bluuebunny/crossref_metadata_2025 huggingface dataset:
Differential Expression of Synaptic Biomarkers in the Cerebrospinal Fluid Differentiates Behavioural Variant of Frontotemporal Dementia from Primary Psychiatric Disorders and Alzheimer’s Disease
Authors: Das Shreyasee , van Engelen Marie‐Paule E. , Goossens Julie , Jacobs Dirk , Bongers Bram , Fieldhouse Jay L.P. , Pijnenburg Yolande A.L. , Teunissen Charlotte E. , Vanmechelen Eugeen , Verberk Inge M.W.
Published: December 2023

Background

The lack of early molecular biomarkers in sporadic behavioural variant of frontotemporal dementia (bvFTD) and its clinical overlap with primary psychiatric disorders (PPD) and Alzheimer’s Disease (AD) hampers its diagnostic distinction. Synaptic dysfunction is an early feature in bvFTD and identification of specific biomarkers might improve its diagnostic accuracy. We aimed to assess the diagnostic performance of synaptic biomarkers in bvFTD compared to PPD, AD and controls, and its association with social cognition, cognitive performance and disease severity.

Method

Participants with probable bvFTD (n = 60), PPD (n = 60), biomarker confirmed AD (n = 60), and cognitively normal AD biomarker negative controls (n = 58) with available CSF, (social) cognitive tests, FTLD‐CDR, and Ekman Faces Test score were included (Table 1). CSF synaptosomal associated protein 25 (SNAP25), neurogranin (Ng), neuronal pentraxin 2 (NPTX2) were measured, along with neurofilament light (NfL), and compared between groups using regression models adjusted for age and sex. Diagnostic accuracy was assessed using ROC analysis and Spearman’s correlation analysis for correlation with cognitive measures was performed.

Result

NPTX2 was significantly lower in bvFTD patients compared to PPD and controls (P<0.001). NfL was higher in bvFTD patients compared to PPD, AD and controls (P<0.001) and showed the highest diagnostic accuracy between bvFTD and PPD (AUC: 0.95, CI: 0.91,0.99, sensitivity: 97% specificity: 82%). Between bvFTD versus AD, SNAP25 showed the highest diagnostic accuracy (AUC: 0.78 CI: 0.70, 0.86, sensitivity: 63% specificity: 83%). The selected biomarker panel to differentiate bvFTD from PPD consisted of NfL and NPTX2 and had the highest AUC among the measured biomarkers (AUC: 0.96, CI: 0.93, 0.99, sensitivity: 95%, specificity: 85%), while that for bvFTD and AD consisted of NfL and Ng (AUC: 0.82, CI: 0.75, 0.90, sensitivity: 63% specificity: 92%). Among cognitive scores of bvFTD patients, SNAP25 correlated significantly with visuospatial ability (r = 0.37, P<0.05). There was no correlation between synaptic markers and the Ekman 60 faces test or FTLD‐CDR scores of disease severity.

Conclusion

Together with NfL, synaptic biomarkers NPTX2 and Ng have added value for the differential diagnosis of bvFTD versus PPD and AD respectively. However, there was almost no association of the CSF biomarkers with cognitive performance of bvFTD and PPD patients.
Hyperspectral retinal imaging as a biomarker for Alzheimer’s disease
Authors: Thach Michelle , de Ruyter Frederique J. Hart , Curro‐Tafili Katie R. , van de Giessen Elsmarieke , Collij Lyduine E. , den Braber Anouk , Tan H. Stevie , Visser Pieter Jelle , Verbraak Frank D. , Osseiran Sam , Grondin Jean‐Sébastien , Orellina Julie Antonelle , Campbell Shannon , Chevrefils Claudia , Sylvestre Jean‐Philippe , Bouwman Femke H.
Published: December 2023

Background

Currently, Alzheimer’s disease (AD) diagnosis relies on biomarkers that are either expensive, invasive or time‐consuming. The retina is easily accessible and may be used as a patient‐friendly and cost‐effective diagnostic tool. Optina Diagnostics’ Mydriatic Hyperspectral Retinal Camera (MHRC) may improve diagnostic abilities of the retina by using rich datasets and artificial intelligence. Here we aim to explore diagnostic possibilities of the MHRC by identifying image features associated with the cerebral amyloid status.

Method

Six cognitively healthy participants with a negative amyloid‐PET scan and twenty‐five participants with a positive amyloid‐PET scan (clinical AD n = 4, preclinical AD n = 21, MMSE ≥17) were recruited from the EMIF‐AD PreclinAD Twin60++ study and Amsterdam Dementia Cohort (Table 1). Retinal imaging was performed using the MHRC that acquires 92 retinal images in an ∼1 second exposure, in steps of 5 nm increments across a spectral range of 450‐905 nm (visible and near‐infrared) on a 31° field‐of‐view (Figure 1). Spatial‐spectral features (n = 2304) were extracted from two or three hyperspectral cubes per participant using different combinations of anatomical masks, spectral regions and texture measures. Morphological features (n = 935) related to the blood vessels (diameter, tortuosity, density and fractal dimension) were also extracted from different retinal zones. Features were assessed with a Tukey’s test for statistical significance to classify the cerebral amyloid status determined by amyloid‐PET scans. Features were considered significant if their p‐value was below 0.05 simultaneously for both our present cohort and an independent cohort of 499 subjects.

