bluuebunny/crossref_metadata_2025 huggingface dataset:
Decoding the non‐canonical role of Discoidin Domain Receptor 2 and its plausible interaction with Amyloid beta in Alzheimer’s Disease
Authors: Das Russa , Mukhopadhyay Debashis
Published: December 2023

Background

Receptor tyrosine kinases (RTK) that perform versatile roles in the disease landscape have been extensively studied in proliferative signaling, but their role in degeneration remains quite unexplored. Interestingly several of these RTKs are perturbed in Alzheimer’s Disease (AD), of which Discoidin Domain Receptor 2 (DDR2) is an interesting candidate. DDR2 belongs to a unique set of RTKs that act as sensors of the Extracellular matrix (ECM) and mediate downstream signaling by binding to its ligand collagen.

Method

We investigated the expression and activity of DDR2 in our AD‐like cell model. We also looked for the expression of collagen levels which are well‐established ligands of DDR2. Docking studies were performed between Amyloid beta and DDR2 ectodomain to predict interactions between the two and some important residues were screened which are further being validated by site‐directed mutagenesis. We also performed Immunocytochemistry studies to investigate the localization of DDR2 under disease conditions.

Result

There is a significant upregulation in the DDR2 expression and activity as observed from western blot analysis and qRT PCR. There were no significant changes observed in the mRNA expression level of collagens in the control versus AD scenario. From the Molecular Docking studies between DDR2 and Aβ, we chose the best‐fitted model and screened a few interacting residues in the protein‐protein interface which were validated by site‐directed mutagenesis. Next, from Immunocytochemistry studies, we observed that DDR2 is naturally localized inside the nucleus of neuroblastoma cells and also present in the nucleus in AD‐like scenarios.

Conclusion

Heightened expression and activity of DDR2 in the absence of collagen, possibly in the presence of Aβ, results in its dysregulated trans‐compartmental distribution across the nucleocytoplasmic interfaces to commence AD‐like pathology. This study overall depicts a preliminary picture of DDR2 playing an essential role in AD and sheds light on its non‐canonical mode of signaling triggered by Aβ which needs further experimental validation.
Lifelong cognitive reserve mitigates the genetic risk of APOE and TOMM40 variants for dementia in Chinese older adults: a cohort study
Authors: Liang Xiaoyan , Li Yuanjing , Liu Rui , Ren Yifei , Fa Wenxin , Zhu Min , Liu Keke , Liu Cuicui , Wang Nan , Tian Na , Wang Yongxiang , Cong Lin , Hou Tingting , Du Yifeng , Qiu Chengxuan
Published: December 2023

Background

Evidence has emerged that cognitive reserve (CR) could mitigate the genetic risk of APOE ε4 allele for dementia and Alzheimer’s disease (AD) in Caucasian and Black populations. Whether CR counteracts dementia risk attributable to TOMM40 variants is unknown. We examined whether lifelong CR might modify the risk of dementia and AD from APOE and TOMM40 variants among Chinese older adults.

Method

This population‐based cohort study included 2052 dementia‐free participants from the Shandong Yanggu Study of Aging and Dementia, who were free of dementia at baseline (2014‐2015) and underwent follow‐up examinations in March‐September 2018. APOE (rs429358 and rs7412) and TOMM40 (rs2075650) were defined using multiple polymerase chain reaction amplification. A lifelong composite CR score was generated from six lifespan intellectual factors and then dichotomized into high and low levels according to the median CR score. Dementia and AD were clinically diagnosed following the international criteria. Data were analyzed using Cox proportional‐hazards models. The interaction between CR and APOE or TOMM40 variants was assessed on multiplicative and additive scales.

Result

During an average of 3.72 years (range, 2.98‐4.46) of follow‐up, dementia was diagnosed in 94 persons, including 70 with AD. Overall, carrying APOE e4 allele (vs. non‐carriers) was associated with multivariable‐adjusted hazard ratio of 1.50 (95%CI: 0.91‐2.50) for dementia and 1.71 (0.97‐3.01) for AD; the corresponding figures were 1.76 (1.09‐2.85) and 1.81 (1.04‐3.15) for carrying TOMM40 G allele (vs. AA), and 0.47 (0.27‐0.80) and 0.52 (0.27‐0.996) for high CR, respectively. There was a significant additive interaction of APOE or TOMM40 variants with CR on risks of dementia and AD. Compared to low CR, having high lifelong CR was associated with a lower risk of developing dementia and AD in APOE e4 carriers, with multivariable‐adjusted hazard ratios being 0.17 (95%CI: 0.04‐0.73) and 0.13 (0.02‐1.02); the corresponding figures were 0.23 (0.07‐0.81) and 0.13 (0.02‐1.02) in TOMM40 G carriers, and 0.22(0.06‐0.74) and 0.12(0.02‐0.91) in APOE‐e4 or TOMM40 G carriers, respectively.

Conclusion

Carrying TOMM40 G or APOE e4 allele is associated with increased risks of dementia and AD in Chinese older adults, and the genetic risk could be counteracted by high lifelong CR capacity.
Examining Automatic Generated Language Features of Chinese Spontaneous Speech for Early Detection of Cognitive Decline
Authors: Wang Yi‐Hsuan , Chou Chia‐Ju , Liu Yi‐Chien , Lee Chia‐Ying , Chang Ya‐Ning
Published: December 2023

Background

Connected speech is sensitive on detecting cognitive decline in early Alzheimer disease. In this study, we apply artificial intelligence to develop an automatic assessment for analyzing speech data.

