bluuebunny/crossref_metadata_2025 huggingface dataset:
Is rs242561 a regulator of tau expression in adult mice?
Authors: DAS Rueben G , Choi Eirene , Sgourdou Paraskevi , Bernard Tia , Dombroski Beth A. , Schellenberg Gerard D.
Published: December 2022

Background

Microtubule associated protein tau (MAPT) is a major risk gene for multiple neurodegenerative diseases including Progressive supranuclear palsy (PSP), Corticobasal degeneration (CBD) and Alzheimer’s disease (AD) where disease specific imbalance in 3R: 4R tau isoforms is noted. Since pathogenic mutations in the coding region of MAPT is minimal in these diseases, it is likely that the deviation from the normal equimolar concentration of 3R: 4R tau is due to altered regulation through its regulatory elements. One such potential regulator is suspected to be MAPT intronic SNP, rs242561. This SNP lies within NRF2‐bound anti‐oxidant response element and is actively transcribed in hippocampus but repressed in most non‐brain tissues. It is also a chromHMM enhancer in substantia nigra. However, expression studies on this SNP are discordant and inconclusive. In the present study we investigate whether rs242561 has any role in tau regulation in mice.

Method

We deleted 756 bp sequence encompassing the syntenic base of rs242561 in mouse by CRISPR‐Cas9 genome editing. Brain tissues from cortex, cerebellum and hippocampus were dissected from adult wild type, heterozygous and homozygogus mice with the deletion to study expression of tau.

Result

We observed reduced level of tau in cortical tissues of adult heterozygous and homozygous mice (heterozygote< homozygote) than the wild type but not in hippocampus and cortex.

Conclusion

Our preliminary study suggests rs242561 might have a role in regulating the expression of tau in adult mice cortex.
Vascular and Microstructural Markers of Cognitive Pathology
Authors: Coffin Claudia Ashlyn , Suerken Cynthia , Bateman James R. , Whitlow Christopher T. , Williams Benjamin J. , Espeland Mark A. , Sachs Bonnie C. , Cleveland Maryjo , Yang Mia , Rogers Samantha D. , Hayden Kathleen M. , Baker Laura D. , Williamson Jeff D. , Craft Suzanne , Hughes Tim M. , Lockhart Samuel N.
Published: December 2022

Background

Arterial stiffness may play a role in the development of dementia, presumably through its effects on white matter integrity and hyperintensities (WMH). However, relationships among arterial stiffness, white matter microstructure, and WMH volumes remain poorly understood. Arterial stiffness increases monotonically with age and its increase is accelerated by cardiometabolic disorders (e.g., hypertension , metabolic syndrome, diabetes). Further exploration of these relationships is key to the development of targeted therapies, early management, and detection.

Method

Arterial stiffness was measured using carotid‐femoral pulse wave velocity (cfPWV) in ADRC participants with baseline systolic blood pressure (SBP) measurements, detailed cognitive testing, cognitive adjudication, and brain MRI. We examined associations of cfPWV and SBP with cognitive function (Montreal Cognitive Assessment [MoCA], Preclinical Alzheimer’s Cognitive Composite [PACC5], and domain measures of memory and executive function) and brain MRI measures of: macrostructure (volume of gray matter [GM] and WMH from T1‐weighted and FLAIR imaging), white matter microstructure (neurite orientation dispersion and density imaging [NODDI] free water [FW] and diffusion tensor imaging [DTI] fractional anisotropy [FA]), and cerebral blood flow (CBF) in white matter (WM) and GM. Age, race, gender, education, and APOE‐4 status were included as covariates and in interaction terms in linear regression analyses.

Result

Among 458 participants with a mean age 70±8 years and cognitive adjudication (44 dementia, 157 MCI, 257 normal cognition; Table 1), higher cfPWV was associated with worse cognitive performance (MoCA, PACC5), as was SBP (MoCA, PACC5, executive domain, language domain; Table 2). Higher cfPWV was associated with differences in WM microstructure (higher FW, lower FA) and higher WMH volume. While no overall associations between cfPWV and CBF were detected, cfPWV had stronger associations with FW, FA, and WMH in men. Higher SBP was associated with higher FW, higher WMH volume, and lower WM and GM CBF (Table 3). SBP had stronger associations with WMH in younger participants (<70y) and GM CBF in Black/AA participants and participants with impaired fasting glucose. No other interactions were detected.

Conclusions

Arterial stiffness is associated with microstructural and macrostructural differences and poorer global and executive cognitive function.
Investigating Aß42, P‐Tau and NFL as blood‐based biomarkers for diagnosis of Alzheimer’s disease in Pakistani population
Authors: Ahmed Tehniat F , Imtiaz Fauzia , Ahmed Affan , Zaman Uzma , Shahbaz Naila
Published: December 2022

Background

Overlapping symptoms of different neurodegenerative dementias and heterogeneity in the presentation of Alzheimer’s disease (AD) pose a challenge to its diagnosis in clinics. The AT(N) research framework proposed by National Institute of Ageing‐Alzheimer’s Association in 2018 assigned its diagnosis a molecular construct. However, in Pakistan the diagnosis of AD still rests on clinical exclusionary approach. As an initial step towards establishing accessible and affordable biochemical diagnosis of AD in Pakistan, we for the first time investigated the plasma levels of Amyloid‐β42 (Aβ42), Phosphorylated tau (P‐tau) and Neurofilament light (NFL) in patients with Alzheimer’s Clinical Syndrome (ACS) and healthy controls (HC) from Pakistani population.