Result

Explorative analysis identified thirty significant spatial‐spectral features (p‐value range 0.0033‐0.049) for the classification of the cerebral amyloid‐PET status. Examples of such features covering different spectral ranges and retinal anatomic regions are presented in Figure 2. In contrast, only three morphological features were identified (p‐value range 0.017‐0.049).

Conclusion

Phenotypic features extracted from hyperspectral retinal images hold promise to discriminate between amyloid‐PET positive and negative individuals, beyond morphological features available with conventional retinal imaging. More data are collected from several centers to build a classifier of features with the aim to discriminate amyloid‐PET positive from negative subjects. This would yield a patient‐friendly and non‐invasive retinal biomarker for AD.
Preserved absolute pitch and musical working memory in posterior cortical atrophy
Authors: Jiang Jessica , Brotherhood Emilie V , Hardy Chris JD , Yong Keir X X , Foulkes Alexander JM , Warren Jason D
Published: December 2023

Background

The cognitive organisation of working memory for nonverbal sounds and the unusual musical ability of absolute pitch is poorly understood. We recently had the opportunity to investigate this in a musician with absolute pitch who developed posterior cortical atrophy (PCA), the canonical ‘visual variant’ of Alzheimer’s disease.

Method

We studied a 59 year old professional pianist, PA, known premorbidly to have absolute pitch and fulfilling diagnostic criteria for PCA, in comparison to five healthy age‐matched female musicians (three with absolute pitch, two without). Each participant completed the melodic organisation (scale, contour, interval) and rhythm subtests of the Montreal Battery for Evaluation of Amusia (MBEA), an assessment of absolute pitch ability, a standard test of auditory verbal working memory (digit span), an equivalent working memory test for spoken letters and a series of bespoke musical working memory tasks assessing forward and reverse span for pitch sequences, rhythmic sequences and sequences combining these two dimensions.

Result

PA had reduced digit span and letter span relative to healthy musician controls, as anticipated from her diagnosis. However, she had retained absolute pitch and performed normally on MBEA subtests assessing pitch and rhythm patterns and within the healthy musician range on the bespoke tests of pitch and rhythm working memory. Across musical working memory tests, PA showed a profile similar to healthy musician controls with absolute pitch: all performed better on the pitch working memory task than other musical working memory tasks. On the pitch working memory test, PA performed better than the healthy musicians without absolute pitch, all of whom performed worse on the pitch task than other musical working memory tasks.

Conclusion

Our findings suggest that absolute pitch may be preserved and continue to support musical working memory (despite impaired verbal working memory) in PCA. This study has implications for our understanding of the cognitive and neural mechanisms of absolute pitch and nonverbal auditory working memory.
Atlas of Retinal Imaging in Alzheimer’s Study (ARIAS): SD‐OCT in Preclinical Alzheimer’s disease
Authors: Alber Jessica , Thompson Louisa I , Arthur Edmund , Strenger Jennifer , Price Ashley N. , Sinoff Stuart , Snyder Peter J
Published: December 2023

Background

ARIAS is a preclinical Alzheimer’s disease (AD) cohort study, with the aim of following cognitively unimpaired (CU) older adults at high and low risk for AD and studying changes in retinal biomarkers over time. Here, we share baseline Spectral Domain Optical Coherence Tomography (SD‐OCT) data from ARIAS.

Method

SD‐OCT was completed using the Heidelberg SPECTRALIS on 146 CU older adults (aged 55‐80), 83 high risk (APOE E4 carriers, first degree family history of AD), 63 low risk (APOE E4 non‐carriers, no first‐degree family history of AD). We took macular (30×25‐degree) and optic disc centered (radii of 3.5, 4.1, and 4.7 mm) SD‐OCT images. Vendor software was used to segment and compute average retinal thickness and volume in the 9 ETDRS maps for the macular and 7 glaucoma fields for the optic disk. ANCOVA (with age as a covariate) was used to compare retinal layer thickness and volume between the two groups. Bonferroni correction was used for multiple comparisons.

Result

The high risk group had significantly higher thickness/volume than the low risk group in the inner temporal quadrant of the ganglion cell layer (GCL, F(2, 144) = 3.67p<.05), the central quadrant of the inner nuclear layer (INL, F(2, 144) = 3.48,p<.05), the inner nasal quadrant of the outer plexiform layer (OPL, F(2, 144) = 7.35,p<.05). The peripapillary retinal nerve fiber layer (pRNFL) showed increased global thickness (F(2, 144) = 4.30, p<.05), and thickness in the nasal (F(2, 144) = 4.23, p<.05), nasal inferior (F(2, 144) = 3.34, p<.05), and temporal inferior (F(2, 144) = 3.61,p<.05) quadrants in the high risk group compared to the low risk group.

Conclusion

SD‐OCT can be applied to examine retinal thickness in preclinical AD. Thickness/volume of specific quadrants of the GCL, INL, and OPL differentiated high risk CU older adults from low risk CU older adults in a large preclinical cohort. pRNFL global thickness, and thickness in the nasal, nasal inferior, and temporal inferior quadrants, was increased in the high risk group. These results confirm and extend our prior findings of increased retinal layer thickness in preclinical AD. Longitudinal data will confirm whether these layers change over time in preclinical AD.
Blood proteomics to identify AD CSF molecular subtypes
Authors: Tijms Betty M. , Teunissen Charlotte E. , Gobom Johan , Shi Liu , Zetterberg Henrik , Lovestone Simon , Visser Pieter Jelle , Blennow Kaj
Published: December 2023

Background

We identified three distinct molecular subtypes in Alzheimer’s disease (AD) using cerebrospinal fluid (CSF) proteomics: one subtype was characterised by neuronal hyperplasticity with increased amyloid metabolism, the second subtype was characterised by innate immune activation and the third subtype by a disrupted blood‐brain barrier. Each subtype will likely need specific treatment, but for patient selection CSF proteomics might be impractical. Here we investigated if AD molecular subtypes can also be detected in blood.

