bluuebunny/crossref_metadata_2025 huggingface dataset:
Detection of Amyloid status in patients with uncertain diagnosis and associations with remotely‐collected cognitive composites
Authors: Knight Krissy N , Iaccarino Leonardo , Tosun Duygu , Rabinovici Gil D. , Weiner Michael W.
Published: December 2022

Background

In an effort to build efficient and scalable screening tools for early detection of cognitive impairment, the Brain Health Registry (BHR) was created to collect demographic and cognitive information in a remote setting. A select cohort of participants enrolled in the BHR also underwent amyloid PET scans, allowing the utilization of remotely collected cognitive data for amyloid enrichment.

Method

Self‐reported measures were collected through the BHR from 656 older adults co‐enrolled in the Imaging Dementia ‐ Evidence For Amyloid Scanning (IDEAS) study with an in‐clinic diagnosis of unexplained mild cognitive impairment (MCI; n = 522) or dementia of uncertain cause (n = 134) (Table 1). Global Amyloid‐PET centiloid values were obtained via a published PET‐Only processing method. An independent pathology‐based cut‐off of 24.4 was applied to define amyloid status. A comprehensive set of BHR variables were regressed on the continuous centiloid values to quantify the association between online measures with global amyloid burden. Then, logistic regression was employed to determine the ability of BHR variables to detect amyloid positivity. Results from both regression models are provided in Table 2. Accuracy measures are reported in Table 3.

Result

The overall model fit of the BHR data with centiloid values was statistically significant (F = 4.69; p‐val<0.001), while R^2 = 0.09, highlighting the strong association with global amyloid burden and the high variability for this cohort. For both dichotomous and continuous models, family history of AD and subjective memory concern are associated with higher amyloid accumulation; higher Geriatric Depression Scale scores are associated with lower amyloid, while low scores of Memtrax N‐back test are related to higher amounts of amyloid. When applying 5‐fold cross‐validation to the logistic model, the classification accuracy of the BHR variables is 64% (cvAUC = 64%; spec = 67%; sens = 60%).

Conclusion

Despite high variability in BHR data, remotely collected subjective and cognitive information are associated with amyloid in older adults with unexplained MCI or dementia of an uncertain cause. The ability to detect amyloid status with online data points to the large potential for building an online screener and motivates further online data collection.
Effects of Androgen Deprivation Therapy on Alzheimer's disease and Related Dementia Risk in the Million Veteran Program
Authors: Panizzon Matthew S. , Deka Rishi , Anglin Tori , Logue Mark W. , Merritt Victoria , Chang Nai‐Chung N , Carter Hannah K , Jasuja Guneet , Lee Kyung‐Min , Lynch Julie , Pagadala Meghana , Rose Brenton , Seibert Tyler , Teerlink Craig , Tu Xin M , Hauger Richard L.
Published: December 2022

Background

Androgen deprivation therapy (ADT) for prostate cancer depletes circulating testosterone levels and has been shown to increase risk for Alzheimer’s disease (AD) and related dementias (ADRD). It is unclear whether ADT acts independently to increase ADRD risk, or whether effects of this treatment are exacerbated by the genetic risk for AD. We hypothesized that the effect of ADT on ADRD risk will be moderated by AD polygenic risk.

Method

Clinical and genetic data were analyzed from 87,060 United States Veterans, who had a diagnosis of prostate cancer and were participants in the Million Veterans Program (MVP) biorepository study. Clinical conditions, including diagnosis codes for ADRD, cancer, Charlson Comorbidity Index conditions, laboratory values (Gleason score, Prostate Specific Antigen levels), cancer treatments, and vital status were obtained from the Veterans Affairs (VA) longitudinal electronic health record data. A polygenic risk score (PRS) for AD was derived based on summary statistics from the Kunkle et al (2019) GWAS of Alzheimer’s disease. The impact of ADT on ADRD was assessed using a time‐varying Fine‐Gray competing risks regression. Death from any cause was considered as a competing event to the development of ADRD.

Result

There were 17,092 (19.6%) patients who received ADT. 72% of the cohort was of white/European ancestry. The average age at prostate cancer diagnosis was 66 years. The median duration of ADT was 360 days. ADT users were more likely to be African American, and had higher PSA levels and Gleason Scores. ADT exposure and the AD PRS each showed significant main effects on ADRD risk, HRs = 1.16 (95% CI: 1.04 ; 1.29) and 1.10 (95% CI: 1.06 ; 1.15) respectively; however, we did not observe a significant interaction effect. Sensitivity analyses indicate that the association was not confounded by including Gleason score, PSA level, income, or education, and results were not altered significantly by excluding or focusing on the effect of the APOE:E4 locus.

Conclusion

ADT significantly increases risk of ADRD, independent of underlying AD genetic risk factors. Further research is necessary in order to determine the mechanism by which androgen depletion contributes to the pathophysiology of ADRD.
TMEM176B regulates phagosome maturation of glial cells and its increased activity contributes to the therapy of Alzheimer’s disease
Authors: Park Seongjeong , Lee Juho , Yoo Miran , Seo Jinsoo , Chung Won‐Suk , Kim Hye‐Ju
Published: December 2022

Background

Given recent interest in using amyloid b (Aβ)‐targeted antibodies as a therapy for patients with Alzheimer’s disease (AD), removal of Aβ by phagocytosis likely protective early in AD. Impaired phagocytic function of glial cells surrounding Aβ plaques during later stages in AD likely contributes to worsened disease outcomes, therefore enhancing phagocytic activity of glial cells could be a potent strategy for AD therapy.

