bluuebunny/crossref_metadata_2025 huggingface dataset:
Increased levels of Osteopontin are associated with dementia in the presence of cerebral small vessel disease
Authors: Gardener Hannah , Ghare Smita S. , Ariko Taylor , Gutierrez Jose , Wright Clinton B. , Goldberg Ronald B , Cooper Gregory , Shields Christopher B , Barve Shirish , Rundek Tatjana
Published: December 2023

Background

Osteopontin is a proinflammatory cytokine associated with systemic vascular, inflammatory, and autoimmune diseases. It has been recently implicated in neuroinflammation and neurodegeneration. We hypothesized that plasma osteopontin is a deleterious neuroinflammatory marker increased in people with dementia and cerebral small vessel disease (CSVD).

Method

We conducted a pilot study in participants in the longitudinal multi‐ethnic Northern Manhattan Study (NOMAS). Three groups were selected based on their dementia status and evidence of subclinical CSVD, and chosen to be similar in age, sex, and education attainment: No Dementia/No CSVD (n = 19), Dementia/No CSVD (n = 22), and Dementia+CSVD (n = 21). Dementia (any type) was diagnosed by consensus adjudication following a series of comprehensive neuropsychological assessments and a review of medical history. CSVD was indicated by silent brain infarcts, perivascular spaces, cerebral microbleeds, and white matter hyperintensity volumes on MRI. Osteopontin was measured by quantitative solid‐phase ELISA. Multinomial logistic regression was used to examine the difference in osteopontin levels across groups, adjusting for key determinants of CSVD and neurodegeneration in NOMAS, including age, race/ethnicity, BMI, and brain volume.

Result

Osteopontin levels were substantially elevated in the Dementia+ CSVD group (mean = 70.69±39.00 ng/ml) and only slightly increased in the Dementia/No CSVD group (mean = 45.46±19.11) compared to the No dementia/No CSVD group (mean = 36.43±15.72). Osteopontin was associated with dementia+CSVD (Odds Ratio (OR) per ng/ml = 1.06, 95%CI 1.02‐1.11) in unadjusted analysis, and this remained consistent and significant after adjusting for covariates, including brain volume. Osteopontin was strongly correlated with WMHV (Pearson r = 0.46, p = 0.0001), but not with other components of CSVD.

Conclusion

In this pilot study, we observed a significant relationship between increased levels of osteopontin and dementia. This link is predominately driven by vascular contributions to dementia through the presence of CSVD, specifically through the burden of white matter lesions on MRI. Brain volume, a marker of neurodegeneration, does not seem to influence this relationship. Our study provides further evidence to suggest that underlying white matter disease and CSVD are likely targets of deleterious osteopontin expression in dementia.
The associations of diet quality trajectories with cognitive frailty in community‐dwelling older adults
Authors: Lee Ting‐I , Chen Ling‐Wei , Chiou Jeng‐Min , Chen Ta‐Fu , Chen Jen‐Hau , Chen Yen‐Ching
Published: December 2023

Background

Diet quality is an essential modifiable factor that has been associated with cognitive performance and physical function. However, few studies investigated the association of diet quality trajectories with “cognitive frailty.” This study aimed to identify specific diet quality trajectories and explore their relationship with cognitive frailty in Taiwanese community‐dwelling older adults.

Method

This 11‐year cohort study (2011‐2022) recruited 520 non‐demented older adults at baseline (2011‐2013). The global and domain‐specific cognition was assessed by the Taiwanese version of the Montreal Cognitive Assessment and a battery of neuropsychological tests. Physical frailty was assessed by a modified version of the criteria of Fried et al. The presence of both physical frailty and MCI was defined as cognitive frailty. Diet quality was assessed by the modified Alternative Healthy Eating Index, which includes seven components obtained from a semi‐quantitative food frequency questionnaire. Growth mixture modeling was used to identify diet quality trajectories over 11 years. The generalized linear mixed model was used to explore the association of energy‐adjusted diet quality trajectories with cognitive frailty over time adjusting for important covariates.

Result

This study identified four diet quality trajectories: 1) worsening, 2) low‐moderate‐low, 3) moderate‐low‐moderate, and 4) still low. Compared to trajectory 4, trajectory 3 had lower odds of worsening frailty [adjusted odds ratio (aOR) = 0.48; 95% confidence interval (CI): 0.27, 0.85], worsening cognitive‐frailty (aOR = 0.52; 95% CI: 0.30, 0.92), and impaired logical memory‐frailty (aOR = 0.42‐0.53). In addition, trajectory 1 had lower odds of worsening impaired logical memory‐physical frailty (aOR = 0.53; 95% CI: 0.32, 0.86) compared with trajectory 4. No association was found for trajectory 2.

Conclusion

We found that the moderate‐low‐moderate diet quality trajectory lowers the odds of worsening frailty and cognitive frailty. Further studies on different ethnic groups will help researchers to clarify the temporal relationship between diet quality and cognitive frailty.
Real‐time quaking‐induced conversion assay using a small‐scale substrate production workflow for the diagnosis of Creutzfeldt‐Jakob disease
Authors: Chongsuksantikul Adipa , Thanapornsangsuth Poosanu , Saraya Abhinbhen Wasontiwong , Hiransuthikul Akarin , Hemachudha Thiravat
Published: December 2023

Background

The lack of a dedicated surveillance program for prion disease, particularly in low‐ and middle‐income countries (LMICs), has hindered the global effort to address this public health threat. Although CSF Real‐time quaking‐induced conversion (RT‐QuIC) is considered the most reliable test for sporadic Creutzfeldt‐Jakob disease (sCJD), its availability in LMICs is limited due to its cost and technical difficulty in generating the recombinant prion protein substrate (recPrP). This study aimed to evaluate the performance of RT‐QuIC with recPrP produced in‐house through a small‐scale method – i.e. the application of reusable pre‐packed chromatography columns and subsequent dialysis.

