p=0.002); while negatively correlated with Aβ42/40 in plasma(r=‐0.277, p=0.041). However, there was no significant correction between neither MRT nor MV and MMSE, disease duration, Aβ42, Aβ40 and tau protein in plasma (p>0.05).

Conclusion

These results supported that pRNFL thickness measured using OCT may serve as a useful predictor of AD.
The difference of long‐term outcome according to baseline dementia severity in Korean Alzheimer’s disease patients treated with anti‐dementia medications
Authors: Kim Jeong Lan , Lee Miji , Park Yuri , Seo Heewon
Published: December 2020

Background

To describe the difference of long‐term outcome in Alzheimer’s disease (AD) according to initial dementia severity at the time of diagnosis in the clinical setting.

Method

We carried out retrospective chart review of patients who were diagnosed with Alzheimer’s disease on dementia clinic at an University Hospital in Korea from 2012 to 2019. Participants had been treated with donepezil or donepezil and memantine combination. We dichotomized participants into three groups by initial Clinical Dementia Rating (CDR); very mild group for CDR 0.5, mild group for CDR 1, and moderate group for CDR 2. The observation period was four years. All participants were assessed cognitive function, neuropsychiatric symptoms and severity of dementia by the Consortium to Establish a Registry for Alzheimer’s Disease Neuropsychological assessment battery (CERAD‐NP) including CDR, Minimal Mental Status Exam (MMSE), and Neuropsychiatric Inventory (NPI). The annual change of CDR‐SB(CDR‐sum of box), MMSE score, total score of CERAD‐NP, and total score of NPI were analyzed with general linear model multivariate analysis by SPSS version 22.

Result

Two hundred nine patients were finally enrolled. There were 73 participants in very mild group (mean age 80.11±6.99), 109 in mild group (mean age 80.42±7.27) and 27 in moderate group (mean age 83.15±8.29). The annual changes of CDR‐SB, MMSE score, and total score of CERAD‐NP were showed significant difference among three groups (moderate group > mild group > very mild group), except the total score of NPI. The declining rate of the total score of CERAD‐NP and MMSE were faster in the order of the moderate group, the mild group, and the very mind group.

Conclusion

Our result showed that the more advanced cognitive decline when a patient is diagnosed with AD can be associated with faster progression despite of receiving therapy with anti‐dementia medications. It is meaningful that we have studied these long‐term outcome of AD patients in real‐world clinical setting. In conclusion, the earlier treatment of AD, the slower progression of AD.
Ninety‐day ketogenic diet intervention has differential effects on neuronal and astrocytic transcriptional pathways in mouse brain
Authors: Koppel Scott J. , Pei Dong , Wilkins Heather M. , Weidling Ian , Wang Xiaowan , Menta Blaise , Perez‐Ortiz Judit , Kalani Anuradha , Manley Sharon , Koestler Devin C. , Swerdlow Russell H.
Published: December 2020

Background

Glucose hypometabolism and mitochondrial dysfunction are early deficits in Alzheimer’s disease (AD) brains. The ketogenic diet (KD) has been suggested as a treatment for AD. The KD is theorized to support the brain through the generation of ketone bodies that serve as an alternative fuel to glucose and possibly through other unknown mechanisms. Historically many studies examine CNS function as though it is a homogenous bioenergetic compartment and under value how different CNS cell populations may respond to metabolic interventions or contribute to disease. Here, we characterized how a 3‐month KD intervention influences transcriptional pathways in enriched mouse neuron and astrocyte isolations through magnetic assisted cell separation and RNAseq analysis.

Method

All protocols were reviewed and approved by the KUMC Institutional Animal Care and Use Committee. 30 C57Bl6/N mice were maintained for 90‐days on either chow or ketogenic diet. Upon completion of the dietary intervention mice were euthanized, whole brains dissected, and single cell suspensions were generated. Neuronally and astrocytically enriched fractions were generated immunologically using cell‐type specific antibodies and magnetic selection. Isolated total single stranded RNA was processed and sequenced using Illumina Novaseq 6000 Genome Sequencer and analyzed statistically for differentially expressed genes.

Result

KD increased the number of transcriptional pathways activated in mouse neurons whereas astrocytes were observed to have mainly suppressed transcriptional pathways. Molecular pathways with lowest q‐values activated by KD in neurons included endoplasmic reticulum protein processing, insulin signaling pathway, and oxidative phosphorylation. Top disease associated pathways activated by KD in neurons included Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease. Top significant pathways suppressed in astrocytes by KD intervention included axon guidance, glutamatergic synapse, and circadian entrainment.

