bluuebunny/crossref_metadata_2025 huggingface dataset:
Dysphagia Evaluation in a Multidisciplinary VA Cognitive Care Clinic
Authors: Mackowicz Meredith , Yee Joanne , Clark Lindsay R. , Wanninger Ellen , Lewis Brian Lee Young , Kuntz Aaron , Robison Raele , Kind Amy J. , Rogus‐Pulia Nicole M.
Published: December 2022

The VA Cognitive Care Clinic (CCC) provides comprehensive evaluation and longitudinal treatment for older Veterans with neurocognitive disorders and their caregivers through multidisciplinary care including geriatrics, palliative medicine, neuropsychology, and social work. Speech‐language pathology (SLP) was recently incorporated into the CCC team in response to calls for more proactive approaches to diagnosis and management of dysphagia (swallowing dysfunction) in persons with dementia. While dysphagia is estimated to be highly prevalent in this population, prior work has been limited by inadequate dementia characterization. The purpose of this novel quality improvement project was to provide descriptive information regarding the occurrence of dysphagia in persons with dementia seen in CCC.

CCC patients underwent comprehensive neuropsychological and geriatrics assessments that led to a multidisciplinary determination of dementia diagnosis and subtype. Validated dysphagia‐specific clinical evaluation tools included the Eating Assessment Tool (EAT‐10; dysphagia‐specific patient‐reported outcome measure), the 3‐ounce water swallow test to assess swallowing safety (aspiration risk), and the Test of Masticating and Swallowing Solids (TOMASS) to assess swallowing efficiency. A REDCap database was constructed to track CCC evaluation results and patient‐specific variables derived from the electronic health record. Descriptive statistics were calculated for dementia diagnosis, subtype, and dysphagia measures.

124 patients were seen in CCC between 2017 and 2021. Eighty‐eight patients (73%) received a dementia diagnosis with the majority meeting criteria for Alzheimer's disease (53%) or mixed etiology (24%). Sixty‐eight (55%) of these patients were evaluated by an SLP during their initial intake appointment. Twenty of 59 patients (39%) scored 3 or higher on the EAT‐10, indicating concern for dysphagia. Twenty‐six of 64 patients (41%) failed the 3‐ounce water swallow test. Thirty‐one of 62 patients (50%) demonstrated inefficient mastication based on length of total masticatory time on the TOMASS.

Findings from this initial cohort indicate that approximately one‐half of patients with dementia assessed by a SLP demonstrated clinical signs of swallowing safety or efficiency impairment. Patient report of dysphagia‐related symptoms occurred at a significantly lower rate, supporting the need for SLP services in multidisciplinary memory and geriatrics clinics to facilitate early identification of dysphagia and avoid serious dysphagia‐related consequences, including pneumonia and malnutrition.
Exploring lysosomal defects and rescue strategies for Alzheimer’s disease using human transdifferentiated neurons
Authors: Chou Ching‐Chieh , Vest Ryan , Shibuya Yohei , Prado Miguel A , Wilson‐Grady Joshua , Greicius Michael D , Finley Daniel , Wernig Marius , Wyss‐Coray Tony , Frydman Judith
Published: December 2022

Background

Aging is the critical factor of Alzheimer’s disease (AD), the most common neurodegenerative disease. Among the pathological changes in the brain associated with AD, protein aggregates are the characteristic pathological hallmark that is composed of misfolded and toxic proteins. A decline in lysosomal proteolytic activity has been linked to protein aggregation and neuronal death, whereas how the lysosomes become defective and exacerbate neurodegeneration in the brain of AD patients is not well understood.

Method

One of the hurdles is a lack of human neuron system to acquire deep knowledge of aging and AD. Using a powerful cell reprogramming approach, we developed a new cell model for aging and AD based on the transdifferentiation of human adult fibroblasts into cortical neurons (tNeurons) by bypassing stem‐cell stage. We leveraged cell reprogramming, quantitative proteomics, CRISPR genome editing and drug discovery techniques to achieve a better understanding of how aging and AD affect human neurons, with an emphasis on their impact on the lysosomal pathway. We further used tNeurons as a platform to identify pharmacological candidates that exert neuroprotective effect against lysosomal defects, protein aggregation and neurodegeneration in AD.

Result

The transcription factor‐mediated reprogramming approach generated >85% of tNeurons as cortical glutamatergic neurons after 35‐42 days in culture. The tNeurons retained age‐related changes in epigenetic state, DNA damage and protein homeostasis (proteostasis)(Figure 1). The AD tNeurons exhibited an increased levels of Aβ42 peptides and aberrant autophagosome‐lysosome formation in the soma and neurites. Quantitative proteomics further revealed differential expression of proteins in the endosome‐lysosome and autophagy pathway between aged and AD tNeurons. We performed phenotypic and CRISPR screens to identify pharmacological candidates that ameliorate lysosomal defects and protein aggregation in aged and AD tNeurons.

Conclusion

This study is anticipated to highlight that the tNeurons provide a tractable system equipped with a capacity to capture signals of human neuronal aging and neurodegenerative diseases. The outcomes provide novel insights into the role of lysosomes in the aging and neurodegenerative process, and its therapeutic implications for AD.
Preliminary biological evaluations of first brain‐penetrant GPR119‐based radiotracer in rodents and non‐human primates
Authors: Bansode Avinash , Damuka Naresh , Krizan Ivan , Miller Mack , Bashetti Nagaraju , Kumar JV Shanmukha , Ma Tao , Shively Carol A. , Lockhart Samuel N. , Whitlow Christopher T. , Craft Suzanne , Jorgensen Matthew J. , Sai Kiran K Solingapuram
Published: December 2022

Background

G‐protein‐coupled receptors (GPCRs) plays a key role in regulating glucose metabolism. While GPR119 (an important GPCR) agonists have shown potential for improving neurologic and cognitive function in patients with AD and type2 diabetes mellitus (T2DM), clinical interventions targeting GPR119 will require accurate in vivo measures such as PET imaging. We recently synthesized a series of novel piperdine analogs, identifying two analogs (T1 and T2) with high GPR119 binding potency (2‐5 nM) for PET radiochemistry. Here we report their radiochemistry and initial biological evaluations in neuronal cells, normal rodents, and monkeys (vervets).

