bluuebunny/crossref_metadata_2025 huggingface dataset:
Features of internal inconsistency in functional and organic cognitive disorders
Authors: Žunič Nina , Berlot Rok
Published: December 2023

Background

Memory complaints are common in elderly and have various etiologies, including functional cognitive disorder (FCD). Diagnosis of FCD is supported by clinical evidence of incongruity with a neurodegenerative disorder and/or evidence of internal inconsistency ‐ the ability to perform a task well at certain times, but with impaired ability at other times. The prevalence of features suggesting FCD in organic disorders is unclear. We assessed the presence of clinical features of internal inconsistency and other possible discriminators of FCD from organic causes in patients with mild cognitive impairment (MCI) and subjective cognitive impairment (SCI).

Method

Patients attending our tertiary memory clinic in a period of one year with SCI or MCI were included. Exclusion criteria were toxic or metabolic causes of cognitive decline, major psychiatric disorders, co‐morbid neurological conditions that could affect cognition, and uncertainty of diagnosis of organic disorder or FCD. Medical records were reviewed for evidence of internal inconsistency and other suggested discriminators between functional and organic etiology. Demographic, cognitive and clinical data were compared between groups.

Result

We evaluated 39 patients with FCD and 57 with organic disorders. MCI was more common in patients with organic disorders. However, most patients with FCD also had MCI. Patients with FCD were younger and performed better on cognitive assessments, but with significant overlap between groups (Table 1). While patients with FCD more commonly attended the appointment alone and reported greater concern about their symptoms than their supporters, these features were unspecific (Table 2). Patients with FCD reported symptoms that could represent normal experiences and provided detailed descriptions of memory lapses more commonly. While less sensitive, memory perfectionism and symptoms occurring only in specific situations were highly specific for FCD.

Conclusion

Differentiation between functional and organic cognitive disorders based on history and examination can be challenging. Features suggesting internal inconsistency and incongruity with neurodegeneration may also appear in organic causes of SCI and MCI. Their varying specificity and sensitivity for FCD need to be taken into account when considering the diagnosis. Improving the identification of FCD could in turn improve identification of patients with prodromal neurodegeneration.
Systemic inflammation induced by LPS promotes insulin signaling disruption leading to Alzheimer‐like changes in wild type mice
Authors: Domańska Justyna , Więckowska‐Gacek Angelika , Wojda Urszula , Mietelska‐Porowska Anna
Published: December 2023

Background

One of the hypotheses for the ethiology of sporadic Alzheimer’s disease (AD) focuses on systemic inflammation as a driving force of aging. Another known risk factor of AD is obesity and insulin resistance, known to be associated with the activation of pro‐inflammatory cytokines.

The aim of this study was to verify the hypothesis that systemic inflammation induced by lipopolysaccharides (LPS) of Gram‐negative bacteria may disrupt insulin signaling in the brain, leading to the development of neuropathological changes typical of AD. We tested this hypothesis in wild type mice by examining the LPS effect on the initiation and propagation of major neuropathological features of AD, such as amyloid‐β (Aβ) and hyperphosphorylated tau protein (p‐tau) pathologies that start from the entorhinal cortex and progresses to the hippocampus.

Method

3‐months old male C57BL/6J mice were injected with LPS (0.5 mg/kg) for 3 days. Mice were then analyzed at 4, 8, 12 and 16 months of age for brain markers of: insulin resistance (p‐IRS‐1(Ser616)), p‐tau pathology (p‐tau (Thr231)) and amyloid pathology (APP levels) in the entorhinal cortex and hippocampus.

Result

The results revealed an increase in p‐IRS levels from 4 months of age in both brain structures. In the entorhinal cortex an increase in p‐tau levels was observed in 8‐month‐old mice with no change in APP levels. Conversely, in the hippocampus, a decrease in levels of the full form of APP was observed in the 16‐month‐old group, with no change in p‐tau levels.

Conclusion

LPS, as an infectious, pro‐inflammatory agent, leads to the development of AD neuropathology. In the absence of genetic alterations typical of AD, LPS induces insulin resistance in the brain, and then leads to an increase in tau phosphorylation in the entorhinal cortex in the early stage of the disease progression, followed by the amyloidopathy in the hippocampus, with a significant delay.

National Science Centre, Poland: UMO‐2014/15/D/NZ4/04361.
Assessing head muscles measured with MRI as alternative to estimate muscle mass in older persons with dementia
Authors: Borda Miguel Germán , Westman Eric , Baldera Jonathan Patricio , Duque Gustavo , Skoog Ingmar , Aarsland Dag
Published: December 2023

Background

Current evidence suggests an association between sarcopenia and multiple negative outcomes. Traditional methods to diagnose sarcopenia are based on dual‐energy X‐ray absorptiometry (DXA) and whole body magnetic resonance imaging. These tests are complicated, time‐consuming and expensive. We aim to bring a more accessible way to diagnose sarcopenia, making its detection easier in a neurological and dementia setting where brain MRI are regularly ordered. Therefore, we aim to compare the traditional methods of muscle mass and function vs. muscle quantification using the tongue and the masseter muscle in a standard brain MRI to diagnose sarcopenia in clinical settings.

Method

The H70 study, is a longitudinal study of people born in the Gothenburg area of Sweden aged 70 at baseline. We included 791 participants with available clinical data and MRI. DXA and bioimpedance analyses were used as reference measures. Images were analyzed using 3Dslicer.(figure 1) Adjusted speermarRo coefficients were calculated to assess the correlation between the gold standard (DXA) and the muscle mass of the tongue and masseters.