Method

Changes in TMEM176B expression according to the progression of AD pathology was assessed by measuring TMEM176B protein in human AD brain lysates and TMEM176B transcripts in Ab‐treated primary rat astrocytes. The roles of TMEM176B in phagosome maturation of glial cells was investigated by measuring Rab5, Rab7, LAMP1, LAMP2, cathepsin D, and LC3B in presence of Aβ. Intracellular pH of glial cells was detected using fluorescent dye‐based pHrodo Red AM intracellular pH indicator (Invitrogen, Carlsbad, CA). In 5xFAD and 3xTg AD mice model, therapeutic effects of AAV‐TMEM176B was examined. AAV (adenovirus‐associated virus)‐TMEM176B (1 – 2×1010 GC) was intracerebroventricularly injected, and Aβ plaque and p‐tau in brains were assessed 3 months later. Behavioral studies such as Y‐maze, Morris water maze, and novel‐object‐recognition were conducted to exam the effect of TMEM176B overexpression in alleviation of cognition decline.

Result

In human AD brains, Tmem176B expression was increased in moderate AD (Braak III‐IV) was decreased in severe AD (Braak V‐VI). TMEM176B was upregulated by acute Aβ treatment in primary rat astrocytes, and was gradually downregulated concomitantly with impairment of Aβ phagocytosis activity by chronic exposure to Aβ. The TMEM176B agonistic compound augmented phagosome maturation and phagosomal acidification, which led to increased Aβ phagocytosis and lysosomal degradation. Studies confirmed that intracerebroventrical administration of AAV carrying TMEM176B in AD mice results in enhanced glial phagocytosis followed by lowered Aβ burden in brain. Moreover, overexpression of TMEM176B by AAV injection significantly improved cognition impairment of AD mice.

Conclusion

Data from these studies suggest that TMEM176B plays a direct and critical role in phagolysosmal function of glial cells and AD pathogenesis and highlight this ion channel as a potential therapeutic target for treating AD.
Serum metabolites associate with biofluid neurofilament light chain in Alzheimer’s disease
Authors: Kim Jun Pyo , Nho Kwangsik , Saykin Andrew J.
Published: December 2022

Background

Neurodegeneration is one of the main components of A/T/N (amyloid/ tau/ neurodegeneration) classification. Recently, neurofilament light chain (NFL), a neuronal protein that is expressed in myelinated axons, has been increasingly recognized as a biomarker of neurodegeneration. In this study, we performed large‐scale association analysis of serum metabolites with NFL in Alzheimer’s disease.

Method

We performed cross‐sectional and longitudinal association analysis of serum metabolome with plasma and CSF NFL in Alzheimer’s disease (AD), after adjusting for multiple testing (N=1,317 for 140 metabolites). Subjects who had both NFL and metabolomics panel data were included. Metabolites were measured using a targeted metabolomics approach using the AbsoluteIDQ‐p180 kit.

Result

We identified 70 metabolites including acylcarnitines sphingomyelins, biogenic amines, amino acids, and glycerophospholipids as significantly associated with baseline plasma NFL, where we identified sex‐specific and APOE ε4‐specific metabolites. Of those, eight metabolites (C16:1, C18:1, SM(OH) C14:1, SM(OH) C16:1, SM C20:2, PC.aa.C28.1, PC.ae.C30.2, and PC.ae. C32.2) were also associated with baseline cerebrospinal fluid NFL and 10 metabolites (C9, C10:2, citrulline, creatinine, SDMA, PC.ae.C34.2, PC.ae.C36.2, PC.ae. C36.3, SM C20:2, and SM C16:0) were associated with change rates of plasma NFL in AD. Metabolites with significant associations were related to biological functions including amyloid precursor protein processing, neuroinflammation, nitric oxide production, and renal function. There were two significant interactions between sex and two medium‐chain acylcarnitine metabolites (C8 and C10) on plasma NFL levels.

Conclusion

Our present study provides insight into the association of serum‐based circulating metabolites with biofluid biomarker evidence of neurodegeneration, which is closely related to overt clinical symptoms in AD. Metabolites found in our study are related to various biological functions or associated with known risk factors of AD.
Aβ oligomer elimination decreases tau oligomer concentration in CSF and enhances cognition in cognitively impaired aged Beagle dogs ‐ a model of sporadic Alzheimer’s disease
Authors: Kutzsche Janine , Schemmert Sarah , Bujnicki Tuyen , Willuweit Antje , Willbold Dieter
Published: December 2022

Background

Disease‐modifying therapies to treat Alzheimer’s disease (AD) are of fundamental interest for aging humans, societies, and health care systems. More and more data suggest that the toxic protein assemblies of Aβ and tau behave prion like. The drug candidate RD2 (alias PRI‐002) has been developed to directly disassemble and disrupt toxic Aβ oligomer prions. The anti‐prionic compound is BBB penetrable and has demonstrated target engagement in vitro, ex vivo and in vivo. Treatment with RD2 has yielded improved cognition and deceleration of neurodegeneration in three different transgenic mouse models in three different laboratories. Cognitively impaired aged Beagle dogs are one of the very few non‐transgenic AD animal models that may simulate the situation of spontaneous late onset AD, i.e. sporadic AD, which is the most common form of AD in humans. The aim of this study was to investigate the efficacy of RD2 to enhance short‐term memory and cognition in cognitively impaired aged Beagle dogs ‐ a non‐transgenic model of sporadic AD.