Conclusion

Neurons and astrocytes have substantially different responses to KD in terms of their transcriptional pathways. Treatment of neurologic disease with drugs that target molecules common to multiple CNS cell types may have diluted, antagonistic effects. Beneficial effects of KD or other therapies may be improved through the identification and targeting of not only disease relevant pathways, but disease relevant cellular compartmentalization of pathways and in doing so improve our ability to treat AD and other neurodegenerative diseases.
Plasma phospho‐tau217 can detect Alzheimer‐like pathology in Parkinson’s disease with dementia and dementia with Lewy bodies
Authors: Hall Sara , Stomrud Erik , Janelidze Shorena , Londos Elisabet , Dage Jeffrey L. , Hansson Oskar
Published: December 2020

Background

Parkinson’s disease with dementia (PDD) and Dementia with Lewy bodies (DLB) are considered synucleinopathies; however, neuropathology studies have revealed the common occurrence of comorbid Alzheimer’s disease (AD) pathology. Especially AD‐like tau pathology may contribute to cognitive decline in PDD/DLB. In vivo, the presence of co‐pathologies can be detected with PET imaging or CSF testing. However, recent advances in blood biomarkers make it feasible to investigate their utility for identifying AD co‐pathology. In this study we investigate plasma P‐tau217 and P‐tau181 in patients with PDD and DLB.

Method

We included 36 patients with PDD (n = 5) or DLB (n = 31), all part of the BioFINDER 2 study. Plasma was analyzed for P‐tau217 and P‐tau181. Also, CSF was analyzed for P‐tau217, P‐tau181, and Aβ42/Aβ40. 32 patients had undergone [18F]RO940 PET scans to detect AD‐like tau aggregates.

Result

Plasma P‐tau217 had significant correlations with plasma P‐tau181 (Rs = 0.683, p < 0.001), CSF P‐tau217 (Rs = 0.678, p < 0.001) and negatively with CSF Aβ42/40 ratio (Rs = ‐0.568, p < 0.001). Both plasma P‐tau217 and plasma P‐tau181 correlated with [18F]RO940 retention in both a temporal meta‐ROI (stage I‐IV) (β= 0.61, p < 0.001 and β = 0.55, p = 0.002) and an extratemporal neocortical meta‐ROI (stage V‐VI) (β = 0.68, p < 0.001 and β = 0.57, p = 0.005). Plasma P‐tau217 predicted [18F]RO940 PET positivity with an AUC = 0.84 using the temporal meta‐ROI (stage I‐IV) and an AUC = 0.92 using the extratemporal neocortical meta‐ROI (stage V‐VI). Furthermore, plasma P‐tau217 predicted [18F]RO940 positivity with a significantly higher accuracy compared with plasma P‐tau181. The performance of plasma P‐tau217 in predicting [18F]RO940 positivity was similar to that of CSF P‐tau217. Additionally, plasma P‐tau217 predicted CSF Aβ positivity with an AUC = 0.91, also with a higher accuracy compared with plasma P‐tau181.

Conclusion

Plasma P‐tau217 might be a useful marker for AD co‐pathology in PDD and DLB, and may be useful for stratification of patients in clinical trials. Future studies are needed to determine whether plasma P‐tau217 provide important prognostic information in patients with PDD or DLB.
Knowledge, beliefs and attitudes towards dementia risk assessment and reduction among individuals with a parental family history of dementia
Authors: Vrijsen Joyce , Maeckelberghe Els , de Vries Jeroen , Abu‐Hanna Ameen , De Deyn Peter Paul , de Winter Andrea , Reesink Fransje E , Voshaar Richard C Oude , Buskens Erik , De Rooij Sophia , Smidt Nynke
Published: December 2020

Background

Individuals with a parental family history (PFH) of dementia have an increased risk to develop dementia, as they do not only share their genes but also their psychosocial behavior (Borenstein et al., 2016). This study will explore the knowledge, beliefs and attitudes towards dementia‐risk‐assessment and dementia‐risk‐reduction by changing health behavior among middle‐aged descendants of people with recently diagnosed late‐onset dementia.

Method

The study population consists of middle‐aged descendants of individuals who are recently (last 6 months) diagnosed with late‐onset dementia (Alzheimer’s Disease, Vascular Dementia) at a hospital memory clinic in the Netherlands. Eligible participants are invited by the medical specialist of their parent to participate in a focus group discussion. Focus group discussions are audio recorded and transcribed. Transcripts are analyzed thematically using Atlas‐Ti 8.1 by two independent researchers. The results are categorized into the following five themes derived from the Health Belief Model: (1) dementia and dementia risk factor literacy; (2) perceived severity; (3) perceived susceptibility; (4) perception towards dementia‐risk‐assessment and reduction; (5) benefits and barriers.

Result

Three focus group discussions were conducted, each with 4‐6 participants, until saturation of information was achieved. The study population (n=15) consisted of 12 females and had a mean age of 47 years (range 26 to 65 years). The majority (80%) of the participants had a high socioeconomic status. Participants had poor knowledge of the risk and protective factors for dementia. The majority of the participants perceived the threat (i.e. perceived severity and susceptibility) of the disease as high, as participants were anxious about the heritability of dementia. Due to their unawareness of the potential for risk reduction by lifestyle improvement they did not see the need to assess their dementia risk. After gaining this knowledge, participants’ beliefs and attitudes became more positive towards dementia‐risk‐assessment and reduction.