Method

79 samples of picture description speech data were collected. All participants were native Chinese speakers including 31 normal controls (59‐88 yrs) and 49 patients (amnestic mild cognitive impairment and early Alzheimer’s disease) (58‐88 yrs). We extracted 16 linguistic features from the manually transcribed text. These linguistic features were generated by well‐trained linguists or automatically processed by the machine. We also trained decision tree models with those two sets of linguistic features. Seventy percent of the data was used for training and the remainder was used for testing. We also applied a cross‐validation method to avoid overfitting.

Result

Total words, unique words, and content words generated from linguists or machines were highly correlated (about r = 0.99, p < .001). However, the correlations between verb ratio, mean length of sentences, and filler ratio were relatively low (about r = 0.75, p < .001). With manually corrected features, the model could achieve 91.67% accuracy. Among them, the pronoun ratio and MLU (mean length of utterance) appeared to be equally crucial for model prediction. By contrast, with automatically generated features, the model achieved 83.33% accuracy only. MLU and MLS (mean length of sentences) were essential features for prediction.

Conclusion

Automatic assessment could also achieve a good accuracy rate compared to humans (83.33% v.s. 91.67%). Some linguistic features such as fillers or sentences were still highly dependent on the expert’s judgment. Interestingly, MLU was critical in the prediction model of automatic or experts.
The effect of the Home‐based tDCS on behavioral and electrophysiological parameters in patients with both MCI and depression: A randomized double‐blind placebo‐controlled trial
Authors: Kim Do Hoon , Moon Yoo Sun
Published: December 2023

As depressive symptom is considered as a prodrome, a risk factor of progression from mild cognitive impairment (MCI) to dementia, improving depressive symptoms should be considered a clinical priority in transcranial direct current stimulation (tDCS) intervention in patients with MCI. We aimed to comprehensively evaluate the efficacy of the home‐based and remotely monitored tDCS in patients with both MCI and depression, by integrating cognitive, psychological, and electrophysiological indicators. In a 6‐week, randomized, double blind and sham‐controlled study, thirty‐seven community‐dwelling patients were randomly assigned to either an active or a sham stimulation group, and received 30 home‐based session of 2 mA tDCS for 30 min located anode over left and cathode over right dorsolateral prefrontal cortex. We measured depressive symptoms, neurocognitive function, and resting‐state electroencephalography (EEG). Active tDCS was not significantly different from sham tDCS in the effects of both depressive symptoms and cognitive functions. However, compared to sham stimulation, active tDCS decreased and increased the activation of delta and beta frequencies, respectively. Moreover, the increase in beta activity was correlated with the cognitive enhancement only in the active group. It was not possible to reach a definitive conclusion regarding the efficacy of tDCS on depression and cognition in patients with both MCI and depression. Nevertheless, the relationship between the changes of electrophysiology and cognitive performance suggests potential neuroplasticity enhancement implicated in cognitive processes by tDCS.
Efficacy of a mobile based multidomain intervention to improve cognitive functions and health related outcomes among Korean older adults with a high risk of dementia
Authors: Chung Ji Yeon , Lee Jaegyeong , Kim Junhyoung , Park Ayeong , Hong Rak‐Kyeun , Heo Mina , Lim Da‐Hye , Kim Hoowon , Ko Myungjin
Published: December 2023

Background

Subjective cognitive decline is a self‐reported experience of declining cognitive function showing normal performance in cognitive assessments, which is a known risk factor for dementia. Recent studies highlight the importance of nonpharmacological multidomain interventions that can target multiple risk factors of dementia in older adults. We investigated the efficacy of the Silvia program, a mobile‐based multidomain intervention, to improve cognitive function and health‐related outcomes of older adults with a high risk of dementia. Additionally, we compared its effects to a conventional paper‐based multidomain program on various health indicators related to risk factors of dementia.

Method

This prospective randomized controlled trial involved 77 older adults with a high risk of dementia recruited from the Dementia Prevention and Management Center in Gwangju, South Korea during May to October 2022. Participants were randomly assigned to either the mobile‐ or paper‐based group. Interventions were administered for 12 weeks, where pre‐ and post‐assessments were conducted.

Result

The Korean version of the Repeatable Battery for the Assessment of Neuropsychological status (K‐RBANS) total score did not show significant differences between groups. The mobile group showed better improvement in K‐PRMQ scores and PSS scores than the paper group. Differences within groups showed that mobile‐based interventions significantly improved the Korean version of the prospective and retrospective memory questionnaire (K‐PRMQ), State‐Trait Anxiety Inventory‐X‐1 (STAI‐X‐1), Perceived Stress Scale (PSS), and e EuroQoL 5‐Dimension 5‐Level (EQ‐5D‐5L) scores, while paper‐based interventions significantly improved PSS, and EQ‐5D‐5L scores.

Conclusion

The Silvia program was more effective than paper‐based intervention in improving self‐reported memory failures, stress, anxiety, and health‐related quality of life. However, longer periods of administration for more than 12 weeks may be needed to achieve significant improvements in cognitive function by objective measures
Associations between normal cognitive aging and neurodegeneration
Authors: Hemminghyth Mathilde Suhr , Breitve Monica Haraldseid , Rongve Arvid , Chwiszczuk Luiza J. , Fladby Tormod , Kirsebom Bjørn‐Eivind
Published: December 2023

Background

Multiple cognitive domains, including learning, memory and psychomotor speed, show significant reductions with age. These changes are thought to reflect normal cognitive aging. However, since cerebrospinal fluid (CSF) neurodegenerative biomarkers, such as total‐tau (t‐tau) and Neurofilament light chain (NfL), also show age‐related increases in normal aging, we aimed to investigate whether age‐associated cognitive decline may be mediated by age‐associated neurodegenerative changes.