Method

36 cognitively impaired aged Beagle dogs have been randomized for five months in three cohorts, placebo, low dose (3 mg/kg RD2 once daily) and high dose (30 mg/kg RD2 once daily). Treatment was done orally and for three months, followed by two months without treatment. Cognitive testing, blood and CSF drawing was done at baseline and then monthly.

Result

We demonstrate that once daily oral treatment with RD2 significantly reduced cognitive deficits in cognitively impaired aged Beagle dogs even beyond the end of the treatment. This and treatment dependent CSF tau oligomer decrease clearly suggest a neuroprotective and truly disease‐modifying effect of RD2 treatment.

Conclusion

Direct elimination of Aβ oligomers by disassembling them into monomers is an interesting therapeutic strategy for AD disease modification including beneficial symptomatic effects.
The impact of individual vascular risk factors on longitudinal neurodegeneration in cognitively unimpaired individuals
Authors: Da Ros Lucas Uglione , Ferrari‐Souza João Pedro , Hauschild Lucas Augusto , Brum Wagner Scheeren , Bellaver Bruna , Leffa Douglas Teixeira , Ferreira Pamela C.L. , Bieger Andrei , De Bastiani Marco Antônio , Pascoal Tharick A , Zimmer Eduardo R.
Published: December 2022

Background

Vascular risk factors (VRFs) have an important role in the etiology and progression of Alzheimer´s Disease (AD). We recently described that VRF burden interacts with AD pathophysiology increasing plasma neurofilament light (NfL) levels, a biomarker of neuroaxonal damage. However, whether individual VRFs interact with AD pathophysiology to promote longitudinal neurodegeneration remains to be elucidated. Here, we aimed to assess the impact of individual VRFs in the longitudinal trajectory of plasma NfL in cognitively unimpaired (CU) individuals.

Method

We assessed 269 CU individuals from the ADNI cohort with available baseline medical data and cerebrospinal fluid (CSF) Elecsys biomarkers (Aβ1‐42 and p‐tau181), as well as longitudinal measures of plasma NfL. Individuals with both Aβ1‐42 and p‐tau181 positivity were defined as having preclinical AD (A+T+). The VRFs assessed in our analysis were history of cardiovascular disease (CAD), hypertension (HTN), diabetes mellitus (DM), hyperlipidemia (HLP), stroke or transient ischemic attack, smoking, atrial fibrillation, and left ventricular hypertrophy. Only those VRFs with at least 5% prevalence in the studied population were included in our analysis.

Result

The following VRFs were included in the final analysis based on prevalence: HTN, CAD, DM, and HLP. Linear mixed‐effects (LME) models revealed that no individual VRF significantly interacted with AD pathophysiology to increase longitudinal values of plasma NfL (HTN X AD pathophysiology X time, β =0.97 p=0.63; CAD X AD pathophysiology X time, β = 2.68, p= 0.36; HLP X AD pathophysiology X time, β= ‐2.1, p=0.3). DM was not present among individuals positive for AD pathophysiology. On the other hand, VRF burden significatively interacted with AD to increase NfL levels (VRF burden x AD pathology x time; β = 5.08, P = 0.016).

Conclusion

We observed that no individual VRF interacted with AD pathophysiology to promote longitudinal neurodegeneration in CU individuals. Our findings suggest that the cumulative number of VRFs, rather than any VRF individually, impacts on neurodegeneration in the context of AD.
6‐month global cognitive function in Mexican older adults recovered of COVID‐19: a prospective cohort study using telemedicine
Authors: Mimenza Alberto , Palma Abdías Ambrosio , Funes José Alberto Avila , Aguilar‐Navarro Sara Gloria
Published: December 2022

Background

SARS‐CoV2 infection affects the central nervous system, one of the manifestations is the cognitive function impairment (1,2). It is currently unknown to what degree and which cognitive domains are involved in this disease (3,4). This study aims to know the effect on global cognitive function in older adults recovered of COVID‐19

Method

A prospective cohort study recruited adults aged over 60 years old. As dependent variable, the Global Cognitive Function (GCF) was assessed using the Mini‐Mental State Examination (MMSE) test via telemedicine in patients recovered of moderate and severe COVID‐19 6 months after hospital discharge. Patients with uncontrolled neurological, metabolic, and psychiatric diseases were excluded. Multivariate models were constructed, as well as Cox regression model to assess the association between GCF impaired with history of moderate and severe COVID‐19, adjusted for age, sex, and education