Result

There was a higher prevalence of women (55,7%). When comparing the different tests to assess muscle mass, we found significant and positive coefficient between both tongue and masseter. Total lean tissue mass (DXA) & Tongue volume (Cm3) Rho = 0,375, total lean tissue mass (DXA) & Total masseter volume (Cm3) Rho = 0,326. < 0.001. (table1,2 Figure 2.)

Conclusion

There is a significant positive correlation between total lean tissue mass using DXA and muscle mass calculated with MRI measuring tongue and masseter. Clinical longitudinal Implications of these measurements will be tested in further steps of this research and exposed at the conference.
The role of immunological signaling in disrupted proteostasis in the gut‐brain axis
Authors: Martin‐Peña Alfonso , Lopez‐Scarim Joshua , Gomes Beatriz , Tansey Malu Gámez
Published: December 2023

Background

The pathophysiological mechanism underlying the progressive neurodegenerative process in Alzheimer’s disease (AD) is not well understood. Hence, there is no disease‐modifying treatment. It is then imperative to identify the triggering molecular factors of the disease and the mechanisms supporting molecular spreading of toxic assemblies. Our search for these key clues in the periphery is founded on the fact that peripheral dysfunction, particularly in the gastrointestinal (GI) system, can arise decades before the onset of the classic symptoms in neurodegenerative disorders. In fact, the risk of AD increases significantly in patients with inflammatory bowel disease (IBD) when compared with the non‐IBD population. Furthermore, Tau accumulates in Crohn’s Disease guts and in sigmoid colon of AD and FTD patients. Thus, we are investigating the physiological and molecular mechanisms that support Tau spreading in the prodromal stages, particularly, along the gut‐brain axis.

Method

To test whether corrupted proteins expressed in the gut will spread their pathology to the brain, we employed the Gal4/UAS system and expressed wild‐type or mutant human Tau in selected populations of gut epithelium cells. We then monitor behavior on aging flies expressing Tau in the gut epithelium using Drosophila activity monitors and analyzed their circadian patterns of activity along with several sleep parameters.

Result

We observed that flies selectively expressing full‐length‐2N4R human Tau in enteroendocrine cells of the gut exhibited a significant impairment in their daily activity pattern that specifically affected their behavior during the light phase (day) but not during the dark period (night). Interestingly, these flies also showed an increased sleepiness during the day without affecting their nocturnal sleep pattern.

Conclusion

Our results support the presence of spreading mechanisms for Tau from gut epithelial cells to the brain; hence, affecting the neuronal physiology that sustain daily activity patterns. We are now investigating the pathways and mechanisms that pathological Tau in the gut employs to target these brain regions responsible for the behavioral phenotypes: transsynaptic spreading or humoral signaling via the innate immune system. We are dissecting the 3 major pathways of innate immunity in Drosophila (Imd‐Toll‐TNF) for their role in disease progression and the involvement of their target antimicrobial peptides.
Caspase‐2 Inhibition for Treatment of Alzheimer’s Disease
Authors: Rios Anna M , Chen Claire W. , Jacotot Etienne D , Troy Carol M
Published: December 2023

Background

The enzyme caspase‐2 plays a central role in cellular apoptosis and is involved in the early stages of β‐amyloid 42 and tau deposition, making it a promising therapeutic target for Alzheimer’s Disease (AD). Caspase‐2 is highly expressed in the brains of patients with AD (1, 4) and those with mild cognitive impairment, which often precedes AD. This indicates the upregulation of caspase‐2 early in disease progression, which is not observed in healthy adult brains (1‐3).

Method

New irreversible small peptidomimetics (LJ2a and LJ3a) inhibit human caspase‐2 with a remarkably high inactivation rate. (5) In primary hippocampal neurons treated with β‐amyloid oligomers, submicromolar concentrations of LJ2a and LJ3a prevent synapse loss. Using a tamoxifen‐inducible Cre system for the global removal of caspase‐2, a series of experiments were performed on mice stereotaxically injected with β‐amyloid 42. This model was used to validate caspase‐2 blockade by assessing the cellular specificity of caspase‐2 activation, the induction of downstream targets, and cell death marker expression via immunohistochemistry and western blot.

Result

Replication of these experiments remains underway.

Conclusion

Presentation of current data can inform the rationality for using caspase‐2 inhibitors as a therapeutic treatment.

References:

1. Jean, Y. Y. et al. Caspase‐2 is essential for c‐Jun transcriptional activation and Bim induction in neuron death. Biochem J 455, 15‐25, https://doi.org/10.1042/BJ20130556 (2013).

2. Wang, L., Miura, M., Bergeron, L., Zhu, H. & Yuan, J. Ich‐1, an Ice/ced‐3‐related gene, encodes both positive and negative regulators of programmed cell death. Cell 78, 739‐750 (1994).

3. Kumar, S., Kinoshita, M., Noda, M., Copeland, N. G. & Jenkins, N. A. Induction of apoptosis by the mouse Nedd2 gene, which encodes a protein similar to the product of the Caenorhabditis elegans cell death gene ced‐3 and the mammalian IL‐1 beta‐converting enzyme. Genes & development 8, 1613‐1626 (1994).

4. Liu, P. et al. A soluble truncated tau species related to cognitive dysfunction is elevated in the brain of cognitively impaired human individuals. Sci Rep 10, 3869, https://doi.org/10.1038/s41598‐020‐60777‐x (2020).

