bluuebunny/crossref_metadata_2025 huggingface dataset:
Analysis of structural and functional connectivity MRI biomarkers in Alzheimer’s disease
Authors: Smeets Dirk , de Barros Nuno Pedrosa , Billiet Thibo , Sima Diana M. , Mohtasib Rafat , Alghamdi Jaman , Jobbeir Aman , Masawi Ahmed , Ribbens Annemie , Van Hecke Wim
Published: December 2020

Background

MRI allows detecting functional and structural connectivity changes in Alzheimer’s disease (AD). However, the relative importance of the corresponding MRI‐biomarkers is not fully understood. Moreover, several of these connectivity changes are not only driven by AD but also by healthy aging, which can limit the use of these biomarkers. Therefore, we looked at how 31‐different MRI biomarkers change due to aging and the presence of AD. Furthermore, we trained a set of machine‐learning‐models to distinguish AD from control subjects. The models were used to rank the features in terms of classification‐performance and analyze the impact of including age.

Method

20 AD patients and 20 age and gender‐matched healthy controls underwent MRI scanning (3T GE), including T1‐weighted, diffusion‐MRI, and resting‐state‐fMRI (rsfMRI). Whole‐brain (WB), white matter (WM), gray matter (GM), cortical GM and left and right hippocampi volumes were measured using T1‐images and icobrain. rsfMRI between regions of the default mode network was assessed using group independent component analysis. Median diffusivity and kurtosis values in GM and WM were determined. T‐tests between groups and ANOVA analysis using a Generalized‐Linear‐Model that included age and AD‐status as covariates were conducted for each feature. For assessing the ability of each feature to separate AD subjects from controls, a Support‐Vector‐Machine (SVM) model was trained using each feature separately and each feature with age. Performance was measured using 10‐fold cross‐validation.

Result

Figure 1 shows the table with the ANOVA results. Generally, rsfMRI features showed only a significant association with disease‐status, whereas structural and diffusion‐derived features showed both an association with age and disease‐status. Figure 2 shows the classification performance for the different SVM models. Regarding classification performance, the models trained with the total volume of the hippocampus achieved the highest performance (accuracy:77%, sensitivity:64%, specificity:89%). Despite several of the features changing with both age and AD‐status, the inclusion of age in the SVM‐models didn’t provide an advantage in classification performance.

Conclusion

Multiple MRI‐biomarkers are able to detect structural and functional connectivity changes associated with AD. From those, the hippocampi volumes are the ones that better distinguish AD patients from cognitively‐healthy subjects.
Correlation between regional brain atrophy, cognitive function, adipose tissue and CSF biomarkers in mild cognitive impairment
Authors: Fernández Miguel Ángel Rivas , Lojo‐Seoane Cristina , Galdo‐Álvarez Santiago , Aldrey‐Vázquez Jose M. , Vieites Ana Nieto , Fernández Alba , Pías‐Peleteiro Juan M. , Ferreiro‐Caneiro Uxia , Domínguez‐Vivero Clara , Mallo Sabela C. , Gil Luis , Pereiro Arturo X.
Published: December 2020

Background

Characterization of mild cognitive impairment (MCI) for clinical and research purposes involves identification of biological and neuropsychological markers in order to predict possible progression to dementia. The main aim of this work was to analyze the correlation of anthropometric measurements and plasmatic levels of leptin, testosterone and estrogens with cognitive, CSF and MRI regional atrophy markers in a sample of MCI participants.

Methods

Eighty‐one patients from the Compostela Aging Study diagnosed as MCI according to the Petersen criteria (Petersen, 2004; Albert et al., 2011) underwent neuropsychological assessment (CAMCOG‐R memory, CVLT short and long delayed free recall, subjective memory complains), CSF (Aβ42, t‐Tau and p‐Tau) and plasmatic analyses as well as an MRI study (parahippocampal and entorhinal cortex thickness measurements) (Table 1). Spearman’s correlation was used to evaluate the relationship between anthropometric measurements and blood test results with memory scores, CSF and MRI regional atrophy markers.

Results

Episodic memory scores correlated with CSF measurements (Aβ42, t‐Tau, p‐Tau) and parahippocampal and entorhinal cortical thickness (right and left) (Table 2). BMI, suprailiac, pectoral and subscapular skinfolds, circumference of waist, hip, arm and calf were negatively correlated with t‐Tau and p‐Tau levels. BMI, triccipital, thigh and pectoral skin folds as well as calf circumference were positively correlated with parahippocampal and entorhinal cortical thickness. Suprailiac, triccipital and thigh skin folds were positively correlated with episodic memory scores. Leptin plasma levels showed a negative correlation with CSF biomarkers (t‐Tau and p‐Tau) and a positive correlation with parahippocampal cortex thickness. Testosterone and estradiol levels showed a negative correlation with scores on memory tests and enthorhinal cortical thickness.

Conclusions

Our findings suggest that body composition is associated with episodic memory function, CSF biomarkers and cortical atrophy in patients with MCI. Leptin levels and sexual hormones may play a role in this association. These results point to a role of fat tissue and its regulating mechanisms in AD pathology and progression from MCI to dementia.
Who am I with my Lewy bodies? A self‐concept study
Authors: Tisserand Alice , Noblet Vincent , Botzung Anne , Blanc Frédéric , Philippi Nathalie
Published: December 2020

Background

Neurodegenerative diseases are marked by changes in personal identity, including the self‐concept (SC), which refers to a collection of knowledge about oneself, made up of personal semantic information. Modifications of the Self have been extensively investigated in Alzheimer's disease (AD), whereas it has never been studied in dementia with Lewy bodies (DLB). Yet, key regions for Self‐processing such as the medial prefrontal, the anterior cingulate and the insular cortices, are damaged early in the course of DLB. Thus, the purpose of this study was to investigate the SC integrity and to explore its neuroanatomical correlates in early DLB as compared to AD and normal ageing.