Result

We studied 607 patients, of which 108 survived the SARS‐CoV‐2 infection. One patient dies during the follow‐up. 107 patients were analyzed, median age was 70 years (SD 7.3), 54% were women, with 9.2 (SD 3.8) years of education, the mean of MMSE was 26.2 (SD 3.2). Regarding the severity of the COVID‐19, 74% presented a moderate infection and 26% was severe. 12% had GCF impaired, of which 14.3% were severe COVID‐19 and 11.4% with moderate infection. Cognitive domains most affected were episodic memory (43%) and constructional praxis (86%) in all patients, without statistic difference for infection severity. Factors associated with GCF impaired was the history of depression (HR 6.8; 95%CI: 1.4‐31.5, p = 0.01), higher education (HR ‐0.20; 95%CI: 0.68‐0.95, p = 0.01), and C‐RP level (HR 1.07; 95%CI: 1.01‐1.13, p = 0.01)

Conclusion

Global cognitive function in older adults recovered of severe COVID‐19 was impaired 6 months after hospital discharge. Cognitive domains of episodic memory and constructive praxis were the most altered. Future studies are needed in this geriatric population to confirm this long‐term outcome, especially in those patients with risk factors such as history of depression, lower education, and severe illness
Utility of the Repeatable Batter for the Assessment of Neuropsychological Status (RBANS) as Endpoint in AD Trials
Authors: Negash Selam , Randolph Christopher
Published: December 2022

Background

The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) is a brief neurocognitive battery that is commonly used in clinical settings to detect and track early symptomatic Alzheimer’s disease (AD) and other neurodegenerative conditions that involve neurocognitive compromise. The RBANS has also been used as an endpoint in trials involving presymptomatic and early symptomatic AD. As the RBANS generates scores that are scaled to population norms, it theoretically may be subject to floor effects in more impaired populations. The present study examined screening RBANS data from several multinational clinical trials of presymptomatic and early symptomatic AD as a function of CDR sum of box (CDR‐SB) stages.

Method

Aggregated data from six multinational clinical trials of presymptomatic and early symptomatic AD were analyzed. There were 19,126 subjects with screening CDR‐SB scores ranging from 0–7. RBANS total scale index score was evaluated as function CDR‐SB scores at each stage. Descriptive statistics, including skewness and kurtosis, were also summarized. Frequency distributions of RBANS total were plotted at each CDR‐SB stage.

Result

The overall mean for the RBANS total scale index score was 84.3 (SD = 17.3). The distributions of RBANS total scale index score remained reasonably normal across the range of CDR‐SB, but the largest magnitude of change on the RBANS total scale index score as a function of CDR‐SB was over the range of CDR‐SB 0–1.5 (CDR‐SB = 0: n = 4,154, mean = 100.7, SD = 12.35, skewness = 0.19, kurtosis = 0.37; CDR‐SB = 1.5: n = 1,575, mean = 78.7, SD = 12.91, skewness = 0.22, kurtosis = 0.24).

Conclusion

The findings from this study suggest that the standard normative‐referenced index scoring of the RBANS may be most useful in preclinical trials, although alternative scoring approaches de‐linking the raw scores to population norms (e.g., baseline z‐score transformations) could provide greater sensitivity to change in samples with more significant neurocognitive impairment.
Reorganizing tasks in primary dementia care – A randomized, controlled, crossover intervention trial to test the efficacy and cost‐effectiveness of advanced nursing care in Germany
Authors: Mühlichen Franka , Raedke Anika , Platen Moritz , Michalowsky Bernhard , Mohr Wiebke , Scharf Annelie , Kleinke Fabian , Penndorf Peter , Hoffmann Wolfgang
Published: December 2022

Background

The increasing prevalence of dementia with the constant availability of general practitioners is a significant challenge for healthcare systems worldwide. Advanced nursing practice (ANP) was implemented in several countries as one possible solution to overcome this challenge. However, this concept of care is not yet implemented in Germany. The InDePendent study (“Advanced nursing practice and interprofessional dementia care”) is the first study in Germany, aiming to implement and evaluate a model of ANP for persons with dementia (PwDs) living at home and their caregivers where tasks were reorganized between dementia‐specific qualified nurses and physicians.

Methods

The Independent study is a multi‐center, cluster‐randomized, controlled, crossover interventional trial. Whereas the waiting‐control group receive care as usual, the InDePendent intervention of the intervention group aims to provide optimum care for PwD and their caregivers by integrating multimodal strategies of an individualized care within the framework of the German healthcare system by a reorganization of tasks between general practitioners and nurses. Dementia‐specific qualified nurses, who passed a specific state exam, conduct the interventions. Based on evidence‐based guidelines a comprehensive set of 115 intervention modules were defined. Each module consists of predefined trigger conditions and recommendations of actions. The intervention starts with a set of assessment instruments for PwD to identify the unmet needs, individual situation and resources of PwD and caregiver. Subsequently, an intervention tasks list was generated to address each of the identified unmet needs. The tasks lists were carried out by the dementia‐specific nurse in close cooperation with general practitioners. For the first time in Germany, nurses were able to carry out tasks that are usually carried out by general practitioners, like prescription of care aids and outpatient care.