Method

We included 114 cognitively healthy participants aged 40‐80 years from The Norwegian Dementia Disease Initiation Study. All had normal concentrations of CSF Aβ42/40 ratio. Cognitively healthy was defined as demographically adjusted T‐scores ≥35 on standardized cognitive tests. We fitted mediation models using structural equation modelling (SEM), with either CSF NfL or t‐tau as a mediator between age and CERAD learning, CERAD recall, TMT‐A and TMT‐B. All variables were standardized prior to analyses; in addition, both t‐tau and NfL were log transformed due to skewness.

Results

See table 1 for demographic and clinical characteristics. Whilst neither NfL nor t‐tau showed statistically significant mediation of age‐related cognitive decline, our results nevertheless suggest a partial mediation of NfL on age‐related cognitive decline. Here, relationships between age and CERAD learning, CERAD Recall, and TMT‐A performance were weakened whereas higher NfL was associated with worse performance, in particular for delayed memory recall. This was not observed for t‐tau in any models. See figure 1‐2.

Conclusion

Age‐related decline in verbal learning, memory and psychomotor speed may be partially attributable to NfL‐associated neurodegenerative changes in cognitively healthy adults. As NfL reflects axonal degeneration, these results may reflect white matter neurodegeneration in aging.
Entraining brain oscillatory activity at alpha frequencies in dementia with Lewy bodies
Authors: Benussi Alberto , Cantoni Valentina , Rivolta Jasmine , Gadola Yasmine , Zoppi Nicola , Padovani Alessandro , Borroni Barbara
Published: December 2023

Background

Dementia with Lewy bodies (DLB) is characterized by a marked shift of electroencephalographic (EEG) power and dominant rhythm, from the alpha towards the theta frequency range. Transcranial alternate current stimulation (tACS) is a novel non‐invasive brain stimulation technique that allows entrainment of cerebral oscillations at desired frequencies. The objective of the present study was to evaluate safety and efficacy of occipital alpha tACS in DLB patients.

Method

We performed a double‐blind, randomized, sham‐controlled, cross‐over clinical trial in 12 DLB patients. Patients were randomized to receive real (60 minutes of 3 mA peak‐to‐peak stimulation at 12 Hz) or sham stimulation over the occipital cortex (Oz according to the 10‐20 international EEG system). Patients underwent clinical evaluation (clock‐drawing test, trail‐making test part A and B, the quantitative pentagon drawing test subitem), neurophysiological assessment (short‐latency afferent inhibition to evaluate cholinergic circuits) and EEG recordings, at baseline and after real/sham stimulation.

Result

Occipital alpha tACS was safe and well tolerated in all patients. We observed a significant increase in clinical performance scores, in neurophysiological measures of cholinergic transmission and in occipital alpha power spectrum density after real stimulation but not sham stimulation.

Conclusion

Occipital tACS delivered at alpha frequencies may be a novel therapeutic approach in patients with DLB.
Biochemical and molecular heterogeneity of human TDP‐43 proteinopathies in age‐related dementias
Authors: Porta Sílvia
Published: December 2023

The deposition of TAR DNA‐binding protein 43 (TDP‐43), especially phosphorylated TDP‐43 (pTDP‐43), into cytoplasmic and intranuclear inclusions is the pathological hallmark of frontotemporal lobar degeneration (FTLD‐TDP) and amyotrophic lateral sclerosis (ALS). Such TDP‐43 inclusions are also a common comorbid pathology in other neurodegenerative diseases, including Alzheimer’s disease (AD) and Limbic‐predominant Age‐related TDP‐43 Encephalopathy (LATE). The stereotypical distribution of TDP‐43 pathology in FTLD‐TDP/ALS as the disease progresses suggests a hierarchical regional spreading of TDP‐43 aggregates over time. Although the mechanisms underlying progression in these diseases are still unknown, increasing evidence supports a model where misfolded proteins released from a cell harboring pathological inclusions act on recipient cells to form de novo pathology by corrupting normal endogenous proteins to adopt pathological conformations. In vitro studies have shown cell‐to‐cell transmission of TDP‐43 aggregates and axonal transport of TDP‐43 oligomers providing evidence for neuron‐to‐neuron transmission of pathological TDP‐43. We have demonstrated that pathological TDP‐43 extracted from post‐mortem FTLD‐TDP brains, when injected into the brain of doxycycline‐regulatable transgenic mouse models expressing human cytoplasmic TDP‐43 and to a lesser extent in WT mice, led to the formation of de novo TDP‐43 pathology. Interestingly, TDP‐43 pathology progressively spreads throughout the mouse brain in a regional and time‐dependent manner via the neuroanatomic connectome.

The distinctive distribution and morphology of TDP‐43 pathology in cortical areas of FTLD‐TDP cases characterize different FTLD‐TDP subtypes, moreover, their different clinical manifestations suggest that distinct pathological TDP‐43 strains could play a role in such heterogeneity. We have recently shown that brain‐derived pathogenic TDP‐43 seeds from different FTLD‐TDP subtypes correlated with distinct biochemical banding patterns of sarkosyl‐insoluble TDP‐43 protein with distinctive seeding properties in vitro and in vivo. Although our experimental animal model does not fully recapitulate the characteristic neuropathological distribution and spreading patterns of TDP‐43 pathology found in the brains of each of the human FTLD‐TDP subtypes, TDP‐43 pathogenic seeds from different FTLD‐TDP subtypes induce distinct morphological types of TDP‐43 and spreading patterns in mouse brains.