5. Bosc, E., Anastasie, J., Soualmia, F. et al. Genuine selective caspase‐2 inhibition with new irreversible small peptidomimetics. Cell Death Dis 13, 959. https://doi.org/10.1038/s41419‐022‐05396‐2 (2022).
Characterization of brain metabolism, volume, and vasculature of the 5xFAD mouse model of Alzheimer’s Disease across lifespan.
Authors: Jullienne Amandine , Szu Jenny , Quan Ryan , Trinh Michelle V , Norouzi Tannoz , Noarbe Brenda P , Silvola Rebecca , Bedwell Amanda A , Eldridge Kierra , Speedy Rachael , Persohn Scott C , Territo Paul R , Obenaus Andre
Published: December 2023

Background

The MODEL‐AD Consortium seeks to develop the next generation of Alzheimer’s Disease models based on human data. A popular model of familial AD is the 5xFAD mouse, characterized by early amyloid‐β deposition and cognitive decrements. Despite numerous studies, the 5xFAD mouse has not been comprehensively phenotyped for vascular and metabolic features over its lifespan.

Method

Male and female 5xFAD and WT littermates underwent in vivo 18F‐FDG‐PET imaging at 4, 6, and 12 months of age to evaluate regional glucose metabolism. A separate cohort of mice (4, 8, 12 months) underwent “vessel painting” that labels all cerebral vessels with a fluorescent dye. “Vessel painted” brains were analyzed for vascular characteristics such as vessel density, junction density, vessel length, network complexity, number of collaterals and vessel diameter.

Results

Our analyses revealed that vessel length, vessel and junction densities increased from 4 to 12 months on the cortical surface in both 5xFAD and WT mice. The number of collateral vessels between the middle cerebral artery (MCA) and the anterior and posterior cerebral arteries decreased with age but their diameters were significantly increased only in 5xFAD mice. MCA average vessel length was decreased in 5xFAD mice compared to WT. Analysis of 18F‐FDG cortical uptake found significant interactions between WT and 5xFAD mice spanning 4‐12 months of age in retrosplenial, somatosensory and visual cortices. Broadly, 5xFAD males had increased 18F‐FDG uptake at 12 months of age compared to WT mice. In most cortical regions, female 5xFAD mice had reduced FDG uptake compared to WT across the lifespan. In males these metabolic increases coincided with decreased vessel characteristics.

Conclusion

The 5xFAD mouse exhibits AD‐like cognitive deficits with age that are associated with increasing amyloid‐β deposition. No significant differences were found in cortical vascular features although males and females exhibited opposite effects in 18F‐FDG uptake. The MCA supplies blood to large portions of the motor cortex and increased vessel lengths and decreased collaterals along with higher metabolic rates in 5xFAD mice may be related to increasing behavioral deficits via metabolic insufficiency or other mechanisms.
The virtual adaptation of Innovations in Dementia Empowerment and Action – IDEA
Authors: Hoy‐Ellis Charles Pitre , Fredriksen‐Goldsen Karen I , Jones Brittany R , Kim Hyun‐Jun , Teri Linda , La Fazia David M. , McKenzie Glenise , Petros Ryan , Institute The Goldsen
Published: December 2023

Background

In contrast to their counterparts in the general population, sexual and gender minority (SGM) older adults and their care partners, have distinct susceptibilities that complicate living with dementia, including significant disparities in comorbid chronic conditions, social isolation, and systemic marginalization, such as discrimination and limited access to health services and supports. We developed a culturally responsive, psychosocial behavioral intervention for SGM older adults living with dementia and their care partners, the first‐ever randomized controlled clinical trial (RCT), Innovations in Dementia Empowerment and Action (IDEA). Initially designed to be delivered (and initially delivered) in‐person and in‐home, challenges associated with COVID‐19 (e.g., quarantining, socially isolating) also provided a unique opportunity to adapt and recalibrate IDEA to be fully delivered via virtual technologies.

Method

We were guided by principles of accessibility, quality, ease of delivery, and sustainability to ensure rigor during the adaptation process. Implementation needs included identifying a HIPPA‐compliant online virtual platform that was easy to use; adapting elements and materials in the intervention manual as needed; providing training for intervention coaches in best practices for virtual delivery; and training participants in the use of virtual technologies.

Result

Preliminary findings suggest intervention coaches and most participants deemed the adapted intervention and virtual delivery to be acceptable. of IDEA. Only two of 22 dyads expressed discomfort with the virtual delivery to the degree they chose not to participate. Regarding difficulty in delivering the intervention virtually, 87% of coaches indicated that it was not at all or only a little difficult;12% somewhat difficult; and only 1% difficult. Virtual delivery also allowed us to expand beyond our initial 3‐site catchment area to 28 states, which also greatly increased access for rural and isolated SGM.

Conclusion

Delivering the adapted IDEA intervention virtually provided preliminary, potentially beneficial evidence to advance dementia interventions to address the growing, diverse population of people living with dementia and their care partners. Further systematic research is required to fully evaluate the benefits and limitations of virtual dementia interventions, including whether specific subgroups are better served by differing delivery modalities.
Cognitive activity, cognitive function, and neurological blood biomarkers
Authors: Krueger Kristin R , Desai Pankaja , Beck Todd , Wilson Robert S. , Evans Denis A , Rajan Kumar B
Published: December 2023

Background

More frequent engagement in cognitive activity is associated with better cognitive function in older adults, but the mechanism of action is not fully understood. Debate remains whether increased cognitive activity provides a meaningful benefit for cognitive health or if decreased cognitive activity represents a prodrome of cognitive impairment. Neurological biomarkers provide a novel way to examine this relationship in the context of cognitive aging.