Expected results: We expect statistically significant differences between waiting‐control‐group and intervention‐group across the primary (unmet needs) and secondary outcomes (quality of life, caregiver burden, acceptance, cost‐effectiveness). This study can provide evidence concerning the safety, efficacy, and cost‐effectiveness of ANP in Germany, supporting the implementation of the ANP concept into German routine care.
Trial Enrichment using Siamese Neural Networks and PET imaging
Authors: Weatheritt Jack , Peraza Luis R , García David Vállez , Collij Lyduine E. , Gispert Juan Domingo , Barkhof Frederik , Wink Alle Meije , Wolz Robin
Published: December 2022

Background

Biomarker‐based patient selection is expected to increase success rates in AD clinical trials (e.g. identifying subjects that are at highest risk of cognitive decline). We present a computationally feasible modelling framework that provides a score for predicted decline based on a model trained through a Siamese Neural Network.

Method

In this proof‐of‐concept study, we use baseline data from the 1469 ADNI subjects (388 control, 798 MCI, 272 AD) with an FDG PET scan. 80% of the data was used to train a Siamese neural network after clustering subjects into ‘stable’ or ‘decline’ through the method of Bhagwat et al (2018), see Figure 1. 20% of the data was left out for testing.

The model outputs points in a metric space, indicating likelihood of future decline (measured using 2‐year MMSE change from baseline). The first PCA component of the model metric space is used as a screening criterion (See Fig 2). Subjects below the threshold (screen failure rates of 30% and 50%) are not included in the trial simulation. Sample sizes are estimated assuming a 25% effect size, 95% alpha and 80% power (Fig 3). Enrichment performance of the model is compared with FDG SUVR and baseline MMSE score.

Result

The neural network provides a separable metric space of future declining and stable subjects. ‘Screening’ out 30% and 50% of subjects based on model‐predicted decline resulted in a sample size reduction of 45% and 64% respectively, a 5% and 10% improvement over the enriched FDG SUVR cohort. MMSE score yields marginal enrichment. Saliency analysis showed the model is sensitive to the precuneus, hippocampus, temporal lobe and cerebellum.

Conclusion

Deep learning models enable automated trial enrichment strategies, instead of handcrafted features and centralised processing. The saliency analysis shows that the nonlinear framework has identified the relevant regions for the pathology, providing additional support to their use. More work is needed to assess the ability of the developed method to capture multi‐modal biomarker (e.g. Amyloid, Tau, Neurodegeneration) data to obtain a more precise prediction of decline and to assess the trial operational and economic impact of the proposed screening process.
Improving Dementia Screening in India with Telemedicine and Artificial Intelligence: A Scalable Solution to Address Clinical Gaps in Care
Authors: Kainth Tejasvi , Singh Gagandeep , Prasanna Prateek , Manjila Sunil , Rao Anitha
Published: December 2022

Background

Over 4.4 million people live with Alzheimer’s and related dementia (ADRD) in India. There is significant clinical service gap of 90% and only 1 in 10 patients affected with ADRD in India receives screening, diagnosis, treatment, and care. Combining telemedicine with an “Expert system,” can help evaluate, screen, and triage patients with ADRD and reduce the time to diagnosis. We demonstrate early results from a feasibility study that uses state‐of‐the‐art Artificial Intelligence (AI), data analytics, and a HIPAA‐compliant Telehealth platform to screen patients over 65 years in India for ADRD.

Method

We integrated AI‐based platform and a standardized cognitive test into the telemedicine‐based primary‐care workflow. A primary care provider (PCP) screened every consenting patient aged 65 years and older on a telemedicine platform in India. The screening used an algorithm‐based intake tool, baseline Mini‐Mental Status Exam (MMSE), and clinical judgment of the PCP. We compared the final screening assessment generated by AI with the MMSE evaluation and clinical judgment of PCP for nine patients.

Results

Nine patients (4 females, 5 males) in age group of 65‐90 years consented and enrolled in this initial study. Using the intake data as inputs, the AI model predicted MCI in 5 out of 9 patients (55%) and mild ADRD in 4 out of 9 patients (44%). The clinical severity from the tele‐encounter was rated as mild ADRD in 3 out of 9 patients (33%) and no ADRD/Mild Cognitive Impairment in 6 out of 9 patients (66%). Neuropsychological testing with the MMSE demonstrated scores from 24‐30 in 7 out of 9 patients (77%) and <24 in 2 out of 9 patients (22%). The AI model accurately predicted the severity in 6 out of 9 patients (66.6%) of cases.

Conclusion

It is feasible to combine AI and telemedicine to improve ADRD screening and clinical service gaps for healthcare delivery in India. AI severity models also demonstrated adequate predictability to triage patients who have cognitive impairment using digital intake data. The accuracy of the AI prediction models may be further improved with supplemental electronic medical data and translating the intake to a local language.
Public policy and Alzheimer care in India
Authors: Sethurathinam Pushpanathan S
Published: December 2022

Background

In India we do not have proper data in respect of Alzheimer disease and its impact on the social and demographic set up.

