bluuebunny/crossref_metadata_2025 huggingface dataset:
Anti‐inflammatory biochemical mechanisms of lithium in hippocampal tissue of triple transgenic animals for Alzheimer’s disease
Authors: Wagner Carlos , Couto Caíque de Oliveira Portugal , Forlenza Orestes Vicente , De‐Paula Vanessa V.J.
Published: December 2023

Background

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder of multifactorial etiology. The toxicity of senile plaques and neurofibrillary tangles are associated with structural changes that lead to brain tissue atrophy. Pro‐inflammatory cytokines are present in abnormal amounts and this accelerates the progression of the disease. Our objective is to determine the proteins of the ontological pathways, identified in the proteome, altered in the hippocampus of 3xTg‐AD animals chronically treated with lithium at therapeutic and subtherapeutic doses.

Method

48 (3xTg‐AD;Tg) will be used. The animals received lily for 8 months of treatment and were divided into 3 groups (control, Li 1mM and Li2 mM). The hippocampal tissue was subjected to the proteome. The inflammatory pathways of the identified proteins will be compared by Gene Ontology, using the ClueGO software. Ethics Committee (1876/2022).

Result

The genes of the Toll‐Likes receptor family was analyzed into the STRING bioinformatics program, in order to study the ontological pathways and molecular function. As parameters, we set the significance at 0.7 with the limitation of 50 interactions per gene. Thus, the results demonstrate that the ontological alterations are: immune response‐activating signal transduction, activation of immune response, regulation of defense response, positive regulation of immune response, regulation of response to stress, immune response, positive regulation of response to stimulus and immune system process

Conclusion

The results seem promising for understanding the inflammatory pathways related to toll‐likes. However, the results with the hippocampus tissues are under analysis.
Mitochondrial calcium function is altered by lithium in hippocampal cell culture and triple transgenic for Alzheimer’s disease
Authors: De‐Paula Vanessa V.J. , Forlenza Orestes Vicente
Published: December 2023

Background

Calcium (Ca2+) regulate many functions in neuronal and glial cells. The Mitochondrial Calcium Uniporter (Mcu) complex is thought to be the primary pathway for Ca2+ entry into mitochondria. The Mcu protein has an important role in regulating mitochondrial Ca2+ homeostasis. Dysregulation of mitochondrial Ca2+ homeostasis has been implicated in various pathological conditions, such as Alzheimer disease. AD pathology is characterized by the progressive accumulation of amyloid β‐peptide and neurofibrillary tangles. In AD patients a significant increase in an oxidative damage and decrease in energy metabolism resulting in a mitochondrial calcium disbalance. Lithium has been used for decades to treat neurodegenerative diseases, as it has an action on several intracellular organelles, including mitochondria. The lithium regulates calcium channels, decreases oxidative stress and increases autophagic processes. Therefore, we aim to analyze whether chronic treatment with lithium in primary cultures of hippocampal neurons and in the hippocampus of triple transgenic animals for Alzheimer’s disease (3xtgAD).

Method

The cultures were treated for 7 days (dose of 0.02; 0.2 and 2mM) and 3xtgAD for 8 months (doses of 1mM and 2mM). The hippocampus were analysed by proteomic and transcriptomics.

Result

Our results showed that lithium increases Mcu and Micu 3 proteins, showing that lithium has an effect on the modulation of mitochondrial calcium channels that should be explored.

Conclusion

Mitochondrial calcium is an important mechanism for understanding neurodegenerative diseases and lithium can reverse Alzheimer’s disease‐related dysfunction.
A core outcome set (COS) for dementia with Lewy bodies
Authors: Leroi Iracema
Published: December 2023

Background

Methodological heterogeneity in the outcome measurements adopted in DLB trials impedes effective evidence synthesis, rigorous meta‐analysis, and clinical translation. We aimed to develop a Core Outcome Set (COS), an agreed standardised set of outcomes that should be measured and reported, as a minimum, in all clinical DLB trials.

Method

We adopted a multi‐faceted approach to COS development, adopting the principles of the Core Outcome Measures in Effectiveness Trials (COMET) initiative. We conducted systematic reviews of outcomes used in intervention trials, qualitative studies, and health economic studies in DLB. A resulting shortlist of outcome measures formed the basis of an e‐Delphi consensus process, piloted among members of the study group, before it was administered in two rounds to clinicians, scientists, policy and third sector leads. Lay stakeholders, including people with DLB and their caregivers, also contributed to the e‐Delphi process. Consensus on inclusion was determined by at least 70% of respondents grading an outcome measure as “critical for inclusion” and less than 15% grading as “not important”. After appraisal of each outcome using Consensus‐based Standards for the selection of health Measurement Instruments (COSMIN) guidelines, a consensus meeting was conducted, in which all participants were invited to agree on final outcomes and rate each outcome on impact, relevance and clinical feasibility.

Results

Through validated mechanisms we constructed a COS including measurements of motor, cognitive, neuropsychiatric, autonomic, health economic, health provision, and quality of life. A diverse group of international and intersectional stakeholders have lent approval to its use.

Conclusion

We propose a COS; a benchmark which all DLB trials should meet. This standardised approach will could optimise research resources, facilitate multicentre collaboration, and minimize methodological bias.
Highly specific gene therapy in a rat model of sporadic Alzheimer’s disease: use of adeno‐associated viral vectors to overexpress IGF1 in hippocampal astrocytes
Authors: Peralta Facundo , Escobedo Ana Abril Vidal , Hanotte Juliette López , Villar Maria Florencia Zappa , Reggiani Paula Cecilia , Pardo Joaquín
Published: December 2023

Background

Sporadic Alzheimer’s disease (sAD) is the most prevalent neurodegenerative disease. The cerebral histopathological study shows that the hippocampus (Hc) is severely affected and presents marked astroglial reactivity and in consequence, neuronal trophic support decreases. We set out to develop an astrocyte‐targeted therapy that prevents the detrimental actions of reactive astrocytes, enhance their neuroprotection, and restore their modulatory properties in our sAD rat model mediated by the intracerebroventricular (icv) injection of streptozotocin (STZ).