Method

[18F]T1/T2 radiochemistry was performed in TRASIS‐AIO automated module following [18F]¯‐based nucleophilic substitution of corresponding precursors. [18F]T1 and T2 in vitro assays were performed in three patient‐derived cell lines with different GPR119 expression (MDM‐MD‐231<NCI‐H1716<HepG2), with and without GPR119 agonists and non‐radioactive T1/T2. Dynamic 0‐60 min brain microPET/CT imaging and biodistribution were performed in normal balb/c mice (n=4). Healthy adult female vervets (n=6, 4.5‐6.7 kg) underwent 0‐90 min brain PET imaging. Standard uptake value (SUVmax) and time‐activity curves (TACs) were calculated for whole brain PET/MR images.

Result

Both [18F]T1 and T2 were produced in high radiochemical purities (>98%) and specific activities (∼3800‐4500 mCi/µmol), decay corrected to end of synthesis. Radioactive cell uptake was lower in MDM‐MD‐231 cells (lowest GPR119 expression) and higher in HepG2 cells (higher GPR119 expression); uptake also significantly increased with GPR119 agonists and T1/T2 treatments compared to baseline. [18F]T2 showed slightly better brain uptake in mice compared to [18F]T1 (SUVmax= 0.35±0.07 Vs. 0.55±0.09 g/mL). Biodistribution of [18F]T2 (%ID/mg = 1.01±0.09) also showed high brain uptake. SUVmax (avg=2.6±0.1 g/mL) and TACs of both [18F]T1 and [18F]T2 in monkey brains demonstrated rapid distribution across BBB within 10 min and favorable clearance within 90 min of tracer injection (Fig 1).

Conclusion

Radiochemistry was successfully automated and optimized. Cell uptake showed direct relationships between radiotracer uptake and GPR119 expression. MicroPET imaging, biodistribution in rodents and monkey PET imaging demonstrated excellent brain uptake and favorable pharmacokinetics, indicating BBB penetration. These data suggest for the first time that [18F]T1 and T2 have potential for imaging GPR119 in brains of humans with AD or T2DM.
Impact and attitudes toward genetic counseling and testing in individuals at high risk for familial Alzheimer’s Disease.
Authors: Llibre‐Guerra Jorge J , Mora‐Henao Beatriz , Restrepo‐Fernández Carlos M , Varga‐Cuadros Gabriel A , Londoño Luz E Varela , Manco Juan D Barbaran , Aguilar Laura Ramirez , Aguillon David , Leon‐Varela Yudy M , Londoño Marisol , Quiroz Yakeel T. , Ziegemeier Ellen , McDade Eric , Bateman Randall J. , Lopera Francisco
Published: December 2022

Background

Pre‐symptomatic genetic testing for individuals with dominantly inherited Alzheimer’s disease (DIAD) is now attracting interest due to the existence of therapeutic trials available to this population. Although the impact and the main drivers influencing the decision to seek genetic testing have been widely studied in High‐Income Countries, these reasons remain relatively unknown in Latin America (LatAm).

Methods

This study was designed to explore attitudes toward genetic testing and the impact of finding a disease‐causing mutation for early‐onset Alzheimer’s disease. The genetic counseling sessions, included a culturally sensitive program, developed in collaboration with local experts. Asymptomatic, first‐degree relatives of patients with Alzheimer’s disease dementia from an extended Colombian family (∼300) with a presenilin 1 pathogenic variant (p. I416T) were interviewed before and after genetic testing. Pre and post genetic counseling and testing measurements included the Montgomery Depression Scale, the Zung Anxiety Rating, and Genetic Counseling Outcome Scale. Primary analyses examined change in anxiety and depression scores 3 months after disclosure using linear mixed effects models and chi‐squared tests. Secondary outcomes included short Health Anxiety Inventory and knowledge about Alzheimer disease.

Results

Twenty‐five participants were invited and enrolled in the study (Figure 1). Nineteen individuals completed the genetic counseling sessions and 8/18 (44.4%) learned their genetic status. Three months after genetic status disclosure, we found no significant differences between the group that learned their genetic status and those how did not learn their genetic status in anxiety (mean = 13.5, SD = 3.2 vs. 15.1, SD = 2.5, p = 0.2) or depression (mean = 5.4, SD = 2.3 vs mean = 8.0, SD = 6.5, p = 0.6) scores. For both groups, anxiety and depression scores remained below cutoffs for clinical concern and without significant changes relative to baseline values levels.

Conclusion

Our pilot study shows that a structured genetic counseling and testing protocol for individuals at‐risk of DIAD is safe and and may provide psychological benefits. Future studies should include larger cohorts and expand to other countries in LatAm.
An AI‐based approach to detect cognitive impairment from digital voice recordings of neuropsychological assessments
Authors: Amini Samad , Hao Boran , Zhang Lifu , Song Mengting , Gupta Aman , Karjadi Cody , Kolachalama Vijaya B. , Au Rhoda , Paschalidis Ioannis
Published: December 2022

Background

Reliable cognitive impairment screening tools that are easy to administer and minimally time consuming are greatly needed. Given the high sensitivity of neuropsychological (NP) exams in detection of cognitive decline, we seek to develop an automated screening tool to detect dementia and mild cognitive impairment (MCI) based on digital voice recordings of NP assessments. This could enable wide‐spread screening for dementia and accelerate preventative efforts.

