bluuebunny/crossref_metadata_2025 huggingface dataset:
Spike S1 peptide associated neuroinflammatory and cytokine induction is associated with modified behavior in in vivo models
Authors: Paidi Ramesh Kumar , Pahan Kalipada
Published: December 2023

Background

Coronavirus disease (COVID‐19), a severe acute respiratory syndrome coronavirus 2 (SARS CoV‐2) is a damaging illness leading to severe health crisis and economic crisis worldwide. Numerous brain complication has been reported in COVID‐19 patients and surprisingly has persisted after COVID‐19 infection recovery in patients. The underlying mechanism are not clear. So far, there is no proper therapeutic strategy against COVID‐19 and its complications on the brain.

Method

Initially we validate the effect of recombinant Spike S1 in A5339 cells (Paidi, Jana et al. 2021, Paidi, Jana et al. 2021, Paidi, Jana et al. 2021) and as well as mouse primary astrocyte cultures, in terms of cytokine induction and neuroinflammatory markers. In the current study, mice were administered recombinant spike S1 intranasally for 14 days. Initially we evaluated the physiological and behavioral alteration for 12 days. SARS‐CoV‐2 binds to angiotensin‐converting enzyme 2 (ACE2) for entering host cells, we so investigate the lung histology and its cytokine induction. Further, we evaluate the cytokine and neuroinflammatory levels in the brain, and its relevance to behavioral modifications in the mouse.

Result

In the present study, Spike S1 treatment prominently elevate the cytokine levels and inflammatory markers in invitro models. Intranasal intoxication of C57/BL6 mice with recombinant SARS‐CoV‐2 spike S1 led to fever, increase in IL‐6 in the lungs and brain. We found that the impairment in spatial learning memory functions and motor disabilities, mimic some of the important symptoms of COVID‐19. Our studies show Spike S1 induced cytokine levels in lungs and as well as in the brain.

Conclusion

Our results suggest a simple, but reliable means of developing a Spike S1 mediated in vivo model which exhibits severe lung pathology and reinforce the validity of this animal model to study COVID‐19 pathogenesis and potential therapies.

Keywords

Spike S1, COVID‐19; IL‐6; Cognitive functions; Motor disabilities, Cytokine induction;
Conceptual saliency: Core and peripheral semantic knowledge in Alzheimer’s disease
Authors: Ulep Maileen G. , Lienard Pierre
Published: December 2023

Background

Semantic memory impairment in Alzheimer’s disease (AD) is indicative of an actual degradation of semantic knowledge – the conceptual and factual knowledge necessary to engage with others and the physical world – rather than merely to a retrieval deficit. Historically, studies in semantic knowledge in AD have relied on predetermined sets of stimuli to probe knowledge. The analysis presented here compares the contents, sequences and organization of lists of salient concepts generated by 19 patients at the mild to moderates stages AD and by 15 age‐matched cognitively normal control individuals by means of a free‐listing task, for two semantic categories, living kinds and man‐made objects. The free elicitation by participants prevents the imposition of a priori ideas by the experimenter, which might not correspond to the native knowledge of the specific cultural group studied.

Method

Data collection starts with the ‘demarcation’ of a domain of knowledge X by a sample of participants who are being asked to write the names of as many items as they can conjure up, which they think belong to that domain X. Terms that appear earlier, or with higher frequency, on free‐lists indicate high consensus among respondents (i.e., the concept is an important component of the category); those items are considered as more salient in the domain under investigation.

Result

Evidence of knowledge devolution is detected in the lists of participants with AD for both semantic categories. However, the core conceptual information and central aspects of the structuration of those knowledge domains are preserved to an extent. The peripheral conceptual knowledge is showing the greatest disease impact.

Conclusion

The study starts the investigation of the aspects of living kinds and artefactual categorial knowledge especially resilient as neurodegeneration sets. Semantic knowledge holds the information about what one knows. Its integrity is critical in daily functioning, and interactions with others and the world at large. Because semantic memory supports various aspects of daily life, it is a prime candidate for therapeutic targets that can lead to meaningful outcomes for both patients and their care partners.
Categorical reasoning in Alzheimer’s disease: What is preserved?
Authors: Ulep Maileen G. , Lienard Pierre
Published: December 2023

Background

Semantic knowledge impairment appears to be a robust early indicator of Alzheimer’s disease (AD) pathology. The disruption of semantic cognition has been detected in preclinical AD. We investigate the ability of patients with mild to moderate AD to categorize items belonging to two semantic domains critical in daily life, living kinds and artefacts.

Method

The categorial reasoning competence of 12 patients with AD and 16 age‐matched normal controls, in the semantic domains of living kinds and man‐made objects are compared by means of an unconstrained pile‐sorting experiment. The participants are left to decide how to lump a list of items, hence, to select organizational schemes of their choosing. Unconstrained pile‐sorting has the potential to better reveal the most salient concepts and principles that orient the classificatory decisions of the participants.

Result

The experimental findings highlight both preserved and disrupted abilities. Important structural principles organizing knowledge in both semantic categories seem to remain well preserved and to still drive patients’ core reasoning. Patients and controls do differ in the specific contents of their piles, even though the number of piles generated by each group does not diverge. Patients with AD were less systematic in their categorization strategies than control participants. The performance of patients displays evidence of a broad weakening of conceptual associations at levels of categorizations requiring finer details.