Method

AAV generation: Bicistronic serotype 9 adeno‐associated viruses (AAVs) driven by the gfaABC1D promoter (astrocyte specific) [Lee et al 2008. https://doi.org/10.1002/glia.20622] were generated by the 3‐plasmid system. Two vectors harbouring the cassettes gfaABC1D‐IGF1‐ires‐tdTomato (AAV‐IGF1) and gfaABC1D‐GFP‐ires‐tdTomato (AAV‐GFP) were constructed. AAVs characterization was performed by RT‐qPCR and immunohistochemistry (IHC). Gene therapy in Hc with AAV‐IGF1: Young male rats were used and divided into 3 groups: SHAM, GFP and IGF1. On Experimental Day (ED) ‐28, animals received bilateral injections of artificial cerebrospinal fluid (aCSF) (SHAM) or AAV‐GFP/IGF1(GFP/IGF1). At ED 0, animals received icv aCSF (SHAM) or STZ (GFP/IGF1) (3mg/kg) bilaterally. Among the ED +17/+26 behavioural tests were performed (Open Field Test, Novel Object Recognition Test, and Barnes Maze).

Result

Transgenes overexpression was confirmed by RT‐qPCR and IHC. Vectors specificity was determined since 100% of the cells with red fluorescence (tdTomato+) were GFAP+. We also observed that a single injection of the vector is sufficient to transduce Hc throughout its rostro caudal extension. Animals belonging to the AAV‐GFP+STZ group showed a significant deterioration in the behavioural tests, while AAV‐IGF1+STZ animals did not show significant differences compared with the SHAM control in tested behaviours.

Conclusion

We explored a targeted therapeutic approach with high specificity to hippocampal astrocytes, which allowed us to modulate astrocyte IGF1 expression, thus promoting neuroprotective effects and preventing behavioural decline in animals with sAD. Consequently, our results are encouraging and suggest that astrocyte manipulation can be approached as a promising therapeutic means.

*PCR and JP have equal contribution in this work
Differences in Functional Connectivity between Normal Controls and Mild Cognitive Impairment in Motion Detection Tasks
Authors: Gu Ming , Deng Jinxian , Sun Boxin , Kavcic Voyko , Giordani Bruno , Li Tongtong
Published: December 2023

Background

It has long been observed that the abnormal brain functions in Alzheimer’s disease (AD) and mild cognitive impairment (MCI) are closely related to the weakening or loss of functional connectivity across certain brain regions. At the same time, the decreased cross‐connectivity is often accompanied by increased connectivity between some other regions, and this was considered to reflect the compensatory mechanisms of the brain. In this research, we investigate the differences in time‐varying functional connectivity between normal controls (NC) and MCI patients in motion detection tasks.

Method

Our research is based on task‐based EEG (64‐channel), where the participants were asked to perform a motion direction discrimination task. The current dataset includes 60 consensus‐diagnosed, community‐dwelling African Americans (ages 60‐90 years, 30 NC and 30 MCI) recruited through the Wayne State Institute of Gerontology Healthy Black Elders Center and the Michigan Alzheimer’s Disease Research Center with subjective cognitive complaints.

We evaluated the time‐varying functional connectivity at different time periods of the motion‐detection task across all the possible EEG region pairs, in terms of the Pearson correlation vector of the current source density. For each task trial, the successive time periods being examined included: stimulus onset to Go/NoGo indication, Go/NoGo indication to motion‐stop, and the button‐press period. For each subject, we calculated the mean, maximum and minimum of the Pearson correlation vector for each EEG region pair and each time period as features, and then selected the features where NC and MCI show a significant difference (p‐value<0.05 in the t‐test).

Result

Our analysis indicated that NC shows significantly higher connectivity across EEG region pairs Right Frontal‐Left Central (through most periods), Left Temporal‐Medial Central and Left Temporal‐Occipital (in button‐press period). On the other hand, MCI shows signigicantly high connectivity across Medial Parietal‐Occipital (through all the periods), which may reflect the compensatory mechanisms of the brain.

Conclusion

HC and MCI do show significant difference in functional connectivity during the motion detection task, and the EEG regions pairs Medial Parietal‐Occipital, and Right Frontal‐Left Central shown to be excellent choices for biomarker development for the discrimination of NC and MCI.

Funding: NSF‐2032709/Li; NIH‐ P30AG05376004/Paulson; NIH‐1R21AG046637‐01A1/Kavcic and NIH‐1R01AG054484‐01A1/Kavcic;
Depression and Hippocampal Subfield Volume in Older Adults
Authors: Twisselmann Alicia M , Tennant Victoria R , Hall Brandon J , Liu Joshua D , Hazra Nalini , Wheeler Koral V , Davison Marylan , Matsiyevskiy Elizabeth , Hall James , Borzage Matthew , Johnson Leigh , Yaffe Kristine , Toga Arthur W. , O'Bryant Sid E. , Braskie Meredith N ,   for the HABS‐HD Study Team
Published: December 2023

Background

Major Depressive Disorder (MDD) is associated with higher risk for developing Alzheimer’s Disease (AD), (Bennett & Thomas, 2014). Both conditions are associated with smaller hippocampal subfield volumes, and both preferentially affect females (Shi et al., 2021). We examined the relationship between depression diagnosis and hippocampal subfield volume, by carrier status for AD genetic risk variant APOE4 and sex. We hypothesized that the association between depression and subfield volume would be stronger in females due to the higher rate of depression.