Method

We selected from EMIF‐AD MBD 149 individuals with AD across the clinical spectrum who had plasma proteomics as well as a CSF subtype definition available. We compared CSF subtypes on plasma levels using general linear models. We selected a subset of proteins that best predicted AD subtype by trying a random forest classifier on 70% of the patient sample, and computed prediction accuracy statistics on patients that were left out.

Result

Plasma levels of 407 (13%) proteins differed between AD subtypes (figure). The plasma profiles specific to AD subtype showed altered levels for corresponding molecular processes: The CSF hyperplasticity subtype (n = 53) showed low plasma levels of 76 proteins associated with neuron development and axon guidance. The CSF innate immune activation subtype (n = 48) showed low plasma levels of 142 proteins related to regulation of immune response. The CSF blood‐brain barrier subtype (n = 48) showed the low plasma levels of 189 proteins associated with blood vessel morphogenesis. The random forest could classify subtypes with an overall accuracy of 77% (range 70%‐85%), and the top 5 contributing proteins were FGF10, CTCF, TCN2, PLXNA1, and EMILIN3.

Conclusion

It is possible to detect distinct AD CSF molecular subtypes in blood. The next step is to validate this in independent cohorts, and to test if subtypes are related to different treatment responses.
How our emerging understanding of Alzheimer’s disease and dementia risk factors is enhanced using UK Biobank
Authors: Llewellyn David J
Published: December 2023

We have long known that there are large individual differences in the risk of developing Alzheimer’s disease and other dementia subtypes. Indeed, the hope is that this variation gives us clues that may provide new opportunities for targeted interventions and dementia prevention. Thousands of studies in recent decades provide compelling evidence that there are dozens of modifiable and non‐modifiable dementia risk factors. This provides cause for optimism, though critics stress several limitations that need to be addressed. The thorny issue of possible confounding remains, and the causal status of many dementia risk factors is challenging or even impossible to establish in randomized controlled trials. Most prior studies are modest in size and there is large variation in the associations observed between studies that is difficult to explain. Lastly, the window of opportunity for early intervention is difficult to assess from studies of older adults whose underlying pathologies may already be well established. UK Biobank provides us with a fundamentally different type of resource to help address these limitations and accelerate the pace of our discoveries. So, what’s new? For the first time we can investigate genetic, lifestyle and environmental risk factors for dementia in half a million middle‐aged and older adults. This has been a game changing shift in the size and richness of the data available to us, which in turn has changed the scientific questions that are possible to address. For example, we established for the first time that lifestyle factors do not interact with polygenic risk, suggesting that lifestyle interventions may decrease dementia risk regardless of genetic variation (Lourida, et al., 2019, JAMA). We can now investigate single or multiple risk factors for dementia with greater confidence. For instance, recent studies of frailty and cardiometabolic multimorbidity in combination with genetic, neuroimaging, and other rich data provide practical examples (Ward, et al., 2022, JNNP; Tai, et al., 2022, Lancet Healthy Longevity). Mendelian randomization and causal machine learning are particularly promising approaches when evaluating causality. Future enhancements to UK Biobank will facilitate even more powerful insights into the natural history of dementia, raising new possibilities for precision dementia medicine.
Extending understanding of the genetic architecture of cerebral small vessel disease using advanced imaging measures in UK Biobank
Authors: Debette Stéphanie
Published: December 2023

Cerebral small vessel disease (cSVD) is a leading cause of stroke and a major contributor to cognitive decline and dementia in the population (Debette JAMA Neurol 2019). Covert cSVD, which is detectable with brain MRI but does not manifest as clinical stroke, is highly prevalent in the general population, particularly with increasing age. Large collaborative genomic studies through consortia like CHARGE or ISGC have led to substantial progress in the identification of common genetic variants that are associated with cSVD. In this presentation, we will provide an overview of such collaborative studies, prominently involving the unique UK Biobank resource, that have recently extended our understanding of the genetic architecture of cSVD, revealing over 70 independent loci associated with this condition, especially with MRI‐markers of cSVD (Bordes, Nat Rev Neurol 2022; Duperron, Nat Med AIP). In silico functional explorations of the observed genetic associations point to a major role of blood pressure‐related pathways, but also mechanisms independent of vascular risk factors, such as extracellular matrix, membrane transport, vascular development, myelination, and blood‐brain barrier. Leveraging next‐generation sequencing data in UK Biobank and other resources, these studies also shed new light on the continuum between monogenic and multifactorial cSVD, with several genes (HTRA1, COLA4) harboring both rare mutations and common variants contributing to the disease (Mishra, Brain 2019). Further, we recently showed that MRI‐cSVD risk loci identified in middle‐ and older age in UK Biobank and other cohorts are associated with white matter microstructure on diffusion imaging (DTI, NODDI) and perivascular space burden already in young adults in their twenties (e.g. at VCAN, OPA1, SLC13A3) suggesting that processes contributing to cSVD may find their root much earlier in life than previously thought (Duperron, Nat Med AIP; Sargurupremraj, Nat Commun. 2020). We provide preliminary insights on how these association patterns change across the adult lifespan and discuss how this can inform dementia prevention, including, in combination with other omics resources, for proof‐of‐concept genomics‐driven drug discovery (Duperron, Nat Med AIP; Mishra, Nature. 2022; Mishra, Brain. 2022).
Annonaceae fruit consumption is associated with cognitive decline and dementia in degenerative parkinsonism
Authors: de Langavant Laurent Cleret , Flamand‐Roze Emmanuel , Petit Aimee , Tressieres Benoit , Gharbi‐Meliani Amin , Chaumont Hugo , Michel Patrick Pierre , Bachoud‐Levi Anne‐Catherine , Remy Philippe , Edragas Regine , Lannuzel Annie
Published: December 2023