Method

Twenty prodromal to mild DLB patients were compared to twenty‐one prodromal to mild AD patients, and to twenty‐one healthy control subjects, matched in terms of age and educational level. For all participants, SC was assessed using the Twenty Statements Test (TST) during which the subjects were asked to produce up to twenty affirmations answering the question: who am I? Behavioral performance was compared between the groups. 3D MRI images were acquired for DLB patients and correlational analyses were performed using voxel‐based morphometry (VBM).

Result

Behavioral results obtained in the TST showed significantly decreased performances in both DLB and AD groups compared to healthy control subjects (p<0.001). Moreover, DLB patients tended to produce less Self‐affirmations than AD patients. Additionally, correlational analyses between behavioral scores and neuroimaging data in the DLB group revealed positive correlations between the number of produced Self‐affirmations and grey matter volume in the medial and orbitofrontal prefrontal cortices and in the lateral temporal cortex, among other regions (central sulcus, hippocampus, cerebellum).

Conclusion

Our behavioral results confirmed that SC is affected from the early stage in both DLB and AD, and tends to be even more deteriorated in DLB. Interestingly, VBM analyses revealed that decreased performance in DLB patients was related to focal atrophy in regions such as medial prefrontal and lateral temporal cortices, which are central in the networks of Self‐processing and semantic memory, respectively.
Characterising vascular cognitive impairment compared to cognitively healthy ageing with respect to reaction time, the intra‐individual variability of RT, and error production, practice effects and the task used in their measurement
Authors: Richards Emma V. , Bayer Antony , Tales Andrea
Published: December 2020

Background

To improve the characterisation and the understanding of VCI by examining reaction time (RT), the intra individual variability of RT (IIV), errors, practice, the effects of processing load (e.g. the influence of distracting information) and the effects of hesitancy in cognitively healthy (CH) ageing compared to patients with Subcortical Ischaemic VCI (SIVCI). In addition, the potential influence of the task used to measure these factors upon these results was investigated. The DSM5 requires a measure of brain processing speed to aid in the diagnosis of vascular dementia, but there is no indication of which test to use.

Method

Tasks comprised of the Trail Making Task (TMT), a clinical test used to measure RT, a visual search task, commonly used in research to measure RT, IIV, errors the effect of distracting information and practice, and an iPad based test ‘iReact’ used to measure hesitancy in response to a stimuli, in the same group of participants. Finally, for the SIVCI group, task performance was investigated with respect to the level of CT or MRI‐visible white matter disease.

Result

Results were test dependent, for the TMT results revealed poor completion rates, with 75% of VCI being unable to complete, results also differed depending on analysis used. The visual search task revealed a greater range of results; RT, IIV, errors production and the effect of distracters were significantly worse for those with SVCI compared to CH adults. iReact test results revealed that SIVCI were significantly more hesitant and varied in their response than CH adults. White matter disease was also identified as a poor marker of cognitive function, possibly due to silent lesions, and that RT related function is a better indicator of brain function.

Conclusion

Subcortical Ischaemic Vascular Cognitive Impairment is characterised by slowed RT, Increased IIV, detrimental effect of distracting information, raised error production, lack of positive practice effects on IIV, very slow response initiation and disproportionately high IIV in response initiation.
Quantitative thresholds for 18F‐florbetaben PET for the detection of low amyloid load
Authors: Roé‐Vellvé Núria , Bullich Santiago , Marquie Marta , Barthel Henryk , Villemagne Victor LL , Sanabria Angela , Tartari Juan Pablo , Sotolongo‐Grau Oscar , Dore Vincent , Koglin Norman , Mueller Andre , Perrotin Audrey , Jovalekic Aleksandar , de Santi Susan , Tarraga Lluis , Stephens Andrew W , Rowe Christopher C , Sabri Osama , Seibyl John , Boada Mercè
Published: December 2020

Background

A pathology‐proven cutoff for NeuraCeq (18F‐florbetaben) was previously developed in end‐of‐life cases to discriminate Alzheimer’s disease (AD) patients from elderly Aβ‐negative non‐demented controls (NDC). However, these cutoffs could be of limited use in early stages of AD. Here, we developed and validated 18F‐florbetaben cutoffs to detect low Aβ deposition and established amyloid pathology.

Method

The low Aβ deposition threshold was derived from a sample of young healthy controls (YHC) (n=70, 27.6±5.1 y), as 2 standard deviations above the mean. The established pathology cutoff was derived using ROC curve analysis on a sample of visually determined Aβ‐negative NDC (n=62, 67.8±6.8 y) and Aβ‐positive AD dementia patients (n=62, 70.6±8.0 y). Validation was based on longitudinal samples: (1) subjective cognitive decline (SCD) volunteers (n=166; 64.9±7.2 y) and (2) mild cognitively impaired (MCI) subjects (n=45, 72.7 ± 6.5 y). The standard centiloid (CL)methodology was applied for quantification.