Method

CSF specimens from patients suspected of having prion disease were consecutively collected and stored between October 2015 and November 2022. Those with available CSF for RT‐QuIC analysis were included in this study. Electronic medical record data were reviewed to clinically classified participants as probable sCJD or non‐sCJD. CSF RT‐QuIC was performed using in‐house recPrP and 2nd generation (improved‐QuIC) protocol (Orrú et al., 2015). Its specificity and sensitivity for diagnosing probable sCJD were reported, along with details of other clinical data and investigations.

Result

Among 38 eligible participants, with a median (interquartile range) age of 64 (56.5‐70) years and 15 (39.5%) female, 12 had probable sCJD and the remaining 26 unequivocally suffered from non‐prion disorders. MRI and EEG were suggestive of sCJD in 100% (12/12) and 50% (6/12) of sCJD participants, respectively. PRNP gene sequencing was performed in all sCJD and 7 non‐sCJD participants, all of whom had MM genotype without mutation. RT‐QuIC was positive in 11/12 sCJD participants (sensitivity 0.92, 95% confidence interval (CI) 0.65‐0.99) and negative in all non‐sCJD participants (specificity 1.00, 95%CI 0.87‐1.00). CSF tau/p‐tau ratio showed sensitivity and specificity of 0.67‐1.0 and 0.85‐1.0, respectively.

Conclusion

RT‐QuIC using recPrP generated through a small‐scale workflow demonstrated great performance in detecting sCJD. Given its performance results along with its low cost, this technique could feasibly be implemented in LMICs and potentially be the first step towards establishing local prion disease surveillance programs that will strengthen the global efforts.
Prospective evaluation of plasma phopshorylated tau in real‐life memory clinic in Thailand
Authors: Luechaipanit Watayuth , Thanapornsangsuth Poosanu , Booncharoen Kittithatch , Supharatpariyakorn Thirawat , Sarutikriangkri Yuthachai , Tangnimitchoke Suchart , Likitjaroen Yuttachai , Sukprakun Chanan , Tepmongkol Supatporn , Hemachudha Thiravat
Published: December 2023

Background

Despite the substantial accuracy of plasma phosphorylated tau (p‐tau) in diagnosing Alzheimer’s disease (AD) in research cohorts, data on real‐life memory clinic patients are limited. Additionally, previous biomarker studies have often been geographically restricted, raising concerns about generalizability to underrepresented populations. We prospectively assessed the diagnostic accuracy of plasma p‐tau181 in a memory clinic in Thailand.

Method

Patients at their early symptomatic stages (i.e. no more than mild dementia) who presented with memory impairment were consecutively enrolled between October 2021 and August 2022. They prospectively underwent routine clinical assessment and plasma p‐tau181 quantification (Simoa). Within 10 weeks, amyloid and tau‐positron emission tomography (PET) were performed using [18F]‐Florbetaben and [18F] PI‐2620, respectively. The diagnostic performance of plasma p‐tau181 (using a predefined cut‐off derived from an independent cohort), neurocognitive specialists and regional tau‐PET (Braak stage III‐IV) were compared head‐to‐head using amyloid‐PET as the reference standard.

Result

Among 51 participants enrolled, 36 (70.6%) were female. The median age was 72 years (interquartile range: 64.5‐76.0). Amyloid‐PET was positive in 43 (70.6%) of the participants. Plasma p‐tau181 had an area under the curve (AUC) of 0.84 (95% confidence interval (CI) 0.73‐0.94), sensitivity of 0.80 (95%CI 0.64‐0.90), specificity of 0.75 (95%CI 0.51‐0.90), and accuracy of 0.78 (95%CI 0.65‐0.88) for detecting amyloid‐PET positivity in early symptomatic patients. In comparison, clinical diagnosis by neurocognitive specialists had an AUC of 0.70 (95%CI 0.56‐0.85), sensitivity of 0.65 (95%CI 0.49‐0.79), specificity of 0.75 (95%CI 0.51‐0.90), and accuracy of 0.69 (95%CI 0.55‐0.80), whereas tau‐PET had an AUC of 0.88 (95%CI 0.79‐0.97). The AUC of p‐tau181 was not significantly different from clinical diagnosis (p = 0.15) or tau‐PET (p = 0.48), however, tau‐PET significantly outperformed clinical diagnosis (p = 0.03).

Conclusion

The diagnostic performance of plasma p‐tau181 is substantial in the diverse population of a specialized memory clinic. Its discriminative accuracy was comparable to a second‐generation tau‐PET and showed tendency towards superiority to clinical assessment. The findings of our study may serve as a guide for the cost‐effective implementation of plasma p‐tau into real‐life clinical practice.
Genotype Phenotype characterisation, Imaging profile and novel genetic mutations from a large cohort of Frontotemporal Dementia from India
Authors: Ramakrishnan Subasree , Pon Arun Gokul , Bosco Susan , Arshad Faheem , Arunachal Gautham , Kulanthaivelu Karthik , Alladi Suvarna
Published: December 2023

Background

Degenerative dementia like Frontotemporal dementia (FTD) are complex heterogeneous disorders with variable phenotypes, patterns of atrophy and pathogenicity. Advanced genetic studies from India are sparse and earlier techniques mostly reported negative results. Current study aims to evaluate the clinical, radiological and genetic profile of FTD/FTD overlap syndromes, to perform whole exome sequencing and to explore genotype phenotype correlations.