Method

We used natural language processing methods to create a screening tool that identifies different stages of dementia based on automated transcription of digital voice recordings. The transcribed sentences were classified into 8 main sub‐tests including memory assessment, naming and language skill, verbal fluency, general questions, etc. Using the idea of transfer learning, we encoded the participants' sentences into quantitative data. This data and the participants’ demographic variables such as age, sex, Apoe gene, and education were employed to train and test three binary classification tasks, (I) Normal cognition versus Dementia, (II) Normal/MCI versus Dementia, and (III) Normal versus MCI.

Result

We evaluated the performance of the classification tasks using the digital voice recordings of NP assessments, collected from the Framingham Heart Study, containing 410 cognitively intact subjects, 387 MCI, and 287 subjects with dementia. The average Area Under the Curve (AUC) on the held‐out test data reached 92.6%, 88.0%, and 74.4% for differentiating Normal from Dementia, Normal or MCI from Dementia, and Normal from MCI, respectively. Looking at the importance of the sub‐tests in differentiating MCI from Normal, we note that general questions can be more useful for assessment of MCI, whereas verbal fluency would not be as useful in this task.

Conclusion

The proposed approach offers a fully automated identification of MCI and dementia based on a recorded NP test, providing an opportunity to develop a remote screening tool that could be easily adapted to any language.
LatAm Fingers Initiative: Bringing Diversity Upfront
Authors: Crivelli Lucia
Published: December 2022

Background

LatAm FINGERS is the first Latin‐American non‐pharmacological trial to prevent cognitive decline. It coordinates 12 Spanish and Portuguese‐speaking countries and includes a multicultural heterogenic population. We aim to describe the challenges and barriers of adapting a successful high‐income‐born intervention for an ethno‐racially diverse population.

Method

We identified a tripartite challenge: 1) to guarantee a representative sample of a diverse population. This required the inclusion of low‐educated participants from rural and metropolitan areas with different ethnic backgrounds and standards on normal cognition, sedentarism, and dietary habits, 2) to harmonize our inclusion /exclusion criteria and outcomes with the original FINGER trial and the US POINTER trial, and 3) to provide a feasible intervention program for all included countries. For this purpose, multidisciplinary workgroups of experts from all the participating countries were assembled. Each workgroup was appointed to a specific aspect of the trial (e.g., cognitive outcomes, physical activity, nutrition).

Result

The LatAm fingers trial was launched in December 2021 and is in the recruitment stage. First, cognitive status for inclusion was defined using standardized cognitive measures adjusted for age and education from each region. The second challenge was tackled by including the international tools that are also valid for the 12 countries and replacing others with Latin American analogous tests validated in low‐educated populations. Finally, feasibility was accomplished by adapting the original intervention using a respectful perspective of diverse and cultural assets and exploring opportunities from local products and traditions. For example, the dietary intervention prioritized the use of autochthonous aliments but maintained the properties and composition of the original FINGER diet.

Conclusion

The LatAm Fingers trial was able to bring dementia prevention strategies created in high‐income countries to low‐income and low‐educated populations. Our results support that intervention trials are feasible in diverse populations and in Latin America. Furthermore, including investigators from the populations to be included assures a respectful view of cultural characteristics and facilitates adaptation and feasibility.
Deciphering the genetic interaction between klotho and APOE with novel mouse models
Authors: Carter Gregory W , Preuss Christoph , Garceau Dylan , Kotredes Kevin P , Sasner Michael
Published: December 2022

Background

Apolipoprotein E4 (APOE4), a common variant of APOE, is a major genetic risk factor for LOAD, but APOE4 carriers do not always develop LOAD. Several large‐scale genetic studies have identified a common haplotype of the aging factor klotho that modify disease risk in APOE4 carriers. In humans, klotho harbors two common missense variants (rs9536314, p.F352V; rs9527025, p.C370S) that define the klotho V/S (KL‐V/S) haplotype, which is protective against LOAD in APOE4 carriers, and the klotho F/C (KL‐F/C) haplotype, which is not. We sought to understand this genetic interaction using novel mouse models.

Methods

We introduced the human klotho variants into the mouse. Mouse klotho differs at the key amino acid position p.C370S rendering the native mouse haplotype as “KL‐F/S”, matching neither of the observed human haplotypes. We have replaced this native haplotype with the homozygous protective KL‐V/S and common KL‐F/C haplotypes using CRISPR/Cas9. To validate the effects of these klotho haplotypes on klotho secretion, soluble p‐KL serum levels of four month old mice were compared after cheek bleeding using ELISA. We also measured p‐KL in eight month old amyloidogenic App
SAA mutant mice, which have amyloid plaques in the brain.

Results

Genomic modifications in mouse klotho were confirmed by PCR and Sanger sequencing. Secreted p‐KL was decreased in KL‐F/C mice harboring the novel mouse risk haplotype when compared to age matched B6 controls and KL‐V/S mice. In contrast, KL‐V/S mice showed no significant differences in soluble p‐KL serum levels when compared to B6 controls. Secreted p‐KL levels in KL‐V/S mice were significantly elevated when compared to the App
SAA mice, whereas young KL‐F/C mice showed similar levels to the aged App
SAA model.