Result

The low Aβ‐deposition detection cutoff was 13.5 CL, and the threshold for established Aβ pathology was 35.7 CL. In the validation samples, the rate of Aβ accumulation in the “low amyloid load” interval (13.5‐35.7 CL) was significantly different from zero (p<0.05), (2.1±2.1 %/year (SCD), 2.6±1.5 %/year (MCI)), which was also observed for “established Aβ deposition” (>35.7 CL) (3.4±3.2 %/y (SCD), 1.4±1.8 %/y (MCI), (p<0.05)). The accumulation rate for Aβ‐negative subjects (<13.5 CL) was not significantly different from zero (‐0.1±1.1 %/year (SCD), 0.1±1.6 %/year (MCI)).

Conclusion

An interval between 13.5 and 35.7 CL is optimal for the detection of early Aβ deposition and to identify subjects that are likely accumulating Aβ. Further validation tests using additional samples are ongoing.
Changes in anterior temporal and posterior medial hippocampal network connectivity in Alzheimer’s disease
Authors: Dautricourt Sophie , de Flores Robin , Landeau Brigitte , Poisnel Géraldine , Vanhoutte Matthieu , Delcroix Nicolas , Vivien Denis , De la Sayette Vincent , Chetelat Gael
Published: December 2020

Background

Hippocampal connectivity is affected early in Alzheimer’s disease and plays a crucial role in episodic memory dysfunction. Different hippocampal subnetworks have been identified, namely the anterior temporal (AT) and the posterior medial (PM) networks that are specifically related to separate subregions of the medial temporal lobe (MTL) thought to be differentially affected in AD. The aim of this study was to assess the specific connectivity of these two networks and its changes in Alzheimer’s disease, using both a cross‐sectional and a longitudinal approach.

Method

Fifty‐three cognitively impaired patients on the Alzheimer’s continuum with mild cognitive impairment or dementia, all amyloid‐β (Aβ)‐positive, and 68 Aβ‐negative cognitively unimpaired elderly controls were included. They underwent structural T1‐MRI and resting‐state functional MRI (fMRI) scans at baseline and at 18‐month follow‐up as well for 30 patients. Seed‐based analyses were performed, using individual automatic segmentation of MTL subregions as seeds, to assess the functional connectivity within the AT (from the perirhinal cortex and anterior hippocampus seeds) and the PM (from the parahippocampal cortex and posterior hippocampus seeds) networks. First, we compared the functional connectivity of the two networks within the controls to highlight their specificities. Second, we compared MTL subregion connectivity within each network between groups, and between baseline and follow‐up in the patients, to assess AD‐related changes compared to controls and over time.

Result

AT and PM networks showed distinct connectivity patterns in controls (Fig. 1). Patients showed decreased connectivity between the anterior hippocampus and regions of the PM network, and increased connectivity between anterior MTL subregions, compared to controls (Fig. 2). Over the 18‐month follow‐up period, decreased connectivity was found between both the anterior and posterior hippocampus and regions of the PM network, while increased connectivity was observed between several anterior MTL subregions and regions of the AT network (Fig. 3).

Conclusion

AD is characterized by both decreased MTL connectivity with the PM hippocampal network and increased connectivity with the AT hippocampal network. The specific assessment of the two main hippocampal subnetworks shed light on the overall pattern of AD‐related hippocampal changes involving both connectivity default and possible compensation or erroneous hyperactivity patterns.
Mesoscopic compensations for microscopic impairments in mid‐age individuals with family history of dementia
Authors: Su Li ,   the PREVENT‐Dementia Study
Published: December 2020

Background

In the PREVENT‐dementia study, we investigated multi‐level functional MRI changes in cognitively normal middle‐aged subjects. At the mesoscopic level, regional cerebral hypoperfusion is characteristic of Alzheimer’s disease (AD). At the microscopic level, AD showed a reduced BOLD activity. However, previous studies using these techniques report conflicting findings in cognitively‐normal individuals at high risk of AD.

Method

210 subjects between age 40‐59 underwent 3T arterial spin labelling (ASL) MRI and task MRI (tMRI). During the task, subjects made an indoor/outdoor judgment for images of scenes. After a delay of 30‐40 minutes, they identified the stimuli that were previously learnt. As a measurement of stability in neural representations, we quantified the multi‐voxel pattern similarity in parahippocampus regions between the encoding and retrieval parts of the experiment. ASL cerebral perfusion and tMRI responses were statistically compared between subjects with parental history to those without, and carriers of the Apoε4 with non‐carriers.

Result

Regional hyperperfusion was found in APOE e4 carriers (left cingulate and lateral frontal and parietal regions p<.01) and in those with positive FH (left temporal and parietal regions p<.01). For the tMRI task, we found no overt impairments of memory performance. However, there was a significant change in multivoxel activation pattern in parahippocampus areas for subjects with parental history (p<.01), reflecting a failure to maintain stable memory representations between the learning and testing parts of the experiment. This effect was not seen in the subjects with APOE ε4.

Conclusion

The novel findings on the implicit memory related MRI task suggest that the microscopic functional impairments may begin as early as mid‐age. The absence of APOE ε4 genotype effect on the task MRI implies that family history may include other genetic and/or environmental risk factors. Hyperperfusion in individuals at increased risk of AD may reflect a nonspecific mesoscopic functional ‘compensation’, offsetting the effects of early neural damages including the reduction in parahippocampus functions.
Lifestyle differences modulate the effects of cognitive reserve on functional connectivity
Authors: Ersözlü Ersin , Rauchmann Boris , Peters Oliver , Priller Josef , Schneider Anja , Wiltfang Jens , Jessen Frank , Düzel Emrah , Bürger Katharina , Teipel Stefan J. , Christoph Laske , Spottke Annika , Ramirez Alfredo , Cardenas‐Blanco Arturo , Wagner Michael , Perneczky Robert
Published: December 2020

Background

Cognitive reserve (CR) refers to the individual differences in cognition relative to brain aging or neurodegenerative changes. Recently, various studies tried to quantify a marker that represents CR. Among others, the residual approach suggested being relatively reliable as it has been studied not only with cross‐sectional but also with longitudinal observations. However, it is unknown if brain connectivity changes in the resting‐state are related to reserve factors e.g. lifestyle factors.