Background

High consumption of Annona muricata fruit (soursop, graviola, guanabana, corossol) has been previously identified as a risk factor for atypical parkinsonism in the French Caribbean islands. Annonaceae fruits are consumed worldwide in tropical areas. We tested whether consumption of Annonaceae products could worsen the clinical phenotype of patients with any form of degenerative parkinsonism.

Method

We analyzed neurological data from 180 Caribbean parkinsonian patients and specifically looked for dose effects of lifelong, cumulative Annonaceae consumption on cognitive performance. Using unsupervised clustering, we identified one cluster with mild/moderate symptoms (N = 102) and one with severe symptoms including cognitive impairment (N = 78).

Result

We showed that even low cumulative consumption of fruits/juices (>0.2 fruit‐years) or any consumption of herbal tea from Annonaceae worsen disease severity and cognitive deficits in degenerative parkinsonism including Parkinson’s disease (OR fruits‐juices: 3.76 [95% CI: 1.13‐15.18]; OR herbal tea: 2.91 [95% CI: 1.34‐6.56]).

Conclusion

We suggest that more restrictive public health preventive recommendations should be made regarding Annonaceae products which could increase the risk cognitive impairment and dementia in tropical areas.
Functional neuroanatomy of music perception in frontotemporal dementia
Authors: Core Lucy , Warren Jason D , Agustus Jennifer L
Published: December 2023

Background

Despite considerable interest in music as an index of brain function and a therapeutic modality in dementia, the neural correlates of music processing in different dementias remain poorly defined. In the frontotemporal dementia spectrum, behavioral variant frontotemporal dementia (bvFTD) and semantic variant primary progressive aphasia (svPPA) are often associated with striking changes in musical function and/or retained musical skills, suggesting frontotemporal dementia may be an instructive disease model in which to assess brain mechanisms of music processing in neurodegenerative pathologies. Here we addressed this issue using activation fMRI in patients with frontotemporal dementia.

Method

Nineteen patients (10 svPPA, nine bvFTD) and 26 healthy age‐matched controls underwent 3‐Tesla ‘sparse’ fMRI in which they listened passively to musical melodies. In a 2×2 factorial design, stimulus conditions were manipulated to probe two key dimensions of music processing: semantic memory (familiarity: familiar vs. novel melodies) and perceptual features (temporal structure: isochronous vs. anisochronous melodies). Post‐scan behavioral testing assessed participants’ ability to discriminate melodies under each of the two manipulated stimulus dimensions. Information about participant demographics and musical background was also collected.

Result

The healthy older control group showed separable profiles of activation in posterior superior temporal cortex for processing musical temporal structure, and in anterior temporal and inferior frontal cortices for processing musical familiarity. Compared with healthy older listeners, syndromic groups showed differential patterns of engagement of these distributed neural networks. In post‐scan behavioral testing, patients with bvFTD also exhibited significantly impaired musical familiarity judgments relative to healthy controls.

Conclusion

Frontotemporal dementia syndromes show distinct functional neuroanatomical signatures of music perception. Future work should explore fMRI of music processing as a probe of neural function in particular molecular pathologies and a candidate marker of therapeutic potential in dementia.
Prevalence of subjective cognitive decline and its association with physical health problems among urban community dwelling elderly population in South India
Authors: Kantipudi Suvarna Jyothi , Menon Jayakumar
Published: December 2023

Background

The incidence of cognitive disorders is increasing in India1. Stage II of the preclinical Alzheimer’s Disease (PCAD) is characterised by subjective complaints of decline in cognition, termed Subjective Cognitive Decline (SCD)2,3. Objective assessments of cognition is normal in that stage. There are no studies from India that looked at SCD in the community. Our study aims to look at the prevalence of SCD in an urban dwelling elderly population and its correlates.

Method

418 individuals above the age of 60 were screened using Subjective Memory Complains Questionnaire (SMCQ) and also screened for medical and psychiatric illness. Objective measurement of cognitive functions was done using MOCA.

Results

372(92.5%) had reported at least 1 subjective complaint using the participant version of the Subjective Memory Complaint Questionnaire(SMCQ). Among those without any reported subjective complaints,17(56.6%) had objective cognitive impairment on assessments. In total,13 (3.49%) had normal cognition and 179(48.12%) of the evaluated subjects had pre‐MCI SCD. There is no statistically significant association between physical health parameters of Diabetes mellitus and Hypertension or any sociodemographic variables except educational attainment. The mean subjective complaints score is lesser and means objective cognition scores are higher in those with higher secondary school educational attainment (p value<0.001) when compared to those who don’t.