Conclusion

Early deviations in cognitive performance of individuals with AD from cognitively normal adults might only appear when careful analyses of contents are conducted. To our knowledge, it is the first study to use this task as developed in cognitive anthropology to investigate semantic knowledge in AD. We propose that the detection of early deviations in performance of patients with AD might be enhanced by the combination of detailed analysis of contents and a quantitative approach.
Akinetic Mutism and Cognitive‐Affective Syndrome caused by unilateral PICA infarction
Authors: Han Jeong Ho , Yang Youngsoon , Choi Eun Joo
Published: December 2023

Background

Akinetic mutism (AM) is characterized by sparse volitional motor and speech activation with reasonably preserved arousal and vigilance functions. Akinetic mutism, the most severe of these disorders, is most commonly associated with bilateral hemispheric pathology, although unilateral lesions may produce this condition as well.

Method

Case: Our patient is a 42‐year‐old right handed man who presented to the emergency department with an acute onset of akinetic mutism. His family described him as a calm and intelligent individual with a good cultural knowledge level and without any evident cognitive abnormality before he suddenly experienced akinetic mutism. On examination, he was alert but produced no spontaneous speech and had only rare, spontaneous movement of his arm and leg. With repeated prompting, he followed single‐step commands.

Result

Magnetic resonance imaging demonstrated an infarction in the distribution of the left posterior inferior cerebellar artery. During the course of 7 days, as the patient became more interactive, he demonstrated normal language function. As he became more communicative, cognitive impairment became apparent. Neuropsychological evaluation were performed after approximately 12 days after onset because of the impossibility of test administration during the acute phase. Impaired performances were evident on executive function testing with difficulties in planning, abstract reasoning, set‐shifting and perseveration. Furthermore, attention disorders and memory dysfunction were mild observed and were probably due to the poor ability of planning and organization. Language tests revealed mild deficits in the semantic sphere with paraphasia, anomia and circumlocutory expressions. During psychometric testing, the patient presented agitated and anxious behavior with affective air hunger and episodes of crying. Brain SPECT were performed after approximately 14 days after onset. Brain SPECT demonstrated hyporperfusion in Lt. cerebellar and frontal cortex.

Conclusion

The syndrome of akinetic mutism is typically the result of bilateral hemispheric injury, usually involving the anterior cingulate gyri. Other locations for lesions producing akinetic mutism include the thalami, globus pallidus, internal capsule, and frontal white matter. We describe a man with akinetic mutism and cognitive impairment due to an ischemic stroke in the distribution of the left PICA.
Association between topographic distribution of dilated perivascular spaces and Alzheimer’s disease pathologies measured by 18F‐florbetaben and PI‐2620 PET
Authors: Booncharoen Kittithatch , Thanapornsangsuth Poosanu , Sarutikriangkri Yuthachai , Likitjaroen Yuttachai , Thanprasertsuk Sekh
Published: December 2023

Background

Dilated perivascular spaces (DPVS) has been hypothesized to be implicated in the development and/or progression Alzheimer’s disease (AD). However, evidence of a relationship between its topographic distribution and burden of AD pathologies has not been well‐established. We thus aimed to evaluate whether beta‐amyloid (Aβ) and tau burdens measured in positron emission tomography (PET) are associated with topographic distribution of DPVS.

Method

Fifty‐one patients with amnestic mild cognitive impairment or mild dementia due to possible AD were recruited. Aβ burden was measured as Centiloid (CL) scale from 18F‐florbetaben PET. Burden of tau on regions comprising Braak stage III‐IV of neurofibrillary pathology (Braak H, et al. 2006) was measured as standardized uptake value ratio (SUVR) from tau tracer PI‐2620 PET. DPVS were assessed in the basal ganglia (BG‐DPVS) and in the subcortical white matter (WM‐DPVS) in T1‐sequences of brain MRI. DPVS severities were rated by an established 4‐point semiquantitative score and were then classified as high degree (score>2) or low degree (score≤2) (Martinez‐Ramirez, et al. 2013). The patients were further categorized into 3 groups including patients with higher, equal, and lower score of BG‐DPVS compared to WM‐DPVS (BG>WM, BG = WM, and BG<WM, respectively) (Thanprasertsuk, et al. 2014). Multivariate analyses controlling for age, sex, and MoCA score were applied to ensure independent relationships of DPVS to Aβ‐CL and tau‐SUVR.

Result

Patients with high degree of WM‐DPVS (n = 18), compared to ones with the low degree (n = 33), had higher burdens of both Aβ‐CL (median[IQR], 74.29[55.90‐102.02] versus 35.06[11.34‐57.57], p<0.001) and tau‐SUVR (1.46[1.24‐2.15] versus 1.16[1.07‐1.49], p = 0.001). Based on DPVS category, there were differences in both Aβ‐CL (p = 0.001) and tau‐SUVR (p = 0.009) among the BG>WM (n = 20), BG = WM (n = 13), and BG<WM (n = 18) groups, with apparently high disease‐specific pathologies of AD in the BG<WM group (Aβ‐CL = 74.29[46.60‐105.20], and tau‐SUVR = 1.50[1.24‐2.14]). There were no differences in Aβ‐CL and tau‐SUVR between patients with low and high degree of BG‐DPVS.

Conclusion

Our results suggest that WM‐DPVS is associated with the deposition of Aβ and tau in AD patients, while BG‐DPVS appears to have less substantial association.
Progranulin gene mutation of frontotemporal dementia in China: A case report and literature review
Authors: Chu Min , Nan Haitian , Jiang Deming , Liu Li , Wu Liyong
Published: December 2023

Background

Progranulin (GRN) mutations of Frontotemporal dementia (FTD) were rarely reported in China. This study was to report one novel GRN mutation and summarize the genetic and clinical features of patients with GRN mutations in China.