Method

Subjects presenting with cognitive decline to neurology OPDs of two tertiary care hospitals of Karachi, Pakistan were recruited through convenience sampling after being diagnosed with ACS by the attending neurophysician. Following informed consent, demographic and lifestyle details, along with 5cc blood in EDTA tubes were obtained. Plasma was aliquoted and stored at ‐800C after centrifugation. For analysis it was thawed at 4°C and protein levels were measured through ELISA. Data of 28 subjects with ACS and 28 age‐matched healthy controls was analyzed using USCN Business Co. Ltd kits CE946Hu and SEE038Hu for Aβ42 and NFL respectively, and Bioassay Technology Laboratory kit E4844Hu for P‐tau.

Result

The only demographic variables associated with health status were education and depression status of the subjects (p=0.03 and 0.003 respectively). Mean values of NFL and P‐tau showed significant difference between ACS and control groups (p=0.003 and 0.006) while Aβ42 showed no significant difference (p=0.114). ROC analysis revealed that plasma P‐tau and NFL could significantly differentiate ACS from HC group (p=0.007 and 0.003) with AUC 0.717 and 0.735 respectively. Significant negative correlation with MMSE score of subjects was seen for both plasma P‐tau (r = ‐0.389; p=0.004) and NFL (r= ‐0.424; p=0.001) levels.

Conclusion

Plasma P‐tau and NFL hold promise for distinguishing AD patients from healthy controls. This is the first such study conducted in Pakistan. Larger, similar studies can help employ non‐invasive tests for AD screening in the country.
Tablet training at home for people with dementia and their caregivers during pandemic
Authors: Blekou Patra , Sakka Paraskevi , Zoi Panagiota , Kalligeros Nikolaos
Published: December 2022

Technology has provided some wonderful tools both for people with dementia and their caregivers by creating applications that empower seniors to live more actively and independently and remotely connect with family and friends.

Since covid‐19 pandemic started, Alzheimer Athens has been offering to its members a wide range of digital services, providing online support, cognitive training, physical exercise programs, as well as opportunities to relax, socialize and have fun. However, in Greece, low level of digital literacy of elderly people with dementia and their caregivers have been key obstacles to the use of appropriate technological tools (PCs, tablets, smartphones etc.).

To address this issue and explore the impact of tablet training on cognitive status, social engagement and quality of life, Alzheimer Athens has developed a 12‐month program of tablet training at home. The program started in August 2021 and will be completed in July 2022. In total, 120 people with dementia and their caregivers receive a free tablet and attend a series of 16 weekly workshops teaching basic skills allowing participants to feel confident using a tablet. Internet access is also provided free of charge for 12 months.

Social isolation, loneliness, social support, and quality of life of participants were assessed before and after the intervention. Data on tablet use and attitudes toward technology tools were also collected. The overall experience of the 60 people with mild cognitive impairment and early dementia who participated in the first phase of tablet training intervention was extremely positive. The vast majority of them started using Alzheimer Athens digital services shortly after the training had been completed!

Detailed results of the questionnaires used to assess all aspects of the intervention, will be reported at the end of it. We aspire our preliminary and very encouraging findings will help us develop more successful interventions utilizing new technologies and create better health outcomes for people with dementia in the future as we move into a post‐COVID‐19 world.
In‐season docosahexaenoic acid supplementation does not prevent white matter damage during a single American football season: Implications for neurodegeneration prevention
Authors: Raikes Adam C. , Hernandez Gerson D , Mullins Veronica A. , Wang Yiwei , Lopez Claudia M , Killgore William D. S. , Chilton Floyd , Brinton Roberta Diaz
Published: December 2022

Background

Repetitive sub‐concussive head impacts (RSHIs) are common in American football, result in changes to white matter microstructural integrity, and are suggested as a potential risk factor for neurodegenerative diseases, including Alzheimer’s disease. RSHI‐induced white matter degradation may accelerate neurodegenerative processes, necessitating effective preventative and therapeutic approaches in this population. Prior studies indicate potential neuroprotective and remyelinating effects of docosahexaenoic acid (DHA). Here, we conducted a double‐blind, randomized, placebo‐controlled trial to assess the effects DHA supplementation during a National Collegiate Athletic Association football season on neuroimaging measures of white matter integrity.

Method

Thirty‐eight participants were randomized to treatment (6g DHA/EPA) or placebo (6g oleic/linoleic acid) group for seven months of five‐times‐per‐week supplementation. 27 participants completed the trial and had complete neuroimaging datasets (n = 16 placebo; n = 11 treatment). White matter integrity changes from preseason to immediately post‐season were quantified using voxel‐wise fractional anisotropy and diffusivity (mean, axial, radial) as well as deterministic tractography using quantitative anisotropy (QA). Gray matter volume as well as intra‐regional, edge‐wise, and network level functional connectivity were obtained as secondary measures along with serum neurofilament light (NfL) as a peripheral biomarker of axonal damage.

Result

There were no voxel‐wise, between‐group differences in voxel‐wise DTI analyses. Compared to placebo, the treatment group had increased QA in ascending corticostriatal fibers and decreased QA in long association and commissural fibers. Increased mean (ρ = 0.47), axial (ρ = 0.44), and radial (ρ = 0.51) diffusivity and decreased QA (ρ = ‐0.52) in the corpus callosum and bilateral corona radiata were correlated with increasing NfL levels during the season irrespective of treatment group. Default mode/frontoparietal network connectivity (g = 0.96, p = 0.024) was greater in the treatment group.