Method

In the present study we defined a CR Marker based on residuals calculated through a multimodal (multi‐linear) regression model adapted from a recent study using pathological changes of AD such as atrophy, demographic and genetic information as predictors. The data of 546 participants including healthy controls, participants with subjective cognitive decline, 62 patients with MCI, and 64 patients with AD from the German multicentric DELCODE cohort was assessed. To examine neural substrates of defined CR marker, we constructed a weighted undirected partial correlation matrix in the GraphVar toolbox and analyzed graph theoretical metrics in global topography with various network thresholds. Permutation‐based FDR‐correction has been used in statistical analyses with graph measures. Then we examined the possible associations between CR and lifestyle factors specifically the Lifetime Experiences Questionnaire(LEQ).

Result

CR was positively correlated (r=0.247, p=0.012) with higher scores in LEQ which includes leisure, educational and physical activities across the lifespan. We demonstrated that LEQ interacts with CR in functional connectivity changes, we used a multivariate regression model, in which LEQ was binarized using median values of total normalized scores. At the global level, interaction between CR and binarized LEQ score has been found with clustering coefficient (p=0.02), transitivity (p=0.017), but not with global efficiency(p=0.45). Moreover, component of LEQ scores corresponding to young adulthood, mid‐life, and late‐life didn’t interact with CR. However, LEQ of late‐life showed interaction at marginal level(uncorrected p=0.03).

Conclusion

Overall, CR and lifestyle differences appear to be reflected by changes in brain connectivity with increased global information processing capacity in participants exhibit higher CR. These findings foster understanding of early AD and will be useful to help identify individuals with vulnerability or resistance to AD pathology.
Transcriptome characterization of the motor cortex suggests microglial‐related key events due to TDP‐43 aberrant inclusions
Authors: Dols‐Icardo Oriol , Montal Victor , Dolcet Sonia Sirisi , López‐Pernas Gema , Cervera‐Carles Laura , Querol‐Vilaseca Marta , Muñoz Laia , Molina‐Porcel Laura , Pegueroles Jordi , Turón‐Sans Janina , Blesa Rafael , Lleó Alberto , Fortea Juan , Rojas‐García Ricard , Clarimon Jordi
Published: December 2020

Background

TAR DNA binding protein 43 (TDP‐43) is an RNA binding protein with a central role in transcription regulation. Evaluation of the transcriptome in affected brain tissues with aggregated TDP‐43 will allow us to better understand the pathological processes occurring in a variety of neurodegenerative disorders.

Method

We performed massive RNA sequencing in the motor cortex (BA4) of amyotrophic lateral sclerosis (ALS) patients (n = 11) and controls without lesions (HC; n = 8). Differential gene and isoform expression between patients and controls were evaluated with DESeq2. Gene ontology and KEGG pathway enrichment analyses were applied using default parameters in Metascape 3.0. The Multi‐Subject Single Cell deconvolution algorithm (MuSiC) was used to perform cell‐type deconvolution of our bulk RNAseq data. Formalin‐fixed and paraffin‐embedded motor cortex sections were used for immunohistochemistry, with IBA1 and ps409/410‐TDP primary antibodies. For immunofluorescence, anti‐MHCII markers (HLA‐DP,DQ,DR) and anti‐IBA1 were employed.

Result

Differential gene expression between ALS patients and HC disclosed 108 up‐regulated and 16 down‐regulated genes in the motor cortex (Figure 1; adj. p < 0,05). Gene ontology and KEGG pathway analyses revealed an enriched involvement of the inflammatory response in ALS. The assessment of changes at the isoform expression level also pointed towards an enrichment of the immune response as a dominant pathway, but also revealed a postsynaptic involvement. Characterization of cell type variability from bulk RNA‐seq data, using available single‐nucleus RNAseq data comprising 70.634 cells from Alzheimer’s disease and HC subjects (n = 48) (Mathys et al., Nature 2019) as reference, revealed an overrepresentation of microglial cells in the ALS motor cortex as compared to HC (p = 0,025) (Figure 2). Our deconvolution analysis also showed that a specific microglial subpopulation, recognized as the recently described disease associated microglia (DAM) was disproportionately present in ALS (p = 6,6 × 10−3) (Figure 3). Immunofluorescence through the combination of IBA1 and MHC class II markers confirmed the over representation of this cell subtype in the motor area of ALS cases.