Methods

We examined the association of cognitive activity, cognitive function, and concentrations of three biomarkers in community‐dwelling participants of a longitudinal, population‐based study. Cognitive activity was measured at baseline by asking participants to rate the frequency of 7 activities: 1) Viewing television, 2) Listening to the radio, 3) Visiting a museum, 4) Playing games, such as cards, checkers, crosswords, or other puzzles or games, 5) Reading books, 6) Reading magazines, and 7) Reading newspapers. Cognitive function was measured with a battery of four tests (Mini‐Mental State Examination, Digit Symbol Test, and the immediate and delayed recall of the East Boston Test) averaged into a composite score. At baseline, we evaluated the concentration of total tau (tau), neurofilament light (NfL), and glial fibrillary acidic protein (GFAP).

Results

The study sample comprised 1,168 older participants, primarily non‐Hispanic Blacks (60%) and women (63%). At baseline, they were an average of 77 years old with 12.6 years of education. Mixed‐effects models showed that cognitive activity was associated with better cognitive functioning at baseline and over time. These relationships remained after each biomarker was added to the model. Over an average of 6.4 years of follow‐up, cognitive activity was associated with cognitive decline in the model with tau (estimate = 0.0123; p‐value = 0.03) and was mildly attenuated in the models with NfL, (estimate = 0.0110; p‐value = 0.06), and GFAP (estimate = 0.0111; p‐value = 0.06). Biomarkers did not modify the association between cognitive activity and cognitive function over time.

Conclusion

The benefits of cognitive activity on cognition appear to be independent of biomarkers: tau, NfL, and GFAP. More frequent cognitive activity may benefit the cognitive health of older adults with a wide range of potential disease risk and presentations.
Dysregulation of Alzheimer’s disease‐related gene expression in brain tissue of patients with major depression
Authors: Aleksynas Robertas , Mota Bibiana Castagna , Callado Luis F , Sastre Magdalena
Published: December 2023

Background

Major depressive disorder (MDD) is linked with a 2‐fold higher risk of developing Alzheimer’s disease (AD), yet the mechanisms behind this association are unclear and are confounded by psychotropic drug use. We, therefore, aimed to investigate AD‐related transcriptional changes in post‐mortem MDD brains without symptoms of dementia and their matched controls, taking into consideration psychotropic medication‐use history.

Method

NanoString Technologies nCounter® analysis using their Alzheimer’s Disease Panel (770 genes) was performed on mRNA extracts from post‐mortem prefrontal cortex tissue of suicide victims with ante‐mortem MDD diagnoses, including 6 drug‐free cases and 6 with a previous history of psychotropic medication use whose serological screening included antidepressants, antipsychotics, benzodiazepines. The results were compared with 12 age and sex matched non‐neurological controls. The data was analysed using nSolver advanced analysis software and built‐in statistical analyses.

Result

When comparing total MDD cases vs. healthy controls, genes involved in lipid metabolism and myelination (e.g., CDK18, 1.9‐fold; ABCA2, 1.91) and cytokines (CSF1, 1.93; LIFR, 1.26) were found upregulated in MDD, whereas the most downregulated genes included neurotransmitter synthesis and storage (RAB3A, 0.79), neurotransmitter release (CAMK4, 0.741) and vesicle trafficking (NPTX2, 0.519). In a comparison of MDD drug‐free group vs. MDD with drug use group, patients with drug use displayed upregulations of genes related to lipid metabolism and myelination (NKX6‐2, 4.5) autophagy (ABCA2, 3.32) and cytokines (CSF1, 2.53; LIFR 1.34), whereas drug‐free patients showed higher expression of neurotransmitter release (GRIA3, 0.742), transcription‐splicing (DDX42, 0.807) and trophic factor (NTRK2, 0.732) genes. TSPO, a gene related to microglial activation, was the most significantly upregulated gene (3.23‐fold) in MDD patients taking psychotropic medications.

Conclusion

The study provides evidence that alterations in pathways involving neuroinflammation, metabolism and neurotransmission in the brains of MDD patients might provide the link with AD and highlights the need to investigate the role of psychotropic medications in modulating AD‐related pathways.
Multi‐cohort cerebrospinal fluid proteomics identifies robust molecular signatures for asymptomatic and symptomatic Alzheimer’s disease
Authors: Ali Muhammad , Timsina Jigyasha , Wang Lihua , Do Anh , Western Daniel , Sung Yun Ju , Cruchaga Carlos
Published: December 2023

Background

Alzheimer’s disease (AD), the most common form of dementia, is characterized by the accumulation of Amyloid‐β (Aβ42) and hyperphosphorylated Tau 181 (p‐tau181) proteins in the brain. Changes in these proteins in AD brains and cerebrospinal fluid (CSF) are detected years before AD symptoms. Studying AD proteome in CSF can reflect its diverse underlying pathophysiology and pave the way for reliable diagnostic and therapeutic advancements.

Method

We present one of the largest CSF AD proteomic profiles (7,029 protein analytes) in CSF of 3,065 individuals in three stages. Discovery was performed in 836 samples from the Knight ADRC and 618 samples from the FACE cohorts using the ATN framework (AT‐ = 680 and AT+ = 490). The identified proteins were tested in 832 individuals (AT‐ = 235 and AT+ = 358) from the ADNI and Barcelona‐1 cohorts. The proteins that passed multiple Bonferroni corrections on the meta‐analysis were utilized for AD prediction models and pathway enrichment analysis to gain mechanistic insights into AD pathophysiology.