Method

We examined 1726 cognitively intact older adults from the Health and Aging Brain Study ‐ Health Disparities (HABS‐HD) cohort (Table1) who had available hippocampal high resolution MRI scans (Siemens Skyra or Vida‐3T). Scans were segmented into CA1, CA23DG, and subiculum using Automatic Segmentation of Hippocampal Subfields (ASHS) software and subfield volume was averaged bilaterally. We used separate multiple linear regressions to assess the association between depression and each hippocampal subfield volume, covarying for age, sex, years of education, number of MRI slices segmented, intracranial volume, and scanner. We corrected for multiple comparisons across regions using FDR correction. We also evaluated CA1 and CA23DG volume to depression diagnosis, stratifying by APOE4 positivity and sex and testing for formal interactions.

Result

See Table 2 for results. Depression was associated with smaller CA1 and CA23DG volume across all participants. Depression was associated with smaller CA1 and CA23DG in the APOE4 negative group, but not the APOE4 positive group. The depression by APOE4 interaction was significant for CA23DG volume (𝛽 = 0.25, p = 0.049). Depression was associated with smaller CA1 and CA23DG volumes in males, but not in females, with trend level interaction effects in the CA1 (𝛽 = 0.13, p = 0.095) and CA23DG (𝛽 = 0.17, p = 0.067).

Conclusion

Depression was associated with smaller CA1 and CA23DG volumes in older adults consistent with past literature. In contrast to our hypotheses, depression was associated with lower hippocampal subregional volumes more in those with lower risk for Alzheimer’s disease (male and APOE4‐ adults).Variability induced by other AD risk factors may mask the relationship between depression and hippocampal subregion volume when AD risk is higher.
Effects of lithium on phosphatidyinositol‐3‐kinase signaling pathways in triple transgenicanimals of Alzheimer’s disease
Authors: Couto Caíque de Oliveira Portugal , Wagner Carlos , Forlenza Orestes Vicente , De‐Paula Vanessa V.J.
Published: December 2023

Background

Alzheimer’s disease (AD), a severe, progressive and multifactorial disease. Among the altered biological pathways, we have the phosphatidyl inositol 3 kinase (PI3K), an important cell signaling mediator that loses its function as a result of changes in the Tau protein and Aβ toxicity. Our aim is to determine the ontological pathways related to PI3K in 3xTg‐AD animals chronically treated with lithium at therapeutic and subtherapeutic doses. Also determine the unique, statistically significant proteins of the biological pathways in the ontological pathway altered in hippocampal tissue.

Method

The animals' hippocampus (WT and 3xTg‐AD) were divided into three subgroups: Li0 (standard chow); Li1 (ration containing 1.0 g of lithium carbonate/Kg); and Li2 (ration containing 2.0 g of lithium carbonate/Kg). Primary cultures of hippocampal neurons were treated with doses of 0.02; 0. 2 and 2mM. The identified protein pathways will be compared by Gene Ontology, using ClueGO, a Cytoscape software plug‐in. The analyzes for comparison with neurons and subsequent tissue identification will be performed by ‘Benjamini & Hochberg False Discovery Rate’ (p≤0.05 setting) for test correction for ‘biological process’. Ethical committee (1293/09).

Result

Our results on PI3K showed enrichment of pathways: response to hormone, cell migration, cellular response to endogenous stimulus, positive regulation of response to stimulus and regulation of catalytic activity.

Conclusion

Initial results are promising for the pharmacological understanding of lithium as a neuroprotector for Alzheimer’s disease.
Cholesterol accumulation promotes ABCA1 degradation in astrocytes via Caveolin‐1 mediated endocytosis in ApoE4
Authors: Wang Shaowei , Li Boyang , Kerman Bilal Ersen , Sun Yi , Bennett David A. A , Arvanitakis Zoe , Remaley Alan T , Yassine Hussein N.
Published: December 2023

Background

Apolipoprotein E4 (ApoE4) dysregulates cholesterol metabolism in the brain promoting the accumulation of lipid droplets, synaptic dysfunction and associates with a greater Alzheimer’s disease risk. We previously demonstrated that ApoE4 reduces the function of ATP‐binding cassette transporters A1 (ABCA1) which has important roles in cholesterol transport. The mechanisms of how ApoE4 induces less ABCA1 activity are poorly understood.

Method

ABCA1 binding proteins were analyzed with mass spectrum after immunoprecipitation. Immortalized astrocytes, primary astrocytes, mouse brain and human postmortem brain samples were used to test the association of ABCA1 and caveolin‐1 levels. Small interfere RNA was used to knockdown caveolin‐1 expression and 3H labelled cholesterol was used to test the cholesterol efflux of ABCA1.

Result

Here, we enriched ABCA1 binding protein complexes from ABCA1‐overexpressing cells treated with recombinant ApoE3 or ApoE4 proteins for a proteomic screen implicating endocytosis as a major pathway differentiating ApoE3 from ApoE4. Among the protein targets discovered, caveolin‐1 expression increased after ApoE4 treatment. Caveolin‐1 and ABCA1 interactions were confirmed using immunoprecipitation experiments. Cholesterol accumulation in astrocytes induced caveolin‐1 expression and promoted ABCA1 degradation. Greater caveolin‐1 and lower ABCA1 expression was observed in brains of 8, 18 and 22 months‐old ApoE4‐TR mice compared with the corresponding ApoE3‐TR mice. Isolation of single cell types from adult mouse ApoE‐TR brains confirmed lower ABCA1 and greater caveolin‐1 expression was largely driven by astrocytes and not microglia or neurons enriched fractions.