Conclusions

Taken together, these data suggest the native mouse klotho allele may acts similarly to the protective KL‐V/S haplotype, while the KL‐F/C haplotype leads to lower secreted klotho and potentially greater disease risk. These models are therefore suitable for experiments to elucidate how klotho variants protect from LOAD pathologies, and will enable detailed studies of how this protection is specific to the APOE4 genotype.
Blood plasma biomarkers improve prediction accuracy over and above genetic predictors of Alzheimer’s disease
Authors: Stevenson‐Hoare Joshua O , Heslegrave Amanda , Leonenko Ganna , Fathalla Dina , Bellou Eftychia , Luckcuck Lauren , Marshall Rachel , Sims Rebecca , Morgan Paul , Hardy John A. , de Strooper Bart , Williams Julie , Zetterberg Henrik , Escott‐Price Valentina
Published: December 2022

Background

Prediction models of Alzheimer’s disease using genetic information, such as polygenic risk scores, have been able to reach high levels of prediction accuracy. However, since confirmation of the disease is only possible post‐mortem, these levels of prediction accuracy are typically only achievable in pathologically confirmed cohorts. In living individuals who have been clinically assessed for AD, prediction accuracy by genetics is still good but much lower. Biomarkers can indirectly assess AD pathologies, and so may be able to bridge the prediction accuracy gap. Blood plasma biomarkers may have additional clinical utility as they are cheaper and more accessible compared to traditional CSF or PET methods.

Method

We measured five blood plasma biomarkers known to be linked to AD pathologies (Aβ40, Aβ42, GFAP, NfL, P‐tau181) in a cohort of AD cases (N=1439, mean age 68) and elderly screened controls (N=508, mean age 82). We also gathered information on APOE genotype, age at sample collection, sex, and age at onset and disease duration in cases.

Result

Linear regression models showed that all biomarker measurements were associated with age at onset in cases and most were associated with disease duration. Biomarkers were also associated with age at sample collection in both cases and controls, demonstrating their effectiveness for tracking neurological change over time. Using logistic regression, we found prediction accuracies for AD status for each biomarker individually of AUC=0.56‐0.66 and by APOE and PRS AUC=0.73. A model combining all biomarkers had an AUC=0.75. The best prediction accuracy was achieved by combining all biomarkers with genetics and age at sample collection, which reached an AUC=0.81, and explained variance of R2=0.29.

Conclusion

We found that blood plasma biomarkers predicted AD status and were associated with disease duration. Furthermore, biomarkers explain some variance not captured by genetic factors and therefore improve accuracy when combined in predictive models. Biomarkers also have the advantage of specificity over clinical assessments, which may confuse dementia subtypes due to phenotype similarity. Therefore, blood plasma biomarkers can be a useful tool for the assessment and prediction of AD on their own or in combination with genetic predictors.
Tau phosphorylation is more closely associated with amyloid‐β plaques than with tau neurofibrillary tangles
Authors: Vermeiren Marie , Therriault Joseph , Servaes Stijn , Lussier Firoza Z , Tissot Cécile , Pascoal Tharick A , Chamoun Mira , Bezgin Gleb , Benedet Andréa Lessa , Ashton Nicholas J. , Karikari Thomas K , Rodriguez Juan Lantero , Stevenson Jenna , Rahmouni Nesrine , Kunach Peter , Wang Yi‐Ting , Arias Jaime Fernandez , Vitali Paolo , Massarweh Gassan , Soucy Jean‐Paul , Saha‐Chaudhuri Paramita , Blennow Kaj , Zetterberg Henrik , Gauthier Serge , Rosa‐Neto Pedro
Published: December 2022

Background

While fluid phosphorylated tau (pTau) epitopes are interpreted to be biomarkers of tau pathology according to the A/T/(N) framework, it is unclear to what extent they are preferentially associated with the defining histopathological hallmarks of Alzheimer’s Disease (AD): amyloid‐β plaques and tau neurofibrillary tangles.

Method

We studied 171 individuals, including young adults (n=27), cognitively unimpaired elderly (n=85), individuals with mild cognitive impairment (n=36) and individuals with Alzheimer’s clinical syndrome (n=23), who were evaluated with [18F]AZD4694 amyloid‐PET, [18F]MK6240 tau‐PET, four tau phosphorylation sites in CSF (pTau181, pTau217, pTau231, pTau235) and two phosphorylation sites in plasma (pTau181, pTau231). To better understand the role of soluble biomarkers in AD diagnostic and research purposes, we evaluated associations between soluble pTau sites and cerebral amyloid‐PET and tau‐PET concentrations. Voxel‐wise linear regressions between fluid and imaging biomarkers were performed. Results for plasma and CSF pTau181 were replicated in an independent sample of 258 individuals included in the Alzheimer’s Disease Neuroimaging Initiative cohort (ADNI).

Results

We observed that for all plasma and CSF epitopes, pTau is more closely associated with amyloid‐PET than with tau‐PET. Squared correlation coefficients (Spearman’s R2) between CSF pTau epitopes and neocortical [18F]AZD4694 SUVR range from 0.48 to 0.63, while those for the temporal meta‐ROI [18F]MK6240 SUVR vary between 0.33 and 0.45 (p<0.001 for all phosphorylation sites). Using the R package “Cocor”, for CSF pTau181, pTau217 and pTau231 the difference in correlation coefficients between both measures of imaging biomarkers appear significant (p<0.01). Voxel‐wise linear regression analyses further support these results, in particular showing sizable associations for CSF pTau231 with amyloid‐PET. In addition, soluble pTau is more closely correlated with medial temporal than with neocortical tau. All soluble pTau concentrations rise significantly with increasing amyloid‐β plaque load. In contrast, soluble pTau plateau as tau‐PET concentrations increase, starting at Braak stage III. These findings were replicated using plasma and CSF pTau181 in the ADNI cohort.