Method

Comprehensive clinical, genetic, and neuroimaging examinations were conducted on a 58‐year‐old patient who was diagnosed with semantic variant primary progressive aphasia. A literature review was also conducted and the clinical and genetic features of patients with Progranulin mutations in China were summarized.

Result

Marked lateral atrophy and hypometabolism on the left‐side frontal, temporal and parietal lobes of the patient were found on neuroimages, and amyloid and tau positron emission tomography ruled out pathological protein deposition. A novel heterozygous 45‐bp deletion (c.141414_1444delCCCTTCCCCGCCAGGCTGTGTGCTGCGAGGATCGCCAGCACTGCT) was identified through Whole Exon Sequencing of the patient’s genomic deoxyribonucleic acid. Nonsense‐mediated messenger ribonucleic acid decay was implicated in the degradation of the mutated messenger ribonucleic acid, and it was defined as pathogenic by American College of Medical Genetics and Genomics guidelines. In the literature review, we found Chinese reports of 13 patients with Progranulin mutations. A 1.2%–2.6% prevalence, an early disease onset and a female predominance were reported in Chinese patients with GRN mutations.

Conclusion

Our findings expand the mutational profile of Progranulin mutations in China and provide a basis for potential treatments for Progranulin.
A study of sleep quality, cognitive impairment and functional abilities in patients with dementia
Authors: Yadav Beer Bahadur , Prakash Om
Published: December 2023

Background

Sleep quality is affected with cognitive impairment and functional ability in patients with dementia.

Method

Thirty patients with dementia and thirty normal controls were studied. Subjects were evaluated for global cognitive impairment using Hindi Mental State Examination (HMSE) and activities of daily living using Everyday Ability scale for India (EASI). Dementia severity was assessed using Clinical Dementia Rating scale (CDR). A comprehensive sleep‐wake profile was obtained using a set of questionnaires Semi‐Structured Sleep Performa and Pittsburgh Sleep Quality Index (PSQI).

Result

Patients were matched for age and gender. The severity of cognitive impairment (r value‐0.62, p<0.01) and functional ability (r value 0.59, p<0.01) was proportional to the poor sleep quality index.

Conclusion

Sleep‐wake profile was altered in patients with dementia. This study helps to provide insights into sleep disturbances association with degree of cognitive impairment and degree of functional ability.
No Interaction Between BDNF Val66Met and APOE ε4 on PET‐Based Amyloid and Tau Measurements
Authors: Shaw Alannah , Malek‐Ahmadi Michael H. , Devadas Vivek , Wang Qi , Su Yi , Reiman Eric M.
Published: December 2023

Background

The interaction between the BDNF Val66Met gene and APOE ε4 gene on Alzheimer’s disease (AD) pathology is not fully understood. We aimed to determine how this interaction impacts PET based amyloid and tau measurements, hippocampal volume, and auditory verbal learning tests (AVLT) performance in cognitively unimpaired (CU) older adults.

Method

Data from 216 participants were used in this analysis. For the whole data set, the mean age was 75.56 ± 7.52 years, mean education was 16.82 ± 2.40 years, and 55% of the participants were female (118 females and 98 male). Linear regression models that adjusted for age, sex, education, were used to quantify main effects and interactions between APOE ε4 carrier status and BDNF Val66Met carrier status. Outcome measures included AV‐45 SUVR, tau meta‐ROI, hippocampal volume, AVLT Delayed Recall, and AVLT Total Recall.

Result

There was a main effect on APOE ε4 carrier status on amyloid load (β = 0.11, 95% CI (0.04, 0.17), p = 0.001), but no main effect for BDNF on amyloid load (β = ‐0.003, 95% CI (‐0.06, 0.06) p = 0.91). The interaction between APOE ε4 carrier status and BDNF Met carrier status was not significant (β = 0.03, 95% CI (‐0.07, 0.13), p = 0.58). There was no main effect on APOE ε4 carrier status on tau load (β = 0.003, 95% CI (‐0.06, 0.06), p = 0.93). There was also no main effect on BDNF on tau load (β = ‐0.0006, 95% CI (‐0.05, 0.05), p = 0.98) and the interaction between APOE ε4 carrier status and BDNF Met carrier status was not significant (β = 0.03, 95% CI (‐0.06, 0.12), p = 0.49). There were no significant main effects or interactions on hippocampal volume and cognitive measures.

Conclusion

This cross‐sectional study found no significant interaction between APOE ε4 carrier status and BDNF met carrier status on measures of amyloid and tau load as well as hippocampal volume and cognition. These findings cast doubt on the BDNF Met allele’s role in moderating AD‐related pathological changes.
Test‐retest validity of light reflex pupillometry in a memory clinic cohort
Authors: Gramkow Mathias H. , Clemmensen Frederikke Kragh , Waldemar Gunhild , Hasselbalch Steen G. , Frederiksen Kristian Steen
Published: December 2023

Background

The pupillary light reflex and the contributing cerebral functions can be objectively assessed using a pupillometer. Light reflex pupillometry (LRP) has been found to be altered in Alzheimer’s disease (AD) and has potential as a diagnostic aid in this disease as a novel biomarker. Little is known about the variability of LRP in patients seen in memory clinics (including patients with AD). We aimed to quantify the test‐retest validity of LRP in these patients to elucidate possible pitfalls in using pupillometry and to ascertain the feasibility of implementing this clinical tool in a memory clinic setting.