Method

Subjects with dementia fulfilling standard criteria’s for FTD/FTD Overlap and AD were recruited from Dept. of Neurology, NIMHANS, India Demography, pedigree analysis, clinical, cognitive and neuropsychological evaluation and blood sampling for genetic analysis by next generation sequencing and MRI as per ADNI protocol were performed. RT‐PCR was done for analysing c9orf.

Results

133 FTD/FTD overlap were recruited. Mean age at onset was 56 ± 9.8 years in FTD There were 87 men and 75 women. Family history was documented in 43%. 42% had family history in first degree relatives, 11% had history in second degree and 4% in third degree relatives. Mean ACE scores were 43.8± 24.7. Frontotemporal atrophy was noted in 90% in MRI (n = 115). 41% had Grade 1 (mild) global cortical atrophy score .MRI also revealed characteristic features like diffusion restriction, white matter lesions (CSF1R) basal ganglia calcification with bone cysts(TYROBP) and Corpus callosal atrophy(TREM2)

11 novel gene mutations including one each of CSF1R, TREM2, TYROBP, SQSTM1, GRN, MAPT, PSEN2 and four cases of C9orf were detected (Pathogenic in 11 and Variant of unknown significance in 26), out of the 100 samples sequenced and analysed (ACMG guidelines). VUS like GBA, PANK2, PLAG26, PRNP, LRRK2, DCNT etc. were also identified. Sanger validation confirmed the pathogenic mutations. Novel variants of CSF1R, TREM2 and TYROBP, primary microgliopathy as causative genes are being first time described from India. SQSTM1 presented as bvFTD without ALS overlap, GRN as non‐fluent aphasia, MAPT as bvFTD and PSEN2 as non‐fluent PPA and two patients with C9orf presented as bvFTD and two others as FTD‐ALS.

Conclusion

Genotype‐phenotype correlations along with neuroimaging and pedigree analysis has aided in early diagnosis, prognostication and novel and unique genetics causes shedding light on underlying FTD mechanism from our cohort.
Development of the MIITRA QSM template: a high‐resolution magnetic susceptibility template of the older adult brain in the MIITRA atlas space
Authors: Abid Rasheed , Ridwan Abdur Raquib , Wu Yingjuan , Niaz Mohammad Rakeen , Zhang Shengwei , Evia Arnold M , Bennett David A. A , Arfanakis Konstantinos
Published: December 2023

Background

A QSM template of the older‐adult brain is not yet available. This study constructed a high resolution QSM template of the older‐adult brain for the MITRA atlas using data from a large, diverse, community cohort of non‐demented older‐adults.

Method

Magnetic susceptibility maps were generated for the 400 older‐adult paricipants used in the construction of MIITRA using the Morphology Enabled Dipole Inversion(MEDI) on the 3D 5‐echo GRE data(0.7×0.7×1.3mm3) and upsampled to 0.7×0.7×0.65mm3 using nonlocal upsampling. The first GRE echo of each participant were N4 bias field corrected, then upsampled to 0.7×0.7×0.65mm3 using non‐local upsampling and converted to synthetic T1w images using mri_synthsr. The original 3D T1w MPRAGE(1×1×1mm3) data were upsampled to 0.5×0.5×0.5mm3. The synthetic T1w images were linearly registered to the upsampled T1w data and the resulting transformations were used to forward‐map magnetic susceptibility values from the native space of each participant to exact physical locations in MIITRA space. A sparse representation based data‐fusion approach was used on the transformed signals to generate the final 0.5×0.5×0.5mm3 resolution template, denoted as MIITRA_QSM(Fig.1). Since no other magnetic susceptibility template of the older‐adult brain is currently available, we compared MIITRA_QSM to a young adult template named MuSus‐100(1×1×1mm3,100 participants,mean age 24 years) in terms of image quality and magnetic susceptibility properties.

Result

Visual showed that MIITRA_QSM template includes fine details, has the expected QSM contrast, highest values in subcortical, brainstem, and cerebellar structures known for their high magnetic susceptibility(especially in older adults), lower values in the white compared to gray matter, and higher values in white matter of the frontal lobe compared to parietal and occipital lobes. When compared to MuSus‐100, MIITRA_QSM showed better delineation of cortical structures and higher image sharpness(Fig.2), as well as higher magnetic susceptibility values in most subcortical brain structures(Fig.3A), Cortical structures from the two templates exhibited more similar magnetic susceptibility values(Fig.3B).

Conclusion

Magnetic susceptibility values in specific subcortical, brainstem and cerebellar structures are higher in the MIITRA_QSM template compared to a young adult template, probably due to increased metal deposition in these structures with aging. The new template is expected to greatly enhance the accuracy of voxel‐wise and atlas‐based QSM studies on older‐adults.
Lifestyle Modification Exerts Protection Against Obesity‐Induced Neurodegeneration Via CD147‐Related Mechanism
Authors: Chanchalotorn Siwakorn , Pantiya Patcharapong , Thonusin Chanisa , Chunchai Titikorn , Ongnok Benjamin , Arunsak Busarin , Chattipakorn Nipon , Chattipakorn Siriporn C
Published: December 2023

Background

CD147, also known as extracellular matrix metalloproteinase inducer, is a key mediator of inflammatory and immune responses in various kinds of neurodegenerative disease (1). However, the role of CD147 in obesity‐induced neurodegeneration has not been previously investigated. Therefore, this study aims to investigate the alteration of CD147 expression in the hippocampus of obese rats, both with and without lifestyle modification.