Conclusion

In‐season DHA supplementation was insufficient to prevent or protect against axonal damage as it occurred during the season. However, there may be neuroprotective effects on functional connectivity despite structural damage. If RSHIs are a risk factor for future neurodegeneration, then alternative therapeutic merit further investigation. These present outcomes do not support the use of in‐season DHA supplementation as a preventive strategy to reduce brain injury resulting from collegiate football.

Acknowledgement

Study funded by the Center for Innovation in Brain Science, University of Arizona. DHA provided by Pharmavite
Clinical features in prodromal disease: Comparing dementia with Lewy bodies with Alzheimer’s disease
Authors: Wyman‐Chick Kathryn A , Boeve Bradley F. , Weintraub Daniel , Armstrong Melissa J , O'Keefe Lauren R , Rosenbloom Michael H , Barrett Matthew J
Published: December 2022

Background

Dementia with Lewy bodies (DLB) is a common neurodegenerative disorder; however, DLB can be difficult to differentiate from Alzheimer’s disease dementia (AD), particularly in the early stages. Research criteria for prodromal DLB were published in 2020 and further studies are needed to validate and refine future clinical criteria.

Method

We analyzed data from the Uniform Data Set from the National Alzheimer’s Coordinating Center (NACC database is funded by NIA/NIH U01‐AG016976). Annual visits occurred across 39 Alzheimer’s Disease Research Centers between September 2005 and September 2021. We identified non‐demented participants [i.e., normal cognition, impaired‐not mild cognitive impairment (MCI) or MCI] at baseline who subsequently received a clinical diagnosis of DLB or AD. Core clinical features (CCF) for DLB (i.e., motor features, visual hallucinations, probable REM sleep behavior disorder (pRBD), cognitive fluctuations), and supportive neuropsychiatric features (NPF; anxiety, apathy, and depression) were assessed through clinical exam and informant responses up to five years prior to dementia diagnosis.

Result

The sample consisted of 160 participants with DLB and 480 age/sex‐matched (1:3) participants with AD at first visit with dementia diagnosis. There was no significant difference in the number of visits prior to dementia diagnosis. The AD group was more racially and ethnically diverse than the DLB group. At the time of diagnosis, DLB participants demonstrated greater functional impairment. Descriptive results indicate CCF and NPF are common in DLB up to five years prior to conversion to dementia; however, motor slowing and NPF were reported in over 20% of the AD participants within the prodromal phase. The presence of 2 or more CCF yielded the greatest AUC (0.786; 95% CI: 0.743, 0.830) in distinguishing DLB from AD one year prior to dementia diagnosis. Combinations of 1 or more CCF with 1, 2, or 3 NPF resulted in significantly lower AUCs (0.725, 0.651, 0.547, respectively) due to decreased specificity.

Conclusion

CCF and supportive NPF are common in the prodromal phase of DLB; however, parkinsonism and NPF also occurred in the prodromal AD group. Parkinsonism may provide lower discrimination than cognitive fluctuations, visual hallucinations, or pRBD in differentiating DLB from AD in the prodromal phase.
Selective inhibition of ACE‐2‐interacting domain of SARS‐CoV‐2 by AIDS peptide attenuates Spike S1 associated behavioral and neuronal inflammation in in vitro and in vivo models
Authors: Paidi Ramesh Kumar , Pahan Kalipada
Published: December 2022

Background

Coronavirus disease 2019 (COVID‐19) is a serious contagious illness caused by the virus strain severe acute respiratory syndrome coronavirus 2 (SARS CoV‐2). Covid‐19 patients are suffered from various brain complications, but underlying mechanism is not clear. So far, there is no proper therapeutic strategy against Covid‐19 and its implications on the brain.

Method

Since SARS‐CoV‐2 binds to angiotensin‐converting enzyme 2 (ACE2) for entering into host cells, to target COVID‐19 from therapeutic angle, we designed a hexapeptide corresponding to the ACE2‐interacting domain of SARS‐CoV‐2 (AIDS) that inhibits the association between receptor‐binding domain‐containing spike S1 and ACE‐2. Initially, we have validated the effect of AIDS peptide and the its role in Spike S1 associated neuroinflammatory alteration in mouse primary glia cultures. For in vivo, recombinant spike S1 was administered Intranasally for 14 days. Wild type and mutant AIDS peptide were administered post 5 days treatment of spike S1. Post two weeks treatment, we performed several behavioral assessment and biochemical evaluation

Result

Increased INOS levels and microglia activation was observed by Spike S1 treatment in mice primary microglia. AIDS peptide prominently attenuates Spike S1 associated inflammatory markers in glia cultures. Intranasal intoxication of C57/BL6 mice with recombinant SARS‐CoV‐2 spike S1 led to fever, increase in IL‐6 in lungs as well as in brain, and impairment in spatial learning memory functions and motor disabilities, mimicking some of the important symptoms of COVID‐19. Intranasal treatment with wtAIDS, but not mAIDS, peptide reduced fever, enhanced locomotor functions and cognitive and memory functions in SARS‐CoV‐2 spike S1‐intoxicated mice. Our studies show wtAIDS peptide attenuates Spike S1 inducted cytokine levels in the brain.

Conclusion

Our results illustrated that, selective targeting of ACE2‐to‐SARS‐CoV‐2 interaction by wtAIDS may be beneficial for COVID‐19 associated memory and learning deficits via maintaining the cytokine levels
Physical activity reverted the increased risk of dementia associated with cardiovascular risk factors: findings a population‐based cohort study
Authors: Feter Natan , Dumith Samuel C , Leite Jayne S , Cunha Larissa , Rombaldi Airton
Published: December 2022

Background

Cardiovascular risk factors are associated with a higher risk of dementia. However, whether physical activity could revert this increased risk remains uncertain. We analyzed the effect of physical activity on the risk of dementia stratified by cardiovascular risk factors.