Conclusion

Individuals with a positive PFH of dementia have insufficient knowledge about the risk factors of dementia and how they can reduce their risk. The public, especially those with a PFH of dementia, should be informed about dementia, the advantages and disadvantages of dementia‐risk‐assessment and how they can reduce their dementia risk.
Validation of the Oxford Cognitive Screen‐Plus: Tablet‐based cognitive testing in patients with amnestic mild cognitive impairment
Authors: Hübner Clara Margarethe , Demeyere Nele , Preul Christoph , Finke Kathrin
Published: December 2020

Background

The Oxford Cognitive Screen ‐ Plus (OCS‐Plus) is a tablet‐based cognitive screen developed for detection of mild cognitive impairment in various settings. We validated it in the target group of aMCI/dementia patients.

Methods

Patients with aMCI (N=57) and mild dementia (N=13) were assessed with OCS‐Plus at the Jena University Hospital Memory Center. Comparison of their data with a) those of established dementia testing, third part interview and depression and anxiety questionnaire and b) with those of a demographically matched control group (N = 67) were conducted to explore construct validity and discriminatory power.

Results

Significant correlations of the OCS‐Plus scores with those of established assessments indicated good convergent validity, divergent validity was indicated by a lack of significant correlations with depression and anxiety scores. Among different scores, the delayed memory score demonstrated the best discriminatory power with sensitivity of .74 and specificity of .75.

Conclusion

The OCS‐Plus is able validly to differentiate between healthy control participants and aMCI patients and potentially to differentiate aMCI from mild dementia.
The cerebrospinal fluid stromal cell‐derived factor 1 (CXCL12) concentration in Alzheimer’s disease
Authors: Dulewicz Maciej , Kulczynska‐Przybik Agnieszka , Borawski Bartlomiej , Klimkowicz‐Mrowiec Aleksandra , Pera Joanna , Slowik Agnieszka , Mroczko Barbara
Published: December 2020

Background

Alzheimer’s Disease (AD) is one of the most common age‐related neurodegenerative diseases. Many molecular mechanisms are underlying in the foundations of AD, e.g. inflammation, tauopathy, amyloid Beta cascade pathology or imbalance of calcium. Neuroinflammation is highly related to proinflammatory proteins and chemokines, widely distributed in the central nervous system (CNS). Interestingly, in AD pathology chemokines with CXC motif were detected in human fluids. The stromal cell‐derived factor 1 (SDF1), known as chemokine CXCL12, was a proinflammatory chemokine, highly expressed in the CNS. Their role is not clearly defined and still not fully understood, but they may regulate synaptic transmission in excitability neurons and modulate neuroglial communication. CXCL12 was detected in plasma and hippocampus AD patients. Levels of this chemokine were considerably decreased compared to the control group. In our investigation, the purposes were the quantitative assessment of CXCL12 levels in the cerebrospinal fluid and evaluation of the potential usefulness of this protein in the diagnosis of AD patients.

Method

The cerebrospinal fluid levels of CXCL12 and classical AD biomarkers, such as Aβ‐42, Aβ‐42/Aβ‐40, hTau and pTau181 were assessed by immunoenzyme assays. The study included 15 patients with AD and 15 non‐demented controls.

Result

In our research, we showed that the concentration of CXCL12 was significantly higher in cerebrospinal fluid of AD patients compared to non‐demented controls. The increased CSF levels of CXCL12 were significantly correlated with Aβ‐42, Aβ‐42/Aβ‐40 ratio and pTau181 in AD subjects.

Conclusion

These results point at the CXCL12 is a promising indicator of the inflammatory AD pathology. Furthermore, it seems to be an essential factor for future investigation and may prove to be useful for differential diagnostics.
The ANeED study: Ambroxol in new and early dementia with Lewy bodies
Authors: Rongve Arvid , Holst‐Larsen Elin , Steingildra Stina , Tzoulis Charalampos , Haugarvoll Kristoffer , Myhr Kjell‐Morten , Aarsland Dag
Published: December 2020

Background

The mechanisms by which GBA and APOE mutations result in PD or DLB are not fully understood, however there is evidence that it may be connected to reduced levels of GCase enzyme activity. CNS penetration has been confirmed for Ambroxol, and has been shown to increase glucocerebrosidase activity and protein levels in animal and human studies. One small open study with Ambroxol 420mg TID in PD for 186 days found excellent target engagement and improved motor symptoms, and a RCT with 50 PDD patients is ongoing in London, Canada.