Method

Some studies have been conducted in Kerala West Bengal and some parts of North India. The present study is aimed at analyzing the challenges faced by family caregivers and also institutional caregivers. The methods employed cause both quantitative and qualitative. The study was conducted in care centers run by ARDSI (Alzheimer’s Related Disorder Society of India) and family caregivers were interviewed at homes were Alzheimer’s patients are living. A total of197 caregivers and 70 Alzheimer’s patients were selected for the study overs a period of one year from Jan 2021to Jan2012. To analyze the burden level Zarit Burden Interview was adopted.

Results

The study revealed that caregiving is a complex experience which involves strong inter professional collaboration and proper education among caregivers regarding elimination of social stigma. The results also revealed more than 80% of the caregivers belong to female gender and more than 90% of the Alzheimer’s patients are in the age group of 65 years and above. In Indian conditions institutional caregiving is highly selective and it has been utilized by high income group of families as they have to spend around 25000 per month for keeping the AD patient at care homes.

Conclusion

Through the study it has been identified Government support in taking care of Alzheimer’s patients has been extraordinarily effective in the entire Kerala state whereas from available literature, such type of care centers are yet to be established in other states. Regarding family caregivers more awareness programs are needed which will facilitate proper care of Alzheimer’s patients without any social stigma.
Cognitive changes and circadian timekeeping disturbances in aging
Authors: Montgomery Karienn S , Powell Andrew s , Reyes Jocelin s , Jackson William C , Earnest David J
Published: December 2022

Background

Cognitive changes in aging and Alzheimer’s disease (AD) are often accompanied by pronounced disturbances of circadian timekeeping, especially sleep‐wake cycle. Normal circadian timekeeping has an important impact on human health and performance by providing the temporal coordination of internal processes to insure their occurrence at the “right time” relative to each other and to the external environment. Aging of the rodent circadian system is characterized by changes comparable to those in human aging and AD. Common disturbances in the sleep‐wake rhythms of aged rodents include alterations in the light‐dark entrainment of this circadian rhythm. However, not all aged rodents show these changes, demonstrating the variability characteristic of human aging in pre‐dementia. The aging population also shows variability in onset and magnitude of cognitive impairment, but the relationship between these deficits with circadian rhythm disturbances has not yet been identified.

Method

Initially, we tested young (3‐5 mon) and aged (18‐24 mon) C57Bl6 mice on wheel running activity continuously for 30‐40 days for circadian rhythm of locomotor activity. We then assessed learning and memory in the same mice using the Barnes maze task. Next, we wanted to determine if behavioral deficits occurred earlier in the lifespan (middle age) and whether changes in circadian activity occur prior to cognitive impairment.

Result

Aged mice were significantly impaired in all measures of activity rhythm entrainment and cognition. Interestingly, we observed a gender‐specific relationship between cognitive impairment in the Barnes maze and activity onset in aged female mice (20‐24 mon). Changes in activity rhythm entrainment were observed as early as 12‐14 months in middle aged mice. We also tested these mice for cognition (Barnes maze, novel and spatial recognition tests, 3 chamber sociability test) and motor behavior (rotarod, open field and digigait).

Conclusion

This data will be the foundation of our model to further understand the relationship between circadian synchronization and age‐related cognitive impairment, and to probe possible mechanisms of action.
Inhibition of Tau Protein Aggregation Using Small Molecule Inhibitors and Immunotherapies
Authors: Martic Sanela
Published: December 2022

Background

Tau protein aggregation is one of the biomarkers of neurodegenerative diseases and is a viable drug target. Small molecules and immunotherapies have been tested targeting tauopathies. Understanding of the inhibitor mode‐of‐action is needed in order to develop effective drugs against neurodegeneration.

Method

The full length tau protein (2N4R, 441) was used in vitro with aggregation inducers: heparin and arachidonic acid. We have used small molecule inhibitors based of dopamine receptor agonist as inhibitors of tau aggregation in vitro. The inhibition of tau aggregation was also conducted in vitro using anti‐tau antibodies. The biophysical methods including electron microscopy and fluorescence spectroscopy were used to measure inhibitor efficiency.

Result

The anti‐tau antibodies which target epitope in R1‐R4 repeat domain were most effective in inhibition aggregation. The small molecules containing catechol groups were effective aggregation inhibitors and were in micromolar range, which was similar to the efficacy of methylene blue.

Conclusion

The tau aggregation was inhibited in vitro using dual approach, with small and large molecules, indicating that both strategies are viable against tauopathies. Future work will require design of multifunctional inhibitors to improve selectivity and potency.
A simple, automated, speech‐based and AI‐enhanced screener for mild cognitive impairment and amyloid beta positivity
Authors: Fristed Emil , Skirrow Caroline , Meszaros Marton , Lenain Raphael , Meepegama Udeepa , Papp Kathryn V. , Ropacki Michael T. , Weston Jack
Published: December 2022

Background

Vocal and linguistic changes in Alzheimer’s dementia have been documented. The current study assesses whether a fully automated speech‐based artificial intelligence (AI) system can detect early clinical impairment and amyloid positivity, which characterise the earliest stages of Alzheimer’s disease (AD).