Methods

Data from baseline (2002‐2003) to wave 9 (2018‐2019) of the English Longitudinal Study of Ageing (ELSA) were analyzed (n = 6,021). The wave that dementia was first detected after baseline was defined as the event time. Self‐reported physical activity (inactive, low, moderate, high) at baseline was measured using a validated questionnaire. Smoking, excessive alcohol consumption, hypertension, diabetes, and obesity were analyzed as cardiovascular risk factors. Participants with simultaneous presence of 2+ risk factors were classified with a high cardiovascular risk for dementia. Socioeconomic, behavioral, and health variables were added in the Cox proportional hazard regression model as possible confounders. The incidence and the risk of dementia for physical activity, cardiovascular risk factors, and their interaction were calculated.

Result

Between baseline and wave 9, 6.21% (95% confidence interval [CI]: 5.63 to 6.85) of the participants were diagnosed with dementia. Participants with 2+ cardiovascular risk factors had a higher risk of dementia (hazard ratio [HR]: 1.31; 95%CI: 1.04, 1.63) than low‐risk adults. Physical activity level was inversely associated with the risk of incident dementia in participants who were smokers (p for linear trend = 0.027), had hypertension (p for linear trend = 0.015), and obesity (p for linear trend = 0.014). Low physical activity level (e.g., engaging in moderate‐intensity physical activity once per week) reduced the risk of dementia in participants with hypertension (HR: 0.41; 95%CI: 0.24, 0.70), and obesity (HR: 0.37; 95%CI: 0.21, 0.67). Physical activity attenuated the increased risk of incident dementia provoked by accumulated cardiovascular risk factors. High risk participants with low (HR: 0.51; 95%CI: 0.29, 0.88), moderate (HR: 0.38; 95%CI: 0.21, 0.67) and high (HR: 0.46; 95%CI: 0.22, 0.98) physical activity level had lower risk of dementia than the high risk, inactive group. Sensitivity analyses confirmed the above‐mentioned findings.

Conclusion

Physical activity starting at moderate‐intensity activities once per week attenuated the increased risk of dementia associated with cardiovascular risk factors in older adults.
KDM6A expression is associated with a sex‐disease interaction in activated microglia
Authors: Brase Logan , Dunn Amy R , Dumitrescu Logan , Kaczorowski Catherine C. , Hohman Timothy J. , Karch Celeste M. , Harari Oscar , Benitez Bruno A.
Published: December 2022

Background

There is increasing evidence indicating sex‐specific patterns in disease manifestation and sex differences in the rates of cognitive decline and brain atrophy. Women are protected, relative to men, at the prodromal phases but later exhibit steeper cognitive decline and higher brain atrophy rates1. Sex‐related differences in AD‐associated genes are starting to emerge. The X‐linked gene, KDM6A, avoids X‐inactivation and the resulting elevation in expression confers resilience in women2. KDM6A is also dysregulated in disease associated microglia (DAM) in the 5XFAD mouse model3. We sought to identify if activated microglia was the effector cell type for the KDM6A resilience effect in the brain using single‐nucleus RNA‐seq (snRNA‐seq).

Methods

Using snRNA‐seq data from the parietal cortex of 56 pathologically confirmed control, sporadic AD (sAD), and autosomal dominant AD (ADAD) samples from the Knight ADRC and DIAN cohorts4, we applied a linear mixed model to confirm the female specific upregulation of KDM6A in the major brain cell types and their alternative transcriptional states. We then applied a sex‐AD interaction linear mixed model to identify the cell types and expression states that potentially contribute to disease resilience through KDM6A expression.

Results

KDM6A is expressed in all major brain cell types, with the highest expression in oligodendrocytes, followed by endocytes, microglia, astrocytes, OPCs, and neurons (http://ngi.pub/SNARE/). All cell types showed increased KDM6A expression in females compared to males (oligo P=4.22×10‐15, microglia P=1.07×10‐41, astro P=1.30×10‐13, OPC P=2.55×10‐5, neuron P=7.55×10‐8). We identified a sex‐AD interaction in KDM6A expression within activated microglia (sAD P=9.12×10‐3; ADAD P=2.28×10‐3; Fig. 1), but no evidence in the overall DAM signature. Female sAD and ADAD samples showed higher expression compared to controls, while male sAD and ADAD samples had less expression than controls. Furthermore, we observed sex differences in KDM6A expression within transcriptional states of oligodendrocytes, OPCs, astrocytes and neurons. We are validating these results in additional generated data and publicly available data sets.

Conclusion

These results suggest that the role of KDM6A in AD resilience could be mediated through activated microglia, but current data cannot rule out additional cell types as effectors in KDM6A resilience.
Long‐term care Facilities and Dementia. Development of a framework to assess design quality in healthcare structures for people with dementia
Authors: Mangili Silvia , Brambilla Andrea , Capolongo Stefano
Published: December 2022

Background

Life expectancy has experienced rapid growth (from 77.6 to 81.3 years), resulting in an increase in Non‐Communicable Diseases (NCDs) and years lived with disability. One of those is dementia, with about 7 million people affected in Europe and the number is set to double by 2050. Those patients are complex due to the serious changes in the cognitive sphere, altering perceptions of the space. They are the most frequent users of healthcare facilities, but these structures often are not suitable to them. To this end, a rethinking is now urgent, and the use of Evidence‐Based Design (EBD) could be the way to create safe and suitable environments. This study aims to develop an evaluation framework of the main aspect in the design of a built environment for people with dementia.