Method

Seven‐week‐old male Wistar rats were divided into 4 groups (n = 5 per group), including 1) rats fed with a normal diet for 28 weeks [ND], 2) rats fed with a high‐fat diet (HFD) for 28 weeks [HFD], 3) rats fed with a HFD for 12 weeks followed by 40% caloric restriction for an additional 16 weeks [HFD‐CR], or 4) rats fed with a HFD for 12 weeks followed by exercise plus HFD for an additional 16 weeks [HFD‐EX]. At the end of week 28, cognitive function was determined by a novel object location test. The rats were then euthanized on the following day for molecular studies in the hippocampus.

Result

We found that hippocampal CD147 level exerted a strongly negative correlation with the level of cognitive function (Figure A). In addition, CD147 expression and its downstream consequences – p‐NFκB, MMP‐9, and TNF‐α – were upregulated in HFD‐fed rats (Figure B‐E). The HFD‐fed rats also exhibited an increase in activated microglia (CD68), along with decreased blood‐brain barrier protein (claudin‐5), dendritic spine density, and cognitive performance (Figure F‐I). Strikingly, both caloric restriction and exercise effectively reduced the expression of CD147 and its downstream consequences, as well as restored CD68, claudin‐5, dendritic spine density, and cognitive function in HFD‐fed rats (Figure B‐I).

Conclusion

Our findings suggested that CD147 is one of the detrimental mediators in obesity‐induced neurodegeneration (Figure J). Interestingly, an attenuation of obesity by lifestyle modification exerts protection against cognitive impairment via CD147‐related mechanisms (Figure J). Therefore, an inhibition of CD147 is considered as a therapeutic target to prevent cognitive impairment in obese individuals.

Reference

1. Kaushik DK, Hahn JN, Yong VW. EMMPRIN, an upstream regulator of MMPs, in CNS biology. Matrix Biol. 2015;44‐46:138‐46.
Vagus Nerve Stimulation Provides Neuroprotection Against Doxorubicin‐induced Chemobrain Via Activations of Both Muscarinic and Nicotinic Acetylcholine Receptors
Authors: Siripakkaphant Christsanutth , Ongnok Benjamin , Prathumsap Nanthip , Khuanjing Thawatchai , Chunchai Titikorn , Arunsak Busarin , Pantiya Patcharapong , Chattipakorn Nipon , Chattipakorn Siriporn C
Published: December 2023

Background

Chemotherapy, particularly treatment with doxorubicin (Dox), is known to cause neurotoxicity in the brain known as chemobrain. Dox administration causes neuroinflammation, mitochondrial dysfunction, and subsequent cognitive decline (1). Additionally, cancer survivors who received Dox were found to have an increased risk of developing dementia (2). Interestingly, the activation of the parasympathetic nervous system by vagus nerve stimulation (VNS) exerted neuroprotective effects on Alzheimer’s disease (3). However, the neuroprotective effects of VNS against Dox‐induced chemobrain have never been investigated. Moreover, whether the therapeutic effects of VNS are achieved via stimulation of nicotinic acetylcholine receptors (AChRs) or muscarinic acetylcholine receptors (mAChRs) needs further investigation.

Method

Twenty male Wistar rats were divided into sham‐operated and VNS device‐implanted groups. After 2 weeks of recovery, all sham‐operated rats were divided and received either 0.9% NSS (Control; n = 4) or 3 mg/kg Dox for 6 doses (Sham; n = 4) via intraperitoneal injection. In addition, all VNS device‐implanted rats were treated with 3 mg/kg Dox for 6 doses and then randomly divided into 3 groups to receive either 0.9% NSS (VNS; n = 4), a mAChR antagonist (atropine; 1 mg/kg/day, VNS+Atro; n = 4), or a nAChR antagonist (mecamylamine; 7.5 mg/kg/day, VNS+Mec; n = 4). At the end of treatment protocol, cognitive function was assessed using the novel object location (NOL) task. The brains were obtained for further molecular studies.

Result

Dox treatment impaired cognitive performance in rats, as demonstrated by a decrease in the preference index in the NOL task (Figure A). Microglia in the CA1 region of Dox‐treated rats exhibited decreased process complexity and increased microglial volume, indicating reactivation of microglia (Figure B and C). Notably, Dox administration caused mitochondrial dysfunction in the brain, as evidenced by increased levels of mitochondrial reactive oxygen species (ROS) and mitochondrial membrane depolarization (Figure D and E). Importantly, the intervention with VNS rescued long‐term cognitive function in Dox‐treated rats by ameliorating all chemobrain pathologies (Figure A‐E). In contrast, the therapeutic effects of VNS were completely abolished by blocking either mAChRs or nAChRs using their antagonists (Figure A‐E).

Conclusion

The findings suggested that VNS protected against Dox‐induced chemobrain through activations of both nAChRs and mAChRs.
Plasma Neurofilament Light Chain predicts neuroimaging alterations and functional decline in frontotemporal dementia
Authors: Borrego‐Écija Sergi , Juncà‐Parella Jordi , Ruiz‐García Raquel , Sarto Jordi , Martínez Neus Falgàs , Esteller Diana , Guillén Núria , Fernandez‐Villullas Guadalupe , González Yolanda , Pérez‐Millan Agnès , Tort‐Merino Adrià , Bosch Beatriz , Fort‐Aznar Laura , Antonell Anna , Naranjo Laura , Lladó Albert , Balasa Mircea , Sanchez‐Valle Raquel
Published: December 2023

Background

Plasma Neurofilament light chain (pNfL) is a promising biomarker to discriminate Frontotemporal dementia (FTD) from other diagnoses such as Alzheimer’s disease (AD) or psychiatric disorders. Currently, the diagnostic criteria for FTD syndromes are structured hierarchically into “Possible”, “Probable” and “Definite” levels depending on the degree of confidence set by biomarkers. We aim to study the diagnostic and prognostic values of pNfL in the different confidence levels of FTD diagnosis.