Method

We will execute a national multicenter phase III RCT clinical intervention study with Ambroxol in prodromal and mild DLB in Memory Clinics in Norway. We will include persons living with prodromal (DLB‐MCI) or mild DLB with MMSE >=15 to Ambroxol or placebo. We will stratify participants based on genotypes for APOE and GBA and the CSF biomarkers A‐beta, total and phosphorylated tau protein. We will build a national trial platform for drug trials in neurodegenerative disorders in Norway and aim to include more centers in Europe for next phase studies via the European DLB Consortium (E‐DLB). We will execute a PPI program to raise awareness and reduce stigma for people living with DLB and their families.

Result

The ANeED‐study has received funding from the national Norwegian health authorities. Formal approvals for ethics, data protection and Medicine Agency are ongoing. We are planning a national start‐up meeting in Norway in September 2020, and we are currently building a national platform in Norway to be able to run clinical intervention studies in neurodegenerative disorders. We are building a PPI program to recruit patients and caregivers to clinical studies.

Conclusion

Phase III studies with Ambroxol in PD, PDD and DLB are currently being planned. APOE, GBA and GCase are central to the disease process in both PD, PDD and in DLB. Patients, carers and health providers now need to be offered participation in clinical studies also when diagnosed with one of the α‐synucleinopathies. Preliminary data find Ambroxol to be potentially disease modifying in these disorders.
Immune response and endocytosis pathways are associated with the resilience against Alzheimer’s disease
Authors: Tesi Niccoló , Van Der Lee Sven J. , Hulsman Marc , Jansen Iris E. , Stringa Najada , van Schoor Natasja , Scheltens Philip , van Der Flier Wiesje , Huisman Martijn , Reinders Marcel J.T. , Holstege Henne
Published: December 2020

Background

Developing Alzheimer’s disease (AD) is influenced by multiple genetic variants that are involved in five major AD‐pathways: immune response, β‐amyloid metabolism, endocytosis, cholesterol/lipid metabolism and angiogenesis. The extent to which these pathways are involved in the resilience against AD have thus far been poorly addressed. Here, we investigated the association of each molecular mechanism with (i) the increased risk of AD, and (ii) the resilience against AD until extreme old age, by comparing pathway‐specific polygenic risk scores (pathway‐PRS).

Method

We focused on 29 genetic variants identified in GWAS studies of AD to calculate a pathway‐PRS for the five major pathways involved in AD. For our pathway‐PRS, we developed an integrative framework that allows multiple genes to associate with a variant, and multiple pathways to associate with a gene. We studied the pathway‐PRSs in the Amsterdam Dementia Cohort of well‐phenotyped AD patients (N = 1,909), Dutch population controls from the Longitudinal Aging Study Amsterdam (N = 1,654), and our unique 100‐plus Study cohort of cognitively healthy centenarians who avoided AD (N = 293). Moreover, we estimated the contribution of each pathway to the genetic risk of AD in the general population.

Result

All pathway‐PRSs (except for angiogenesis) significantly associated with increased AD‐risk and, in the opposite direction, with resilience against AD (p < 0.05). The pathway that contributed the most to the overall modulation of AD‐risk was β‐amyloid metabolism (29.6%), which was driven mainly by APOE‐variants. After excluding APOE variants, all pathway‐PRSs (except for angiogenesis) associated with increased AD‐risk (p < 0.05), while specifically immune response (p = 0.003) and endocytosis (p = 2.2 × 10−4) significantly associated, in the opposite direction, with resilience against AD. Indeed, the variants in these pathways were the main contributors to the overall modulation of genetic risk of AD in the general population (45.5% and 19.2%, respectively).

Conclusion

The genetic variants associated with the resilience against AD indicate which pathways are involved with maintained cognitive functioning until extreme ages. Our work suggests that a favorable immune response and a maintained endocytosis pathway might be involved in neuro‐protection mechanisms of AD, which highlight the need to investigate these pathways, next to β‐amyloid metabolism.
Predictors of preclinical Alzheimer’s disease in persons with subjective cognitive decline
Authors: Janssen Olin , Jansen Willemijn J. , Vos Stephanie J.B. , Maserejian Nancy Nairi , Ossenkoppele Rik , Verhey Frans R.J. , Jessen Frank , Visser Pieter Jelle ,   the Amyloid Biomarker Study Group
Published: December 2020

Background

To identify at‐risk individuals that will likely benefit from disease‐modifying treatment and improve selection for clinical trials, the role of unobjectified cognitive complaints (subjective cognitive decline, SCD) in preclinical Alzheimer’s Disease (AD) needs to be refined. Although persons with SCD are at increased risk of developing dementia, it is unclear whether SCD is a symptomatic indicator of preclinical AD. We aim to identify SCD characteristics that are associative of amyloid positivity and are thus indicative of preclinical AD.