Conclusion

In conclusion, cholesterol accumulation induced by ApoE4 promotes ABCA1 degradation in astrocytes partly through a caveolin‐1 dependent endocytosis pathway.
Plasma pTau181 and biomarker combinations to identify Alzheimer´s disease at any stage along the AD continuum compared with both controls and non‐AD dementia
Authors: Doecke James D , Bellomo Giovanni , Vermunt Lisa , Alcolea Daniel , Halbgebauer Steffen , in ’t Veld Sjors G.J.G. , Mattsson‐Carlgren Niklas , Veverova Katerina , Fowler Christopher J , Boonkamp Lynn , Koel‐Simmerlink Marleen , Hussainali Zulaiga , Ruiters Daimy N. , Gaetani Lorenzo , Toja Andrea , Fortea Juan , Pijnenburg Yolande A.L. , Lemstra Afina W. , van der Flier Wiesje M. , Hort Jakub , Otto Markus , Hansson Oskar , Parnetti Lucilla , Masters Colin L , Lleó Alberto , del Campo Marta , Teunissen Charlotte E.
Published: December 2023

Background

The latest generation of plasma biomarkers (phosphorylated Tau181 (pTau181), Glial fibrillary acidic protein (GFAP), Neurofilament light (NFL) and the Amyloid‐beta ratio (Aβ42/40) have demonstrated high accuracy to detect AD pathology in either CSF/PET by many single‐center studies. Here we assess which markers (alone/combined) can best identify any stage along the AD continuum from a group of controls and other non‐AD dementias in a large international multicentre study.

Method

Plasma samples (n = 1298) were collected from six international centers (JPND bPRIDE consortium), including 198 cognitively unimpaired (CU) Aβ‐, 181 CU Aβ+ (preAD), 170 stable mild cognitive impairment (sMCI), 155 MCI due to AD (MCI‐AD), 25 MCI due to Lewy Body Dementia (MCI‐DLB), 46 MCI due to Frontotemporal Dementia (MCI‐FTD), 182 AD dementia, 171 DLB, and 170 FTD. Markers included Aβ40, Aβ42, GFAP, NfL and pTau181 using Simoa. Univariate and multivariate modelling (including their ratio’s and interactions, age, gender and APOE ε4 status) and ROC analyses were performed to assess biomarker capability to separate clinical groups along their disease continuum.

Result

pTau181 had the strongest differences between clinical groups (Figure 1) and the best AUC value to separate any AD stage from non‐AD dementia stages and controls (AUC>0.90) for the AD vs CU, sMCI or FTD comparisons. In comparison, the AUC for AD vs DLB was lower (complete sample: AUC:0.77 (95%CI:0.72‐0.82), while the pTau181/Ab42 ratio performed slightly better (p = 0.06, AUC:0.81 (95%CI:0.76‐0.85). Stratifying the AD vs DLB comparison into Aβ‐ and Aβ+ subgroups however, showed substantially increased performance for pTau181 in Aβ‐participants (Aβ‐ AUC: 0.94 [95%CI:0.86‐1.0], Aβ+ AUC: 0.68 [95%CI:0.61‐0.75]) with pTau181 higher in AD participants irrespective of Aβ status. Multivariate modelling showed that a combination of GFAP/Ab42 ratio, Aβ40 and pTau181 and their interaction, and APOEε4 was best to demarcate preAD, MCI‐AD and AD from CU (AUC values 0.89, 0.95 & 0.97 respectively).

Conclusion

pTau181 performed well to separate the complete AD continuum from controls and FTD but was lower for the AD/DLB comparison prior to stratification for Amyloid status. Multivariate assessment revealed that a combination of markers including pTau181, Aβ and GFAP was the best predictor of any stage of the AD continuum.
Similarities and differences in cognition as a function of sex: A longitudinal study of healthy control participants from the Parkinson Progression Markers Initiative
Authors: Ohlhauser Lisa , MacDonald Stuart , Gawryluk Jodie
Published: December 2023

Background

As the global population of older adults continues to rise, there is an urgent need to understand the expected cognitive changes in healthy aging. Despite sex‐based differences in life expectancy and age‐related diseases such as Alzheimer’s disease, limited research has explicitly examined sex differences in aging. The objective of the current study was to answer three primary questions using longitudinal data for sample of healthy adults: 1) How does cognition change over time? 2) What are the sex differences in cognition? and 3) What are the sex differences in rates of cognitive change over time?

Method

Longitudinal data from the healthy control group of the Parkinson’s Progression Markers Initiative was used to examine cognitive changes in healthy adult males (n = 125, mean age = 61.61, SD = 10.97) and females (n = 68, mean age = 59.44, SD = 11.56). Participants underwent annual neuropsychological testing for up to five years. A series of 2‐level linear mixed models estimated within‐person change in cognition over time (i.e., level‐1) and between‐group differences in longitudinal change trajectories as predicted by sex (i.e., level 2). Each neuropsychological measure was modeled separately as a single outcome variable, for a total of seven models.

Result

Stability in neuropsychological scores was seen over five years. At baseline, males scored higher on the Benton Judgement of Line Orientation Test, while females scored higher on the Symbol Digit Modalities Test, the Semantic Fluency Test, and the Hopkins Verbal Learning Test‐Revised. Rates of cognitive change over time did not significantly differ by sex. Higher age and lower education at baseline predicted lower neuropsychological scores.

Conclusion

Stability in cognition was found across five years in a sample healthy control participants from a large multi‐site longitudinal study. Sex differences in cognition were found in several domains, including visuospatial ability, processing speed, verbal fluency, and verbal memory. However, rates of cognitive change over time did not significantly differ by sex. Higher age and lower education were predictive of lower cognitive functioning. Great intraindividual variability in cognitive trajectories was observed. Future research should continue to examine factors that predict individual trajectories of aging in healthy individuals.
Mild Dementia and the FIFA World Cup! A case report
Authors: Hussein Sahar M , Abass Talal , Musa Susan , Shamoun Sereen , Abdelrahman Nadir G
Published: December 2023

Background

The use of reminiscence therapy (RT) to prevent abnormal behaviors in patients with moderate dementia has been well‐established. It has many positive effects in the domains of quality of life, cognition, communication and mood. We are presenting a case where RT decreased abnormal behaviors.