Result

In discovery, we identified 3,565 proteins to be significantly (FDR < 0.05) altered. Of these, 2,543 passed FDR in replication with a consistent direction. In the meta‐analysis, we identified 2,233 proteins to be significantly (P‐Bonferroni < 0.05) altered in the AD CSF proteome. Some of the highly significant proteins included YWHAG (P‐Bonf < 4.5×10−219), SMOC1 (P‐Bonf < 5.8×10−208), NRGN (P‐Bonf < 3.2×10−119), and NEFL (P‐Bonf < 1.8×10−37). By using lasso, we identified a set of 39 proteins with high predictive power (Discovery AUC = 1.0; Replication AUC = 0.99) representing a robust and precise AD diagnostic biomarker. Enrichment analysis highlighted several neurological disorders (e.g. AD, tauopathy, and synucleinopathy) and neuronal functions (neuron projection morphogenesis, synapse assembly and organization, and neuron differentiation) as significantly enriched in the altered AD CSF proteome.

Conclusion

Our findings show the promising potential of AD CSF proteomics as a reliable and robust AD prediction model. We identified proteins and biological pathways that are compromised in AD, thereby, increasing our understanding of AD biology. Our findings may accelerate the development of effective intervention therapies that target the earliest molecular triggers of AD.
App‐based augmented reality to assess cognitive impairment in early Alzheimer’s disease
Authors: Brem Anna‐Katharine , Muurling Marijn , de Boer Casper , Curcic Jelena , Atreya Alankar , Coello Neva , Conde Pauline , Fröhlich Holger , Grammatikopoulou Margarita , Hinds Chris , Lazarou Ioulietta , Lentzen Manuel , Harms Robbert , Bügler Maximilian , Narayan Vaibhav A , Kozak Rouba , Nikolopoulos Spiros , Vairavan Srinivasan , Visser Pieter Jelle , Wittenberg Gayle , Aarsland Dag ,   RADAR‐AD Consortium
Published: December 2023

Background

Augmented reality apps merge real world with virtual experiences and can be used to remotely assess complex instrumental activities of daily living (iADL) that are affected early in Alzheimer’s disease (AD). Our aim was to compare standard clinical measures with an augmented reality app to assess iADL that are related to memory and spatial navigation in early AD and its feasibility in the home‐setting.

Method

We administered an augmented reality app (Altoida Inc., Washington DC, USA) in an on‐going cross‐sectional study (RADAR‐AD: Remote Assessment of Disease and Relapse – Alzheimer’s Disease) in three groups: 1) amyloid negative healthy controls (HC, N = 49); and amyloid positive 2) preclinical AD (PreAD, N = 17); and 3) prodromal AD (ProAD, N = 29) (Table 1). Altoida’s research algorithm DNS‐MCI (Digital Neuro Signature) produces the outcome of a machine learning model trained to identify cognitively normal individuals from those with cognitive impairment). DNS‐MCI reflects performance in app‐based tasks assessing memory and visuo‐spatial function (placing and finding virtual objects, fire drill simulation) further including attention and motor performance (reaction time, finger tapping, navigational trajectory). At baseline, app‐based tasks were performed in the clinic together with a standard neuropsychological assessment and iADL questionnaires (Figure 1). Participants were furthermore given the option of using Altoida in the home environment.

Result

The DNS‐MCI score could significantly distinguish HC and PreAD participants from the ProAD group and was correlated with all neuropsychological tests and iADL questionnaires (Figures 1 and 2). Participants used the app on average 3‐4 times at home (Table 1). Baseline in‐clinic assessments were strongly correlated with at‐home assessments (r = 0.53, p<.001).

Conclusion

App‐based augmented reality tasks are applicable in the home setting and successful in capturing cognitive impairment in early AD. Future research should focus on fine graining algorithms to also detect possible subtle impairment in preAD.

This work has received support from the EU/EFPIA Innovative Medicines Initiative Joint Undertaking (grant No 806999). www.imi.europa.eu. This communication reflects the views of the RADAR‐AD consortium and neither IMI nor the European Union and EFPIA are liable for any use that may be made of the information contained herein.
Pharmacological treatment and use of monoclonal antibodies in Alzheimer’s disease: Analysis on a medical management in Argentina
Authors: Guillen Jonathan Cubas , Rojas Galeno , Demey Ignacio , Sarasola Diego , del Hierro Xavier Merchan , Persi Gabriel Gustavo , Aldinio Victoria , de Silva Nahuel Pereira , Boccazzi Julian Fernandez , Seguí Josefina , Muniagurria Santiago , Gilbert Afra , Gatto Emilia
Published: December 2023

Background

Alzheimer’s disease (AD) is the most common cause of cognitive impairment and dementia. The objective of this work is to describe the pharmacological management of AD and the opinion on future pharmacological therapies in Argentina.

Method

A cross‐sectional, descriptive study was carried out. An opinion anonymous survey about pharmacological treatments was designed. The survey was distributed electronically by the Argentine Neurology Society (ANS) to physicians who assessment patients with cognitive disorders (CD). Answers of specialists in CD (SCD) and non‐specialists in CD (NSCD) about recommended treatments (RT), non‐recommended treatments (NRT) and off‐label therapies were analyzed. Physicians who would indicate or were hesitant to indicate anti‐monoclonal beta amyloid protein antibodies (MABs) therapy were considered as potential MABs prescribers. A descriptive statistical and frequency assessment were performed.