Conclusion

The presence of insoluble TDP‐43 inclusions in affected brain tissue leads to RNA dyshomeostasis, with genes related to inflammation and synaptic functions as major altered transcriptome signatures. The recently described DAM play a key role in ALS and maybe other TDP‐43 related proteinopathies.
Impact of the APOE gene on amyloid deposition in participants with abnormal soluble amyloid levels
Authors: Cacciaglia Raffaele , Molinuevo Jose Luis , Salvadó Gemma , Suárez‐Calvet Marc , Fauria Karine , Minguillón Carolina , Shekari Mahnaz , Farrar Gillian , Buckley Christopher , Blennow Kaj , Zetterberg Henrik , Gispert Juan Domingo ,   the ALFA Study
Published: December 2020

Background

Amyloid pathology can be quantified both in the cerebro‐spinal fluid (CSF) and in positron emission tomography (PET) images, even though they measure two distinct amyloid pools. While CSF Aβ reflects the clearance of soluble amyloid species from the brain, PET imaging informs on the presence of insoluble fibrillary plaques. Many studies have shown the concordance of the two measures in individuals along the Alzheimer’s disease (AD) continuum. Here, we assessed whether APOE‐ε4, the major genetic risk factor for AD, affects the pattern of cerebral Aβ‐load as a function of CSF Aβ levels.

Method

The first consecutive 276 cognitively unimpaired (CDR=0) individuals of the ALFA+ study, aged between 48 and 74, with valid structural MRI and [18F]Flutemetamol (FTM) PET, APOE genotyping and CSF samples were included. Aβ‐40 and Aβ‐42 concentrations were determined with the NeuroToolKit (Roche Diagnostics International Ltd.) on a Elecsys cobas e‐411 instrument and parametric standardized uptake value ratio images (SUVr) were calculated with the whole cerebellum as reference region. A voxelwise regression to predict FTM uptake was performed, with the following independent variables: Age, Sex, APOE‐ε4, and CSF Aβ‐42/40. Statistical threshold was set to p<0.001 with a cluster extent correction of 100 voxels.

Result

As expected, CSF Aβ‐42/40 was strongly and negatively associated to cerebral FTM uptake (Fig. 1a‐1b). Age and APOE‐ε4 gene dose mapped onto distinct spatial patterns of FTM binding across the whole sample (Fig. 2b‐2c). Importantly, we found a significant interaction between Aβ‐42/40 and APOE‐ε4 indicating that carriers had a negative association between fluid and imaging Aβ measures in the bilateral hippocampus, as well as the bilateral middle temporal and temporo‐parietal junction (Fig. 3).

Conclusion

Compared to non‐carriers, APOE‐ε4 carriers show higher cerebral amyloid load for any given level of CSF Aβ 42/40 in areas which are not typically vulnerable to Aβ deposition yet undergoing neurodegeneration early in the AD continuum, such as the hippocampus. This suggests that APOE‐ε4 may influence the biological mechanisms regulating the equilibrium between soluble and deposited amyloid, which may transcend the hindering effect caused by Aβ fibrillary plaques and render medial temporal lobe structures particularly vulnerable when Aβ metabolism becomes deficient.
Dorsolateral prefrontal cortex excitability assessed using TMS‐EEG and its relationship with neuropsychiatric symptoms in Alzheimer’s dementia
Authors: Joseph Shaylyn , Zomorrodi Reza , Ghazala Zaid , Knezevic Dunja , Blumberger Daniel M. , Daskalakis Zafiris J. , Mulsant Benoit H. , Pollock Bruce G. , Rajji Tarek K. , Kumar Sanjeev
Published: December 2020

Background

Neuropsychiatric symptoms (NPS) are common in patients with Alzheimer’s Dementia (AD) and cause substantial distress to patients and caregivers. Mechanisms underlying NPS are not well known. Studies have found increased cortical excitability in patients with AD. Studies in other neuropsychiatric disorders have found increased cortical excitability in association with NPS. We hypothesized that cortical excitability will be negatively associated with cognition and positively associated with NPS in AD.

Method

This cross‐sectional study included participants diagnosed with probable AD using the NIA‐AA core clinical criteria. Cognition was assessed using Montreal Cognitive Assessment (MoCA) and NPS were assessed using the Neuropsychiatric Inventory‐Questionnaire (NPI‐Q). NPIQ agitation‐hyperactivity domain scores were calculated by combining scores on agitation, aggression, anxiety, disinhibition and irritability domains. Motor threshold and Transcranial Magnetic Stimulation (TMS) intensity sufficient to induce 1 millivolt (mV) peak to peak motor evoked potential were calculated as per established methods. TMS at the 1mV intensity was applied to the dorsolateral prefrontal cortex (DLPFC) at a frequency of 0.1 Hz. Electroencephalography was collected during TMS. Cortical excitability was assessed using rectified area under the curve (AUC) for TMS‐evoked potential (TEP) during early (25‐80 ms) and late phases (80 – 200 ms). Individual TEP peak amplitudes were also calculated.

Result

The study included 25 participants (female = 17, Mean (SD) age = 74.3(7.1) Years, Mean (SD) MoCA score = 17.5 (4.6)). There was a negative correlation between MoCA and the TEP early AUC at the DLPFC site of stimulation (Spearman’s rs = ‐ 0.589, n = 24, p = 0.002). In contrast there was a positive correlation between NPI‐Q agitation ‐ hyperactivity domain scores and the TEP early AUC (Spearman’s rs = 0.422, n = 24, p = 0.04). There was also a positive correlation between total NPIQ and early TEP (P30) amplitude.