Method

Case: An 83‐year‐old man with moderate dementia immigrated to the US. He lives with his family who provided care. No alcohol, tobacco use or illicit drug use was reported. The patient was evaluated by a geriatrician. The patient scored 12/30 in Montreal Cognitive Assessment indicating moderate cognitive impairment. Laboratory tests were unremarkable except Vitamin B12 level (slightly low 181). He was started on Donepezil and Vitamin B. Since his arrival to the US, the patient intermittently displayed abnormal behaviors including agitation, sleep disturbance and mood changes. Family members utilized his personal stories, hobbies and interests for behavioral interventions. A soccer‐focused RT method was applied. Several Youtube videos containing old matches during the FIFA World Cup were used whenever abnormal behavior was triggered.

Result

Family reports that the patient’s behaviors were relieved and interestingly improved using the soccer‐focused RT.

Conclusion

This case report highlights the importance of a thorough evaluation of patients with dementia to include their life story and interests. In this case, behavioral modalities including RT were tried with considerable benefits. Technology‐based tools present a fertile land to explore regarding RT use in patients with moderate dementia.

References:

Bob Woods et al. Reminiscence therapy for dementia. Cochrane Database Syst Rev . 2018 Mar 1;3(3):CD001120. https://doi.org/10.1002/14651858.CD001120.pub3

Laura Coll‐Planas et al. Developing Evidence for Football (Soccer) Reminiscence Interventions Within Long‐term Care: A Co‐operative Approach Applied in Scotland and Spain. J Am Med Dir Assoc. 2017 Apr 1;18(4):355‐360. https://doi.org/10.1016/j.jamda.2017.01.013. Epub 2017 Mar 7. PMID: 28283380

Teuntje R Elfrink et al. Life story books for people with dementia: a systematic review. Int Psychogeriatr . 2018 Dec;30(12):1797‐1811. https://doi.org/10.1017/S1041610218000376. Epub 2018 Jul 18. https://pubmed.ncbi.nlm.nih.gov/30017005/

TikTok Video: #artist #painter #father #daughter #dementia #beauty #life #memories https://www.tiktok.com/@reyssongs/video/7171555440759754027 accessed 1/23/22
Dementia Associated Diseases, Driving Status, and Cognitive Function: Perception Does Not Match Performance – Truth and Consequence for Driving Shared Decision Making
Authors: Kaczmarek Olivia , Weller Joanna , Gopie Ian , Baek Steven , Bumstead Barbara , Buhse Marijean , Zarif Myassar , Gudesblatt Mark
Published: December 2023

Background

Dementia associated diseases (DAD) refer to a group of disorders clinically characterized by progressive cognitive impairment (CI). CI may reflect abnormalities across multiple cognitive domains (CD) to varying degrees and combinations and interfere with the ability to carry out activities of daily living (ADL). Determination of driving ability in routine care relies on patient, family, and clinician shared‐decision making, as availability of routine on‐road driving assessment might be limited. Incorporation of patient reported outcomes (PRO) in routine care has increased, becoming more important for patient care and treatment decisions. Neuro‐QoL Cognitive Function Questionnaire (CF) provides an opportunity to assess self‐reported cognition routinely. The relationship of CF to objective computerized multi‐domain cognitive testing and self‐reported driving has not been explored. Providing easily available objective screening might be of great value for all involved in the decision to continue or stop driving in view of the profound impact loss of driving has on independence.

Method

A retrospective review of PwDAD who provided self‐reported driving status and completed both objective and subjective cognitive function (CF) measures. Subjective CF was measured by CF score which pertaining to comprehension, cognition, attention, and learning. The validated computerized cognitive assessment battery (CAB‐NT), includes 7 cognitive domains: memory(Mem), executive function(Exe), attention(Att), information processing speed(Inf), visual‐spatial(Vis), verbal function(Ver), motor skills(Mot) and a global cognitive summary score(GCS). T‐tests and regression analysis was utilized for analysis assuming both equal and unequal variances, with significance (p< 0.05).

Results

496 PwDAD, average age 73.4±8.9, 61.2% female. T‐test showed significant differences between driving status yes/no for both CF and all CAB‐NT domains. However, regression analysis showed a small effect size between CF and CAB‐NT cognitive domains scores.

Conclusion

Self‐reported driving status in PwDAD corresponds to both perceived/subjective CF and objective measures of cognitive function. However, the relationship between subjective and objective cognitive function measures is problematic. With various CDs involved in the safe effective operation of a motor vehicle, it is necessary to objectively assess this risk with objective measures. Evidence of incongruent relationship between objective and subjective cognitive function enhances the importance of incorporating objective measures of cognitive ability to safely maintain an active driving status.
Synaptic tauopathy in a model of Alzheimer’s disease and traumatic brain injury
Authors: Sauerbeck Andrew D , Beck Alyssa , Harman Jacob , Kummer Terrance T
Published: December 2023

Background

Synapse loss is an early, pathogenic hallmark of Alzheimer’s disease (AD) and related neurodegenerative conditions. We recently demonstrated that traumatic brain injury (TBI) – the best‐established environmental risk factor for AD – also causes synapse loss, thus establishing a potential pathomechanistic connection between these conditions. One likely contributor is the microtubule associated protein tau. Phosphorylated isoforms of tau can be identified in the brain after TBI and are classically associated with AD‐related pathology. The extent to which these pathoisoforms reach synapses and contribute to their loss, however, is minimally explored.