Method

Patients fulfilling criteria for FTD were classified as “Possible”, “Probable” or “Definite” FTD based on the current diagnostic criteria. pNfL levels were determined with SiMoA, and then compared to Control and AD groups, as well as within the different levels of confidence in the FTD diagnosis.

Result

187 subjects were included: 37 controls, 79 AD and 71 FTD (11 Possible, 49 Probable and 11 Definite). The FTD group showed higher concentrations of pNfL than the Control (p < 0.001, AUC: 0.817) and the AD groups (p < 0.001, AUC: 0.677) (Figure 1A and 1B).

Within the FTD group, pNfL levels differed across the different diagnostic confidence levels (Figure 1C). Subjects with Probable and Definite FTD showed higher levels of pNfL than subjects with Possible FTD (p < 0.001 and p < 0.01 respectively). By contrast, the Possible FTD group did not show differences in pNfL concentrations with the control group. In that sense, the diagnostic value of pNfL varied according to the different grades of diagnostic confidence (Figure 1D), with cases with probable or definite FTD exhibiting an excellent AUC to distinguish from controls (AUC 0.860 and 0.908 respectively), but with no discrimination between possible FTD and controls (AUC 0.583).

pNfL presented an excellent performance in the differentiation of structural or functional impairment in the neuroimage (AUC 0.94, and AUC 0.86 respectively) (Figure 2). Finally, higher baseline pNfL levels were associated with worse clinical progression in FTD cases (Figure 3).

Conclusion

pNfL were higher in FTD patients compared to controls or AD patients. However, we found significant variation across the different confidence levels of FTD diagnosis. Finally, pNfL predicted neuroimage alterations and a worse clinical progression in FTD patients.
The Effects of Estrogen on the Risk of Developing Dementia using the UK Biobank Data
Authors: Park Hee Kyung , Marston Louise , Mukadam Naheed
Published: December 2023

Background

The incidence of dementia increases with postmenopausal women, which prompted the investigation of the role of estrogen in the development of dementia. We aimed to investigate the role of estrogen in the UK Biobank.

Method

A total of 273,201 women were included in this study. Comprehensive interviews, medical history, body mass index (BMI), and the apolipoprotein E (APOE) genotype were obtained. Reproductive characteristics, including estrogen length and history of surgery, were used as exposure variables. The Cox Proportional Hazard model was used to estimate hazard ratios (HR) for the development of dementia, adjusting for age, education, the Townsend deprivation score, the APOE genotype, family history of dementia, BMI, smoking status, diabetes mellitus, hypertension, and hyperlipidemia.

Result

The mean estrogen length was 37.25 years (8.03 years). About 19% of women had a history of surgery. Compared to women with the lowest overall exposure to estrogen (Estrogen length ≤33), women with higher levels of cumulative estrogen had a decreased risk of dementia (34≤Estrogen length ≤37, HR = 0.79, 95% CI = 0.72‐0.89, p<0.001; 38≤Estrogen length ≤42, HR = 0.72, 95% CI = 0.65‐0.79, p<0.001; 43≤Estrogen length, HR = 0.77, 95% CI = 0.70‐0.85, p<0.001). Compared to women without a history of surgery, women with a history of surgery had an increased risk of dementia (HR = 1.08, 95%CI = 1.00‐1.17, p = 0.038).

Conclusion

This study found that longer estrogen length had a decreased risk for dementia and a history of surgery had an increased risk for dementia. The results of this study suggested that estrogen might have a protective role in women’s development of dementia. The exact biological mechanism of the protective effects of estrogen in the brain needs to be elucidated in the future.
Association between oral health and cognitive frailty in community‐dwelling older adults
Authors: Chen Jen‐Hau
Published: December 2023

Background

Cognitive frailty indicates the presence of both physical frailty and mild cognitive impairment (MCI) and has been associated with an increased risk of adverse health outcomes (e.g., mortality). Poor oral health has been related to cognitive impairment and physical frailty, respectively. However, the association between oral health and cognitive frailty remains unclear. This study aimed to explore the association between oral health and cognitive frailty in community‐dwelling older adults.

Method

This 10‐year cohort study (2011‐2021) is a part of an ongoing prospective cohort study. At baseline (2011‐2013), 605 non‐demented community‐dwelling older adults (aged 65+) with four biennial follow‐ups. Cognitive frailty was defined as the coexistence of MCI and physical frailty. Extended definitions of cognitive frailty were also assessed and defined as the coexistence of impaired cognitive domains and physical frailty. Oral health variables included tooth defects, dentition, and periodontal status. The generalized linear mixed model was used to explore the longitudinal association between oral health and cognitive frailty, adjusting for age, sex, lifestyle, comorbidity, and so on.

Result

The mean age of the study participants was 72.7 at baseline, and 53.4% were female. We found that tooth defect was associated with worsening of impaired memory‐frailty [adjusted odds ratio (aOR) = 1.13; 95% confidence interval (CI) = 1.03‐1.24] and impaired verbal fluency‐frailty (aOR = 1.07; 95% CI = 1.00‐1.11) over time; Dentition was associated with worsening of impaired executive function‐frailty (aOR = 1.10; 95% CI = 1.02‐1.18) over time; Periodontal status was associated with worsening of impaired memory‐frailty (aOR = 1.07; 95% CI = 1.02‐1.13) and verbal fluency‐frailty (aOR = 1.05; 95% CI = 1.00‐1.11) over time. No significant associations were found for traditional cognitive frailty and impaired attention‐frailty.