Our experimental data support the hypothesis that distinct TDP‐43 strains may contribute to phenotypic heterogeneity of TDP‐43 pathology through different mechanisms of disease pathogenicity in TDP‐43 age‐related dementias.
Traumatic Brain Injury and Cognitive Aging Among Older Veteran Men – A Twin Study Accounting for Genetics and Medical Conditions
Authors: Chanti‐Ketterl Marianne
Published: December 2023

Background

Traumatic brain injury (TBI) is associated with increased risk of dementia, but whether TBI influences cognitive trajectories in later life is less clear. Identifying those at high‐risk of cognitive decline creates intervention opportunities to delay dementia. Since twins share many genes and environmental factors, we capitalize on the twin‐study design to investigate the association between lifetime TBI and cognitive decline.

Method

Participants (n = 8,662) members of the National Academy of Sciences‐National Research Council’s Twins Registry of World‐War‐II Male Veterans born between 1917‐1927 with self or proxy‐reported history of TBI and from one to four assessments over 12 years using the modified‐Telephone Interview for Cognitive Status (TICS‐m). We used linear random‐effects‐mixed models to examine the association between TBI and TICS‐m in the full sample and among co‐twins discordant for TBI. Additional TBI predictor variables included: number and severity (with/without loss‐of‐consciousness[LOC]) of TBI; and age of first TBI (age <25 vs 25+). Models were adjusted for age (centered‐at‐70‐years), age‐squared, education, wave, twin pairs and for lifestyle behaviors and medical conditions. In a subset, we assessed the impact of APOE on TICS‐m.

Result

History of any TBI, TBI with LOC, and older age of TBI were associated with lower TICS‐m scores at 70‐years (p‐values<0.001). TBI with LOC, more than one TBI, and older age of TBI were associated with faster cognitive decline (p‐values<0.05). Among monozygotic twin pairs discordant for TBI (589 pairs), a history of TBI and having TBI at older age was associated with lower TICS‐m scores (p‐values<0.01); those with more than one TBI and TBI at older age showed greater cognitive decline (p‐values<0.05) compared to their cotwin without TBI. Across all twins, APOE‐e4 carriers with TBI, more than one TBI, TBI with LOC, and older age of TBI had lower TICS‐m scores and greater cognitive decline compared to APOE‐e4 non‐carriers.

Conclusion

These findings support an association between TBI and lower cognitive score and more rapid cognitive decline in later life. The results in the monozygotic pairs, who share all genes and many exposures particularly in early life, provide evidence of a causal relationship between TBI and poorer late life cognitive outcomes.
Diagnosis in an early‐onset dementia clinic in the period 2016‐2021 and impact of COVID‐19 pandemic
Authors: Guillén Núria , Contador José , Tort‐Merino Adrià , García Andrea , Martínez Neus Falgàs , Esteller Diana , Sarto Jordi , Castellví Magdalena , Vilas‐Riotorto Vanessa G , Juncà‐Parella Jordi , Borrego‐Écija Sergi , Bosch‐Capdevila Beatriz , González Yolanda , Fernandez‐Villullas Guadalupe , Antonell Anna , Balasa Mircea , Sanchez‐Valle Raquel , Lladó Albert
Published: December 2023

Background

The diagnosis of early‐onset neurodegenerative dementias (<65 years) can represent a challenge due to their lower frequency respect to late‐onset dementias and atypical forms of presentation. Cognitive impairment has emerged as a frequent complaint after COVID‐19 infection.

Method

We retrospectively reviewed (2016‐2021) the demographic and clinical data of the new referrals at our early onset dementia clinic (Hospital Clínic Barcelona). We used Fisher’s Exact test and ANOVA in Stata/IC 16.1 to analyze differences between patients visited in 2021, 2020 and the period 2016‐2019.

Result

We evaluated 296 patients in 2021, 104 in 2020 and 98 patients/year in 2016‐2019. In 2021, patients had an age at onset (AAO) of 50.1 years, lower than 2020 (53.4) and the period 2016‐2019 (53.0) (p<0.05). The percentage of women in 2021 (69.6%) was higher than 2020 (57.7) and 2016‐2019 (56.0) (p<0.05). Diagnostic delay was lower in 2021 (2.1 years) than 2020 (3.3) and 2016‐2019 (3.0) (p<0.05). No differences were found in Minimental (MMSE) scores (Table 1).

In the period 2016‐2021, the number of neurodegenerative diseases (ND) remained steady, the number of subjective cognitive decline (SCD) decreased and the number of non neurodegenerative causes (NNC) experienced a large increase (Table 1), representing 77.7% of visits in 2021.

We did not find differences in the type of ND diagnosis in each period (Figure 1A). ND subgroups did not show differences in AAO, sex or MMSE. In 2021, NND presented lower AAO, higher percentage of women, lower diagnostic delay (Figure 1B) and higher MMSE scores than previous years. No differences were found in the SCD group.

Cognitive impairment after Covid‐19 accounted for 16.7% of NND in 2020 (n = 8, AAO 50.6 (11.8), 62.5% female, MMSE 26.8(2.3)) and 66.6% of NND in 2021 (n = 153, AAO 49,0 (10.0), 80.1% female, MMSE 27.8 (2.6)).