Conclusion

Cortical excitability in the DLPFC is inversely associated with cognition and positively associated with NPS in AD. Specifically, increased excitability found during the early TEP duration suggests potential role of aberrant glutamatergic transmission and overall gamma amino butyric acid and glutamate imbalance. These findings may have important implications for developing treatment interventions targeting cortical excitability in AD.
Iatrogenic transmission of Alzheimer's disease: Evidence based on experimental inoculation of Alzheimer's brains into a primate
Authors: Dhenain Marc , Lam Suzanne , Gary Charlotte , Herard Anne‐Sophie , Koch James , Petit Fanny , Gipchtein Pauline , Sawiak Stephen , Caillierez Raphaelle , Eddarkaoui Sabiha , Colin Morvane , Aujard Fabienne , Deslys Jean‐Philippe , Duyckaerts Charles , Brouillet Emmanuel , Comoy Emmanuel , Pifferi Fabien , Picq Jean‐Luc ,   French Neuropathology Network
Published: December 2020

Background

Epidemiologic data suggest that, in humans, iatrogenic administration of compounds (cadaver‐sourced human growth hormone, dura mater graft) or cerebral surgeries with tools contaminated with Aβ and tau induce aggregated Aβ and possibly tau lesions. Aβ and tau lesions could thus be iatrogenically transmitted to humans. Several studies in mice have shown that experimental inoculation of amyloid and/or tau‐positive brain samples into transgenic (tg) mouse models overexpressing Aβ or tau promotes either Aβ or tau aggregation in the brain of the recipient animal. Unlike rodents, primates naturally express Aβ or tau under normal conditions and they have a biochemical and physical cerebral environment that is closer to that of humans than that of mice. The aim of this work was to evaluate the impact of human brain samples inoculations in the mouse lemur primates.

Method

12 adult mouse lemurs, aged from 3 to 4 years old, were included in this study. Human brain homogenates from AD patients or control (CTRL) age‐matched subject were bilaterally inoculated in the hippocampus and subjacent cortex (n = 6/group). We performed longitudinal cognitive, electroencephalography (EEG) and morphological MRI studies up to 18 months post‐inoculation followed by immunohistopathological examination of brain tissues.

Result

Mouse lemurs inoculated with Alzheimer brain homogenates displayed progressive cognitive impairments (clinical tests assessing cognitive and motor functions), modifications of neuronal activity (detected by electroencephalography), widespread and progressive cerebral atrophy (in vivo MRI assessing cerebral volume loss using automated voxel‐based analysis), neuronal loss in the hippocampus and entorhinal cortex (post mortem stereology). They displayed parenchymal and vascular Aβ depositions and tau lesions for some of them, in regions close to the inoculation sites.

Conclusion

This study is the first one to highlight neuronal and clinical dysfunction following inoculation of Alzheimer’s disease brain homogenates in a primate. Based on controlled experiments, it suggests the possible iatrogen transmission of Alzheimer pathology. Acknowledgments: We thank the “GIE NeuroCEB” Brain Bank, the France‐Alzheimer Association, the Fondation Plan Alzheimer, and the CEA Bottom‐Up program.
Long‐chain omega‐3 polyunsaturated fatty acids, brain atrophy, cognitive decline and dementia risk
Authors: Thomas Aline , Baillet Marion , Proust‐Lima Cécile , Féart Catherine , Foubert‐Samier Alexandra , Helmer Catherine , Catheline Gwenaelle , Samieri Cécilia
Published: December 2020

Background

Long‐chain omega‐3 polyunsaturated fatty acids (n‐3 PUFA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), mainly provided together by fish intake in the human diet, are important constituents of neural membranes. Epidemiological studies reported associations between long‐chain n‐3 PUFA intakes or blood concentrations, and lower risks of dementia and related outcomes (cognitive decline, brain atrophy). However, evidence has been inconsistent according to the type (e.g., EPA, DHA or total n‐3 PUFA) and/or the exposures (intake versus blood status) investigated. Moreover, previous studies displayed short follow‐up periods (generally less than 5 years). In this study, we took advantage of the long follow‐up for dementia and related outcomes in a large cohort of older persons, the Three‐City (3C) study, to look for robust associations of an omega‐3 index in plasma (EPA+DHA), with the long‐term evolution of three complementary outcomes: atrophy of the medial temporal lobe (MTL, a biomarker of dementia), cognitive decline and incidence of dementia.

Method

We included 1279 participants (aged ≥65) from the 3C study, non‐demented at the time of blood measurements at baseline. Face‐to‐face neuropsychological assessments at baseline and follow‐up visits (7 visits over 17 years) were used to evaluate global cognitive decline (n=1185), memory decline (n=1039), and for the systematic detection of incident dementia. An ancillary study included 467 participants with up to three repeated brain imaging exams over 10 years (FreeSurfer 5.1 segmentation). Linear mixed models were used to assess the associations between plasma EPA+DHA and trajectories of global cognition, memory and MTL volumes. The association between EPA+DHA and the risk of dementia was estimated by a Cox model.

Result

Higher levels of plasma EPA+DHA were associated with a lower risk of dementia (HR for 1SD = 0.87 [95% CI, 0.76‐0.98]), and a lower decline in global cognition (P = .04 for change over time), memory (P = .06) and MTL volume (P = .02).

Conclusion

The consistency of the long‐term associations found between higher levels of plasma EPA+DHA and three dementia related outcomes in this large cohort of older adults provides compelling evidence for the interest of long‐chain n‐3 PUFA in dementia and cognitive decline prevention.
Body & Brain Project: Effectiveness of a 6‐month multicomponent training on cognitive function, quality of life and functional capacity of older adults with dementia
Authors: Barros Duarte Gabriel Moleiro , Borges‐Machado Flávia , Bohn Lucimere , Sampaio Arnaldina , Ribeiro Oscar , Carvalho Joana
Published: December 2020

Background

Evidence is warranted to attest the therapeutic role of exercise as a non‐pharmacological adjuvant treatment for dementia. Multicomponent Training (MT) characterizes exercise sessions combining two or more physical fitness components (i.e. endurance, strength, balance, and flexibility), and it has been suggested as a feasible training modality for dementia patients. This study aims to analyze the effectiveness of a MT intervention on cognitive function, quality of life and functional capacity of older adults diagnosed with dementia.