Conclusion

Phosphorylated tau epitopes measured in CSF and plasma better reflect cerebral amyloidosis than neurofibrillary tangles in the brain. The current findings support careful interpretation of fluid pTau concentrations when implementing the A/T/(N) framework.
Knock‐in of P301L tau homolog in Drosophila leads to neuronal loss and widespread neurodegeneration
Authors: Bukhari Hassan , Feany Mel
Published: December 2022

Background

Mutations in tau protein, such as P301L, play an important role in the pathogenesis of Alzheimer’s disease and frontotemporal dementia. A knock‐in of P301L tau homolog in Drosophila led to extensive neuronal loss and widespread neurodegeneration.

Method

The human P301L tau homolog in Drosophila, P251L tau, was knocked in by using CRISPR/Cas9 gene editing. Markers of neurodegeneration were quantified by immunostaining. Mitochondrial bioenergetics was quantified by a seahorse analyzer. Single‐cell RNA sequencing analysis was done on the 10 days old P251L tau and control Drosophila brains.

Result

The results show that the P251L tau Drosophila brain shows an age‐dependent increase in DNA damage compared to the control. Other markers of neurodegeneration such as vacuolation, proliferating cell nuclear antigen (PCNA) and tau inclusion bodies were also found to be elevated in the tau P251L Drosophila brain. Furthermore, a decrease in mitochondrial bioenergetics, oxygen consumption rate, and extracellular acidification rate was also found in the P251L tau compared to the control Drosophila brain.

Conclusion

The CRISPR/Cas9 mediated knock‐in of human P301L tau homolog in Drosophila leads to extensive neuronal loss and widespread neurodegeneration.
The Brain Health Platform: Combining Resilience, Vulnerability and Performance to assess brain health and risk of Alzheimer’s disease and related disorders
Authors: Galvin James E , Kleiman Michael J , Chang Lun‐Ching
Published: December 2022

Background

One of the great challenges in conducting ADRD research in community samples is the standardized measurement of medical, social, and environmental factors that may increase the risk of ADRD (vulnerability) or may provide some protective benefits from ADRD (resilience). While all physicians can diagnose mild cognitive impairment (MCI) and ADRD, it is much more difficult to assess the status of brain health and identify those at risk for future impairment. We developed and validated a novel clinical tool, the Brain Health Platform, to quantify brain health and identify risk factors for MCI and ADRD.

Method

We combined the Resilience Index (RI), a brief, quantifiable measure of 6 modifiable factors of brain health and risk of MCI and ADRD, the Vulnerability Index (VI), a weighted measure of cognitive impairment risk that assesses modifiable and non‐modifiable risk factors, and the Number Symbol Coding Task (NSCT), a brief, 90‐second executive task that incorporates attention, planning, and set‐shifting, to measure objective cognitive performance, into the Brain Health Platform to assess overall brain health and the presence of cognitive impairment. We tested this in a combined clinical and research sample (n = 400; 53 controls, 347 impaired) compared with a Gold Standard clinical‐cognitive‐behavioral evaluation.

Result

The Brain Health Platform was able to correctly segregate healthy controls from MCI and ADRD in time‐ and cost‐efficient fashion. We applied a linear discriminant analysis using the NSCT, RI and VI to predict control, MCI and ADRD groups performing 5‐fold cross validation with 1000 replications. The area under the curve for Controls vs MCI was 0.823±0.09, for Control vs ADRD was 0.974±0.03 and for MCI vs ADRD was 0.884±0.06. In an exploratory fashion, we also demonstrated the ability of the Brain Health Platform to assist in differential diagnosis.

Conclusion

The Brain Health Platform can intake the inputs of three brief assessments (RI, VI, NSCT) and output a patient risk score to determine the cross‐sectional status of an individual’s brain health, from which effective, personalized, precision‐medicine‐like prevention interventions, including lifestyle changes, medications and clinical trial enrollment, can be implemented in at‐risk individuals to decrease the development or progression of cognitive decline.
Distinct patterns of neurodegeneration after TBI and in Alzheimer’s disease
Authors: Graham Neil SN , Cole James H , Schott Jonathan M , Sharp David J
Published: December 2022

Background

Traumatic brain injury (TBI) is an established risk factor for dementia, with Alzheimer’s disease reportedly more prevalent post‐injury. Experimental injury models relate axonal injury to the generation of toxic proteinopathies including amyloid and hyperphosphorylated tau, but epidemiological data relating brain injury and Alzheimer’s disease specifically are inconsistent. Using longitudinal volumetric MRI, it is possible to assess commonalities and differences between chronic post‐traumatic neurodegeneration, Alzheimer’s disease and ageing in vivo, to better understand the long‐term consequences of TBI.

Method

Serial volumetric T1‐weighted MRI was performed on two occasions a year apart in 55 patients after moderate‐severe TBI, a group of 23 age‐matched healthy volunteers, a group of 15 older healthy controls (healthy ageing group), as well as 45 patients with Alzheimer’s disease alongside 23 age‐matched controls comprising the MIRIAD dataset. Jacobian determinant (JD) brain atrophy rates in white, grey matter and CSF were quantified, spatial patterns defined and systematically compared between the groups. Diffusion imaging was acquired in TBI patients at baseline, facilitating the generation of the fractional anisotropy metric of axonal integrity via diffusion tensor imaging.

Result

Atrophy rates were significantly increased in white matter only after TBI (P<0.01), in contrast to increases in both white matter and grey matter in Alzheimer’s disease (P<0.001). Common subcortical white matter regions showed atrophy in both Alzheimer’s disease and TBI, but deep white matter atrophy was TBI‐specific, and cortical atrophy Alzheimer’s disease‐specific. Post‐TBI atrophy patterns were distinct from ageing, which more closely resembled Alzheimer’s disease, and were predicted by the extent of axonal injury on diffusion tensor imaging at baseline (P<0.05).