Conclusion

In 2021 we visited approximately three times more patients than in 2016‐2020, among which we observed an increase in NND, mainly patients with cognitive impairment after Covid‐19. On contrast, we found a similar number of ND diagnosis and reduction in SCD.
Altered Metabolic Connectivity within the Limbic Cortico‐Striato‐Thalamo‐Cortical Circuit in Presymptomatic and Symptomatic Behavioral Variant Frontotemporal Dementia
Authors: Liu Li , Wu Liyong
Published: December 2023

Background

Behavioral variant frontotemporal dementia (bvFTD) is predominantly considered a dysfunction in cortico‐cortical transmission, with limited direct investigation of cortical‐subcortical transmission. Thus, we aimed to characterize the metabolic connectivity between areas of the limbic cortico‐striato‐thalamic‐cortical (CSTC) circuit in presymptomatic and symptomatic bvFTD patients.

Method

Thirty‐three bvFTD patients and 33 unrelated healthy controls were recruited for this study. Additionally, six asymptomatic carriers of the MAPT P301L mutation were compared with 12 non‐carriers who were all from the same family of bvFTD. Each participant underwent neuropsychological assessment, genetic testing, and a hybrid PET/MRI scan. Seed‐based metabolic connectivity based on [18F]‐fluorodeoxyglucose PET between the main components within the limbic CSTC circuit was explored according to the Oxford‐GSK‐Imanova Striatal Connectivity Atlas.

Result

BvFTD patients exhibited reduced metabolic connectivity between the relays in the limbic CSTC circuit, which included the frontal region (ventromedial prefrontal cortex, orbitofrontal cortex, rectus gyrus, and anterior cingulate cortex), the limbic striatum, and thalamus compared to controls. In the bvFTD patients, the involvement of the limbic CSTC circuit was associated with the severity of behavior disruption, as measured by the frontal behavior inventory, the disinhibition subscale, and the apathy subscale. Notably, asymptomatic MAPT carriers had weakened frontostriatal connectivity but enhanced striatothalamus and thalamofrontal connectivity within the limbic CSTC circuit compared with noncarriers.

Conclusion

These findings suggested that aberrant metabolic connectivity within the limbic CSTC circuit is present in symptomatic and even asymptomatic stages of bvFTD. Thus, metabolic connectivity patterns could be used as a potential biomarker to detect the presymptomatic stage and track disease progression.
Montreal Cognitive Assessment MoCA‐XpressO: Validation of a Digital Self‐administered Cognitive Pre‐screening Tool for the General Adult Population
Authors: Klil‐Drori Sivan , Bodenstein Katie C , Kojok Lara , Gruber Johanna , Sun Shuo Mila , Ghantous Youssef , Nasreddine Ziad S
Published: December 2023

Background

The population is aging worldwide, and the prevalence of Alzheimer’s dementia is expected to increase, adding demand for cognitive screening. A brief pre‐screening tool may allow self‐tracking of cognitive function and identify the “worried well” population, whom if pre‐screened will show no objective cognitive impairment, consequently reduce demand for cognitive screening. Therefore, we developed the MoCA‐XpressO, a brief home‐based cognitive pre‐screening tool. The purpose of this tool is to establish if further cognitive testing is necessary.

Method

We conducted a validation study for MoCA‐XpressO compared to MoCA test (version 8.1) as gold standard. Participants were recruited from MoCA clinic and a family practice. Ethics approval was received, and all participants provided informed consent. A crossover study design was applied to the MoCA‐XpressO and standard MoCA test; participants were randomized for the order of administration. Inclusion criteria included age ≥50, fluency in English and/or French, and minimum 6 years of education. Exclusion criteria included MoCA total score<11, and completion of MoCA during recent 3 months. Logistic regression model was built, and the accuracy of the model was evaluated by the sensitivity, specificity, and area under the Receiver Operating Characteristic (ROC) curve.

Result

The MoCA‐XpressO evaluates 3 cognitive domains: processing speed, executive functions, and memory. Preliminary analysis (n = 44) showed a strong association between (1) MoCA Memory Index Score (MIS) and MoCA‐XpressO memory task score (p‐values<.001); (2) MoCA Executive Index Score and MoCA‐XpressO logical task score (p‐values<.03); and (3) total scores of MoCA test and MoCA‐XpressO (p‐values<.005). The ROC curve of the logistic model has an Area Under the Curve (AUC) around 0.85. With a cutoff probability of 0.45, the sensitivity was 89.2% and the specificity was 62.5%; with a cutoff probability of 0.6, the sensitivity was 71.4% and specificity was 87.5%. Full analysis (n≥80) will be available in July 2023.

Conclusion

The high values of AUC (0.85), indicate that MoCA‐XpressO may be strongly predictive of the standard MoCA. This suggests MoCA‐XpressO is a valid home‐based cognitive pre‐screening tool, also allowing self‐tracking of cognition over time. MoCA‐XpressO may differentiate the “worried‐well” from cognitively impaired population, consequently, reduce the high demand for cognitive screening in healthcare systems.
Factors related to Cognitive Impairment in Neuro COVID severe respiratory failure patients´
Authors: Previgliano Ignacio J , Poliszuk Julieta C , Sayat Mauro Castro , Nuñez Myriam , Siroti Catalina , Carabelli Valeria P , Previgliano Martin J , Foster Carolina , Montiel Guillermo
Published: December 2023

Background

Cognitive Impairment (CI) is part of the Post Intensive Care Syndrome. Little is published between it presentation in neuro Covid patients with severe respiratory failure. The aim of this study is to evaluate CI presentation and related factors in a homogeneous cohort admitted to Intensive Care Unit (ICU), Respiratory Intensive Care Unit (RICU) or both.