Methods

We included 1,336 persons with SCD from 14 centers included in the Amyloid Biomarker Study. Amyloid‐ß deposition was measured with positron emission tomography or cerebrospinal‐fluid biomarkers and dichotomized as normal or abnormal according to study‐specific cut‐offs. SCD characteristics included were subjective decline in memory, informant confirmation of SCD, concerns about complaints, feelings of worse performance, subjective decline in attention and concentration, depression, anxiety, and setting. Generalized‐estimating‐equations adjusting for center were used to examine the association between SCD characteristics and amyloid positivity.

Results

Average age was 66.5 years, 52% were female, mean education was 14.2 years, 33% was APOE‐ε4 positive, 19% was amyloid positive, 21% was t‐tau positive, and 30% was p‐tau positive. Increased age (p<0.001) and APOE‐ε4 carriership (p<0.001) were associated with a higher probability of amyloid positivity. Subjective decline in memory was associated with an increased probability of amyloid positivity (25% vs. 19% for persons without subjective decline specific to memory, mean difference 9%, p=0.036). The probability of amyloid positivity differed according to setting and was higher in a memory clinic setting (29%) compared to research setting (15%) and population setting (5%). The other SCD characteristics were not associated with amyloid positivity. Age, APOE‐ε4 carriership, subjective decline in memory, and setting remained independent predictors of amyloid positivity when analysed combined.

Conclusion

Based on these analyses, age, APOE‐ε4 carriership, subjective decline in memory, and setting are characteristcs that may help identify preclinical AD in persons with SCD.
Integration of demographics, genetics, imaging and metabolomics data to identify Alzheimer’s disease patients
Authors: Damotte Vincent , Marot Guillemette , Meirhaeghe Aline , Amouyel Philippe , Bellenguez Céline , Chouraki Vincent ,   Alzheimer’s Disease Neuroimaging Initiative
Published: December 2020

Background

Availability of omics data offers new opportunities to improve diagnosis of Alzheimer Disease (AD). Most of existing efforts have focused on one dimension at a time (genetics, metabolomics, imaging...) without considering them simultaneously. We integrated clinical, genetic, metabolomics and imaging data of individuals from the Alzheimer Disease Neuroimaging Initiative (ADNI) dataset in order to build models to accurately classify AD and cognitively normal (CN) individuals.

Method

Samples were divided into training (65 AD and 82 CN samples) and validation datasets (33 AD and 41 CN samples). Three modalities were considered in this analysis: metabolomics, imaging and a third modality containing known demographic and genetic AD risk factors. After quality control, 6 known risk factors, 119 metabolomic variables and 283 imaging variables were included. Sparse Partial Least Squares‐Discriminant Analysis (sPLS‐DA) was performed in order to classify individuals into AD and CN categories, based on a small number of variables. This method was used to build three models, one for each of the three modalities separately. We then built two additional models with the three modalities considered as (1) one super modality (i.e. combining the three modalities into one modality), or (2) independent modalities. For each model including the genetics modality, we built three different models, including as the genetic variable(s) either Apolipoprotein E4 (APOE4) status only, or the Desikan’s polygenic hazard score (PHS) only, or the two genetic variables: APOE4 genotype and the PHS but computed without APOE4. Classification performance of each model was assessed on the validation dataset, using Area Under the Curve (AUC), sensitivity, specificity, negative and positive predictive values (NPV and PPV).

Results

Seven models out of eleven had an AUC above 0.8. The best model was built using the super modality and including the PHS as the genetic variable, with an AUC of 0.89 [0.82‐0.96]. Sensitivity, specificity, NPV and PPV were 79%, 100%, 85% and 100%, respectively.

Conclusion

We built diagnostic models in order to classify AD and CN individuals. The best model was highly efficient, with an AUC of 0.89 and needs to be further validated in an independent cohort.
Inflammasome activation and reduced sTREM2 release in LPS stimulated organotypic brain slices
Authors: Schilcher Irene , Loeffler Tina , Flunkert Stefanie , Hutter‐Paier Birgit
Published: December 2020

Background

Immune activation in the CNS and production of neurotoxic mediators are linked to various neurodegenerative diseases, especially to Alzheimer’s disease (AD). On the one hand, the finding of TREM2 variants as genetic risk factor for AD and on the other hand, the current focus of research on the inflammasome activation are giving evidence for the importance of glial cells in AD. The further characterization of glial cells, ideally in co‐culture with neurons, during inflammatory processes are necessary to better understand the disease. Also screening of anti‐inflamamtory drug candidates in an in vitro system maintaining the interplay of different cell types is highly relevant to provide results of translational value. To assess whether organotypic slices are a suitable tool to investigate inflammasome activation and involvement of TREM2 we tested several LPS stimulation paradigms in this system.

Method

To study neuroinflammation in an intact neuronal system, organotypic slices from the hippocampus were prepared from early postnatal wild type mouse pups. To stimulate inflammation, slices were incubated with lipopolysaccharide at numerous concentrations and cytokine and sTREM2 release into the supernatant was measured by multiplex Mesoscale Discovery (MSD) immunosorbent assay at several time points. NLRP3 and Caspase 1 expression were examined with protein simple WES technology. Dexamethasone or MCC950 served as reference items to counteract the inflammatory response.