Method

Three analyses were conducted: systematic literature review, analysis of existing tools, and case study analysis. The first was conducted on scientific databases using meaningful keywords. In the second the assessment tools in the field of healthcare facilities used worldwide were analyzed. The third explored best practices of dementia architecture. The three analyses were compared to outline the main characteristics that the environment dedicated to the dementia patient must possess to be inclusive and prosthetic.

Result

The final union of results obtained from the analysis has allowed defining a set of requirements that the space must have to be prosthetic for the patient. Those findings have been identified by comparing the two analyses were then divided into three main macro‐areas (physical, cognitive, and social aspects) and 31 criteria. The results were also validated through the involvement of stakeholders and experts in the topic, both from architectural and medical field to establish the relationship between physical factors and patient outcomes.

Conclusion

The framework is a starting point for the development of inclusive projects for people with dementia and cognitive disabilities because it is urgent to investigate which are the main aspects to be considered in the design and renovations of facilities to make them as much as possible therapeutic and prosthetic, creating places where the wellbeing of patients is the priority.
Cholinergic Hub Vulnerability in Typical and Atypical Alzheimer’s Disease Presentations
Authors: Murray Melissa E.
Published: December 2022

Background

The nucleus basalis of Meynert (nbM) is a critical hub that supplies cholinergic input throughout the cortex. Prior to even entorhinal cortex involvement, the nbM is observed to be vulnerable to tau pathology. Neuropathologic and neuroimaging studies provide strong evidence suggesting evaluation of nbM volume may be highly informative as an early biomarker of Alzheimer’s disease.

Method

The relevant AD biomarker literature with neuropathologic validation will be highlighted. Data will be provided from the FLorida Autopsied Multi‐Ethnic (FLAME) series of neuropathologically diagnosed AD cases. To enhance translational neuropathologic studies of the nbM, differences in neuronal density will be compared in the context of both typical and atypical (non‐memory) clinical presentations of AD using digital pathology to quantify nbM neurons in the postmortem tissue.

Result

In the FLAME series, we observed greater nbM neuronal loss in individuals with atypical clinical presentations (median=23/mm2) compared to typical AD dementia (median=26; p=0.002). Atypical clinical variants will be compared to provide a didactic learning experience, in addition to discussing the nbM’s influence on cortical tangle accumulation. Moreover, we will emphasize the paradoxical nature of greater nbM neuronal loss in young‐onset AD (median=21) compared to late‐onset AD (median=28; p<0.001).

Conclusion

Evaluation of cholinergic hub vulnerability may greatly inform our understanding of clinical heterogeneity in AD and provide key insight into early biomarker interpretation.
[18F]RO‐948 Tau PET Retention and Correlation with Fluid Tau Biomarkers in the Early AD Continuum
Authors: Shekari Mahnaz , Milà‐Alomà Marta , Falcon Carles , Niñerola‐Baizán Aida , Tonietto Matteo , Borroni Edilio , Klein Gregory , Ashton Nicholas J. , Karikari Thomas K , Rodriguez Juan Lantero , Snellman Anniina , Ortiz‐Romero Paula , Vanmechelen Eugeen , Minguillón Carolina , Fauria Karine , Perissinotti Andrés , Molinuevo Jose Luis , Zetterberg Henrik , Blennow Kaj , Grau‐Rivera Oriol , Suárez‐Calvet Marc , Gispert Juan Domingo
Published: December 2022

Background

Tau positron emission tomography (PET) imaging enables the in vivo visualization of tau aggregates occurring during the progression of Alzheimer’s disease (AD). Tau PET imaging is a promising biomarker for clinical diagnosis and tracking of disease progression. However, the sensitivity of tau PET in detecting early tau pathology within the early AD continuum and its association with fluid tau biomarkers remains to be established.

Method

Forty‐seven cognitively unimpaired individuals from the ALFA+ cohort had [18F]RO‐948 and [18F]flutemetamol PET, T1‐weighted magnetic resonance imaging (MRI), cerebrospinal fluid (CSF), and plasma tau biomarkers available (Table1). CSF amyloid(A) and tau(T) positivity were defined using CSF Aß42/40 ratio and ptau181 measured by the exploratory NeuroToolKit and Elecsys® immunoassays, respectively, according to pre‐established thresholds (Milà‐Alomà et al., 2020). Centiloid (CL) values were obtained from [18F]flutemetamol PET scans using a validated pipeline. [18F]RO‐948 uptake was measured in entorhinal (BraakI/II), limbic (BraakIII/IV), and neocortical (BraakV/VI) regions and normalized to the inferior cerebellum to render SUVR values. Regional positivity thresholds per Braak stage were calculated as the median plus two robust standard deviations. Associations between [18F]RO‐948 SUVRs and fluid tau biomarkers were evaluated using Spearman’s rho correlations. P‐values<0.05 were considered statistically significant. [18F]RO‐948 SUVRs were modeled against CL values using the data‐driven robust LOWESS method.

Result

In BraakI/II, 5 cases were considered to be positive, 3 in BraakIII/IV and 2 in BraakV/VI (see Table2 for thresholds), all of them being A+T+. Significant correlations with fluid biomarkers were observed in all Braak stages (Table3, Figure1). [18F]RO‐948 SUVR in BraakI/II showed a linear trend with CL values and inflection points between 20 and 30 CLs were observed for all Braak stages (Figure2).