Method

Prospective, observational study. Patients admitted to Critical Care Units with Neuro COVID symptoms. Demography, severity scores, inflammation markers, length of stay (LOS), delirium, mortality, CI assessed by MoCA and ICU acquired weakness (ICUAW) were recorded and compared between RICU, ICU and RICU/ICU patients. Statistical analysis was performed by means of ANOVA, Student test and Classification And Regression Tree (CART)

Result

From June 01st to August 31st2020, 206 patients were admitted to Critical Care Units. Of them 67 (33%) presented initial neurological symptoms (headache 76%, dizziness 34%, ageusia 30%, anosmia 33%, myalgia 27%, encephalopathy 22%, visual alterations 4%), 35 were admitted to ICU and 32 to RICU, due to severe ARDS (average Pa/FiO2 123), 5 patients were move from RICU to ICU. 35 received invasive mechanical ventilation, 27 noninvasive and 5 both. There were no differences in demography, severity scores (APACHE, SOFA and Pa/FiO2) neither in inflammation markers (D dimer, ferrtin). There were significant differences in all variables: LOS (12, 43, 71 p<0.05), mortality (0%, 34%, 25% p 0.87), GCS (15, 14 p < 0.05) delirium (0%, 88%, 100% p <0.05), CI (0%, 46%, 33% p 0.28) and ICUAW (0%, 53%, 75% p 0.82). By means of Classification And Regression Tree (CART), a predictive model, which explains how an outcome variable’s values can be predicted based on other values, mechanical ventilation, impaired consciousness at admission, delirium and ICUAW were identify as the related variables to CI.

Conclusion

Among patients with neuro COVID symptoms and severe ARDS the need of mechanical ventilation, less GCS on admission, delirium and ICUAW arerelated to CI at discharge.Mechanical ventilated patients have also longer LOS and higher mortality rates. Neither initial neurological symptoms nor ARDS or NIV were related to those variables, and specifically to CI.
Objective measurement of apathy and its differentiation from depression in dementia based on physiological reactivity to stimuli presented in virtual reality environment
Authors: Ravona‐Springer Ramit , Koren Or , Wilf Meytal , Lapid Michal , Plotnik Meir
Published: December 2023

Background

We aimed to develop a tool for objective measurement of apathy and its differentiation from depression in the context of cognitive impairment.

Method

We exposed older adults with and without cognitive impairment (CI and CN, respectively) to emotional (i.e., positive), aversive and neutral, and to cognitive (congruent; incongruent) stimuli in a virtual reality environment and measured their physiological reactivity as reflected by autonomic nervous system (ANS) functions [heart rate (HR), heart rate variability (HRV), respiration and galvanic skin response (GSR)], and gaze [time to gaze fixation (TTGF) and total fixation duration (TFD)]. Apathy and depression were measured via the Lille Apathy Rating Scale (LARS)‐ and the Geriatric Depression Scale (GDS), respectively.

Result

Participants' characteristics are presented in Tables 1‐2. Compared to CN, CI participants had lower TFD (ANOAVE: F = 7.471, P = 0.006) and GSR reactivity (F = 6.334, P = 0.014) in response to all stimuli. Among participants with CI, those with apathy (LARS score ≥‐7) (n = 21) had shorter TFD compared to those without apathy (F = 19.259, P = 0.001), and those with depression (GDS score ≥5) (n = 46) had longer TFD compared to those without depression ((F = 33.118, P = 0.001) to all stimuli. For all participants, presence of apathy was associated with lower TFD (F = 13.807, P = 0.001) higher TTGF (F = 10.819, P = 0.001), lower HRV reactivity (F = 4.089, P = 0.043) and respiration depth reactivity (F = 8.026, P = 0.005) in response to all stimuli. In contrast, depression was associated with higher TFD (F = 8.448, P = 0.004), lower TTGF (F = 5.290, P = 0.022) and higher HRV reactivity (F = 5.171, P = 0.023) to all stimuli. Increasing LARS scores were negatively associated with respiration rate (R = ‐0.223, P = 0.025) and TFD (R = ‐0.253, P = 0.021) in response to positive emotional stimuli, and with TFD in response to congruent (R = ‐0.265, P = 0.016) and incongruent (R = ‐0.247, P = 0.024) cognitive stimuli. GDS scores were positively associated with HR (R = 0.219, P = 0.049; R = 0.217, P = 0.05 respectively) and respiration depth (R = 0.216, P = 0.048; R = 0.252, P = 0.021 respectively) reactivity to positive and aversive emotional stimuli.

Conclusion

ANS and gaze reactivity to emotional and cognitive stimuli presented in a VR environment is sensitive to cognitive status and to apathy, even in subtle forms. Moreover, this tool can potentially differentiate apathy from depression in the context of cognitive impairment.
Plasma oligomeric amyloid‐β levels after spiking synthetic amyloid beta according to age
Authors: Minn Dohsik , Kang Sungmin
Published: December 2023

Background

The multimer detection system‐oligomeric amyloid‐β (MDS‐OAβ) measures OAβ level in plasma after spiking of synthetic amyloid beta into the plasma and has shown in clinical studies that Alzheimer’s disease patients have higher tendency level of amyloid‐β oligomerization. Since Alzheimer’s disease is a neurodegenerative disease, this study was to investigate whether young to old age groups in health check‐up subjects shows different level of OAβ in plasma.