Conclusions

There is significant morbidity of cognitive decline in the elderly. Subjective memory complaints are present in most of the elderly(92.5%) and 179(48.12%) had pre‐MCI SCD. SCD is a complex condition that requires further longitudinal studies with biomarker assessment to understand the mechanism of progression to AD.
The Israel National Brain Repository .The establishment and uniqueness of the first brain bank in Israel
Authors: Manzali Sigalit , Ravona‐Springer Ramit , Heymann Anthony , Greenbaum Lior , Cooper Itzik , Gardner Raquel C. , Liraz‐Zaltsman Sigal , Beeri Michal S
Published: December 2023

Background

Post‐mortem human brain tissue is the gold‐standard for neurodegenerative disease diagnosis and is invaluable for elucidating cellular and molecular mechanisms. Therefore, neurodegenerative disease brain banks are a critical component of research to advance diagnosis and develop effective disease modifying therapies. The Israel National Brain Repository (INBR) was established in 2018 at the Sheba Medical Center via a collaboration with the Mount Sinai Neuropathology Brain Bank in New York. Israel is a unique country with a diverse population including substantial populations of individuals of European descent, Middle‐Eastern North African (MENA) descent, and combinations of both.

Method

INBR predominantly recruits from two prospective longitudinal cohort studies whose participants are at high dementia risk: older adults with type 2 diabetes (the Israel Diabetes and Cognitive Decline study) and middle‐aged offspring of people with Alzheimer’s Disease (The Israel Registry for Alzheimer’s Prevention). Participants in both cohorts are phenotyped for cognition, lifestyle, brain imaging, blood biomarkers, and genetics. Biospecimen collection and processing protocols are aligned with other Neurobiobanks in the USA (see flowchart). Additionally, all participants in both cohorts are members of the second largest healthcare provider in Israel, the Maccabi Healthcare Services, permitting linkage to longitudinal medical records dating from 1998.

Result

N = 450 participants have signed intent to autopsy. Among the N = 285 with race/ethnicity data available, 30% are MENA. 14 brain and 6 spinal cord donations have been completed. At time of death, donors had an average age of 81.1 years, 10 had normal cognition, 3 had dementia, and one had amyotrophic lateral sclerosis.

Conclusion

The potential strengths of the INBR is in the population characteristics of Israel, the ethnic diversity and admixture, the linkage to 25‐years of medical records data, and the small size of the country allowing donations to be received from anywhere in the country. The main challenge we face is cultural barriers to brain donation that exist among some segments of Israeli society. The ultimate goal is to capitalize on the strengths and uniqueness of INBR to develop novel therapies for dementia.
ADPrep ‐ A fully automated Alzheimer’s Disease Neuroimaging Preprocessing Pipeline for MRI and multi‐tracer PET data
Authors: Dehsarvi Amir , Denecke Jannis , Biel Davina , Dewenter Anna , Roemer Sebastian Niclas , Steward Anna , Wanger Fabian , Brendel Matthias , Franzmeier Nicolai
Published: December 2023

Background

State‐of‐the‐art preprocessing of MRI and PET data is crucial for Alzheimer’s disease (AD) neuroimaging research. Therefore, standardization and harmonization of neuroimaging preprocessing across sites is key to generate comparable and sharable datasets and to reduce potential bias introduced by different preprocessing strategies. Further, neuroimaging preprocessing requires strong expertise in different programming languages (R/MATLAB/Python/Bash) and software packages (SPM/FSL/AFNI/FreeSurfer), i.e., a major barrier for non‐expert users. Therefore, we developed a docker‐based, state‐of‐the‐art, fully automated, neuroimaging toolbox that integrates robust preprocessing of structural/functional MRI, and multi‐tracer PET (amyloid/tau/FDG/TSPO), generating easy to use spreadsheet and nifti outputs. The toolbox requires no programming expertise and can facilitate neuroimaging analyses, data harmonization and sharing across the AD neuroimaging community.

Methods

The pipeline works on standardized bids‐formatted data and was fully developed in nipype (see Figure 1). Preprocessing for structural MRI includes volumetric and cortical thickness assessments for widely used brain atlases (Desikan‐Killiany/Schaefer/LPBA/Hammers/Neuromorphometrics/Cobra/Destrieux), plus spatially normalized and smoothed grey/white‐matter segments for voxel‐based morphometry and generation of subject‐specific PET‐reference regions. Functional MRI processing includes slice‐timing and motion correction, nuisance regression, spatial normalization, and functional connectivity assessments for the above‐mentioned atlases. PET processing includes generation of spatially normalized SUVR images for different tracer‐specific reference regions, as well as extraction of atlas‐based SUVRs (PVE and non‐PVE‐corrected). Standardized imaging outputs in FreeSurfer space were benchmarked against available ADNI data to illustrate comparability with existing pipelines (see Figure 2). Cluster implementation is provided to ensure large‐scale data processing.

Results

The toolbox was tested successfully on large‐scale multimodal datasets, including several thousand scans from ADNI, ADNI‐DOD, and A4 with an overall processing failure rate of <4%. Using ADNI data as a benchmark, our data closely reproduce global amyloid‐PET (r = 0.99, p<0.001, Fig.2A) and temporal meta tau‐PET SUVRs (r = 0.98, p<0.001, Fig.2B), suggesting that PET‐thresholds can be applied. Runtime is ∼1h for a structural MRI and ∼5hrs for a PET including PVE‐correction.