Conclusion

A progressively lower number of [18F]RO‐948 PET‐positive cases were detected for more advanced Braak stages as expected from neuropathological studies. [18F]RO‐948 uptake started increasing around 20‐30 CLs and correlated with wet tau biomarkers in cognitively unimpaired individuals, suggesting that [18F]RO‐948 PET can be more sensitive to initial tau pathology than previously thought. These preliminary findings demonstrate that the ALFA+ cohort is well‐suited to study early pathophysiological alterations in preclinical AD stages.
Association between nutritional status and dementia staging among Alzheimer’s disease patients in Peru: Preliminary results of the Genetic of Alzheimer’s Disease in Peruvian Population Study
Authors: Montesinos Rosa , Chambergo‐Michilot Diego , Malaga Diego , Ore‐Gomez Maria Fernanda , RIVERA‐FERNANDEZ CLAUDIA , Soto‐Añari Marcio , Reyes‐Dumeyer Dolly , Failoc‐Rojas Virgilio E , Casavilca‐Zambrano Sandro , Custodio Nilton , Tosto Giuseppe
Published: December 2022

Background

Alzheimer’s Disease Related Dementias (ADRD) is estimated to increase up to 152 million in 2050. Dementia‐related mortality increases with older age, male sex, neuropsychiatric symptoms, faster cognitive decline, physical impairment and disease severity. Malnutrition is an important ADRD complication due to its impact on several domains. Prior studies showed that malnutrition is associated with behavioral and cognitive impairment (emotional disinhibition and behavior disturbance, memory impairment) and higher mortality risk among ADRD patients. Prevalence of malnutrition is heterogeneous and may depend on disease severity. We aimed to assess the association between malnutrition and dementia severity in an outpatient cohort of Peruvians, part of the Genetic of Alzheimer’s Disease in Peruvian Population (GAPP) Study.

Method

A cross‐sectional study was carried out in three different sites of different altitude in Peru. We included individuals aged >50 years who attended memory clinics. We used the Mini‐Nutritional Assessment (MNA) scale to assess the nutritional status, and the Clinical Dementia Rating (CDR) to grade the dementia. We stratified the nutritional status in normal (MNA score: 12‐14) and malnourished or risk of malnourished (MNA: 11 or less).

Result

We assessed 295 patients; mean age was 71.9 (SD: 8.3) and 68.8% were females; proportion of demented (CDR> = 1) was 23%. Prevalence of malnourishment and risk of malnourishment was 6.4% and 35%, respectively. When adjusted by demographic covariates and geographical recruitment site, we found malnourishment scores significantly associated with CDR scores (e.g. CDR 2‐3: PR 2.27, 95% CI: 1.95‐2.62). Malnourishment was not associated with cardiovascular risk factors or diseases.

Conclusion

In our Peruvian cohort, malnourishment or risk of malnourishment was found associated with higher risk of ADRD. Prevalence of malnourishment or risk of malnourishment was in line with those reported in other South American countries. Further longitudinal studies should confirm this association.
Examining brain structural and functional changes in mTBI with biomarkers of neurodegeneration
Authors: Cordero Indira Ruth Garcia , Vasilevskaya Anna , Taghdiri Foad , Khodadadi Mozhgan , Tator Charles , Mikulis David , Tarazi Apameh , Mushtaque Asma , Colella Brenda , Green Robin , Tartaglia Carmela
Published: December 2022

Background

Mild traumatic brain injury (mTBI) in former contact sports athletes is a risk factor for dementia. However, it is unknown why only some individuals with mTBI develop dementia, suggesting that head injury exposure alone is not sufficient to produce the condition. We hypothesize that mTBI could be associated with neurodegenerative processes that target specific brain structures and connectivity networks and increase vulnerability to dementia.

Method

46 male former professional athletes with a history of multiple concussions were recruited. To compare participants with evidence of underlying pathology versus participants without any evidence, the sample was divided into neurodegenerative biomarker positive (N+, n = 25) and negative (N‐, n = 21) groups. The division was based on the positivity in at least one of these biomarkers: cerebrospinal fluid total tau (> 300 pg/ml), cortical positron emission tomography tau standardized uptake value ratio (>1.30) and serum neurofilament light‐chain (> 12.5 pg/ml). Groups were matched for age and number of concussions. Cognitive profiles were assessed by comparing the following scores between groups: Trail Making Test ratio, Digit Span Backwards, Paced Auditory Serial Addition Test, verbal fluency, and Rey Auditory Verbal Learning Test (RAVLT). Grey matter volume was calculated by voxel‐based morphometry and compared between groups. Functional connectivity differences were evaluated for the default mode (DMN), the salience (SN) and the dorsal attention (DAN) networks.

Results

(N+) presented more number of intrusions at immediate (p = 0.04, FDR corrected) and short delay recall (p = 0.02, FDR corrected) and worse recognition discrimination index (p = 0.02, FDR corrected) in the RAVLT in comparison to (N‐). In addition, (N+) displayed more atrophy in the left frontal superior and middle gyrus (p < 0.001, extended threshold = 50 voxels) and disconnection of the DAN (p < 0.001, FWE cluster correction) versus (N‐). No significant differences were obtained for the DMN and SN.

Conclusion

Frontal atrophy and DAN abnormal connectivity may underlie cognitive deficits in the (N+) group. Biomarkers of neurodegeneration provide a sensitive tool to detect participants with structural and functional changes and may associate with higher risk to develop dementia after mTBI.
Functional connectivity of basal nucleus of Meynert, locus coeruleus and ventral tegmental area in MCI and mild dementia in Alzheimer’s disease
Authors: Burle dos Santos Guimaraes Fernanda , Balthazar Marcio Luiz Figueredo , de Campos Brunno
Published: December 2022

Background

Cholinergic, noradrenergic and dopaminergic dysfunction plays an important role in Alzheimer’s disease (AD). Basal nucleus of Meynert (BNM), locus coeruleus (LC) and ventral tegmental area (VTA) are its main producer nuclei, respectively. Neuropathological studies have shown that structural changes are present in these areas from the beginning of the disease. As such, we aim to identify changes in the functional connectivity (FC) from these nuclei in patients with mild cognitive impairment (MCI) and dementia (DA) in AD, compared with healthy controls (HCs).