Conclusion

Cognitive frailty is associated with oral health after adjusting for covariates. Inspection of oral health is helpful to predict the risk of cognitive impairment at an early stage. Further research on this topic is warranted to validate our findings.
Associations between metabolic syndrome and markers of brain pathologies: the role of sex‐differences
Authors: Marseglia Anna , Cooper Alexandra , Rydén Lina , Kern Silke , Shams Sara , Olof Lindberg , Blennow Kaj , Zetterberg Henrik , Zettergren Anna , Skoog Ingmar , Westman Eric
Published: December 2023

Background

In old age, cardiovascular and metabolic disorders rarely occur in isolation, but rather cluster together, in the so‐called metabolic syndrome (MetS). Although individual MetS components (obesity, hypertension, diabetes, and dyslipidemia) have been linked to dementia, their combined effect on cognition remains poorly explored. We recently showed that MetS was associated with clinically relevant cognitive decrements in otherwise cognitively healthy septuagenarians. However, the mechanistic underpinnings are unknown. This study investigates the association between MetS and markers of neurodegenerative and cerebrovascular pathologies, considering sex‐differences.

Method

Within the Gothenburg H70‐Birth cohort 1944, we included 741 cognitively intact septuagenarians with available brain MRI (n = 286 with cerebrospinal fluid [CSF] samples). MetS was identified according to standard criteria as the presence of at least three conditions: central obesity, raised blood pressure, raised blood glucose, reduced HDL‐cholesterol, or elevated triglycerides. MRI markers of brain pathology included overall (mean cortical thickness) and Alzheimer’s disease (AD; average cortical thickness in signature areas) neurodegeneration as well as cerebrovascular pathology including small vessel disease (SVD) and DTI’s microstructural white‐matter changes. CSF biomarkers included t‐tau, neurofilament light, and neurogranin (overall neurodegeneration), Aβ42 and p‐tau (AD), and CSF/serum albumin ration (blood‐brain barrier integrity). Analyses included linear, quantile, and logistic regression models as well as interaction and stratification by sex.

Result

Overall, 410 participants (53%) had MetS; 196 were women. In multi‐adjusted regressions (by sex, education, heart disease, and APOE‐ɛ4 allele), MetS was associated with increased likelihood of neurodegeneration (OR = 2.0, 95%CI 1.4–2.9) and AD (OR = 1.8, 95%CI 1.4–2.6), high SVD burden (presence of ≥3 SVD compared to none: OR = 2.1, 95%CI 1.1‐4.3), and greater microstructural white‐matter changes. In the CSF sample, MetS was associated with higher CSF/serum albumin ratio. In analyses stratified by sex, men with MetS (reference: no‐MetS) had increased odds of higher SVD burden, particularly of enlarged perivascular spaces (ePVS; OR = 2.9, 95%CI 1.7–5.0). Such differences were not observed between women with and without MetS. No associations were observed between MetS and amyloid and tau biomarkers.

Conclusion

MetS in late‐life increased the likelihood of neurodegenerative and cerebrovascular pathologies. SVD, especially ePVS, appears more prominent in men with MetS than women.
Incidence and risk of dementia in people with Anxiety over 50 years old – an electronic health records study
Authors: Nimmons Danielle , Bazo‐Alvarez Juan Carlos , Petersen Irene , Walters Kate , Schrag Anette
Published: December 2023

Background

Depression is a well‐established risk factor for dementia, but we know far less about the links between Anxiety and future dementia risk in older people. The aim was therefore to investigate the incidence of dementia in people with and without Anxiety above the age of 50 years over a 10‐year period.

Method

The Health Improvement Network (THIN) was used, a large UK primary care dataset, that includes approximately 15.6 million patients, which is representative of the UK population. All people between 1st January 2008 and 31 December 2018 who had new onset Anxiety over the age of 50 years were identified. At the time of the first record of Anxiety, each person was individually matched to 4 unexposed persons based on their sex and age and Exposure Density Sampling was used, creating a dynamic cohort. Weibull survival regression models were fitted and hazard ratios (HR) were estimated for modelling time‐to‐dementia in those with and without Anxiety; and when determining the risk of developing dementia in those with Anxiety. Hazard ratio estimates were adjusted for sociodemographic and lifestyle factors, and relevant physical and mental health conditions.

Result

In this cohort study, there were 37,824 men and 68,761 women diagnosed with a first episode of Anxiety. Of those who had Anxiety, 2,792 people developed dementia during the follow up period, compared to 19,000 people in the non‐Anxiety group. The incidence of dementia in those with and without Anxiety was 7.21 (95% CI 6.94‐7.48) and 3.22 (95% CI 3.18‐3.28) respectively per 1,000 person‐years. The risk of dementia was increased 2.47‐fold [HR 2.47 (CI 2.37‐ 2.57)] in the Anxiety group when compared to the non‐Anxiety group after adjustment for age, sex, social deprivation, alcohol, smoking, BMI, diabetes mellitus, cardiovascular diseases, learning disabilities, HIV, multiple sclerosis, brain injury and hearing impairment.

Conclusion

The incidence of dementia was greater in those with Anxiety and the risk of developing dementia was more than doubled in people with Anxiety compared to those without. This provides further evidence that Anxiety is a potential risk factor for dementia.
Nuclear Shuttling of IGF1R/INSR in Alzheimer’s disease and its corresponding role in regulation of neurodegeneration
Authors: Sengupta Priyanka , Mukhopadhyay Debashis
Published: December 2023

Background

Alzheimer’s disease (AD) has been long associated with ageing and Insulin dysregulation. The receptors and ligands of the Insulin family including Insulin, IGF1, INSR, and IGF1R mainly has been explored over the years. However, their differential distribution in terms of compartmentalization and trafficking requires investigation.