Conclusions

We propose a user‐friendly multimodal robust neuroimaging preprocessing toolbox, that can be applied to different neuroimaging datasets by non‐expert users. The toolbox provides outputs that can be directly used for statistical analyses. Future work involves implementing other imaging modalities, e.g., diffusion tensor imaging.
Gotcha! A trial of an app‐based therapy for proper name anomia in people with dementia
Authors: Badalova Aygun
Published: December 2023

Objectives

Proper name anomia is a common experience that can become amplified in patients with a diagnosis of dementia (PWD). The Gotcha! app aims to provide practice‐based therapy for PWD to relearn the names of key people in their lives. It has been developed according to the principles of errorless learning, which have previously been shown to improve the remembering the familiar people’s names and benefit the relationship between the PWD and their loved ones. (Clare et al, 1999, 2000, 2003).

Methods

Gotcha! is a digital confrontation naming therapy app which enables patients to train one face per day by using photos that the app represents. During the development phase we carried our qualitative research (thematic analysis) on why PWD get involved in research projects such as ours. Gotcha! therapy block lasts for six weeks and prior to the therapy patients complete a multiple baseline paradigm with eight weekly tests of free naming of the to‐be trained faces. During the therapy, a novel speech verifier is used to provide real‐time feedback (Barbera et al. 2020). Two analyses method is used to investigate the behavioural data: 1) within‐subject non‐parametric analysis using Tau‐U metric (Parker et al. 2011); 2) a parametric group analysis using an ANOVA.

Results

The thematic analysis revealed four themes that will be discussed in more detail on the talk.In terms of the quantitative data, our results from the first 16 subjects showed: 1) Tau‐U. 73% showed a positive trend with better naming during the training phase with 5/10 reaching statistical significance. 2) ANOVA demonstrated a significant effect at the group level of training>baseline phase, F(1,9) = 6.68, p = .029.
GABA transporters gene expression associates with [18F]FDG‐PET signal in regions typically hypometabolic in Alzheimer’s disease
Authors: Carello‐Collar Giovanna , Ferrari‐Souza João Pedro , Machado Luiza Santos , Povala Guilherme , Limberger Christian , Pascoal Tharick A. , Zimmer Eduardo R
Published: December 2023

Background

It is suggested that the [18F]fluorodeoxyglucose(FDG)‐PET signal reflects astrocyte and neuronal activity, with the excitatory glutamate uptake by astrocytes as the trigger for brain glucose metabolism. The inhibitory neurotransmitter γ‐aminobutyric acid (GABA) is taken up by neurons and astrocytes through the GABA transporters (GAT) 1 and 3. However, its role in the [18F]FDG‐PET signal in healthy aging and Alzheimer’s disease (AD) remains poorly investigated. Thus, we aimed to explore associations between neuronal and astrocytic GABA transporters gene expression with [18F]FDG‐PET in cognitively unimpaired (CU) and AD individuals.

Method

We obtained [18F]FDG‐PET imaging data of CU and AD from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) (Table 1). GAT1 and GAT3 gene expression in the brain was obtained from the Allen Brain Atlas (Table 1, Figure 1). We extracted SUVr (pons as reference region) and mRNA values using the RMINC package and performed Pearson’s correlation to test the association between [18F]FDG‐PET and GABA transporters mRNA (p‐value < 0.05).

Result

In brain regions typically hypometabolic in AD, we observed a strong positive association of [18F]FDG‐PET SUVr with GAT1 and GAT3 gene expression in CU (GAT1: r = 0.93; p < 0.0001; Figure 2A, GAT3: r = 0.94; p < 0.0001; Figure 2B) and AD individuals (GAT1: r = 0.9; p < 0.0001; Figure 2A, GAT3: r = 0.92; p < 0.0001; Figure 2B). By contrast, in brain regions typically resilient, we found a weak correlation with CU individuals (GAT1: r = 0.32; p = 0.016; Figure 2C, GAT3: r = 0.26; p = 0.04; Figure 2D) and no significant correlation in AD patients (GAT1: r = 0.24; p = 0.07; Figure 2C, GAT3: r = 0.24; p = 0.059; Figure 2D).

Conclusion

Our results demonstrate a significant strong positive association between [18F]FDG‐PET SUVr and GABA transporters gene expression in CU and AD in hypometabolic regions. These findings suggest that GABA transporters are involved with brain glucose metabolism in regions classically vulnerable to AD pathology.
A portable eye tracking experiment for the assessment of cognitive impairment in presymptomatic frontotemporal dementia
Authors: Convery Rhian S , Goldsmith Sophie E , Nicholas Jennifer M , Kaski Diego , Rohrer Jonathan D. , Russell Lucy L.
Published: December 2023

Background

Eye tracking can be useful for measuring cognitive function in frontotemporal dementia (FTD), as the tasks do not require behavioural or verbal responses. However, most systems are highly expensive and require experiments to be conducted in artificial environments. We developed a fully portable eye tracking protocol using the Tobii Pro Nano, a small, low‐cost eye tracker. The aim was to investigate if the portable experiment can detect presymptomatic impairment in FTD using instructionless tasks of social cognition.