Method

We analyzed data from 43 subjects with altered beta‐amyloide in the cerebrospinal fluid (23 MCI; 20 mild to moderate dementia) and 16 controls. Participants underwent rs‐fMRI and neuropsychological evaluation. FC maps to the whole brain were generated (UF²C‐toolbox) using the BNM, LC and the VTA as seeds separately. The second level analysis was performed with an ANCOVA test including the individual FC maps, transformed to z‐score (Fischer R‐Z transformation) generated with each seed and group and regressing for age and years of education using SPM12‐toolbox. The significance level was defined as p<0.001 at the voxel level and p<0.05 FDR corrected at the cluster‐level. In addition, only anatomical regions with more than 60 voxels were described.

Result

Regarding BNM, compared to HCs, patients with MCI showed significantly decreased FC in the left precentral gyrus and left anterior insula (volume 62.05 and 61.59 voxels, respectively, Figure 1). Similarly, DA patients, when compared to HCs, showed significantly decreased FC in the left and right medial precentral gyrus (volume 104.06 and 82.75 voxels, respectively) and in the right supramarginal gyrus (volume 64.68 voxels, Figure 2). Regarding VTA, unexpectedly, we found that, compared with MCIs, DA patients showed increased FC in the left central operculum (volume 92.29 voxels, Figure 3). There were no other between‐group changes that reached statistical significance for right and LC and VTA.

Conclusion

AD patients present changes in the NBM‐FC to the precentral gyrus, insula and supramarginal gyrus. These findings may embase new research for cholinergic dysfunction and possible biomarkers.
Home health staff knowledge and experience of delirium and delirium superimposed on dementia in older adults
Authors: Fick Donna Marie , Shrestha Priyanka , Boltz Marie , Doan William
Published: December 2022

Background

Previous studies have shown delirium is common in the home setting and can indicate a medical emergency. Many older adults come into the hospital or ER with delirium. However, little is known about the recognition of delirium by home health workers and community nurses. The purpose of this study is to explore the experience of home health staff caring for an older adult with delirium and delirium superimposed on dementia (DSD), with a focus on capturing rich details of these experiences and their knowledge of recognition and management of delirium.

Method

Story circle methodology was employed. Data were collected from 20 staff members (age x̄ = 50, SD = 12.33) of a home health agency that serves 18 counties across rural Pennsylvania via Zoom video conference. Qualitative content analysis was utilized (Sandelowski, 2010). The reporting of this study followed the criteria for reporting qualitative studies in the (COREQ) 32‐item checklist.

Result

Nine themes emerged: (i) Negative emotions; (ii) A sudden change; (iii) Knowing the person with dementia; (iv) Potential causes of delirium; (v) Fear of delirium and staff fear; (vi) Lack of protocol; (vii) Distancing and redirecting for management; (viii) Role of family and care partners; and (ix) Barriers to identification.

Conclusion

This is one of only a few studies that have explored delirium and DSD in the home health setting. This study had several innovations, including the use of story methodology and exploring the views of interdisciplinary team members. Importantly, delirium was a common occurrence in the stories they shared. Delirium often resulted in an ER visit or hospitalization. One of the most important findings was that home health staff had training for dementia and depression, but no training, agency protocol, or standardized assessment tool for delirium. A second important finding was the contribution of family and care partners in the assessment and management of delirium in persons with dementia. Implications for practice, research, and policy will be discussed.
Impact of bilingualism on prevalence of dementia and MCI: A community study from India
Authors: Paplikar Avanthi , Venugopal Aparna , Ballal Divya , Varghese Feba , Ramappa Renuka , Shekar Revathy , Manae Tejaswini , Hoskeri Rakshith , Thanissery Nithin , Arshad Faheem , Banavaram Aravind , Rao Girish , Arora Narendra , Alladi Survana ,   AADAR Dementia Science Research Group, India
Published: December 2022

Background

Active bilingualism provides cognitive reserve/resilience against age‐related neurodegenerative conditions like MCI and dementia. Evidences suggest that bilingualism delay the onset of MCI and dementia by preserving cognitive functioning for a longer period of time. India has a linguistically diverse population where bilingualism is a norm and its effects on cognitive reserve are devoid of immigration, education and socioeconomic status. We conducted a door‐to‐doorcommunity‐based study to investigate the impact of bilingualism on the prevalence of dementia and MCI in healthy older monolingual and bilingual population. The study also examined the effect of bilingualism on cognitive performance.

Method

A total of 1145 older adults (366 monolinguals and 779 bilinguals) were recruited. The cognitive functions of elderly persons of ≥ 60 years old residing in urban Bengaluru, India were assessed using Clinical Dementia Rating Scale (CDR), Addenbrooke’s Cognitive Examination (ACE‐III), TNI, Verbal Learning Test (VLT), and Instrumental Activities of Daily Living‐Elderly (IADL‐E). The Language Use Questionnaire (LUQ) scores were used to categorize speakers into monolinguals and bilinguals. Based on the neurologic, neuropsychological, and functional data, participants were classified into 3 categories: normal cognitive functioning, MCI (based on Petersen’s criteria), and dementia (based on DSM‐IV criteria).