Method

We combined the PS19 mouse model, which exhibits age‐dependent tau aggregation and synapse loss, with early TBI and subsequent aging to investigate tauopathic synaptic alterations in relation to traumatic and AD‐related processes. TBI was induced with a diffuse, closed‐head injury model called modCHIMERA (Sauerbeck et al, 2018) that causes delayed synapse loss. Synaptic analysis was performed with SEQUIN (Sauerbeck et al, 2020, Reitz et al, 2021), a super‐resolution imaging and analysis platform for quantifying synaptic density as well as nanostructure and molecular features in mammalian neuropil.

Result

Both TBI and expression of the P301S mutation resulted in accumulation of pathoisoforms of tau at synapses and regional synapse loss that evolved over time. Temporal and spatial patterns of tau accumulation varied by phosphoisoform. TBI resulted in an additional burden of synapse loss in PS19 animals, suggesting that TBI may increase the risk of AD through a potentiation of synaptic injury. We are exploring the functional consequences of this connection in ongoing experiments.

Conclusion

These studies demonstrate novel subcellular targets of pathological tau isoforms and suggest that tau is a key factor in synapse loss in TBI and AD. This shared mechanism may help explain the elevated risk of AD following TBI. Further characterization of these processes may suggest ways to sever this link, as well as prevent synapse loss in primary AD.
Loss of oligodendrocyte‐derived IL‐33 results in increased amyloid plaque deposition in APP/PS1 mice
Authors: Gonzalez‐Fernandez Estibaliz , Szmacinski Alexandra , Mami Salma , Kim Byungwook , Crawley Ilan , Kim Jungsu , Kang Shin
Published: December 2023

Background

Glial cells in the central nervous system (CNS) express IL‐33, a member of the IL‐1 family. IL‐33 is known to regulate microglial phagocytic activity toward amyloid β. In the aged brain, unlike the young counterpart, IL‐33 is predominantly expressed by oligodendrocytes (OLs), but the role of OL‐derived IL‐33 in Alzheimer’s disease (AD) is unknown.

Method

OL‐specific IL‐33 conditional knockout (cKO) mice were further crossed with APPswe/Psen1 dE9 (APP/PS1) and Mobp‐EGFP transgenic mice. Cortical lysates from one‐year‐old male APP/PS1 (n = 15) and APP/PS1 + IL‐33 cKO (n = 16) mice were used for the quantitative analysis (MSD and ELISA) of amyloid β 1‐42 (Aβ1‐42) and Aβ1‐40. Immunofluorescence and morphometric analysis were also performed to measure Aβ‐covered or LAMP1‐covered areas in different regions of the mouse brain. EGFP+ OLs were also quantified.

Results

Both Aβ1‐42 and Aβ1‐40 levels were significantly increased in the cortex (p<0.0001), and so were Aβ plaque‐covered areas in the cortex, corpus callosum, and hippocampus of APP/PS1 + IL‐33 cKO mice compared with control APP/PS1 (p<0.01). OL‐derived IL‐33 loss also resulted in increased accumulation of LAMP1+ dystrophic neurites (p<0.05). However, cortical EGFP+ OL density was unaltered by IL‐33 cKO.

Conclusion

OL‐derived IL‐33 may play a regulatory role in Aβ clearance during amyloidogenesis, probably via promoting microglial activity, but not in OL survival in the AD brain. These findings support a novel mechanism of instructive interaction between OLs and microglia in disease‐associated neuroinflammation.
Correlation between the health of individuals directly affected by the COVID‐19 pandemic and dementia
Authors: Khanna Deepesh , Patel Nishant
Published: December 2023

Background

This qualitative literature review analyzed the correlation between the health of individuals directly affected by the COVID‐19 pandemic and dementia.

Method

We used EndNote 20 to acquire our sources, where PubMed was the main source of data collection. Search inquiries included “COVID‐19”, “dementia”, “Alzheimer’s” and “demyelination”. A total of 25 studies were published between 2020 and 2022, out of which 13 studies were analyzed. Each publication provides details about the impact of COVID‐19 on either patient with pre‐existing dementia, or its onset due to the side effects caused by vaccination, such as demyelination. Changes were measured by utilizing the NPI scale and recognizing changes to behavioral and psychological symptoms (BPSD).

Result

Not only did the severity of dementia increase with age in the studies observed, but symptoms also increased when shifting to a total lockdown environment. Moreover, patients with increased severity of the SARS‐CoV‐2 infection are associated with an increased risk of developing progressive dementia and Alzheimer’s. The data collected through our literature search presents anticipated findings with previously published literature providing a correlation between COVID‐19 and neuropsychiatric diseases. Overall, the compiled results indicate an increase in anxiety, depression, and apathy levels among patients, insinuating a correlation between COVID‐19 and its impact on progressive dementia. Limitations of this study include the specificity of the subject. As the outbreak is still relatively recent, long‐term implications of the SARS‐CoV‐2 virus are unprecedented and there is limited literature on this topic.

Conclusion

The findings of our study strengthen previously published literature on the psychological impacts of COVID‐19. The importance of this field sheds light on a need for further studies providing data on the long‐term implications between the variables of COVID‐19 and dementia, to provide concrete medical care and prevention methods for future pandemics synonymous with the COVID‐19 pandemic.

References

1.Cinar, N., et al. (2022). “Neuropsychiatric Effects of COVID‐19 Pandemic on Alzheimer’s Disease: A Comparative Study of Total and Partial Lockdown.” Sisli Etfal Hastan Tip Bul 56(4): 453‐460.