Method

In total, 50 patients under diagnostic evaluation in a tertiary memory clinic will be included in the present study. Patients suspected of a neurodegenerative disease are included on the day of a scheduled lumbar puncture (LP). We measure the LRP at baseline (day of LP), 3‐14 days after LP, and 21‐35 days post‐LP using a research grade pupillometer (PLR‐3000, NeurOptics®). Spaghettiograms of measurements will be presented and the intraclass correlation coefficient from a two‐way mixed effects model will be calculated for the eight pupillometric variables provided by the PLR‐3000: Baseline pupil diameter, peak constriction diameter, change in pupillary size, average and maximum constriction velocity, average dilation velocity and T75 (time to reach 75% of baseline pupil diameter after peak constriction). We will study possible influencing factors that could affect the test‐retest variability by studying subgroups of patients based on diagnosis, disease severity, cerebrospinal fluid Aβ‐42, concurrent eye disease and medication.

Result

As of January 2023, 24 patients (9 female) have completed follow‐up. The mean age of patients is 72 years (range 63‐79). Half of the patients were diagnosed with Alzheimer’s disease (MCI or mild dementia). Our preliminary results show moderate‐good test‐retest reliability of most pupillometric variables.

Conclusion

Light reflex pupillometry may be a promising new bedside biomarker for AD. The present study generally demonstrated a moderate‐good test‐retest reliability of LRP in a memory clinic population. The study contributes to the foundation for an exploration of the tool for diagnostic purposes in various diseases, including Alzheimer’s disease.
Vascular dysfunction in behavior‐variant frontotemporal dementia
Authors: Chu Min , Jiang Deming , Qu Miao , Wu Liyong
Published: December 2023

Background

The vascular disturbance was recently found in a postmortem study of frontotemporal dementia (FTD), but whether vascular dysfunction exists in the early stage of FTD remains elusive. The study aimed to explore whether there was evidence of vascular dysfunction in FTD and its relationship with central neurodegeneration and the clinical outcome.

Method

Twenty patients with behavior frontotemporal dementia (bvFTD) were enrolled and underwent assessment of peripheral plasma vascular markers, positron emission tomography/magnetic resonance imaging, and neuropsychological examinations. Group difference was tested using the student’s t‐test and Mann‐Whitney U test. Partial correlation analysis was implemented using age and sex as covariates to explore the association between peripheral vascular markers, neuroimaging, and clinical measures.

Result

All four factors including matrix metalloproteinases‐1(MMP‐1), matrix metalloproteinases‐3 (MMP‐3), Osteopontin, and pentraxin‐3 are increased in the FTD group. The plasma level of MMP‐1 was negatively correlated with the gray matter metabolism of the prefrontal cortex (r = ‐0.5119, p = 0.0210) and the anterior cingulate cortex (r = ‐0.4685, p = 0.0269). MMP‐3 was negatively correlated with the gray matter metabolism of the anterior temporal cortex (r = ‐0.4650, p = 0.0388). Pentraxin‐3 was negatively correlated with age at sampling (r = ‐0.5024, p = 0.0240) and age at onset (r = ‐0.5693, p = 0.0088). No other significant associations were found in other vascular cytokines and clinical measures.

Conclusion

The vascular disturbance was found in patients with bvFTD and associated with the disease‐specific neurodegeneration pattern, indicating vascular dysfunction and perturbance of the BBB participation in the pathogenesis of FTD. The vascular pathway might be a promising target for future potential therapy.
Locus coeruleus integrity exhibits distinct anatomic vulnerabilities to regional tau and amyloid accumulation: parallel and intersecting mechanisms?
Authors: Jacobs Heidi I.L. , Becker Alex , Riphagen Joost M. , Thibault Emma G. , Farrell Michelle E. , Properzi Michael J , Rentz Dorene M. , Sperling Reisa A. , Johnson Keith A.
Published: December 2023

Background

The locus coeruleus (LC) is one of the first regions to accumulate tau in Alzheimer’s disease (AD). As the disease progresses, tau in the LC has been related to increasing allocortical tau. Recent autopsy work reported that LC neurodegeneration correlated with parietal amyloid, suggesting that the LC may impact both Ab and tau, but with regionally varying contributions. We investigated whether cross‐sectional and longitudinal relationships between in vivo LC integrity and regional tau or Ab are uniquely determined by one pathology or exhibit shared vulnerabilities.

Method

213 individuals from the Harvard Aging Brain Study (mean age:71.6 years, 58% female; 11% cognitively impaired; Figure 1) who underwent 3T LC‐MRI, Ab‐ and tau‐PET imaging were included. Of these, 62 individuals received a second MRI and PET session. For the LC, we extracted the 5 highest normalized intensity voxels. PET‐data was referenced to cerebellar gray and partial volume corrected. Linear regressions associated LC integrity to tau or Ab and variance contributions were quantified. Mixed effects models examined LC changes to changes in tau or Ab. Mediation analyses examined whether local Ab mediated relationships between LC integrity and local tau. Analyses were adjusted for age, sex and multiple comparisons using FDR‐correction.

Result

LC integrity was negatively associated with medial‐lateral temporal tau, and widespread Ab. Multivariable analyses demonstrated that LC integrity associated uniquely with tau in medial temporal lobe (MTL) regions and with Ab in frontoparietal regions. LC integrity was associated with both tau and Ab in inferior temporal (IT) and posterior cingulate cortices, and mediation analyses showed that LC integrity – tau associations in these regions were Ab‐mediated (Figure 2). Longitudinal analyses revealed stronger local associations between LC integrity and tau changes, compared to Ab. LC integrity changes were uniquely associated with tau changes in MTL, but longitudinal LC integrity‐IT tau correlations were mediated by local Ab (Figure 3).