Conclusion

Neurodegeneration after moderate‐severe TBI is distinct in location from both ageing and Alzheimer’s disease, with a characteristic central white matter predominance. This likely reflects the underlying spatial distribution of traumatic axonal injury, and may represent ongoing chronic Wallerian degeneration, and/or toxic proteinopathy‐driven neurodegeneration.
Determining best‐in‐practice dyadic discrete choice experiments to enable persons with dementia and informal caregivers to participate in health care decision‐making: a feasibility study
Authors: Wammes Joost D , Swait Joffre , Labrie Nanon , Monin Joan , Grob Esther de Bekker , Vroomen Janet MacNeil
Published: December 2022

Background

Discrete choice experiments (DCEs) are a powerful tool that potentially offer a method to quantify individual and joint care preferences of persons with dementia and their informal caregivers. DCE studies that have included persons with dementia revealed that choice task complexity is a serious challenge to this population, which can lead to heuristic decision making. This feasibility study aims to determine best‐in‐practice dyadic DCE design to enable both persons with dementia and informal caregivers to participate in health care decision‐making.

Method

This study included three DCE rounds: (1) persons with dementia alone, (2) informal caregiver only, and (3) persons with dementia and their informal caregivers in dyads. A flexible DCE design was employed, in which choice task complexity was increased systematically to explore individual cognitive limitations in DCE decision making. Choice tasks were presented by illustrations and simplified language to decrease cognitive burden on persons with dementia. A think aloud approach of survey administration was used to provide insights into individual and joint decision‐making processes. The Telephone Interview for Cognitive Status was used for cognitive screening.

Results

15 persons with dementia, 15 informal caregivers, and 14 dyadic discrete choice experiments were conducted. The majority of persons with dementia (53.3%) was able to complete choice tasks including two scenarios characterized by three attributes and completed on average 6.4 (SD 4.1) choice tasks before dropping out. The dyadic DCEs enabled persons with dementia to complete surveys that were somewhat more complex, and on average a higher number of choice tasks (7.9, SD 3.9). In the dyadic DCEs, informal caregivers assisted the person with dementia to understand the choice task, elicited choice motivation, and provided the means to discuss each other’s preferences.

Conclusion

Persons with dementia that have a mild to severe cognitive impairment can use discrete choice experiments with low choice task complexity. Dyadic DCEs can enable greater empowerment of the person with dementia while promoting joint decision making. Future work should further explore the mapping of severity of dementia and feasible choice task complexity, to enhance our understanding about designing choice elicitation tasks.
Interregional Gene Expression Analysis Identifies Signature of Cerebellar Resistance to AD Tauopathy
Authors: Ayoub Christopher A , Wagner Connor , Kuret Jeff
Published: December 2022

Background

The appearance of neurofibrillary tangles (NFTs) reflects both their spatial location within affected connectivity networks and the intrinsic vulnerability of neuronal populations to their formation. Here we disaggregate human gene expression data on the basis of connectivity to identify differentially expressed genes (DEGs) associated with neuroprotection against tauopathy.

Method

Transcriptomic analysis focused on prefrontal cortex (PFC) and cerebellum, which both associate with the default mode and other AD‐affected networks. However, whereas PFC is vulnerable to tauopathic neurodegeneration, the cerebellum atrophies without NFT formation or cell loss. To identify candidate mediators of selective vulnerability, gene expression patterns in both regions from AD and control brains were calculated and then subjected to cell‐type specific enrichment analysis (CSEA), gene set enrichment analysis (GSEA), and transcription factor interaction network (TFIN) analysis. To validate candidate effector genes, prioritized chaperones were incubated with tau protein to test for suppression of biochemically induced fibrillization. The resulting distribution of soluble and aggregated tau was measured by sedimentation.

Results

CSEA revealed DEGs that changed in parallel between regions originated primarily in glia and microglia. GSEA identified these as belonging to Gene Ontology (GO) categories associated with host response and ion homeostasis. Of 446 genes, 379 were linked in a TFIN, with the most central nodes including transcriptional regulators HBP1, EGR1, SERTAD1, and PER1. In contrast, DEGs changing in opposition were primarily neuronal. GSEA identified 14 heat shock genes, including nine chaperone proteins reported to regulate protein folding. Of 402 candidate vulnerability genes, 319 were linked in a TFIN, in which the most central hubs were long noncoding RNA NEAT1, and transcription factors BHLHE40, ZC3H10, and CREB3L4. Finally, aggregation and sedimentation of tau showed all nine chaperones antagonized biochemical fibrillization of 2N4R tau with octadecyl sulfate at substoichiometric ratios of chaperone to tau.

Conclusions

Our study takes advantage of a selective vulnerability informed approach to gene expression and highlights the role of proteostasis and neuronal genes in protecting the cerebellum from tau lesions. This approach successfully identified biologically active effector genes and can be applied broadly to other neurodegenerative diseases featuring prion‐like pathology and will orient the field toward endogenous strategies of neuroprotection.
Gamma‐Frequency Sensory Stimulation is Safe and Well‐Tolerated Treatment Option for Patients with Alzheimer’s Disease
Authors: Hajos Mihaly , Boasso Alyssa , Hempel Evan , Cimenser Aylin , Seshagiri Chandran , Megerian Jonathan Thomas , Vaughan Brent , Malchano Zach
Published: December 2022

Background

Recent experimental findings demonstrate that sensory‐evoked brain gamma oscillation reduces Alzheimer’s disease (AD) pathologies in AD‐related transgenic mice, including decline in synaptic function, neurodegeneration, and brain atrophy (Adaikkan & Tsai, Trends Neurosci. 2020;43:24‐41). Based on these findings, gamma‐frequency sensory stimulation has been evaluated in multiple clinical trials, including the long‐term Overture a randomized, controlled trial (Clinicaltrials.gov: NCT03556280) assessing safety, tolerance, and efficacy of using Cognito Therapeutics medical device in patients with AD.