Method

This is a non‐randomized controlled trial comprising 41 participants (29 females), from hospitals, daycare centers and municipalities – and was conducted in 8 community‐based settings. Subjects were allocated in exercise group (EG; N: 22; 76.3 years ± 1.40; age range: 61‐90) and control group (CG; N:19; 82.6 years ± 1.27; age range: 73‐90). EG trained twice a week (50 min) for 6 months in a MT regime. CG had a monthly recreational session during the same period. Alzheimer’s Disease Assessment Scale – Cognitive (ADAS‐Cog), Quality of Life – Alzheimer’s Disease (QoL‐AD), and Short Performance Physical Battery (SPPB) tests were applied before and after the 6‐months intervention period.

Result

Baseline medium score on Mini Mental State Examination was 21.1 (± 5.02) points. There was a significant group*time interaction on QoL‐AD total score (F (1,38) = 5.94, η2 = 0.135, p < 0.02) and on SPPB total score (F (1,37) = 14,94, η2= 0.29, p < 0.001) favorable to EG. No significant group*time interaction was depicted in cognitive function (F (1,38) = 0.467, η2= 0.012, p = 0.499). When adjusting for age, EG group maintained ADAS‐Cog score through time, and CG showed an increased score from baseline (27.97 ± 2.89) to post‐intervention time (29.34 ± 3.45), representative of decreased cognitive performance.

Conclusion

Data suggest that a MT intervention may improve functional capacity in patients diagnosed with dementia. It may also positively influence quality of life, once CG experienced a significant decrease after 6 month, despite baseline differences between groups. Further research is necessary to confirm the MT effectiveness on preserving cognitive function. Supported by FCT: CIAFEL (FCT/UIDB/00617/2020), “Body and Brain” Project (POCI‐01‐0145‐FEDER‐031808), and PhD Grant (SFRH/BD/136635/2018); & IPDJ.
Dorsolateral prefrontal functional connectivity predicts transfer of working memory gains after cognitive training
Authors: Faraza Sofia , Waldenmaier Julia , Dyrba Martin , Wolf Dominik , Fellgiebel Andreas , Teipel Stefan J
Published: December 2020

Background

Normal aging is associated with working memory decline. A decrease in working memory performance is associated with age‐related changes in functional activation patterns in the dorsolateral prefrontal cortex (DLPFC). Cognitive training can improve cognitive performance in healthy older adults. We implemented a cognitive training study to assess determinants of transfer of gains to untrained tasks, a key indicator for the effectiveness of cognitive training. We aimed to investigate the association of resting‐state functional connectivity of DLPFC with working memory performance improvement and successful transfer of gains after training.

Method

A sample of 60 healthy older adults (mean age: 68 years) underwent a 4‐week cognitive training of working memory. Baseline resting‐state functional magnetic resonance imaging in order to investigate the functional connectivity of DLPFC. To evaluate transfer and training effects, participants underwent a neuropsychological assessment before and after the training. A second follow‐up assessment was applied 12 weeks after the training. We used cognitive scores of Digit span backwards and Visual block span backwards tasks representing working memory function. The training group was divided in subjects who had and who did not have successful transfer, which was defined as higher improvement in working memory tasks than the control group.

Result

A high functional connectivity of DLPFC of the right hemisphere was a significantly associated with successful transfer of gains and performance improvement in the visuospatial task. Transfer effects were limited and maintenance of gains was restricted to the time period directly after the training. The training group showed performance improvement in the Digit span backwards task.

Conclusion

Functional activation patterns of DLPFC during visuospatial task contribute to successful transfer and performance improvement. Even though transfer is possible in aging, it remains limited.
Assessing the reliability of reported medical history in older adults
Authors: Day Gregory S , Long Allison , Morris John C
Published: December 2020

Background

A reliable history is critical to establish accurate clinical diagnoses, prioritize investigations and select appropriate treatments; yet few studies have considered the factors that influence the reliability of medical histories. Recognizing this, we determined the accuracy of medical history in community‐dwelling older adults engaged in longitudinal studies of memory and aging.

Method

The association between participant‐specific factors and accurate reporting of stroke or diabetes were evaluated using multivariable logistic regression in 1,401 participants enrolled in studies at the Knight Alzheimer Disease Research Center (Saint Louis, Missouri), including 425 participants with dementia (30.3%). History was verified with a reliable collateral source in all participants. Stroke and diabetes were selected as index variables, as gold standard measures—brain MRI for stroke and hemoglobinA1c (HbA1c) for diabetes—were routinely obtained in participants.

Result

25/862 (2.9%) participants endorsed a history of stroke, which was confirmed on MRI in 8/25 (positive predictive value, 17.4%). Stroke was detected on MRI in 38/837 (4.5%) of those without reported stroke (negative predictive value, 95.5%). Older age (OR per decade=1.7, 95%CI: 1.2‐2.5) and use of an unrelated collateral source (OR=2.0, 95%CI: 1.03‐3.7) were associated with greater odds of inaccurate reporting of stroke history. 190/1322 (14.4%) participants reported a history of diabetes, which was confirmed with HbA1c in 105/190 (positive predictive value, 55.3%). HbA1c 6.5% was detected in 29/1132 (2.6%) of those who denied diabetes (negative predictive value, 97.4%). African Americans (OR=1.6, 95%CI: 1.02‐2.6) and those with hypertension (OR=2.6, 95%CI: 1.5‐4.2) or HbA1c compatible with impaired glucose tolerance (OR=4.2, 95%CI: 2.7‐6.4) had greater odds of reporting a history of diabetes. Cognitive impairment was not associated with inaccurate reporting of stroke or diabetes.