Result

Lipopolysaccharide stimulation at numerous concentrations and durations differently changed cytokine and sTREM2 release into the supernantant as wells as NLRP3 and caspase1 expression within the slices. Reference items like dexamethason or MCC950 can downregulate the inflammatory response to various degrees.

Conclusion

Organotypic brain slices are a perfect tool to study neuroinflammatory pathways ex vivo. Disease‐relevant pathways are activated by LPS stimulation and this process can be reversed by some reference compounds. By maintaining the three‐dimensional structure and interplay of different cell types of the postnatal brain, this system closely resembles the in vivo situation while offering several advantages for early screenings, like sampling of supernatant at various time points and higher throughput.
Alzheimer's disease patients getting lost in the community: Is road network structure a significant risk factor?
Authors: Puthusseryppady Vaisakh , Manley Ed , Hane Aung Min , Patel Martyn , Hornberger Michael
Published: December 2020

Background

Getting lost is one of the earliest and most distressing symptoms seen in Alzheimer’s disease (AD). Despite being a prevalent problem in the community worldwide, very few studies have explored real‐world environmental factors that may potentially contribute to patients getting lost. In this study, we aim to investigate whether road network structure plays a contributory role to AD patients getting lost in the community using retrospective and prospective data.

Method

Retrospective data of police case records of a large sample of missing dementia patients in the Norfolk county (n = 210), over a three year period, was used first to test our aim. Here, for each missing patient location, we measured the road intersection density, intersection complexity, as well as orientation entropy at a 1 km radius buffer zone around these locations; these measures were then compared to that of a set of random but matched locations. We then collected data prospectively to test the performance of 18 community‐dwelling patients with AD (aged 50‐80 years) on their ability to find their way in their own neighbourhood using a novel ‘Detour Navigation Task’. Here, we will measure the road intersection density, complexity, and orientation entropy at the locations in their neighbourhood where patients exhibited spatial disorientation.

Result

The 210 patients in the police data went missing from a total of 168 locations in the Norfolk county. Our results show that the locations patients went missing from had significantly increased road intersection density, complexity, and orientation entropy when compared to that of the matched locations. Meanwhile, the performance of the sample of 18 AD patients on the Detour Navigation Task will then be analysed to see whether the neighbourhood locations where the patients felt disoriented exhibited higher road intersection density, complexity, and orientation entropy when compared to locations where they did not feel disoriented.

Conclusion

The results of this study will provide evidence for road network structure as being a significant factor contributing to AD patients getting lost. This can in future help to potentially identify patients at high risk for getting lost as well as inform safeguarding guidelines.
Attention processing speed impairment in early dementia with Lewy bodies correlates with white matter damage on volumetric and diffusion tensor imaging
Authors: Botzung Anne , Mondino Mary , Noblet Vincent , Philippi Nathalie , Blanc Frédéric
Published: December 2020

Background

Attentional deficit is a prominent and distinguishing neuropsychological feature of Dementia with Lewy Bodies (DLB) since the prodromal stages. Our group recently highlighted, using voxel based morphometry (VBM), the importance of the basal ganglia grey matter (GM) integrity for attention processing speed, however, one can hypothesize that white matter (WM) would also be affected. Accordingly, this study aimed at investigating, in early DLB patients, the relationship between impaired attention processing speed and white matter changes using WM‐VBM and diffusion tensor imaging (DTI).

Method

Seventy‐three prodromal to moderate DLB patients (mean MMSE = 26.4) and thirty healthy elderly subjects (mean MMSE = 28.9), matched in terms of age and educational level, were selected to participate in the study. The Trail Making Test A (TMTA) was used to assess attention processing speed. Behavioral performances were compared between patients and control subjects. Three‐dimensional (3D) MRI and diffusion tensor images (DTI) were acquired and correlational analyses were performed in the patient group using GM‐ and WM‐VBM, fractional anisotropy (FA) and mean diffusivity (MD) DTI.

Result

As expected, DLB patients took significantly more time to achieve completion of the TMTA in comparison to control subjects (p = .004), indicating an impairment in speed of processing. Correlational analyses using VBM revealed negative GM correlations in the basal ganglia bilaterally (p < .001), and negative WM correlations in a bilateral but left‐predominant cluster including mainly the corpus callosum and the anterior cingulate region and a smaller cluster in the right anterior cingulum (p < .05 FDR corrected). Using DTI in correlation with TMTA scores (p < .05 FDR corrected), we found reduced FA in bilateral frontal and posterior regions, and increased MD in widespread lateral and medial anterior and posterior regions.