Method

Patients with clinical presentation of AD spectrum (MMSE 14‐26, inclusive) were randomized 2:1 to receive daily, one‐hour, EEG‐calibrated, 40Hz noninvasive audio‐visual stimulation or sham stimulation over a 6‐month period. Therapy was self‐administered at home with the help of a care partner. Safety was evaluated by magnetic resonance imaging (MRI), physical and neurological exams at baseline, 12‐, and 24‐weeks, and monthly assessments of adverse events (AEs). Tolerability was measured by device use data, daily diary, and user experience interviews.

Result

A total of 135 subjects were screened, of whom 74 (55%) were randomized and 53 completed (72%). The safety population included all subjects who performed at least one day of treatment. During the 6‐month (168 days) treatment period, both groups completed daily therapies at a similar rate (147 active vs 139 sham). Treatment‐related AEs occurred in 19 subjects (41.3%) in the active treatment group and 8 subjects (28.6%) in the sham group. The incidence of treatment‐related AEs was similar between treatment groups except for headache (21.7% active group vs 10.7% sham group) and tinnitus (15.2% active group vs 0% sham group). All treatment‐related AEs were mild in intensity except tinnitus and anxiety (1 active group subject) and agitation (1 sham group subject) which were considered moderate. Review of MRI data demonstrated absence of ARIA in all subjects. High adherence rates (over 83%) were observed in both sham and treatment subjects; 60% of enrolled participants entered open label extension.

Conclusion

Gamma‐frequency sensory stimulation is safe and well tolerated by trial participants. Together with efficacy shown on functional and cognitive abilities and brain atrophy (Hajós et al., JPAD 2021;8:S60‐61), gamma‐frequency sensory stimulation can be considered as viable treatment option for patients with AD.
Resting heart rate (variability) predicts cognitive function and suggests different heart‐brain connections in cognitively healthy individuals with abnormal CSF amyloid/tau
Authors: Arakaki Xianghong , Choy Elizabeth Hok Yee , Arechavala Rebecca Johnson , Nolty Anne , Spezzaferri Mitchell , Sin Caleb , Rising Shant , Buennagel David P , Molloy Cathleen , Fonteh Alfred N. , Kloner Robert A , Kleinman Michael T.
Published: December 2022

Background

Both resting heart rate variability (HRV) and resting heart rate (HR) are regulated by the central autonomic network linking prefrontal cortex with cardiac regulation. To better understand the interactions between the heart and cognition we determined the relationships between resting HR/HRV and cognitive function.

Method

We compared and correlated resting HR with Mini‐Mental State Exam (MMSE) in cognitively healthy (CH, n=137) individuals when their CSF amyloid/tau ratios were normal (CH‐NATs, n=51) or pathological (CH‐PATs, n=68), in participants with mild cognitive impairment (MCI, n=54), and Alzheimer’s disease (AD, n=42). We also compared and correlated HRV with behavioral performance (accuracy and response time) or alpha event‐related desynchronization (ERD) during Stroop (interference) or task switching testing between subsets of CH‐NATs and CH‐PATs. Cognitive tasks include: 1) Stroop during low load (congruent trials) and high load (incongruent trials); 2) task switching during low load, repeat trials (color‐color or word‐word) and high load, switch trials (color‐word or word‐color). HRV was assessed from 5‐minute resting ECG recording, including: HR and root mean squared of successive differences (RMSSD) that reflect vagal activities.

Result

No differences of resting HR or HRV were observed between CH‐NATs, CH‐PATs, MCI, and AD. Interestingly, resting HR negatively correlated with MMSE only in CH‐PATs (r=‐0.57, p=0.002), but not in CH‐NATs (r=0.07, p=0.71), CH (r=‐0.09, p=0.57), MCI (r=‐0.14, p=0.41), or AD (r=‐0.11, p=0.59) (Fig 1). For Stroop interference testing, resting HR (preceding task) positively correlated with frontal alpha ERD during high load trails (r=0.78, p=0.017) in CH‐PATs, but not in CH‐NATs (Fig 2). For task switch testing, resting RMSSD positively correlated with accuracy during switch trials (r=0.64, p=0.004) in CH‐NATs, but not in CH‐PATs (Fig 3).

Conclusion

These results suggest: 1) resting HR is linked with cognition in CH‐PATs; 2) resting HR is related to inhibitory control in CH‐PATs: higher HR linked with less negative alpha ERD (less activation); 3) resting HRV predicts task switching performance in CH‐NATs: higher RMSSD linked with higher accuracy. Overall, resting HR and HRV potentially reflect cognition and executive functions that differentiate CH‐NATs and CH‐PATs, suggesting different cerebral‐cardiovascular integration in these two populations.
Association of hippocampal subfield volumes with amyloid‐beta deposition in Alzheimer’s disease
Authors: Baek Min Seok , Lee Narae , Kim Jin Woo , Hong Jin Yong
Published: December 2022

Background

Characteristic atrophy patterns of hippocampal subfield volumes and cortical amyloid‐beta (Aβ) deposition are two important neuroimaging biomarkers in Alzheimer’s disease (AD). We investigated the relationship between hippocampal subfield volumes and cortical Aβ deposition in AD.