Method

We started this study with SHSY5Y cells and checked for differential distribution in nucleus and cytoplasm in case of AD model. We repeated the study in N2A cells. To understand the nuclear shuttling better, we extended our study in differentiated SHSY5Y (into the Acetylcholinergic lineage) and exploited super resolution microscopy for imaging and trafficking. We fractionated the cellular compartments for biochemical evidence. To ascertain the partners and forms of protein that shuttles, antibody based assays were performed. For validation of this phenomena as of uniform occurrence, mice brain tissues and human primary neurons were utilized for imaging studies.

Result

Ligand independent shuttling into the nucleus occurs in case of AD models in presence of amyloid beta (1‐42). There is a 6.4 fold increase in phosphorylation in cytosolic pIGF1R/INSR in case of AD and a 2.5 fold increase in nuclear fractions. The occurrence correlated with the increase in Cyclin D1 production as suggested by ChIP studies. Upon treatment with Sumoylation inhibitor which blocks IGF1R transit into the nucleus, Cyclin D1 levels lowered validating transcriptional control of Cyclin D1 by IGF1R in AD scenario. Thus cell cycle can be directly influenced through interaction of IGF1R with binding partners LEF and TCF in AD.

Conclusion

Canonical ligand independent shuttling of phosphorylated IGF1R/INSR influences the cell cycle in AD thus triggering cell cycle through a direct control mechanism.
Results of a post‐diagnostic intervention for people with dementia and their family carers
Authors: Prins Marleen , Kroezen Marieke , van der Kuil Milan N.A. , van Belzen Elsemieke , van der Roest Henriëtte G. , Draisma Stasja
Published: December 2023

Background

Support directly after the diagnosis dementia is often experienced as inadequate by people with dementia and their family carers. Often, available support is focused on practical matters and not on the emotional impact of the diagnosis. The innovative intervention SHARE [Support, Health, Activities, Resources, Education] was developed in the USA for dyads (i.e. person with dementia and their family carer) dealing with early‐stage dementia. Its primary goal is to enhance communication between members of the dyad and to prepare them for the future. The intervention has been adjusted and pilot‐tested in the Netherlands, with positive results. The aim of this study was to investigate the impact of the intervention on dyads on a number of primary and secondary outcome measures.

Method

A pre‐post study with three measurements (T0; pre‐ intervention, T1; post‐ intervention, and T2; six months post‐intervention) was conducted. Additionally, a process evaluation took place and qualitative data were collected. Primary outcomes were the quality of life of the person with dementia and self‐efficacy of the family carer. Secondary outcomes were stress, quality of the relationship, confidence in the future, usability and applicability of the intervention and (for family carers only) empathy. Data was collected through structured questionnaire research among 50 dyads, structured interviews with 18 dyads, 19 psychologists and 31 referring professionals, analysis of 55 intervention logs and a group discussion with case managers.

Result

No significant effects were found on the primary and secondary outcomes. However, qualitative results demonstrated the added value of the intervention for dyads, psychologists and referring professionals. Usability, acceptability and applicability of the intervention were all positively assessed.

Conclusion

As no significant effects were found, we theorize that the intervention protects dyads. Usually, with a progressive disease like dementia, scores on the primary and secondary outcome measures decline, as time and hence the disease progresses. Our findings may indicate a protective effect of the intervention, among others on a further decline in quality of life of the person with dementia, and it may help maintain a stable level of self‐efficacy for the family carer.
Development of a cognitive composite for preclinical Alzheimer’s disease (CPAD) in Korean older adults
Authors: Kim Minjae , Yi Dahyun , Byun Min Soo , Ahn Hyejin , Jung Joon Hyung , Kong Nayeong , Jung Gijung , Lee Dong Young ,   KBASE research group
Published: December 2023

Background

As tracking subtle cognitive declines in the preclinical stage of Alzheimer’s disease (AD) is difficult with traditional individual outcome measures, need for cognitive composite for preclinical AD is widely recognized. We aimed to develop culturally appropriate cognitive composite that sensitively identifies subtle cognitive decline of preclinical AD in Korean older adults.

Method

A total 225 cognitively normal elderly individuals, who completed baseline and 2‐year follow‐up evaluation including clinical assessments and comprehensive neuropsychological tests and baseline amyloid positron emission tomography (PET) in the Korean Brain Aging Study for the Early Diagnosis and Prediction of Alzheimer’s Disease (KBASE), were included. Tests of episodic memory, orientation, and executive function were carefully selected through review of previously established composite scores. Three candidate composites including Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) word list recall (WLR), logical memory (LM) II, and Mini‐mental status examination (MMSE) in common, and letter fluency test, category fluency test, or Stroop color and word test, were selected.

Result

Student t‐tests demonstrated that only the composite composed of WLR, LM II, MMSE, and LF (Composite 1) showed a significant difference in score decline over two‐year follow‐up period between Aβ positive and negative group (P = 0.03). Linear mixed model analyses also showed that the Aβ x time interaction effect was significant only for Composite 1 (P = 0.026). In contrast, we did not find any significant results for other two candidate composites (Composite 2 and 3). Based on the results, Composite 1 was chosen as the final CPAD.

Conclusion

CPAD can be used to assess subtle cognitive decline of preclinical AD in clinical research settings, especially in clinical trials with Korean older adults with preclinical AD. It also may be used for monitoring progression or treatment benefits in clinical practices.
NT‐proBNP and changes in cognition and brain structure: the Rotterdam Study
Authors: Xiao Tian , Van der Velpen Isabelle , Niessen Wiro J. , Tilly Martijn J. M , Kavousi Maryam , Ikram M. Arfan , Ikram M. Kamran , Vernooij Meike W
Published: December 2023

Background

To investigate the association between NT‐proBNP and changes in cognition and brain structure.