Method

Two studies were completed in the UK and USA: AMYPRED‐UK (NCT04828122) and AMYPRED‐US (NCT04928976). 200 participants with established amyloid beta (Aβ) and clinical diagnostic status (97 Aβ+, 103 Aβ‐ from prior PET scan or CSF tests; 94 cognitively unimpaired (CU), 106 with mild cognitive impairment (MCI) or mild AD) were recruited and completed automated assessments with the Automatic Story Recall Task (ASRT) either in‐clinic or via telemedicine appointment. The AI text‐pair evaluation model ParaBLEU produced vector‐based representations of the abstract, generalized patterns that differed between the original story text and transcribed retellings. These were fed into logistic regression models trained with tournament leave‐pair‐out cross‐validation analysis to predict Aβ status and MCI/mild AD. Potential benefits of screening using the ASRT system were examined via simulation, including: (1) identifying MCI in primary care, and (2) reducing the number of PET scans required in clinical research studies and trials.

Result

Using an average of only 6.56 minutes of speech per participant, the ASRT system predicted Aβ positivity in the full sample (area under the receiver operating characteristic curve (AUC) = 0.77) and in diagnostic subsamples (MCI/mild AD: AUC = 0.82; CU: AUC = 0.71), as well as MCI/mild AD (AUC = 0.83) in the full sample. Simulation indicated that screening with the ASRT system could: (1) increase correct (+8.5%) and reduce incorrect referrals (‐59.1%) compared with the Mini‐Mental State Exam; and (2) enrich samples for Aβ positivity prior to PET scan (‐35.3% and ‐35.5% fewer scans required in MCI and CU individuals, respectively).

Conclusion

With the first disease‐modifying treatment for AD now available, there is an urgent need for improved screening to identify individuals at risk for AD dementia. The ASRT system is a brief, effective, automated, speech‐based cognitive assessment offering scalable screening for MCI/mild AD and amyloid beta biomarker positivity.
Glial activation may mediate Alzheimer’s disease progression
Authors: Rossano Samantha M , Johnson Aubrey S. , Lao Patrick J. , Klein Julia , Tomljanovic Zeljko , Stern Yaakov , Brickman Adam M. , Lee Seonjoo , Kreisl William Charles
Published: December 2022

Background

Glial activation may precede regional tau progression through Braak stages in Alzheimer’s Disease (AD)[1]. However, the role of glial activity in the temporal progression of AD is not well characterized.

Method

Nineteen controls and 22 patients with clinical diagnosis of MCI or AD underwent [18F]florbetaben, [18F]MK‐6240, and [11C]PBR28 PET to measure β‐amyloid, tau, and TSPO (a glial biomarker). Standard uptake value ratios and corrected gray matter volume (%GM) were calculated from prefrontal, temporal, and parietal regions to create composite AD‐centric measures for β‐amyloid, TSPO, and neurodegeneration. Braak‐specific gray matter volumes were used to measure tau and neurodegeneration in early (I/II), middle (III/IV) and late (V/VI) Braak regions. Tau and TSPO were measured with (‐PVC) and without partial volume correction. Correlation analyses were performed between TSPO and β‐amyloid, tau, and MMSE scores. Mediation analyses explored the effect of TSPO in the steps along a proposed model for AD progression (Fig 1).

Result

Greater TSPO‐PVC was associated with greater β‐amyloid (std.β=0.38, p=0.015), and with greater tau‐PVC in middle (std.β=0.45, p=0.004) and late Braak regions (std.β=0.50, p=0.002, Fig 2), even after controlling for %GM. Greater TSPO‐PVC was associated with lower MMSE score (std.β=‐0.53, p=0.006). Similar results were observed for uncorrected PET data. TSPO‐PVC mediated the relationship between tau‐PVC in early Braak regions and tau‐PVC in middle Braak regions (indirect effect=0.118, p=0.017) and the relationship between tau‐PVC in middle Braak regions and neurodegeneration in middle Braak regions (indirect effect=‐0.255, p=0.027). TSPO‐PVC mediated the relationship between neurodegeneration and impaired MMSE performance for early (indirect effect=0.233, p=0.021) and middle Braak regions (indirect effect=0.204, p=0.029), and between neurodegeneration and impaired Trails B performance for early (indirect effect=0.283, p=0.009) and middle Braak regions (indirect effect=0.228, p=0.017).

Conclusion

TSPO is related to β‐amyloid burden, tau pathology in middle and late Braak regions, and cognitive impairment in a manner independent of neurodegeneration. Our results suggest that glial activity impacts the progression of tau pathology from early to middle Braak regions and influences the relationship between neurodegeneration and cognitive impairment in these same regions.

Reference: 1. Pascoal, T.A., et al. Microglial activation and tau propagate jointly across Braak stages. Nat Med 27, 1592–1599(2021).
Understanding reactive astrogliosis in degenerative proteinopathies through the lens of postmortem brain imaging techniques
Authors: Kumar Amit , Fontana Igor C. , Nordberg Agneta K
Published: December 2022