Method

Fifty participants (11 cognitively unimpaired [CU], 10 with mild cognitive impairment [MCI], and 29 with AD) who underwent 18F‐florbetaben positron emission tomography, magnetic resonance imaging, and neuropsychological tests were enrolled. The hippocampal subfield volumes were obtained using an automated brain volumetry system with the Winterburn atlas and were compared among the diagnostic groups, and the correlations with the Aβ deposition and AD risk factors were determined.

Result

Patients with MCI and AD showed decreased volume in the stratum radiatum/lacunosum/moleculare (SRLM) of the cornu ammonis (CA)1 and CA4‐dentate gyrus (DG) than the CU. Decreased SRLM and CA4‐DG volumes were associated with an increased Aβ deposition in the global cortex (R = ‐0.459, p = 0.001; R = ‐0.393, p = 0.005, respectively). The SRLM and CA4‐DG volumes aided in the distinction of AD from CU (areas under the receiver operating characteristic [AUROC] curve = 0.957 and 0.930 respectively, p < 0.001), and Aβ+ from Aβ‐ individuals (AUROC curve = 0.763 and 0.763, respectively, p < 0.001).

Conclusion

Hippocampal subfield volumes demonstrated potential as imaging biomarkers in the diagnosis and detection of AD and Aβ deposition, respectively.
Diagnosis of mixed dementia by double dichotomy
Authors: Rosenberg Gary A , Adair John , Knoefel Janice , Prestopnik Jillian , Hillmer Laura , Erhardt Erik B , Arvind Caprihan
Published: December 2022

Background

Proper classification of patients with dementia is critical in clinical trials. Dual Alzheimer’s disease (AD) and vascular pathology (mixed dementia‐MX) is the most common form of dementia estimated to be as high as 70% in pathological series. However, separation clinically is difficult, which has led to use of biomarkers. A biological definition of AD based on biomarkers has been proposed for research studies with identification of amyloid and tau in CSF or PET. Including in the ATN formula, biomarkers for vascular disease (V), obtained from MRI, separates MX subjects, improving diagnosis of AD and vascular cognitive impairment (VCI).

Methods

We used vascular disease biomarkers from MRI and AD biomarkers from CSF with a double dichotomy statistical approach to more precisely define four major groups of patients in the UNM and Alzheimers's Disease Neuroimaging Initiative (ADNI) cohorts. We compared the UNM dataset (N=80) with subjects from ADNI (N=538). Diffusion tensor imaging (DTI) biomarkers (mean free water and PSMD) were combined with CSF amyloid (A) and tau (T) to identify MX patients. We formed a composite vascular disease score (cVDS) with DTI, and a composite AD score (cADS) with CSF amyloid and phosphoTau181.

Results

Plotting cVDS on the x‐axis and cADS on the y‐axis placed subjects in one of four biologically defined quadrants: bAD (biological AD) in the upper left, bSIVD (biological subcortical ischemic vascular disease) in the lower right, bMX (biological mixed dementia) in the upper right, and bCN (biological controls) in the lower left quadrant (Figure). We identified MX, using a double dichotomy statistical method. The UNM cohort had 25% MX, while in ADNI there were 11.5% (Table). The ADNI group had a higher percentage of bCN (43%) and bAD (35%) than the UNM cohort; this was because UNM was one of 7 sites in the MarkVCID consortium with enriched VCI subjects and ADNI excluded vascular disease subjects.

Conclusions

Our results show that adding a vascular factor (V) to the ATN formula creates a MX group, improving classification of patients by creating a more homogeneous AD group, which permits AD clinical trials with fewer subjects
On the evaluation of disease progression modelling in Alzheimer's Disease
Authors: Saint‐Jalmes Martin , Goudey Benjamin , Beck Daniel , Masters Colin L. , Fedyashov Victor
Published: December 2022

Background

Alzheimer's Disease (AD) is a heterogeneous condition that can be viewed as a continuum involving multiple stages from cognitively normal to mild cognitive impairment and finally dementia. Recent works in Disease Progression Modelling (DPM) have attempted to use biomarkers to construct representations of progression that are more informative of patients' status than clinical diagnosis alone. However, there is no clear consensus (Figure 1) regarding the choice of evaluation methods or metrics to facilitate model comparison. We propose the use a simple, universally applicable biomarker‐based baseline to estimate patient‐realigning time‐shifts and subsequently evaluate it against multiple released DPM methods.

Method

We computed an abnormality score for 2439 patients from the Alzheimer's Disease Neuroimaging Initiative (ADNI) by averaging the normalised values collected for 12 biomarkers representative of amyloid, tau, neurodegeneration, and cognition. Abnormality ranges were determined from 251 amyloid‐positive patients. These scores were compared to values from published DPM models (Figure 3). Additionally, all methods were benchmarked in different ways, including diagnosis classification and cluster analysis.

Result

We found that, despite its simplicity, our abnormality score reasonably separated patients according to their diagnosis (Figure 2). Computed scores also correlated significantly with those of other methods (Figure 3, Pearson correlations up to 0.891). While our approach only required cross‐sectional information, other methods rely on longitudinal data. Our method performed similarly to others in the cutoff‐based disease classification task, with test F1‐scores of 0.734 and 0.890 in the harder tasks of CN/MCI and AD/MCI, respectively (Table 1). In a three‐class setting, all methods including our baseline showed a good level of agreement, with Rand indices all above 0.6 (Figure 4).

Conclusion

A significant challenge in DPM for AD lies in estimating a proxy for patient realignment, which is crucial to describe individuals on a common disease continuum. We have proposed a method to calculate an abnormality score at the baseline visit, which can be trivially extended to longitudinal data and help interpret progression in follow‐ups. We hope that future work considers more principled evaluation procedures, facilitating meaningful comparisons between DPMs.