Conclusion

The LC may have anatomically distinct cortical tau and Ab‐pathways in AD, with MTL correlations being almost uniquely tau‐related, frontoparietal associations uniquely Ab‐related and lateral temporal regions showing Ab‐mediated tau accumulation. Potential underlying mechanisms can include synaptic plasticity alterations, glial activation or neuronal hyperactivation.
Never too late: Episodic memory after basic literacy acquisition in illiterate adults
Authors: Resende Elisa de Paula França , Santos Tomaz Kelle Luisa , Friedlaender Clarisse Vasconcelos , Rocha João Victor de Faria , Lourandes Aida , Ruppert Emma Patrice , Assenção Joanna de Castro Magalhães , Grinberg Lea T. , Rosen Howard J. , Rincon Luciana Paula , Ribeiro Norton Gray Ferreira , Constantina Dulce , Zacarias Ana Paula , Caramelli Paulo , Maciel Francisca Izabel Pereira
Published: December 2023

Background

Formal education acquired early in life protects against dementia, but whether acquiring education later in life can decrease dementia risk is less clear. Episodic memory impairment is one of the first symptoms of Alzheimer’s Disease. Therefore, we aimed to identify whether a late life literacy training delivered to illiterate adults could improve episodic memory as a mechanism of cognitive reserve enhancement, eventually contributing to prevent dementia in this population.

Methods

We ran a clinical trial with 108 illiterate adults cognitively healthy allocated into two groups at baseline: the intervention group (n = 57) that attended classes focused on learning how to read and write and the control group (n = 51), that attended regular classes (not focused on literacy training), for 6 months. We used the Free and Cued Selective Reminding (FCSRT) test to evaluate the episodic memory. Participants also underwent a thorough neuropsychological investigation and rsfMRI. The primary outcome measure was defined as the change in the free recall sum‐of attempts scores of the FCSRT. We used linear mixed effect models to calculate the change over time and between the intervention and control groups controlling for age and sex. ClinicalTrials.gov Identifier: NCT04473235

Results

Seventy seven participants completed the study. The control group had 38 participants aged 58.5 ±8.5 years, being 78.9 women and 92.1 Blacks. The intervention group had 39 participants aged 59.6 ±9.7 years, 79.5 women and 87.1 Blacks, with no significant differences in demographics between groups. Participants improved their episodic memory over time (FCSRT free recall sum of attempts: F = 21.5, p<0.001, FCSRT delayed recall: F = 27.1, p<0.001 and FCSRT efficacy: F = 26.2, p<0.001, but with no difference between the control and the intervention groups. The rsfMRI measurements are under analysis.

Conclusion

Attending a late life literacy program in adulthood improved episodic memory, regardless of whether the intervention was focused on learning how to read and write or just attending regular classes. The results shed light into a possible low cost tool to increase cognitive reserve through improving episodic memory, eventually preventing dementia in vulnerable populations.
Psycho‐social impact of the diagnostic work‐up at a specialized, fast‐track memory clinic
Authors: Abaci Alara , Hendriksen Heleen M.A. , Aspö Malin , Sundell Maria , Wiggenraad Fleur , Rydén Marie , Kivipelto Miia , van der Flier Wiesje M. , Mangialasche Francesca , Visser Leonie N.C.
Published: December 2023

Background

Increasing numbers of concerned individuals seek diagnosis, information, and treatment at memory clinics. Biomarker tests for Alzheimer’s disease (AD) are being increasingly integrated into memory clinic practice, yet data about the implications for patients are lacking. We aimed to investigate the psycho‐social impact of the routine diagnostic work‐up with integrated biomarker assessments.

Methods

This observational study was conducted at the Karolinska University Hospital memory clinic (Solna, Sweden), in the context of the EU‐Fingers and LETHE projects. The harmonized diagnostic work‐up at this fast‐track clinic is comprehensive, including a neuro‐psychological evaluation, MRI, and CSF. All patients receive detailed results. From October 2021‐May 2022, all newly‐referred patients with MMSE>18 were invited, and 78/106(74%) eligible patients (59±5yrs, 50%F) completed >1 questionnaire‐assessments; after the first consultation(T1), just prior to(T2) and immediately after(T3) the disclosure consultation, and three months afterwards(T4). Questionnaires assessed Positive and Negative affect (T1/T2/T3/T4), Quality of Life (T1/T4), Stigma (T4), and Lifestyle change (T4). Patients received the following diagnoses: 51 SCD with negative AD‐biomarkers(SCD‐), 10 MCI with negative AD‐biomarkers(MCI‐), 3 MCI with positive AD‐biomarkers(MCI+), 11 Dementia, and 3 Other. In (repeated‐measures) ANOVAs, we compared time points and/or those with SCD‐/MCI‐ with MCI+/Dementia.

Results

See Table 1 for Means (SD). The trajectories of both positive (p<.01) and negative (p<.01) affect were influenced by diagnosis (Fig. 1); those who received an MCI+/Dementia diagnosis temporarily decreased in positive affect and increased in negative affect, while we observed the opposite in those with SCD‐/MCI‐. For quality of life (Fig. 2), we found no change over time (p = .38), nor an effect of diagnostic group (p = .31). No group difference was found in perceived stigma (p = .52). Those who received an MCI+/Dementia diagnosis reported more healthy‐lifestyle changes, than those with SCD‐/MCI‐ (p<.01).