2. Delgado‐Alonso, C., et al. (2022). “Cognitive dysfunction associated with COVID‐19: A comprehensive neuropsychological study.” J Psychiatr Res 150: 40‐46.
Hippocampal function during an associative memory task is influenced by early bilateral salpingo‐oophorectomy
Authors: Brown Alana , Gravelsins Laura , Gervais Nicole J , Rieck Jenny , Almey Anne , Reuben Rebekah , Karkaby Laurice , Zhao Sophia , Rusu Simone , Duchesne Annie , Witt Suzanne Tyson , Kämpe Robin , Classon Elisabet , Lykke Nina , Theodorsson Elvar , Ernerudh Jan , Lundqvist Elisabeth Åvall , Kjølhede Preben , Engström Maria , Grady Cheryl , Einstein Gillian
Published: December 2023

Background

Women with mid‐life 17β‐estradiol loss due to early bilateral salpingo‐oophorectomy (BSO; removal of ovaries and fallopian tubes) have heightened Alzheimer’s disease (AD) risk (Rocca et al., 2007). 17β‐estradiol loss is related to AD risk factors, including associative memory decrements and decreased functional magnetic resonance imaging (fMRI)‐measured hippocampal activation during encoding (Jacobs et al., 2016; Rentz et al., 2017). Our objective was to investigate the effects of early BSO and 17β‐estradiol replacement therapy (ERT) on associative memory and hippocampal function.

Method

Women with BSO either taking ERT (BSO+ERT; M±SEage= 45±1.03, n = 23) or not taking ERT (BSO; M±SEage= 45.7±1.01, n = 23) were compared to age‐matched premenopausal control women (AMC; M±SEage= 43.7±0.48, n = 37) on fMRI‐measured brain activation during encoding and retrieval trials of a face‐name associative memory task. We compared groups on activation from anterior and posterior anatomical hippocampal regions‐of‐interest during retrieval and encoding (retrieval‐encoding contrast) trials between groups. We also compared hippocampal activation during novel and repeat face‐name pair encoding trials (novel‐repeat encoding contrast). Face‐name pair recognition accuracy between groups was also assessed.

Result

Compared to BSO+ERT, BSO exhibited significantly lower activation during novel compared to repeat encoding trials (Fig.1A) in the right anterior hippocampal region‐of‐interest (Fig.1B). There were no significant group differences in hippocampal activation during retrieval compared to encoding trials, and no group differences in recognition accuracy.

Conclusion

Younger women with BSO either taking ERT or not showed comparable hippocampal activation to age‐matched premenopausal women during retrieval of face‐name pairs. However, during encoding of face‐name pairs, BSO showed significantly lower right anterior hippocampal activation compared to BSO+ERT. ERT may influence associative encoding processes dependent on hippocampal novelty detection, rather than retrieval processes. Expanding on work from others (Phillips & Sherwin, 1992), these results suggest ERT may ameliorate the negative influence of oophorectomy on hippocampal‐dependent memory processes.
Translation and adaptation of a questionnaire for assessing cognitive domains based on the diagnostic criteria of the Diagnostic and Statistical Manual of Mental Disorders ‐ DSM‐5 for neurocognitive disorders
Authors: Diniz Maissa Ferreira , Ferreira Jéssica Diniz , Souza Nicolau Mariana , Diniz Breno Satler , Romano‐Silva Marco Aurélio , Malloy‐Diniz Leandro F , Bicalho Maria Aparecida Camargos , de Paula Jonas Jardim , Mattos Viana Bernardo
Published: December 2023

Background

The Cognitive Domains and Functional Assessment Questionnaire (QACDF) assesses cognitive and functional decline based on the DSM‐5 criteria for Neurocognitive Disorders¹. The QACDF has two versions, one for the patient and another for the informant. It is composed of 30 items, each assessed by a likert scale. This questionnaire has appropriate semantic characteristics for the Brazilian older adult population.

Method

The objective of this study was to translate, adapt and assess the semantic, idiomatic, experiential and conceptual equivalence of the QACDF. Firstly, the QADCF original version in Portuguese was translated to English by two Bilingual translators, a non‐specialist linguist and a specialist in the field. After this, the two translators (T1 and T2) together with a mediator translator synthesized the translations in a common version (T3). Then, the T3 version was back‐translated into Portuguese by a Bilingual translator, blind to the original version². The three versions (original, translated and back‐translated) were assessed by a committee of specialists. The committee was composed of the initial translators, an English native speaker, an expert in the methodology and the main researchers.

Result

The QACDF Items were adjusted to conceive equivalent expressions for the target language, as well as to assess cognitive domains and the functionality of daily living of English speakers. Semantic, idiomatic, experiential and conceptual equivalence were debated by the committee until consensus was reached.

Conclusion

The translation of the instrument followed the proposed methodology by Beaton et col. However, while the Brazilian Portuguese versions have been assessed by two pilot studies, pilot studies are still needed to further adjust the questionnaires for English speakers.
Neuroprotective potential of carbamide forte on LPS‐induced experimental PD
Authors: Ranjan Suray , Sharma Priyanka , Deshmukh Rahul Renukadas
Published: December 2023

Background

Parkinson’s disease is a second most common age‐related neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta region of the midbrain. Increased oxidative stress and inflammation with decreased activity of glutathione peroxidase, superoxide dismutase (SOD), and catalase has been observed in PD patients. Carbamide Forte Brain and Memory Support is blend of 9 herbal brain‐enhancing ingredients to boost short term cognitive function and long‐term brain health and thus expected to be beneficial in cognition and movement disorder.

Method

Adult male/female Sprague Dawley rats were ICV injected with LPS at a dose of 0.2 mg/kg body weight into substantia nigra pars compacta with the help of stereotaxic apparatus. Carbamide Forte was administered per orally at 80 and 160 mg/kg body weight, 4 days after to LPS infusion.