Result

There was a significant difference in the proportion of MCI and dementia patients between monolingual (2.10 % dementia and 7.14 % MCI) and bilingual (0.40 % dementia and 4.64 % MCI) elderly (p < 0.001) (Table 1). Healthy elderly bilinguals performed significantly better on global cognition and delayed verbal recall than monolinguals independent of the effects of age, education and gender (Table 2).

Conclusion

The findings of this large door‐to‐door community study reveals the protective role of bilingualism in developing cognitive impairment due to MCI and dementia. Furthermore, the study demonstrates the effect of bilingualism as a measure of cognitive reserve/resilience through better cognitive status and episodic memory in older people from a socio‐culturally and linguistically diverse population.
Improving Dementia Care Practices: Implementation of an Innovative Interprofessional Delirium Prevention Program for Hospitalized Older Adults
Authors: Ladak Anila ,   Geriatrics
Published: December 2022

Background

Delirium, an acute decline in cognition and attention, is a common and severe problem for hospitalized older adults, with incidence rates ranging from 11% to 56%, and 1.5 to 4.0‐fold increased risk of death. Delirium in older adults with preexisting Dementia is prevalent. Delirium may worsen the cognitive decline, prognosis, and long‐term outcomes of dementia. Despite its multifaceted nature, delirium is preventable in 30% to 40% of cases. A California academic community hospital experienced a higher incidence of delirium (30% to 40%) in adult non‐critical care units as compared to delirium rates (11% to 29%) in similar hospital settings.

Method

This evidence‐based, quality improvement project was a two‐group, pre‐post design using the educational intervention. The project was implemented in two stages: 1) education on completing the Delirium Prevention Bundle (DPB) including the Delirium Risk Factor Identification (DRFI) tool, targeted delirium prevention strategies, and documentation; and 2) the DPB implementation on a 26‐bed geriatric unit at a 250‐bed academic community medical center. Demographic data on patients and staff were collected. Staff delirium knowledge was assessed. Data on delirium incidence rate were collected pre‐post‐intervention. Statistical analyses included descriptive statistics, t‐tests, and chi2 test

Result

Implementation of the DPB education, the addition of the DRFI tool, and documentation template in the hospital Electronic Health Record, was effective in reducing delirium incidence rate from 16% to 14% (p = <.001).

Conclusion

Interprofessional education utilizing the DPB is an effective approach in increasing awareness of preventive care for delirium and decreasing incident delirium in this population.

References:

1. Inouye S. Delirium in older persons. N Engl J of Med. 2006; 354(11):1157‐1165. https://doi.org/10.1056/NEJMra052321

2. Fong TG, Tulebaev SR, Inouye SK. Delirium in elderly adults: diagnosis, prevention and treatment. Nat Rev Neurol. 2009;5(4):210‐220. https://doi.org/10.1038/nrneurol.2009.24

3. Witlox J, Eurelings LS, de Jonghe JF, Kalisvaart KJ, Eikelenboom P, van Gool WA. Delirium in elderly patients and the risk of postdischarge mortality, institutionalization, and dementia: a meta‐analysis. J Am Med Assoc. 2010;304(4):443‐451. DOI: 1001/jama.2010.1013
Targeting the Correct Population for Trials: A Post‐hoc Analysis of Trial of Solanezumab for Mild Dementia Due to Alzheimer’s disease.
Authors: Ezzati Ali , Petersen Kellen K. , Nallapu Bhargav Teja , Davatzikos Christos , Wolk David A. , Rabin Laura , Habeck Christian , Hall Charles B , Lipton Richard B.
Published: December 2022

Background

Up to 50% of placebo treated participants in AD clinical trials do not show clinically meaningful cognitive decline (CMCD) over the course of study. Inclusion of these individuals makes it more difficult to demonstrate the benefits of treatments intended to slow cognitive decline. Here, we used data from the trial of solanezumab for mild AD (EXPEDITION3) to investigate effectiveness of predictive models for enrichment of trials.

Method

A total of 1072 patients with mild dementia and biomarker evidence of amyloid by PET or CSF studies were enrolled in the placebo arm of EXPEDITION3 trial. 893 patients completed the trial and had baseline structural MRIs making them eligible for this analysis. We identified cognitive decliners, individuals with CMCD, based on the score of the 14‐item cognitive subscale of the Alzheimer’s Disease Assessment Scale (ADAS‐cog14; Range 0‐90; change of ≥4 from baseline to week 80) versus stable cognition, individuals without CMCD (change of <4 from baseline to week 80). Random forest classifiers were trained to classify participants into cognitive decliners vs. stable cognition groups using 3 feature‐sets: Model‐1) Demographics + Neuropsychological test (NP); Model‐2) Demographics + biomarkers (APOE4 alleles and volumetric MRI); Model‐3) All available measures. 70% of data was used for training and 30% for validation.

Result

Sample characteristics are summarized in Table 1. CMCD was observed in 55.8% of participants at week 80. In the validation sample, model 2 had the best performance in differentiating the two subgroups (AUC = 0.70), followed by model 3 (AUC = 0.68). Model 1 had poor performance in differentiating the two subgroups with AUC = 0.56. Table 2 summarizes performance metrics of models. Positive predictive value of the best performing model (model 2) was approximately 12% higher than the base prevalence of cognitive decline, and negative predictive value of it was approximately 20% higher than the base prevalence of participants who had stable cognition.

Conclusion

A large portion of biomarker confirmed AD cases enrolled in this trial did not show CMCD on placebo treatment. Predictive models have the potential to improve the design of AD trials through selective inclusion criteria for participants expected to decline and exclusion of those expected to remain stable.