Conclusion

Patients’ feelings fluctuated throughout the diagnostic work‐up, influenced by the received diagnosis. Three months after, diagnostic groups did not differ in psycho‐social impact, except for lifestyle change. More research is needed to investigate the needs, outcomes and experiences of the increasing number of individuals without AD‐pathology who experience symptoms and seek care, to understand whom and when they can benefit (most) and from which healthcare setting/service.
Real‐world use and cost of health and social care services of 18,116 patients living with Alzheimer’s disease
Authors: Edwards Sophie , Hahn‐Pedersen Julie Hviid , Robinson Danielle E , Chan Mei Sum , Bray Benjamin D , Clark Alice , Ivkovic Milana , Michalak Wojciech , Wichmann Christian Ahmad , Berry Sasha D , Evans Marc
Published: December 2023

Background

The increasing prevalence of Alzheimer’s disease (AD) will substantially impact health and social care systems worldwide. In this study, we aimed to estimate the real‐world use and cost of health and social care services in a large cohort of AD patients in the United Kingdom.

Method

We conducted a retrospective cohort study using Discover‐NOW, a real‐world database containing linked primary and secondary care electronic health records of people living in North‐West London, England. A total of 18,116 patients diagnosed with AD were followed from first observed AD diagnosis to end of patient follow up, within the time window from 1 January 2010 to 31 December 2021. The baseline prevalence of 33 comorbidities, survival duration, health and social care resource utilisation and total direct health and social care costs (in 2019 terms) were estimated.

Result

Of 18,116 patients with AD, 8,970 (50%) used social care after diagnosis. Most patients using social care were female (65% vs 62% in the general AD population) and were a similar age at diagnosis (median 82 years) compared to those who did not. Of the patients with social care utilisation, 5,248 (59%) resided in care homes and 2,636 (29%) received domiciliary care at home. Annual direct social and health care costs for each patient receiving social care were £25,664 and £6,248 respectively, constituting an annual total cost of £31,912. Median survival from time of AD diagnosis was 4.9 years in the general AD population and 1.9 years after care home admission. Patients who entered care homes, entered at a median age of 85 years and had higher baseline prevalence of stroke (11% vs 7%), chronic kidney disease (40% vs 35%), and atrial fibrillation (17% vs 13%) than the general AD population.

Conclusion

In AD patients who used social care, social care costs were >4 times other healthcare costs. Slowing or delaying the requirement for social care would have a major impact on reducing the societal and economic burden of AD on patients and society.
Mild brain injury aggravates gliosis, toxic tau, and anxiety in the P301S model of TAUopathy
Authors: Marco Ana Royo
Published: December 2023

Background

Traumatic Brain Injury (TBI) is a known risk factor for developing a neurodegenerative disease later in life, including Alzheimer’s Disease (AD) and other forms of tauopathy such as chronic traumatic encephalopathy (CTE) and frontal‐temporal dementia (FTD). Although several studies highlight the relationship between the severity and frequency of a TBI and the development of these tauopathies, the mechanism behind this association remains unknown. Proper meningeal lymphatic function is required for clearance of waste products and protein aggregates such as amyloid beta and tau from the brain parenchyma. While post‐TBI inflammation is beneficial for clearing debris and promoting tissue repair, prolonged glial activation and decreased meningeal lymphatic drainage have been linked to worsened cognitive function.

Method

A mild TBI (mTBI) was delivered to three‐month‐old young adult mice overexpressing P301S mutant human tau (PS19) through the skull on the right inferior temporal lobe of the brain. Sham and TBI injured mice were tested on behavioral tests at 5 months of age. At 7 months of age, brains were examined for tau pathology and neuroinflammation using confocal microscopy.

Result

Four months after mTBI, the brains of TBI PS19 mice exhibit increased levels of microglia and astrocytes, and increased P‐S202/T‐205‐Tau in the cortex and thalamus of the ipsilateral hemisphere compared to the contralateral side and to Sham PS19 controls. These findings correlate with our behavior study showing increased hyperactivity, risk‐taking behavior, and impaired short term working memory. PS19 TBI mice also present larger ventricles than their uninjured controls suggesting a potential loss of white matter in the cortex and/or hippocampus.

Conclusion

P‐S202/T‐205‐Tau orginated from the cortex near the injury site can aggregate and promote the formation of more toxic tau that spreads to deeper regions of the cortex and in the thalamus primarily through the thalamocortical circuit. Also, microglia and astrocyte activation and production of inflammatory mediators has been associated with synapse pruning and engulfment of damaged neurons expressing ‘eat me signals’ leading to neurodegeneration.
The APOE4 Allele Exacerbates Pathology in a Mouse Model of Prion Disease
Authors: Lizińczyk Anita M , Pankiewicz Joanna E. , Franco Leor A. , Diaz Jenny R , Sullivan Patrick M , Sadowski Martin J.
Published: December 2023

Background

The APOE4 allele is the strongest genetic risk factor in sporadic Alzheimer’s disease (AD). In allele‐dose dependent manner APOE4 increases AD risk, lowers age of onset, and accelerates the rate of dementia progression. Like AD, prionoses are conformational neurodegenerative disorders, which neuropathological hallmarks include accumulation of disease specific misfolded protein(s) and presence of reactive astrocytes and microglia. Accumulation of PrPSc, a toxic conformer of the cellular prion protein‐PrPC, is the initial culprit in prion pathogenesis. PrPSc buildup is associated with the presence of A1 neurotoxic astrocytes and neurodegenerative phenotype microglia (MGnD), which proinflammatory character contributes importantly to neurodegeneration in prionoses. Despite similarities between AD and prionoses, and established effects of APOE4 on misfolded protein accumulation and MGnD activation in AD, effects of the APOE genotype on prion pathology remain uninvestigated.