Result

Infusion of single ICV‐LPS produced significantly decreased in body weight, locomotor activity, motor coordination, antioxidant defense enzymes and significantly increased oxidative stress markers in the striatum. Chronic administration of carbamide forte (for 21days) significantly attenuated LPS induced movement disabilities in Narrow beam walk, Horizontal ladder beam walk test, OFT and also significantly reduce the oxidative‐nitrosative stress and antioxidants enzymesas evidence by decrease in malondialdehyde and nitrite levels and restored the reduced glutathione level in rats & neuroprotective potential of CF with morphological changes seen in our histological assessment. The observed result of the present study is indicative of the therapeutic potential of Carbamide Forte in PD.

Conclusion

It could be concluded that the observed neuroprotective effect of Carbamide Forte may be due to antioxidant and neuroprotective potential.
β‐Asarone attenuates streptozotocin‐induced experimental dementia in rats: Possible role of phosphodiesterases and cyclic nucleotide signaling
Authors: Kumar Narinder , Kumar Ashwani , Deshmukh Rahul Renukadas
Published: December 2023

Background

In recent years, extract of Acorus calamus shown to inhibit phosphodiesterases (PDE) and β‐asarone has been reported to be a major active constituent. The purpose of the present study was to ascertain PDE inhibitory potential of β‐asarone and to explore its therapeutic potential in sporadic Alzheimer’s type dementia (SAD). In the current study, PDE inhibitory potential of β‐asarone was determined using in vitro assay system.

Method

Streptozotocin (STZ) was infused intracerebroventrically [bilaterally (3 mg/kg) ICV] to induce SAD in rats. Spatial and non‐spatial memory was evaluated using Morris water maze and object recognition task in rats.Rats were treated with β‐asarone (12.5, 25 and 50 mg/kg) from day 10 to 21 following 1st STZ infusion. On day 22 rats were sacrificed and the cortical and hippocampal brain regions were used to identify biochemical alterations

Result

STZ infused rats showed significant learning and memory deficit which was linked with increase in oxidative stress (malondialdehyde and nitrite), compromised antioxidant defense (reduced glutathione), mitochondrial dysfunction (deficit in complex I and III activity) and pro‐inflammatory cytokine levels. Significant decrease in both cAMP and cGMP levels were also observed in STZ‐infused rats. β‐Asarone dose dependently attenuated STZ‐induced cognitive deficit, biochemical alterations and restored cyclic nucleotide levels.

Conclusion

The observed results show important role of PDE inhibition and cyclic nucleotide signaling in the beneficial effects of β‐asarone and suggest therapeutic potential of β‐asarone in the management of cognitive disorders.
Self‐reported COVID‐19 and biomarkers of Alzheimer’s disease: interim analyses from an Alzheimer’s disease risk‐enriched cohort
Authors: Akinci Muge , Shekari Mahnaz , Palpatzis Eleni , González Escalante Armand , Contador Israel , Argiris Georgette , Fuentes‐Julian Sherezade , Kollmorgen Gwendlyn , Carboni Margherita , Blennow Kaj , Zetterberg Henrik , Minguillon Carolina , Fauria Karine , Knezevic Iva , Navarro Arcadi , Sánchez‐Benavides Gonzalo , Grau‐Rivera Oriol , Suarez‐Calvet Marc , Gispert Juan Domingo , Arenaza‐Urquijo Eider M
Published: December 2023

Background

COVID‐19‐related SARS‐CoV‐2 infection has been linked with brain abnormalities and cerebrospinal fluid (CSF) biomarkers of Alzheimer’s disease (AD), neuroinflammation, and neuronal injury. Whether COVID‐19 increases the brain’s vulnerability to the development of AD is unclear. In participants at an increased risk of AD, we investigated the association of COVID‐19 with pre‐ and post‐pandemic AD biomarkers.

Method

We included 132 cognitively unimpaired adults from the ALFA+ cohort (52‐71 years, 61.4% women) who provided retrospective self‐reported data on SARS‐CoV‐2 infection (with COVID‐19 vs. without COVID‐19). As of February 2022, 125 (94.7%) participants had available CSF biomarkers (measured with exploratory Roche NeuroToolKit or Elecsys® immunoassays, Roche Diagnostics International Ltd, Rotkreuz, Switzerland) and 76 (57.6%) had [18F]flutemetamol‐PET data acquired before (pre‐pandemic) and after (post‐pandemic) the beginning of the COVID‐19 pandemic (average time lapse between the assessments: 3.5±0.6 years). [18F]flutemetamol PET SUVR maps were obtained using the whole cerebellum as the reference region. First, we performed ANCOVA models to investigate whether COVID‐19 was associated with post‐pandemic CSF biomarkers of core AD pathology (Aβ42/40 and p‐tau), neuronal injury (NfL), and neuroinflammation (sTREM2, GFAP, and IL‐6), while controlling for pre‐pandemic biomarker levels. Covariates were age, sex, years of education, APOE‐ε4 status, and time lapse between the biomarker assessments. Second, we performed a voxel‐wise analysis in SPM‐12 using a matched‐group comparison design (with COVID‐19 vs. without COVID‐19 matched by pre‐pandemic Centiloid values, age, and APOE‐ε4 status) with the post‐pandemic amyloid‐PET scans as the outcome of interest.

Result

Fifteen (12%) participants included in ANCOVA reported COVID‐19. Eleven (14.5%) with amyloid‐PET scans reported COVID‐19 and were matched with 11 participants without COVID‐19 for voxel‐wise analysis. In ANCOVA models, no significant association between COVID‐19 and post‐pandemic CSF biomarkers was found (Table 1). Results from the t‐test voxel‐wise analysis also did not show any differences between participants with vs. without COVID‐19 on [18F]flutemetamol‐PET uptake after correction with false discovery rate.

Conclusion

Our interim analyses did not show any association between self‐reported COVID‐19 and post‐pandemic biomarkers of AD pathology, neuronal injury, and neuroinflammation. The results are pending confirmation of COVID‐19 status using serology data (n = 181) and complete sample size.