Conclusion

WM‐VBM analysis revealed the involvement of the anterior corpus callosum and cingulum in processing speed, which could indicate a disruption of the loops connecting striatal regions and the prefrontal cortex. Changes in both FA and MD were also found: their distribution suggest that attention processing speed might be particularly dependent on the integrity of white matter connections throughout the brain.
Awareness of cognitive decline through the continuum of Alzheimer’s disease and its association to APOE‐ε4 and amyloid load
Authors: Cacciamani Federica , Valladier Arnaud , Maheux Etienne , Koval Igor , Durrleman Stanley , Epelbaum Stéphane
Published: December 2020

Background

Anosognosia is a common symptom of Alzheimer’s disease (AD) dementia. However, the trajectory of the awareness of cognitive decline (ACD) across the predementia phases remains unclear. This study aimed to outline ACD changes through the entire course of AD, and study the impact of APOE‐ε4 genotype and amyloid load on the ACD evolution.

Method

We included 1280 subjects (7403 visits) from ADNI cohort, aged from 55 to 91 (M=73.7). They are progressors from cognitively‐normal and MCI stages, but also subjects with stable MCI and AD. ACD was measured as the subject‐informant discrepancy on the Everyday cognition (ECog). Using a non‐linear Bayesian mixed‐effects model (Schiratti et al., 2015, NIPS), we recombined the short‐term individual measurements into a long‐term progression of ACD. This allows to map the individual visits onto a common disease timeline, so that the real ages are reparametrized into comparable physiological ages. From each individual trajectory, we extracted the physiological age of (i) maximum hypernosognosia, (ii) accurate awareness, and (iii) anosognosia ‐ whose value corresponded to the upper 20th percentile cut‐off (normalized discrepancy of 0.3). These ages were correlated to the number of ε4 alleles and amyloid status (Aβ+ and Aβ‐) on PET or CSF.

Result

An early phase of hypernosognosia (subject's > informant's ECog) preceded a gradual decrease in ACD, eventually leading to a clear anosognosia (Figure 1, with 100 bootstrapped runs). Unawareness started on average 5 years before diagnosis. APOE‐ε4 carriers reached the peak of hypernosognosia and the anosognosia cut‐off earlier than the non‐carriers (all p<.001; Figure 2). Aβ+ subjects reached the peak of hypernosognosia later than Aβ‐, but their ACD started to decline earlier (all p<.05; Figure 3).

Conclusion

The role of cognitive complaints and low ACD in AD is currently highly debated. Our study showed that both are associated with AD pathology, being two conditions that occur in temporal succession. This has strong implications in terms of timely and accurate diagnosis, and in patients’ treatment. Further analyses may study the longitudinal trajectory of ACD in relation to additional AD features, such as brain atrophy and metabolism, especially in the predementia phases.
Biomarker testing in MCI patients: Deciding who to tap
Authors: van Maurik Ingrid S. , Meester Hanneke F.M. Rhodius‐ , Teunissen Charlotte E. , Scheltens Philip , Barkhof Frederik , Palmqvist Sebastian , Hansson Oskar , van Der Flier Wiesje , Berkhof Johannes
Published: December 2020

Background

It is unlikely that biomarker testing contributes to a more accurate prognosis in every patient with Mild Cognitive Impairment (MCI). We therefore aimed to derive a stepwise approach to select MCI patients for cerebrospinal fluid (CSF) testing and determine the optimal proportion of patients to receive CSF testing.

Methods

We selected n=402 MCI patients from the Amsterdam Dementia Cohort (ADC) and n=221 from the BioFinder study, with available demographic information, Magnetic Resonance Imaging (MRI) and CSF data. Three‐year progression probabilities to dementia were predicted for all patients, using previously published model (van Maurik et al. 2019, The Lancet Neurology) based on 1) patient characteristics (age, sex, MMSE; demographic model), or 2) additional MRI (hippocampal volume; MRI model). We incrementally augmented the proportion of patients to receive CSF testing, first the most uncertain 10% of patients (percentile 45‐55 of demographic‐ or MRI model derived probabilities), then 20% (percentile 40‐60), and so on. Prognostic performance of this stepwise model was measured with Harrell’s C. The optimal proportion was selected as the point where the stepwise model performed similar to testing all patients. This proportion provides the range of probabilities where additional CSF testing would be indicated (Table 1). To study generalizability, we replicated this approach in BioFINDER.

Results

On top of demographic characteristics, the stepwise approach showed that 60% of the patients required CSF testing in both cohorts in order to reach optimal prognostic performance (i.e. similar to CSF model; Figure 1A). This proportion corresponded with progression probability between 32%‐56%. This range was similar in BioFINDER (34%‐56%; Table 1). If we took the MRI model as a starting point, the optimal proportion was 60% in the ADC and 70% in BioFINDER (i.e. similar to ATN model; Figure 1B). This corresponded with a probability range of 19%‐40% in the ADC and 19%‐48% in BioFINDER (Table 1).