Conclusion

The accuracy of reported history of diabetes and stroke was low in older community‐dwelling participants, independent of cognitive status. A history of diabetes or stroke should be objectively confirmed when relevant to decision making in clinical and research settings.
Association of domain‐specific cognitive functions with regional pattern of atrophy and functional connectivity across the Alzheimer’s disease spectrum: An analysis from the DELCODE cohort
Authors: Amaefule Chimezie O. , Dyrba Martin , Wolfsgruber Steffen , Peters Oliver , Priller Josef , Schneider Anja , Wiltfang Jens , Bürger Katharina , Laske Christoph , Fliessbach Klaus , Spottke Annika , Düzel Emrah , Metzger Coraline D. , Wagner Michael , Jessen Frank , Teipel Stefan J. ,   The DELCODE Study Group
Published: December 2020

Background

Cognitive decline in Alzheimer’s disease (AD) has been found associated with regional structural atrophy and functional disruption of neural networks, such as the default mode (DMN), visual (VN) and executive networks (EN) in structural and functional imaging (fMRI) studies, mostly using single test scores of cognitive performance among monocentric cohorts. In contrast to single test scores, cognitive domain composite scores could be more reliable than single test scores due to the reduction of measurement error. Using a multicentric resting state fMRI (rs‐fMRI) and cognitive domain approach, we provide a comprehensive description of the structural and functional correlates of the key cognitive domains of AD with a focus on visuo‐spatial deficits, which manifest in the early stages of the disease.

Method

We analyzed MRI, rs‐fMRI and cognitive domain score data of 490 participants from the N700 cohort of the multicenter DELCODE study, including 54 people with Alzheimer’s Dementia (AD), 86 with Mild Cognitive Impairment (MCI), 175 with Subjective Cognitive Decline (SCD), and 175 Healthy Controls (HC) (Table 1). Resulting cognitive domain composite scores (executive, visuo‐spatial, memory, working memory and language) from the DELCODE neuropsychological battery (DELCODE‐NP), were derived using confirmatory factor analysis. Statistical analysis examined the differences between diagnostic groups, and the association of composite scores with regional atrophy and network‐specific functional connectivity.

Result

Cognitive performance significantly differed between diagnostic groups in AD‐spectrum (Table 2). Regional gray matter atrophy was associated with visuospatial and other cognitive impairments in AD‐spectrum (Figure 1). Patterns of network‐specific resting‐state functional connectivity (except VN) was associated with distinct cognitive impairments in AD‐spectrum (Figure 2).

Conclusion

Robust associations between cognitive domain scores and both regional atrophy and network‐specific functional connectivity (except for VN), suggest the utility of the multicentric and cognitive domain approach towards explicating the relationship between imaging markers and cognition in AD‐spectrum.
The power of genetic knowledge of a population: A lesson from the Generation study 2
Authors: Snædal Jón , Thordardottir Steinunn , Eyjolfsdottir Helga , Gislason Thorstein
Published: December 2020

Background

Alzheimer´s Prevention Initiative Generation Program enrolled ApoE4 carriers to focus on individuals with highest likelihood for the disease. The greatest risk for sporadic AD is among ApoE4 carriers, primarily homozygotes (HM) but to some extent for heterozygotes (HT). Frequency of HM is 2‐3% in Caucasians and HT in about 24%, making it difficult to identify suitable participants. DeCode Genetics has collected samples from 160.000 individuals (Iceland pop. 360.000). More than 50.000 have been analysed by whole genome sequencing, allowing targeted invitation to participate in the Generation Study 2. Our site was selected for enrolment of 200 participants (10% of total planned in the study).

Method

From the genetic database of DeCode, individuals were selected after un‐coding by an independent data committee. Of those 1000 (45%) were HM for ApoE4, 1000 (45%) were HT. 200 (10%) non‐carriers were also selected to maintain study site blinded to the genetic status. Individuals meeting eligibility criteria were contacted by phone. Written information was sent if interested, followed by invitation for the screening visit at the site.

Result

Over the selected 2.200 individuals, 315 cases (15.0%) met an exclusion criteria based on their medical records. Of 1749 individuals approached by telephone, 883 (51,5%) declined to receive further information. Letters were sent to 866 individuals out of which 516 (60%) consented to participate in the study. Screening started with confirmation of the ApoE4 genotype and disclosure to the participant. Amyloid status was tested by lumbar puncture or PET scan when it became available. In July 2019, treatment with umibecestat in the Generation program was terminated. At that point, ApoE4 status had been disclosed to 432 participants (HM 38%, HT 54%, NC 8%). A total of 129 participants had been randomized of which 98 were HM and 31 HT with elevated amyloid. 150 participants were still in the screening phase.

Conclusion

Extensive knowledge of the genetic information in a population gives great advantages for prevention studies in diseases with an identified genetic risk factor. Leveraging the unique genetic knowledge among Icelandic individuals has enabled this significant single‐site contribution to recruitment in the Generation Program.