Method

APOE2, APOE3, and APOE4 targeted replacement mice were inoculated with 22L mouse adapted scrapie strain or normal brain homogenate (NBH) and subjected to repetitive behavioral testing. They were sacrificed at 15 or 23 weeks post inoculation (WPI), when they remained presymptomatic or showed overt neurological symptoms. Neuropathological and biochemical analyses were performed at either timepoint, while NanoStringTM analysis of microglia and astrocyte transcriptomic markers was done at 23WPI.

Result

APOE4 mice feature significantly shorter incubation period and more severe burden of neurological symptoms following prion inoculation than APOE2 and APOE3 mice. Neuropathological analysis reveals significantly higher burden of spongiforms changes in the brain cortex and greater load of reactive astrocytes and microglia in APOE4 mice compared to other APOE genotypes. APOE4 mice also show the highest level of total PrP and PrPSc and insoluble/soluble PrP index. Transcriptomic analysis reveals prion inoculation effects marked elevation of PAN and A1 reactive astrocyte markers, MGnD markers, and in pro‐inflammatory chemokines and cytokine receptors transcripts across all APOE genotypes but the NBH‐relative increase is the highest in APOE4 mice.

Conclusion

The APOE4 allele promotes prion neurodegeneration through two separate mechanisms. It is associated with greater PrPSc accumulation and toxicity suggesting its role in the PrPSc metabolism and clearance. It also promotes acquisition of A1 and MGnD neurotoxic phenotypes by astrocytes and microglia, respectively.
Discrimination of Healthy Controls and Patients with Mild Cognitive Impairment based on Time‐Varying Functional Connectivity Analysis of Resting‐State EEG
Authors: Deng Jinxian , Sun Boxin , Li Tongtong , Kavcic Voyko , Hampstead Benjamin M. , Morgan Dave , Liu Mingyan , Giordani Bruno
Published: December 2023

Background

Developing economically viable assessment tools that are highly sensitive to cognitive decline and neural dysfunction is critical for the study of neurodegenerative mechanisms and interventions to promote cognitive resiliency. Due to its high time resolution, accessibility, and affordability, EEG‐based detection of cognitive impairment is attracting considerable attention from the research community.

Method

Our research is based on resting‐state EEG (eye‐closed, 64‐channel), and the current dataset includes 137 consensus‐diagnosed, community‐dwelling African Americans (ages 60‐90 years, 84 Normal Cognition, NC; 53 Mild Cognitive Impairment, 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 first conducted joint time‐frequency‐spatial analysis on the time‐varying functional connectivity of all the possible pairs between the selected EEG regions of interest and generated the feature vectors for each subject. The selected features were then fed into a machine learning algorithm for the discrimination of NC and MCI. By tuning the observing window size (in time‐domain) and the number of features used, we obtained a series of different configurations of the discrimination model between NC and MCI, each with its own accuracy. The overall result is a combined output of the model under different configurations.

Result

The accuracy of the discrimination model was calculated under different window sizes and numbers of features. Our result shows that there are 11 window‐size‐and‐feature configurations which can achieve an accuracy in the range of 80.29%∼86.86%. We selected 21 configurations as voters and get the final discrimination result through majority voting (+1 for NC and ‐1 for MCI). Moreover, we obtained a soft output (i.e., a likelihood score) for each subject by combining all the votes which were weighted using the accuracy of each voter. For the 137‐sample dataset we are working with, the 10‐fold cross‐validation accuracy of the model is 91.97%.

Conclusion

Our analysis indicates that EEG‐based time‐varying function connectivity analysis is a promising technique for early detection of MCI. Potentially, the soft output we obtained for each subject might be used for prediction of possible cognitive decline.
Exploring the role of brain DNA methylomic signatures on gene expression dynamics of frontotemporal lobar degeneration
Authors: Fodder Katerine , Murthy Megha , Rizzu Patrizia , Toomey Christina E. , Hasan Rahat , Humphrey Jack , Raj Towfique , Lunnon Katie , Mill Jonathan , Heutink Peter , Lashley Tammaryn , Bettencourt Conceição
Published: December 2023

Background

Frontotemporal lobar degeneration (FTLD) is an umbrella term describing the neuropathology of a clinically, genetically and pathologically heterogeneous group of diseases, which includes frontotemporal dementia and progressive supranuclear palsy. About 90% of the FTLD cases show either TDP‐43 or tau pathology (FTLD‐TDP or FTLD‐tau, respectively). Though aberrant brain DNA methylation has consistently been associated with Alzheimer’s disease and other neurodegenerative diseases, studies on FTLD are scarce. The main goal of this study was to investigate DNA methylation variation in FTLD bulk brain tissue and brain‐derived nuclei.

Methods

We used bulk frontal cortex genome‐wide DNA methylation profiles (Illumina 450K or EPIC microarrays) from three FTLD cohorts (N = 228). To identify unique and shared differentially methylated loci across FTLD subgroups/subtypes, we performed cohort‐specific epigenome‐wide association studies (EWAS) followed by a meta‐analysis. Additionally, we used weighted gene correlation network analysis to identify co‐methylation signatures associated with FTLD, FTLD pathological subtypes, and other disease‐related traits. To identify disturbed cell‐types and biological processes within disease associated signatures, we then carried out cell‐type and functional enrichment analyses. We also generated and have ongoing analysis of DNA methylation profiles (EPIC microarrays) of neuronal (NeuN+) and glial nuclei (NeuN‐) from FTLD‐TDP cases and controls (N = 40). Wherever possible, we also integrated additional DNA methylation, and gene and protein expression datasets.