Method

In the Rotterdam Study, baseline NT‐proBNP was assessed at baseline from 1997 to 2008. Between 1997‐2016, participants without dementia or stroke at baseline (n = 9,566) had repeated cognitive tests (every 3‐6 years) for global cognitive function, executive cognitive function, fine manual dexterity, and memory. Magnetic resonance imaging of the brain was performed repeatedly at re‐examination visits between 2005 and 2015 for 2,607 participants to obtain brain volumes, focal brain lesions, and white matter microstructural integrity as measures of brain structure.

Result

Among 9,566 participants (mean age 65.1±9.8 years), 5,444 (56.9%) were women, and repeated measures of cognition were performed during a median follow‐up time of 5.5 years (range = 1.1‐17.9). For participants with brain imaging data at baseline (mean age 56.8±6.3 years, 55.5% women), repeated scans were completed over a median follow‐up time of 5.6 years (range = 2.8‐8.1). Higher levels of NT‐proBNP were associated with a faster decline of scores in the global cognitive function, the Word‐Fluency test, and the Purdue Pegboard test, but were not related to a steeper deterioration in brain volumes, white matter microstructure, or focal brain lesions.

Conclusion

Higher baseline NT‐proBNP levels were associated with a faster decline in cognition, but not in structural brain changes. Further studies should focus on the causality of the association between NT‐proBNP and cognition.
Conversational AI for Monitoring Behaviour and Well‐being of People Living with Dementia
Authors: Lima Maria R. , Soreq Eyal , Daniels Sarah , Barnaghi Payam , Vaitheswaran Sridhar , Vaidyanathan Ravi
Published: December 2023

Background

Conversational AI offers an intuitive and natural user interface with significant potential to promote the independence, well‐being, and safety of people living with dementia (PLWD) at home. This technology, such as smart speakers and social robots, can be used to access information, set reminders, assist with activities of daily living (ADL), stimulate communication, encourage behaviour, or alert the caregiver. However, voice technology has yet to demonstrate a direct impact on supporting PLWD in daily living contexts, particularly with health and well‐being monitoring utility. Adaptation to individual changing needs and cognitive abilities for personalised support remains a major research challenge. Further studies are required to assess the impact of conversational technology in different cultural and economic contexts.

Method

We investigate conversational social robots that engage with PLWD to query health and well‐being, map household behavioural patterns, and assist with ADL. We analysed in‐home activity data, including regular interactions with Amazon Alexa, from 14 households with PLWD (75‐94 years, four females) over 388 days. We examined the overall usage of conversational technology over time. We further considered activity sequences preceding or following Alexa interactions to trace behavioural patterns.

Result

A significant decrease in conversational technology usage was observed after the novelty phase (i.e., >3 months) across the cohort. We argue this overall decline in user engagement is due to the lack of perceived utility and adaptation of interactions over time. Initial findings from our data mining approach identified behavioural patterns in household activity before and after user‐initiated interactions with Alexa. Additionally, ongoing studies are exploring the feasibility of implementation in both the UK and India with a specific focus on the impact of conversational AI in dementia care and the challenges associated with different cultural settings.

Conclusion

If well incorporated into the living environment, conversational technology can monitor behaviour and well‐being of PLWD. This may be accomplished by proactively verifying issues detected from other sensors in smart environments and alerting caregivers for appropriate intervention. An early focus must be placed on personalising interactions, ensuring accessibility and cultural feasibility.
Characterization of cognitive profile in young patients in Buenos Aires, Argentina: preliminary analysis of 5 years and comparing pre‐pandemic and in‐pandemic period
Authors: Fernandez Maria Cecilia , Berrios Waleska , Golimstok Angel , Segui Milagros , Deppleler Solange ,   Memory and Behavior Research Group of Hospital Italiano of Buenos Aires
Published: December 2023

Background

Cognitive manifestations are an increasingly frequent reason for consultation among young adults ranging from a subjective cognitive complaint (CC), mood or behavioral disorders to attention disorders or other cognitive functions with an impact on their functionality. The objective of this work is to analyze the cognitive profile of patients evaluated during last 5 years, characterize them and compare the results before the COVID‐19 pandemic and after.

Method

742 cognitive evaluations were analyzed from a database of patients between 40 and 60 years old who consulted for CC and were evaluated with a standard neurocognitive battery (SNB) between July 2017 and July 2022. Demographic data, screening test (MMSE or MoCA), Beck Depression Inventory (BDI‐2) and/or Hospital Depression and Anxiety Scale (HAD), Wender Utah Rating Scale (WURS) and final assessment diagnosis including criteria for cognitive disorders and depression according to DSM V were performed. Period from 2017 to 2019 was considered pre‐pandemic COVID‐19 period and period from 2020 to 2022 as pandemic period.

Result

65.6% were female. Pre‐pandemic, 441 patients were evaluated and 296 during pandemic. The average MMSE/MOCA score was: MMSE (328 total): 26.8 and MOCA (402 total): 24.4. Percentage of normal SNB was 17%, of “cognitive deficit”, without conforming deterioration was 36.8%, mild cognitive disorder (mCD) was 43.4%, mayor cognitive disorder (MCD) greater than 2.6%. Of all the patients, depression diagnosis by Beck/ HAD or DSM V was 59.3%. In addition, 25% of the patients had history of TDAH (Attention deficit disorder and hyperactivity) according to WURS. Only 2 patients were evaluated for Intellectual Disability.

Conclusion

In this preliminary work, we detected that a high percentage of young patients with CC present some alteration in their cognitive function and almost 60% meet criteria for depression that could impact in these functions. In addition, 25% of patients had a history of TDAH. No significant difference was found between pre and pandemic. We are expanding the sample to be able to characterize the alterations with more specificity.