Method

Participants were recruited from the Genetic FTD Initiative (GENFI), including 41 mutation carriers (mean age = 43.0, standard deviation (SD) = 11.0), and 14 non‐carriers (mean age = 40.4, SD = 7.14). Participants completed tasks of simple and complex emotion recognition that involved viewing four images (one target face (simple) or pair of eyes (complex) and three non‐target) followed by a target emotion word and then the original four images alongside the emotion word. A dwell time change score was calculated by subtracting the percentage dwell time for the target image before the word appeared from the percentage dwell time after the word appeared. A lower dwell time change score signifies impaired performance. Linear mixed effects models were used to compare performance on each of the tests, with the dwell time change score included as the variable of interest and age, target type (target, non‐target), and genetic status (carrier, non‐carrier) included in the model as fixed effects.

Result

The average (standard deviation) mean percentage dwell time change score in the target image was lower at 52.2% (15.8) for the mutation carriers compared with 56.5% (7.01) for non‐carriers on the simple emotion task (p = 0.006), and 23.4% (11.2) for carriers compared with 27.3% (7.46) for non‐carriers on the complex emotion task (p = 0.076).

Conclusion

These eye tracking tasks may be a useful tool for assessing deficits in social cognition in presymptomatic FTD, something that has been difficult to measure with pen and paper neuropsychometry. Therefore, this portable eye tracking experiment has the potential to be a low‐cost biomarker for monitoring the progression of FTD in clinical trials, both at home and in the clinic.
Cholinesterase inhibitors are associated with large reductions in hospitalization for cardiovascular events and mortality in patients with Alzheimer’s dementia and heart failure
Authors: Wessberg Marianne Reimers , Xu Hong , Fastbom Johan , Seiger Ake , Eriksdotter Maria
Published: December 2023

Introduction

Cholinesterase inhibitors (ChEIs) are approved for treatment of Alzheimer’s dementia (AD). ChEIs inhibit the enzyme acetylcholinesterase, increasing the duration of action of acetylcholine in the central and peripheral nervous systems. ChEIs are known to be anti‐inflammatory and to have negative chronotropic effects. Observational studies by us and other groups have indeed shown an association with use of ChEIs in AD with lower risk of death and cardiovascular events (CVD) including myocardial infarction, heart failure (HF), and stroke. We next wanted to investigate whether ChEI treatment in AD patients with HF is associated with reduced risk for mortality and for hospitalization due to CVD.

Methods

Data from the Swedish registry for dementia disorders, SveDem,was linked to the Patient‐, Prescribed Drug‐ and Cause of death registries. In a propensity score (PS) matched cohort of patients with AD and HF, the association between ChEI use and all‐cause death or hospitalization due to CVD was examined with Cox proportional hazards models.

Results

The PS matched cohort included 455 patients with HF prior to the AD diagnosis with ChEI and 455 non‐ChEI users. During a median follow‐up time of 2.14 years, 549 deaths occurred. Compared to non‐users, ChEI use was associated with 21% lower risk of death (adjusted HR 0.79; 0.66‐0.96). Galantamine and donepezil (0.64; CI 0.47‐0.87 and 0.80; CI 0.64‐0.98) but not rivastigmine (0.96; CI 0.73‐1.28) were associated with lower risk of death. Any ChEI use was associated with a 47% (CI 0.38‐0.75) reduction in risk of hospitalization due to HF and a 52% reduction (CI 0.32‐072) among donepezil‐users.

Conclusions

This study supports previous reports that treatment with ChEIs in AD is associated with reduced mortality risk. We here show that this association is also found in patients with HF and AD but with differential effects among the ChEIs. Further studies are needed to elucidate the mechanisms. The study also showed a substantial reduction in hospitalization due to CVD. Our results highlight the impact of cardiovascular comorbidities in AD which need to be considered in clinical trials as would the impact of the baseline treatment with ChEIs in new anti‐dementia drug trials.
Exploring the Causal Association between Brain Iron Accumulation and Alzheimer’s Disease: A Two‐Sample Univariable Mendelian Randomisation Analysis
Authors: Zagos Loukas , Elliott Paul , Tzoulaki Ioanna , Dehghan Abbas
Published: December 2023

Background

Alzheimer’s disease aetiology is complex and not fully understood. Brain iron has been increasingly implicated in the pathology of neurodegenerative diseases, and a myriad of epidemiological studies has supported a connection between brain iron accumulation and Alzheimer’s disease, but evidence remains inconsistent. Additionally, genetic studies have suggested that variations in genes that regulate brain iron metabolism may increase the risk of developing Alzheimer’s disease.

Method

In this study we conduct two‐sample univariable Mendelian randomisation analysis, leveraging the largest available summary statistic genetic data from genome‐wide associations studies on quantitative susceptibility mapping phenotypes to explore potentially causal associations between iron deposition measured in 18 brain structures and Alzheimer’s disease.

Result

We identified that higher genetically predicted brain iron accumulation in left putamen was associated with higher odds of Alzheimer’s disease (Odds ratio (OR) per standard deviation (SD) higher genetically predicted median susceptibility: 1.11, 95% confidence interval (CI): 1.03 to 1.20) and higher genetically predicted brain iron accumulation in right putamen was also associated with higher odds of Alzheimer’s disease (OR: 1.10, 95% CI: 1.01 to 1.20). However, genetic predisposition to higher Alzheimer’s disease liability was associated with lower brain iron deposition in right thalamus (beta per unit higher log‐odds of Alzheimer’s disease: ‐0.04, 95% CI: ‐0.08 to ‐0.01), left amygdala (beta: ‐0.04, 95% CI: ‐0.07 to ‐0.01), right amygdala (beta: ‐0.04, 95% CI: ‐0.07 to ‐0.01), left thalamus (beta: ‐0.03, 95% CI: ‐0.07 to ‐0.003) and left putamen (beta: ‐0.04, 95% CI: ‐0.08 to ‐0.002).