Method

Total of 6,150 subjects were studied; 678 subjects in their between twenties and forties (≤40s, the average age was 42.9±5.4), 1,276 in their fifties (50s, 55.0±2.9), 1,945 in their sixties (60s, 64.3±2.9), 1,520 in their seventies (70s, 74.3±2.9) and 731 in more than 80 years old (≥80s, 83.6±3.4). The multimer detection system assay kit (AlzOn, PeopleBio, Inc., South Korea) was used to quantify the levels of OAβ in the plasma. ANOVA test and t‐test were used to compare results for statistics.

Result

The plasma tendency levels of OAβ in the ≤40s, 50s, 60s, 70s and ≥80s were 0.46±0.31ng/mL, 0.51±0.35ng/mL, 0.52±0.24ng/mL, 0.56±0.30ng/mL and 0.57±0.24ng/mL, respectively. There was no difference between the 50s and 60s, and 70s and ≥80s, but the differences among the others were statistically significant (p<0.001). In particular, plasma OAβ tendency levels gradually increased with age. The women’s average level (n, mean±SD; 3,665, 0.53±0.30 ng/mL) was higher than the men’s (2,485, 0.52±0.28)ng/mL, it was statistically significant (p<0.001). The positive rates of ≤40s, 50s, 60s, 70s and ≥80s were 8.0%, 10.7%, 12.0%, 15.3% and 18.1%, respectively, based on the level (>0.78ng/mL) of the manufacturer.

Conclusion

As age increased, the plasma OAβ tendency levels and positive rates were increased. Therefore, as age increases, the possibility of Alzheimer’s disease increases.
Elucidating the role of the AD risk gene SORL1 in hiPSC‐derived microglial cells
Authors: Young Jessica E.
Published: December 2023

Background

hiPSC models, from which all cell types of the CNS can be generated, have provided key insights into cell‐type specific processes implicated by AD genetics. Endo‐lysosomal network (ELN) trafficking is a biological pathway implicated in AD and the endosomal receptor SORL1 is strongly associated with AD risk, however studies of SORL1 function in glial cells are lacking. Because ELN trafficking is highly related to neuroimmune function, we modeled SORL1 deficiency in hiPSC‐derived microglia and tested whether pharmacologic or genetic rescue with components of retromer improve cellular phenotypes.

Method

We used an established isogenic series of hiPSC lines that harbor deficiencies in SORL1 (SORL1 KO or SORL1 +/‐) or missense variants in SORL1 (SORL1Var) associated with AD. We differentiated microglial‐like cells (hiPSC‐MGLs) and used cellular assays that examined the function of the ELN. In hiPSC‐MGLs we measured phagocytosis, lysosome function, and pro‐inflammatory cytokine release. For rescue experiments, we treated cells with TPT‐260, a pharmacologic chaperone that stabilizes retromer, and lentiviral vectors expressing retromer subunits.

Result

In SORL1 deficient and SORL1 variant hiPSC‐MGLs, we document ELN phenotypes that converge on the lysosome, including lysosomal swelling and impaired degradation. Interestingly, we also document decreased lysosomal exocytosis, a calcium‐regulated process by which immune cells release lysosomal enzymes and undegraded substrates to the extracellular space to aid in cellular homeostasis, immune‐related signaling and tissue remodeling. In SORL1 deficient cells, lysosomal impairments were observed with abnormal neuroimmune function including differential expression and secretion of cytokines, in response to pro‐inflammatory stimuli Our preliminary data suggests that enhancement of retromer function, either genetically or pharmacologically, can improve these phenotypes.

Conclusion

Using an hiPSC‐based model, we show that we can uncover dynamic phenotypes that are linked to AD risk genes. Mutations in SORL1 are now frequently discovered in early‐onset AD patients and the SORL1 locus has a strong genome‐wide signal for late‐onset AD. Together, this suggests that therapeutic strategies targeting the SORL1‐retromer pathway are greatly needed. In this study, we elucidate a role for the SORL1‐retromer pathway in neuroimmune function and provide validation that enhancing this pathway can improve cell‐type specific AD phenotypes in a human model.
The use of constant observation for people with dementia in hospitals: a systematic review
Authors: Handley Melanie , Theodosopoulou Danai , Taylor Nicky , Hadley Rebecca , Goodman Claire , Harwood Rowan H , Phillips Rosemary , Surr Claire
Published: December 2023

Background

Constant observation is a model of care used in hospitals to manage a patient’s safety. For people with dementia this is often due to a risk of falling or from displaying behaviours considered to carry a risk of harm. Person‐centred approaches are recognised as best practice for people with dementia, but this can be difficult to achieve for staff providing constant observation in hospital settings. It is therefore important to understand how person‐centred principles can underpin the use constant observation.

Method

A mixed‐methods systematic review was conducted to understand how and why constant observation is used for people with dementia in hospital, how effectiveness is measured and what enables staff to use a person‐centred approach.

Electronic databases (Medline (PubMed), CINHAL, Psychinfo, and The Cochrane Library) were searched between 2010 – 2022. Screening and data extraction were completed against eligibility criteria, with 20% double screened and extracted for consistency. Narrative synthesis combined qualitative and quantitative findings.

Result

Twenty‐four studies were included, reporting findings from 14 intervention studies and ten studies of constant observation practices. Constant observation for people with dementia was often provided by non‐registered staff without specific training for the role. Assessments and processes for assigning constant observation helped clarify the level of observation required and encouraged regular review that linked initiation and discontinuation to a patient’s changing needs. Examples of person‐centred care were mainly derived from studies of volunteers or staff employed to provide activities. These demonstrated that meaningful engagement could reassure a person and improve their mood. Proactive approaches that anticipated a person’s distress were thought to reduce behaviours that carried a risk of harm but supporting evidence was lacking.