Result

155 physicians (10,3% of the total to whom the questionnaire was directed) were surveyed. A 19,35% indicated at least one NRT for dementia and 78,06% prescribed at least one off‐label therapy or a NRT for mild cognitive impairment (MCI). A 31% would indicate MABs. For the management of psychotic symptoms, the most selected drug was quetiapine (88.4%) and for apathy, escitalopram (32,3%). One hundred physicians (64,5% of the total) were considered potential MABs indicators. Nevertheless, 42% of them were unaware of the adverse effects of MABs. Also, 70% would request biomarkers for brain beta amyloid in the initial assessment. There were significant differences in the responses of the SCD and the NSCD regarding indicating MABs (52.17% vs. 23.08, p<0.05) and considering knowledge of its adverse effects (76.09% vs. 38.46%, p<0.05). There were no significant differences between SCD and NSCD in the prescription for RT, NRT, and off‐label therapies.

Conclusion

In the real life, our study shows that two‐thirds of the respondents would be potential MABs prescribers. At the same time, we identified a high rate of NRTs and off‐label medications indications for patients with CD. These results highlight the need for continuous medical education, particularly in low‐income countries such as Argentina considering the cost of biomarkers and the new therapies like MABs for AD and its impact on public health policies.
Trends in the first‐time hospitalisation with dementia: national registry‐based study between 1999 and 2015 from the Czech Republic
Authors: Kučera Matěj
Published: December 2023

Background

The number of people living with dementia in Czechia reached 156 thousand in 2015 with dementia in the Czech Republic with the burden of 44.7 billion Czech koruna. According to estimates, prevalence of dementia is supposed to reach 250 thousand by year 2050, but little is known about current trends of dementia incidence. In our study we aimed to identify trends in age‐ and sex‐specific incidence of first‐time hospitalisation with dementia in the Czechia between years 1999 and 2015.

Method

Data from two national registers in the Czech Republic were used: National Register of Hospitalized Patients and Register of Deaths. Complementary data about population structure per age and calendar year from the Czech Statistical Office for recalculation of the total sample were used. Descriptive analysis was performed to obtain crude and age standardized incidence rates of first‐time hospitalization due to dementia diagnosis. Poisson regression was performed in order to adjust for the calendar year and overall changes in hospitalisation over the study period. In secondary analysis we followed with age stratified crude and sex adjusted models that have been used to estimate the hazard ratio whether a person would receive a hospital diagnosis of dementia per 1 calendar year increase.

Result

The sample consisted of 3 324 399 people (65‐99 years, 57% women). The total amount of first‐time hospitalisations with dementia 164 741. Since 1999 the annual number of new cases increased from 5 433 in 1999 to 14 125 in 2015. The total age‐standardised incidence trends increased statistically significantly over time from 41,80/10 000 in 1999 to 71,30/10 000 in 2015, with a trend of stabilisation in the last three years of the study period. Gender differences have been observed with women having higher incidence rates. Most prominent changes were observed in the oldest 90‐99 age strata.

Conclusion

Our results provide evidence that number of new patients diagnosed with dementia may be currently stabilising and this trend may continue in future.
bioactive sulfonyl hydrazones with indole scaffold, characterization, adme properties, molecular docking studies and investigation of inhibition on choline esterase enzymes for the diagnosis of Alzheimer’s disease
Authors: Angelova Violina T
Published: December 2023

Background

Alzheimer’s disease (AD) is a progressive and neurodegenerative disease that is primarily seen in the elderly population and is clinically characterized by memory and cognitive impairment. This study aimed to find new ChE inhibitors.

Method

The structures of the synthesized compounds were characterized by 1H NMR, 13C NMR and HRMS. The effects of the synthesized hydrazones on acetylcholinesterase and butyrylcholinesterase enzymes were measured using the microplate assay described in the Ellman test, with modifications added by López (2002).

Result

According to the results, all the synthesized compounds inhibited AChE and BChE enzymes. When the IC50 values were compared, the compounds with indole scaffold and donepezil fragment showed potent inhibitory activity on the AChE enzyme. In addition, the predictive properties of all compounds in terms of drug similarity were scanned using five Lipinski rules and ADME. Also, to evaluate the binding interactions between the hydrazone compounds and enzymes, molecular docking studies were performed and the compounds with the best inhibition effect were tested. Promisingly, the compound 3d showed good permeability in the PAMPA‐BBB model and high in vitro antioxidant activity.

Conclusion

Both in vitro and in silico results showed that two compounds could act as promising inhibitors of AChE and the data provided the way to guide future studies.

Funding

This research was funded by the Bulgarian National Science Fund (Grant KP‐06‐Н63/11 14.12.2022).
Cerebellum Hyperactivity and its cortical connectivity in Alzheimer’s Disease (AD) utilizing FDG PET and Resting State Functional Magnetic Resonance.
Authors: Karunanayaka Prasanna , Ahmed Biyar , Elyan Rommy , Kalra Deepak , Eslinger Paul , Yang Qing
Published: December 2023

Background

The role of the cerebellum in Alzheimer’s disease (AD) is not fully understood. There are a few studies that have demonstrated impaired cortical – cerebellar connectivity in AD. Additionally, transgenic mouse studies clearly show amyloid‐β (Aβ) deposition in the cerebellum affecting synaptic transmission and plasticity, sometimes before plaque formation. To characterize metabolic activity in the cerebellum, we analyzed 18F‐fluorodeoxyglucose (FDG) positron emission tomography (PET) and resting‐state functional MRI (rs‐fMRI) data in AD, mild‐cognitive impaired (MCI), and age‐matched cognitively normal (CN) subjects from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Our focus was on the intrinsic functional connectivity of the cerebellum with three brain networks: the default mode network (DMN), dorsal attention network (DAN), and the primary olfactory cortex (POC) in the medial temporal lobe. We hypothesized that the resting state functional connectivity of cerebellar regions (that showed differential FDG metabolic activity) would exhibit impaired brain‐wide network connectivity.