Conclusion

We showed that CSF biomarker testing adds prognostic value on clinical and/or imaging information in 60‐70% of the MCI patients that had less certain probability of progression between 32%‐56% or 19%‐48%. As such, we achieve a generalizable CSF saving recommendation with optimal prognostic accuracy.
The prevalence of young onset dementia: A systematic review and meta‐analysis
Authors: Hendriks Stevie , Peetoom Kirsten , Verhey Frans RJ , de Vugt Marjolein , Koehler Sebastian ,   PRECODE‐Consortium
Published: December 2020

Background

Onset of dementia before the age of 65 years is usually referred to as young onset dementia (YOD). Out of the total prevalence of dementia, it is estimated that 6‐9% are accounted for by YOD, but data to build robust estimates on is very limited in this specific dementia subgroup. Valid epidemiological data on the prevalence of people with YOD is needed to adequately provide dedicated services and care. This systematic review aimed to collate data from published literature and estimate the prevalence of YOD.

Method

A comprehensive literature search in PubMed, Embase, CINAHL and PsychINFO was conducted to identify population‐based studies on the prevalence of dementia in a population aged under 65. Articles published between 1990 and 30 November 2018 were screened independently by two authors in two phases: 1) screening titles and abstracts, 2) screening full texts, according to the PRISMA‐guidelines. Data were extracted and all articles were assessed on quality and risk of bias. Study authors were contacted when data was missing or to obtain full texts. Random‐effect meta‐analyses were pooled estimates and assessed sources of between‐study differences. The study is registered with PROSPERO, number CRD42019119288.

Result

The systematic search yielded 10,370 articles. After screening and cross‐referencing 88 articles were included in the review. Eligible articles were pooled together in meta‐analyses. Subgroups were made amongst others for type of dementia, age ranges and sex. The overall pooled estimate for young onset dementia over all age ranges and all types of dementia was 0.20% (95%CI = 0.15‐0.26). The prevalence for females was 0.25% (95%CI = 0.16‐0.35), whereas the prevalence for males was 0.16% (95%CI = 0.10‐0.23). Prevalence ranged from 0.01% (95% CI= 0.00‐0.01) in the age group 30‐34, to 0.98% (95% CI = 0.72‐1.28) in the age group 60‐64. Heterogeneity across studies was high, articles differed in many methodological aspects. Meta‐regression and subgroup analyses into sources of between‐study differences in prevalence estimates are currently analyzed and will be presented.

Conclusion

Articles eligible for meta‐analysis showed an overall prevalence of 0.21%, with females having a slightly higher prevalence compared to males, and an increased prevalence with increasing age.
Prevalence and pattern of neuropsychiatric conditions among community‐dwelling older Lebanese adults and their relation to cognitive function
Authors: Hachem Rita El , Chaaya Monique , Elbejjani Martine
Published: December 2020

Background

Neuropsychological and behavioral changes are an important source of burden for older adults and present a high and complex co‐morbidity with cognitive decline. Several reports suggest that these constructs may differ in their manifestations across cultures yet the vast majority of data come from higher‐income countries. Data on mental and cognitive health are particularly scarce in Lebanon. We examined the prevalence and overlap of depression, anxiety, and sleep disturbances at older age and their association with cognitive functioning in a community‐dwelling cohort of older adults (65 and above) in Lebanon (n=502; mean age=75.52 (SD=7.22); 56% women).

Method

Depression, anxiety, and reported sleep problems or changes were measured using the Geriatric Mental State (GMS) Agecat Package. Using adjusted linear regression models, we estimated how the presence of these conditions is related to cognitive function, measured with the Community Screening Instrument for Dementia (CSI‐D). Data processing is still ongoing to include more participants.

Result

Preliminary results showed that in our sample, 13.1% had at least one neuropsychological problems and 4.4% had two or more. Estimated prevalence was 10.6% for depression, 1.6% for anxiety, and 10.6% for the presence of sleep disturbances. With regards to overlap, all participants with anxiety had concomitant depression and 50% had sleep problems. Among participants with depression, 15% had anxiety and 33% had sleep disturbances. Among participants with sleep disturbances, 33% had depression and 7.5% had anxiety. The odds of depression, anxiety, or sleep disturbances were 2.9, 2.3, and 1.7 times higher for women than they were for men, respectively. Socioeconomic indicators were not associated with depression, anxiety, or sleep disturbances. The presence of any neuropsychological problem was not related to cognitive scores, and depression and sleep disturbances were not related to cognitive scores; in contrast participants with anxiety symptoms had lower cognitive scores (beta=‐3.28 (95% CI=‐5.074,‐1.492)).

Conclusion

Results suggest an important overlap in the presence of neuropsychological problems in this cohort and a potential differential relationship between anxiety – which was highly correlated to the presence of other mental health problems – and cognitive functioning in Lebanese older adults.