Results

In bulk tissue, the EWAS meta‐analysis identified four shared differentially methylated loci in FTLD, including hypomethylation in OTUD4, a gene we found to be upregulated (mRNA and protein) in FTLD. Two of the four meta‐analysis hits (mapping to OTUD4 and CEBPZ), were found to be co‐methylated within signatures strongly associated with FTLD. Disease‐associated signatures implicate transcription regulation, the ubiquitin system, RNA/stress granule formation and glutamatergic synaptic signalling, and specific brain cell‐types, including pyramidal neurons and oligodendrocytes, in FTLD. Preliminary analysis of the neuronal and glial datasets also revealed FTLD‐associated DNA methylation signatures, which will further inform on cell‐type‐specific changes in FTLD.

Conclusions

Our findings identified novel FTLD‐associated loci, including OTUD4, and point to DNA methylation as an important mechanism in the dysregulation of biological processes relevant to the FTLD pathogenesis, such as RNA/stress granule formation.
Electroconvulsive therapy parameters for behavioral and psychological symptoms of dementia
Authors: Kapustin Daniel , Nidumolu Aditya , Amanullah Shabbir , Hassan Sameh
Published: December 2023

Introduction

Behavioral and Psychological Symptoms of Dementia (BPSD) are a heterogenous group of non‐cognitive symptoms impacting up to 90% of patients with dementia, and include emotional disturbance, psychosis, agitation, aberrant motor behavior, and circadian rhythm disturbance. Multiple reviews have found ECT to be efficacious in treating BPSD that have not responded to other interventions. However, no published guidelines exist to inform clinicians about how protocols for ECT should be implemented in the treatment of BPSD. This study aims to identify ECT parameters commonly utilized for BPSD in the literature.

Methods

MEDLINE and APA PsychInfo were searched from database inception until September 2022. Two reviewers independently screened and full text reviewed the retrieved articles. Articles included in the full text review stage discussed how ECT is implemented for patients experiencing BPSD.

Results

After duplicate removal, 800 unique citations were identified for screening. Of these, 160 were included in full text review. 32 studies were ultimately included (Figure 1). Characteristics of included studies are highlighted in Figures 2 and 3.

Most studies utilized thrice weekly ECT, however, twice weekly was suggested to carry a lower risk of ECT‐related cognitive side effects. The number of sessions needed for response ranged between 2‐15, with improvement typically observed within 3‐6 treatments. The choice between unilateral and bilateral placement rests on weighing the risk of confusion with improved clinical response. Multiple authors recommend starting with unilateral treatment to reduce cognitive side effects and switching to bilateral if response is inadequate after 3‐5 sessions. Typical pulse width was 0.30‐0.37ms for ultrabrief and 1‐2s for brief treatment. Minimum recommendations for adequate seizure duration varied from 25 to 30 seconds on EEG and 15 to 20 seconds by observed motor movements. Stimulus dosage ranged between 1.5‐2.5x seizure threshold for bilateral placement, and 4‐6x seizure threshold for unilateral placement. Maintenance ECT was commonly used to reduce the risk of relapse.

Discussion

ECT is both safe and efficacious for patients with BPSD, and the present review focuses on commonly implemented ECT parameters in the literature. Notably, studies are limited by inconsistent reporting of ECT parameters and short follow‐up durations.
Intra‐cellular accumulation of Aβ and pTau in Alzheimer’s disease is neuronal‐subtype specific
Authors: Caramello Alessia , Jackson Johanna , Hardy John A. , Matthews Paul M
Published: December 2023

Background

Neuronal degeneration in Alzheimer’s disease (AD) is believed to selectively affect a subset of vulnerable neurons (VNs) first. Here we sought to define intrinsic cell characteristics and local pathology involving pTau and b‐amyloid (Aβ) associated with VNs with the long‐term objective of developing cell type‐specific neuroprotective therapies.

Method

We analysed 43 post‐mortem human middle temporal gyri (MTG) from controls and AD donors, bearing either the common variant (CV) or the AD high‐risk R47H/R62H TREM2 variants (TREM2var; Fancy et al., 2022). To identify VNs and characterize their morphology, local β‐amyloid and pTau and glial activation, we developed an antibody panel for imaging mass cytometry (IMC) that included 21 markers for synapses, excitatory and inhibitory neurons, 10 markers for astrocytes, oligodendrocytes, and microglia, and 3 for Aβ, pTau and APP. The SIMPLI pipeline (Bortolomeazzi et al., 2022) was used for image processing, analysis, and clustering. Data and statistical analysis were performed in R using T test corrected for multiple testing.

Result

Individual neuronal populations are not significantly reduced in AD samples compared to controls, both in total number and layer‐specific distribution. While extra‐cellular pTau and Aβ accumulation was increased in AD samples, intra‐cellular signal for Aβ was higher in controls (13.76±5.95% Aβ+ cells) than with AD, particularly in AD TREM2var cases (6.4±2.82%; p = 0.0035). Ab accumulated particularly in VIP+, PCP4+ and RORB+ neurons (6.58x, 4.82x and 4.38x more Aβ+ these neurons in the control vs. AD TREM2var), the former also showing highest proportion of APP expressing cells in controls. Compared to controls, pTau accumulation in AD TREM2var was increased 2‐3x in few neuronal subpopulations (ADARB1, CALB1, GAD1, NPY, VIP), with RORB+ cells having the most striking increase (51.95x).

Conclusion

Intra‐cellular accumulation of pTau and Aβ is cell‐type specific, selectively involving RORB+ and VIP+ neuronal subpopulations. Greater Aβ accumulation was found in samples from Braak stages <III, suggesting these pathological aggregates long anticipate neuronal death. Analysis of brain regions affected earlier in AD will be used to test this hypothesis.