Method

A group of 272 ADNI subjects (CN = 80, MCI = 149, AD = 43) with FDG‐PET scans were analyzed in this study. All 272 subjects did not have consistent rs‐fMRI data therefore, we analyzed 160 subjects (CN = 80, MCI = 84, AD = 29) that had consistent rs‐fMRI data acquisition parameters. The PET preprocessing was performed in SPM12. Partial volume correction was performed using the Van‐Cittert deconvolution technique. The rs‐fMRI data was preprocessed in DPABI; PET and rs‐fMRI data were normalized to the Montreal Neurological Institute template. DMN and DAN masks were downloaded from neurovault.org. The Statistical analyses were performed in DPABI.

Result

The SPM group analysis of PET data identified crus II, right cerebellum 4,5 and vermis lobule 6 as hyperactive (increased glucose metabolism) in AD and MCI compared to CN (Figure 1). Subsequent analyses identified brain regions within the DMN, DAN, and POC that are correlated with hyperactive cerebellar regions. Similarity analyses detected impaired resting state functional connectivity of hyperactive cerebellar regions with the three brain networks (Figure 2).

Conclusion

The hyper‐metabolism in the cerebellum may reflect disruption of local and brain‐wide network connectivity due to neurodegeneration. Observed hyper‐metabolism may be related to inhibitory dynamics of the cerebellum — providing a hypothetical mechanism to explain the susceptibility of brain networks in AD.
Clinical efficacy of Brain and Body Rehab Training (BBRT) multi‐dimensional cognitive intervention digital therapeutic in patients with mild cognitive impairment: a three‐arm, randomized controlled trial
Authors: Li Yatian , Wu Jingnan , Wang Ziming , Xia Huanhuan
Published: December 2023

Background

Despite lacking effective pharmacological therapeutic to delay the progression of mild cognitive impairment (MCI) to dementia, accumulative evidence showed that multi‐domain intervention including cognitive training, exercise, diet, etc., is an effective approach. With miscellaneous audio and visual stimuli, emerging digital therapeutic can be incorporated into the multi‐domain intervention and enhance the effect of cognitive interventions. This study adopted the Brain and Body Rehab Training (BBRT) multi‐dimensional cognitive intervention system to develop the BBRT‐online digital therapeutic (BBRT‐online, Figure 1) and will verify the efficacy of both BBRT and BBRT‐online on older patients with MCI.

Method

This study is a 2‐year, three‐arm, randomized controlled trial, intended to recruit 438 patients with MCI aged 50‐75, with 6 years of education or more, and no neurological disorders or other serious systemic diseases. The participants will be randomly assigned into the BBRT‐online intervention group (n = 200), BBRT intervention group (n = 38), or control group (n = 200). The control group will receive regular health education as the other two groups. Five BBRT‐online training units a day, 15 minutes at least, will execute remotely in the BBRT‐online group. Participants in the BBRT group will attend face‐to‐face BBRT cognitive training twice a week, 1 hour for each at least. Both intervention groups will receive intervention for 12 months and be followed up until the 24th month to assess the persistence of efficacy (Figure 2).

Result

Primary outcome of this study will be the ACE‐III total score. Secondary outcomes will include 1) neuropsychological scale scores including the MOCA‐B scale, NPI scale, AVLT scale, STT scale, BNT test, and SCS intelligent voice‐based cognitive assessment. 2) Biomarker outcomes: Aβ42, T‐tau, and P‐tau. 3) Neuroimaging outcomes. All participants will meet the research nurse at baseline, and at 6, 12, 18, and 24 months for outcome measurements. This study has been registered in the China Clinical Trials Registry (ChiCTR2200065212).

Conclusion

BBRT and BBRT‐online have been widely commercialized. This study will systematically evaluate the clinical effectiveness of both BBRT and BBRT‐online for Chinese MCI patients and provide insights into non‐pharmacological intervention mechanisms for improving cognitive function.
Transcranial Magnetic Stimulation based Network Integrity Assessment in Alzheimer’s disease
Authors: Ozdemir Recep , Fried Peter J. , Buss Stephanie S. , Budson Andrew E , Press Daniel Z. , Pascual‐Leone Alvaro , Shafi Mouhsin
Published: December 2023

Background

Alzheimer’s disease (AD) has a relatively well‐characterized pathology of amyloid‐β and tau accumulation. Yet, disease progression from preclinical to clinical stage remains largely unpredictable at the individual level. Growing evidence shows disrupted synaptic signaling in functionally connected brain networks early in the preclinical stage, and suggests impaired network integrity, assessed with functional connectivity measures, as potential markers for disease symptomatology in AD.