Conclusion

A proactive, person‐centred approach to constant observation is accepted as beneficial for people living with dementia. The reliance on non‐registered staff limited by organisational efforts to reduce risk leads to responses focused on containment. When staff are trained and supported during constant observation, they can connect with patients and provide comfort, potentially reducing behaviours that carry a risk of harm. Aligning patient, staff and organisational priorities will likely improve the inpatient experience of people living with dementia.
Results from multidisciplinary patient‐centered program implemented in a psychogeriatric unit in Brazil
Authors: Buchain Patricia Cardoso , Bassitt Debora Pastore , Alves Tania Correa de Toledo Ferraz , Filho Geraldo Busatto
Published: December 2023

Background

Patient and families/caregivers centered care programs reduce the negative impact of hospitalizations in old age and improve health outcomes. We started an individual‐centered multidisciplinary program that contemplated hospitalization and day‐hospital care at Institute of Psychiatry USP Medical School, Brazil in march 2022 .Our program involves specific goals for inpatients and family members / caregiver’s integrating pharmacology and a multidisciplinary approach.

Method

Our program involves interventions during the hospitalization, day‐hospital and transition to outpatient care. Individual specific needs are assessed at the admission, and an individualized specific plan centered on patient and caregiver is designed and carried on. The therapeutic program provides patients cognitive and functional stimulation and caregivers training in order to adapt to behavior changes and together develop a successful daily routine care at home. The multidisciplinary team involves: medical team, nurse, psychologist, speech therapist, physiotherapist, occupational therapist, nutritionist and social worker. The intervention involves psychoeducation, cognitive and social stimulation/training for patients and/or caregivers/family in groups (60‐90 min), 5‐days a week, twice a day and individual sessions. Assessments include clinical and sociodemographic data, days of hospitalization, clinical global impression, MADRAS, MMSE and KATZ scales.

Result

There were 61 consecutive admissions in the 10 months after the program implementation, main diagnosis at admission were depression and dementia . The mean age was 69,73, gender 40 female, 21 male, average hospital stay was 26,66 (inpatient unit), bed turnover 85,81%. Zero patient was readmitted in a period of 30 days after discharge. Admission mean: CGI 4,98, MADRAS 17,66,MMSSE 16,43 KATZ 3,98 and discharge: CGI 3,47,MADRAS 7,26. MMSSE 19,4.KATZ 4,36 .The reduction in CGI 31,3%, Madras 58,89% and improvement in MMSE 18%, KATZ 9,5%.

Conclusion

Our findings demonstrated confirmed that a patient‐centered program results in improvement in cognition, basic activities of daily life and reduction of depressive symptoms. The present intervention provides consistent recovery of hospitalization. It is an important strategy to improve health quality and recovery for old age psychiatric patients.

Descriptors: psychiatry; aging; multiprofessional intervention
Using retinal neuromodulation to influence both glucose regulation and amyloid buildup
Authors: Zelinsky Deborah
Published: December 2023

Background

Amyloid buildup and glucose dysregulation are two processes attributed to Alzheimer’s Disease progression [1]. Each of these has extensive research regarding their involvement in retinal processing [2, 3]. Amyloid buildup has been measured in retinal and optic nerve locations, linked with circadian and cognitive circuitry. Cognitive changes are shown by thinning in retinal tissue that corresponds with hippocampal volume, and circadian rhythm is disrupted when specific retinal cells involved with sleep are the target of some plaques [4, 5]. The brain and ocular glymphatic systems are also retinal related and implicated in cognitive decline [6, 7].

Method

Optical interventions to selectively stimulate retinal activity can be used to influence retinal neuromodulation.

Result

Retinal stimulation can be used as a way to map the changing brain during neurodegeneration.

Conclusion

The retina is part of the central nervous system and accessible to non‐invasive, external stimulation. Therefore, retinal usage to modulate the glymphatic system and glucose metabolism might change the course of neurodegeneration as both a method for detection and a way to mitigate symptoms.

1. Hammond, T.C. and A.‐l. Lin, Glucose Metabolism is a Better Marker for Predicting Clinical Alzheimer’s Disease than Amyloid or Tau. Journal of cellular immunology, 2022. 4: p. 15 ‐ 18.

2. Wang, L. and X. Mao, Role of Retinal Amyloid‐β in Neurodegenerative Diseases: Overlapping Mechanisms and Emerging Clinical Applications. International Journal of Molecular Sciences, 2021. 22.

3. Tams, A.L.M., et al., Decreased Glucose Metabolism and Glutamine Synthesis in the Retina of a Transgenic Mouse Model of Alzheimer’s Disease. Cell Mol Neurobiol, 2022. 42(1): p. 291‐303.

4. Kim, J.‐I. and B.‐H. Kang, Decreased retinal thickness in patients with Alzheimer’s disease is correlated with disease severity. PLoS ONE, 2019. 14.

5. Lee, S., et al., Amyloid Beta Immunoreactivity in the Retinal Ganglion Cell Layer of the Alzheimer’s Eye. Frontiers in Neuroscience, 2020. 14.

6. Wang, J., et al., Impaired glymphatic drainage underlying obstructive sleep apnea is associated with cognitive dysfunction. J Neurol, 2023.

7. Wostyn, P., The “ocular glymphatic clearance system”: a key missing piece of the Alzheimer’s disease‐glaucoma puzzle found? Eye (Lond), 2021. 35(4): p. 1281.