Conclusion

This work provides a new layer of evidence using genetic association data that supports a potentially causal effect of iron accumulation in putamen on Alzheimer’s disease, which has been proposed in the literature. Iron can promote oxidative stress, which can contribute to neuronal damage and death in the putamen. Additionally, iron can disrupt the normal functioning of the basal ganglia, which in turn may lead to movement disorders, a symptom observed in Alzheimer’s disease. Therefore, despite the lack of evidence from clinical trials, iron‐targeted therapeutic strategies could be a beneficial approach for contributing to the treatment of Alzheimer’s disease.
Monitoring Daytime Napping in Community Dwelling Older Adults Using Contactless Sleep Technologies
Authors: Ravindran Kiran K.G. , Monica Ciro Della , Atzori Giuseppe , Lambert Damion , Revell Victoria Louise , Dijk Derk‐Jan
Published: December 2023

Background

Increased daytime napping and excessive sleepiness are associated with cognitive decline in older adults, especially in people living with dementia (PLWD) [1]. Subjective assessments of naps are burdensome and maybe unreliable in PLWD and hence there is a need for technologies that provide objective longitudinal assessment of the incidence and duration of naps. Here we compare two contactless sleep technologies (CSTs) against sleep diary and actigraphy for monitoring daytime napping in community dwelling non‐demented older adults.

Method

Two under‐mattress CSTs (Withings Sleep Analyser [WSA] and Emfit QS [Emfit]) along with actigraphy (Actiwatch Spectrum [AWS]) were deployed in the home of 17 older adults for a period of 14 days (≥65 years; Mean Age ± SD = 72 ± 4.49; 6 Women). The ground truth nap information was collected using an extended consensus sleep diary that included additional information about naps (timing, duration, and location). We analyzed the agreement of the napping events and duration estimated by WSA, Emfit and AWS against the sleep diary reported events.

Result

The CSTs only detected in‐bed naps whilst the AWS detected both in‐bed and not‐in‐bed naps. Although all the compared devices detected spurious naps unreported in the sleep diary, it was highest in AWS (81% of total naps detected) followed by Emfit (63%) and WSA (16%) as shown in Figure 1. Among the CSTs, WSA accurately detected more in bed naps while registering less spurious naps compared to Emfit but had lower duration agreement to sleep diary (Figure 2). Further, when the contribution of daytime naps to 24‐h total sleep time was computed, the WSA estimate (12.8±6.1%) was closest to the sleep diary estimate (12.9±9.1%) followed by AWS (15.6±9.9%) and Emfit (17.2±11.1%).

Conclusion

CSTs, with their ability to provide both contextual location information and objective measures of napping, such as timing and duration, offer a reliable and unobtrusive alternative to traditional methods such as sleep diary and actigraphy for long‐term round‐the‐clock monitoring of sleep in older adults.

References:

[1] Li, P, Gao, L, Yu, L, et al. Daytime napping, and Alzheimer’s dementia: A potential bidirectional relationship. Alzheimer’s Dement. 2023; 19: 158– 168. https://doi.org/10.1002/alz.12636
LANGaware: biomarker workflows for classifying neurodegenerative and affective disorders across languages and severity levels
Authors: Rentoumi Vassiliki , Vassiliou Evangelos , Pittaras Nikiforos , Demiraj Admir , Paliouras George , Sali Dimitra
Published: December 2023

Background

A wide range of neurodegenerative disorders impair communication faculties, manifested as subtle changes in speech and language. Following trends in Machine Learning (ML), Text and Multimedia Analysis, recent works pursue classification of such disorders by developing biomarkers useful for cognitive status description. However, investigations that gauge biomarker applicability on cases of radically different impairment / symptom severity have been under‐investigated. In this work, we build upon previous research and evaluate LANGaware’s biomarker suite in the drastically different tasks of Dementia and Depression classification. For both cases, we use appropriate Healthy Controls and evaluate the proposed biomarker workflow under a multi‐language experimental investigation.

Method

We utilize audio recordings and transcripts from patient responses to verbal cognitive assessment tasks. These are analyzed with LANGaware’s multimodal biomarker pool, mapping raw data to biomarkers scores that quantify vocal, linguistic and grammatical usage proficiency, structure and patterns, by applying both statistical analysis and explainable template matching. Biomarkers activations are fed to ML workflows composed of gradient boosting learners that employ feature selection, filtering and ensemble‐based learning to arrive at configurations best suited for discriminating the disorder of interest. The pipeline is evaluated using a standard train‐test and cross‐validation setup.

Result

Experimental results indicate that our method achieves weighted F1 test scores of 82.49% for Greek Dementia classification, using a train / test dataset of 1271 / 624 instances and 80.28% on 570 / 243 English data. We use the same pipeline and biomarker pool for Depression classification, reaching 74.03% and 71.36% performance scores, obtained from 73 / 31 and 652 / 42 available train‐test data, for Greek and English respectively.

Conclusion

The above findings show that the proposed biomarker pool generalizes across neurodegenerative and affective disorders of radically different severity. As a result, they constitute valuable decision support tools for accurate, automatic and explainable early diagnosis, facilitating proactive care, improved symptom management and better patient quality of life. Future research efforts include extending our experimental evaluation of LANGaware biomarkers to additional disorders and diseases, as well as expanding the biomarker set to enable analysis of additional modalities.