Method

Here propose a novel TMS‐induced causal connectivity measure reflecting integrity of multi‐synaptic signaling within the stimulated brain networks. In a preliminary sample of 9 cognitively normal older adults (Healthy Controls: HCs) and 11 patients with amnestic mild cognitive impairment or mild dementia (early AD), we applied 150 single pulses of TMS to inferior parietal lobule (IPL), a distinct brain region within the default mode network (DMN) showing decreased metabolism in early AD and recorded TMS evoked neural responses with simultaneous electroencephalography (TMS‐EEG). We also characterized spontaneous brain activity with resting‐state EEG (rsEEG) measurements. We performed source space spectral power analyses and seed‐based power envelope correlations (PEC) to estimate cortical distribution of relative alpha power and spontaneous IPL connectivity as rsEEG measurements. Network integrity was defined as the ratio of significantly activated vertices to the total number of vertices within the DMN following TMS of IPL.

Result

Although relative alpha power (8‐12 Hz) was slightly lower and seed based connectivity was slightly higher within the IPL node in AD participants, no network specific differences was observed across the cortex for both rsEEG measures. On the other hand, DMN integrity was substantially lower in AD participants with an average ratio of 0.53 (0.79 in HC) indicating that almost half of the vertices within the DMN were not activated by TMS.

Conclusion

Overall, these preliminary analyses suggest that perturbation‐based (TMS‐EEG) measures may reveal neurophysiological signatures of brain network dysfunction that are not observable in spontaneous brain oscillations, and thus may characterize defining features of network failure in preclinical and mild AD.
Battery for the Assessment of Cognitive Reserve (BARC): development and clinical validation for the Portuguese population
Authors: Nogueira Joana , Gerardo Bianca , Santana Isabel , Simões Mário Rodrigues , Freitas Sandra
Published: December 2023

Background

The Cognitive Reserve (CR) is widely accepted as the active ability to cope with brain damage. The lack of a quantitative method for the assessment of CR including all the proxies commonly used for this purpose, highlight the need for a development of an assessment battery. The present study aims to present the final scores of the Battery for the Assessment of Cognitive Reserve (BARC).

Method

The BARC includes: (i) the Questionnaire of Literacy (QL), (ii) the Questionnaire for the Assessment of Cognitive Demand Level of Professional Activities (QANECAP), (iii) the Cognitive Reserve Questionnaire (CRQ), (iv) the Irregular Word Reading Test (TeLPI), and (v) the Wechsler Adult Intelligence Scale ‐ Vocabulary test(WAIS‐III). This new approach combined new questionnaires specifically developed by our team with other tests already validated for the Portuguese population, which also targeted the CR proxies. The BARC was administrated to 260 elderly participants (healthy controls: 200; dementia spectrum: 60). We also applied to respective available close informants.

Result

The last preliminary psychometric results of the new questionnaires evidenced the reliable and valid use in the Portuguese population. The validation of the QL and QANECAP allow the pursuit of analysis to establish the final score of the BARC, considering the individual weighting of each test/questionnaire.

Conclusion

We developed a new battery to assess quantitatively the CR, which combined the several CR proxies in one single score. The BARC can be used in both clinical and research contexts.
Present and past hypertension in ADNI3 individuals with sub‐threshold total Hachinski ischemic score reflect greater hyperintensity burden irrespective of cognitive status
Authors: Pedersen Taylor J , Flores Jaqueline A , Sudhakar Tejaswi D , Anderson Cole E , Peskind Elaine R , Li Ge , Iliff Jeffrey J , Rane Swati ,   Alzheimer’s Disease Neuroimaging Initiative
Published: December 2023

Background

The Hachinski ischemic score (HIS) scale is used to exclude as much as possible, individuals with dominant cerebrovascular pathology from those with dominant AD pathology. White matter hyperintensities (WMH) are the gold‐standard for evaluating cerebrovascular pathology and linked to worsening cognitive impairment. HIS ≤ 4 are used to minimize non‐AD pathology in ADNI participants. Here we sought to understand whether HIS scores for hypertension (HMHYPERT) in ADNI3 were associated with greater WMH burden (and hence cerebrovascular pathology) even within individuals with HIS ≤ 4.

Method

We compared HMHYPERT scores between individuals with normal cognition (CN) and with mild cognitive impairment (MCI), and participants and correlated with percent WMH burden. A total of 263 subjects screened for ADNI3 (92 MCI [38 F], age = 73 ± 6; 146 CN [94 F], age = 74 ± 7) who had HIS scores and FLAIR MRI acquisitions within a year of each other. 25 All AD participants were excluded. WMH burden was calculated by segmenting them using the Lesion Segmentation Toolbox and normalizing their volume by total intracranial volume. We used the HMHYPERT as a vascular risk factor, excluding those with any focal neurological symptoms. For analysis, we dichotomized participants into those with HMHYPERT = 0 and HMHYPERT>0. To examine whether a non‐zero HMHYPERT score corresponds to greater WMH burden, we examined the prevalence of WMH in between these 2 groups and within the MCI and CN groups.

Result

Although not significant, HMHYPERT scores were higher in MCI. (Fig. 1A, MCI = 0.48±0.50, CN = 0.39±0.49). We found a greater proportion of MCI subjects had HMHYPERT>0 than CN subjects (Fig. 1B, HMHYPERT = 0: CN = 61.0% and MCI = 52.2%; HMHYPERT > 0: CN = 40.0% and MCI = 48.1%). WMH burden was greater in MCI (0.33±0.53) than CN (0.20±0.32) (Fig. 2A). MCI participants with HMHYPERT>0 had the highest WMH burden followed by MCI participants with HMHYPERT = 0, CN with HMHYPERT >0, and CN with HMHYPERT = 0 had the lowest WMH burden. (Fig. 2B).

Conclusion

Cerebrovascular pathology increases significantly with diagnosis, but its severity increases further with findings of hypertension even when total HIS ≤ 4.