Background

The discovery and validation of biomarkers beyond amyloid‐β and tau is now considered as a research priority in the Alzheimer’s disease (AD) field. In this context, astrocytes ‘key homeostatic cells’ in the central nervous system (CNS) are potential targets thanks to their swift response in AD pathology. Astrocytes tend to changes in brain physiology after CNS injury/insults via a specific defence response called reactive astrogliosis. The role of astrocytes in AD pathology is still under examination, however recent studies have openly suggested that reactive astrogliosis is an early event which may precede other hallmarks of the disease. In our recent work, we have speculated, based on clinical/translational in vivo and in vitro brain imaging studies, that there are two waves, ‘first (early) and second (late)’, of reactive astrogliosis in AD pathology with a distinct, close‐knit relationship with other pathological markers. Reactive astrogliosis also seems to play a critical role in other proteinopathies, such as progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). The PET imaging field is advancing very fast and different astrocytic‐tracers are now available, such as 11C‐Deprenyl (DED) and SMBT‐1 (both targeting MAO‐B) as well as 11C‐BU99008 (detect imidazoline2 binding sites), which we believe is of utmost relevance to shed more light on the role of reactive astrogliosis, including astrocytic heterogeneity and improve our understanding of the underlying mechanism in these proteinopathies.

Method

We used a mixed battery of specialized in vitro radioligand binding assays (saturation and competition studies in brain tissues) and large frozen human brain section autoradiography in AD, PSP, CBD and control brains.

Result

In our studies, we demonstrated that BU99008 could visualize reactive astrogliosis and target multiple binding sites in AD brain. We observed that BU99008 and DED varied in their binding behavior in AD and control brains, suggesting that they might be targeting a specific state/or a different sub‐population of astrocytes.

Conclusion

Postmortem brain imaging techniques are valuable tools for validation (pre‐clinical) of novel PET‐tracers. Our ongoing studies in PSP and CBD brains as well as with SMBT‐1 will provide deeper insight into the role of reactive astrogliosis in these deadly diseases.
An Epigenome‐wide association study of psychosis in Alzheimer's disease dorsolateral prefrontal cortex
Authors: Weymouth Luke Stephen , Kouhsar Morteza P , Creese Byron , Bergh Sverre , Wedatilake Yehani , Torkamani Ali , Smith Adam R. , Selbaek Geir , Sweet Robert , Ballard Clive G , Mill Jonathan , Kofler Julia , Pishva Ehsan , Lunnon Katie
Published: December 2022

Background

Psychosis is a debilitating syndrome occurring in 40‐60% of people with Alzheimer’s disease (AD) and corresponds with a more severe disease course. Evidence suggests that psychosis in AD (AD+P) is associated with a distinct profile of neurobiological changes, but little is known about the molecular processes driving etiology. In this study we performed an epigenome‐wide association study (EWAS) to investigate DNA methylation associated with AD+P in the dorsolateral prefrontal cortex of 192 post‐mortem brain samples.

Method

Brain samples with corresponding in life neuropsychiatric assessments were obtained from the University of Pittsburgh Alzheimer’s disease Research Center (PITT‐ADRC). AD pathology was assessed and classified using CERAD neuritic plaque density score, Braak neurofibrillary tangle stages and NIA‐RI criteria. The presence or absence of delusions and hallucinations was scored on the CERAD Behavioral Rating Scale. DNA was extracted, bisulfite treated and then profiled on the Illumina Methylation EPIC Array.

Result

After data processing and quality control we used linear regression models to compare 152 AD+P samples to 40 AD samples without psychosis (AD‐P). A regional analysis of spatially correlated p‐values highlighted four differentially methylated regions (DMRs) associated with psychosis, which are being replicated in other data sets and validated for cell specificity using fluorescence activated nuclei sorting (FANS).

Conclusion

The development of effective therapies for AD+P is an urgent priority. To address this we have collated a well powered study cohort to interrogate the epigenetic basis of AD+P, finding significant methylomic variation. This variation provides an insight into potential mechanisms and biomarkers which will help to identify drug targets and enable better treatment with existing medications.
Endothelial mitochondrial dysfunction during Cerebral Amyloid Angiopathy and Hyperhomocysteinemia
Authors: Parodi‐Rullan Rebecca M , Fossati Silvia
Published: December 2022

Background

Hyperhomocysteinemia (HHcy), or high levels of homocysteine, is considered a risk factor for vascular disease. Cardiovascular (CV) risk factors, such as HHcy, may lead to exacerbation of cerebral amyloid angiopathy (CAA) due to their detrimental effects on cerebrovascular function. Cerebrovascular function is regulated, in part, by endothelial cells (EC), the most important cellular component of the blood‐brain barrier (BBB). Dysfunctional ECs may lead to deficits in vascular perfusion, clearance, and may eventually result in neuroinflammation, microhemorrhages, and neurodegeneration. EC mitochondria serve as sensors of cellular damage and mediate downstream pathways such as cell death and inflammation. In ECs, mitochondrial dysfunction may lie as the point of convergence of CV risk factors and amyloid β (Aβ)‐induced neurovascular dysfunction. Understanding the mitochondrial deficits elicited by CV risk factors, Aβ, or their combination, may open roads to new therapeutics aimed at preserving mitochondrial function. Indeed, we have previously shown that carbonic anhydrase inhibitors (CAi) reduce amyloid‐induced cell death and mitochondrial dysfunction. Here, we aim to understand the changes occurring in EC mitochondria during Aβ‐ and mixed (Aβ+HHcy)‐ vascular pathologies. In addition, we will assess the therapeutic potential of CAi in such pathologies.

Method

Human brain microvascular ECs were challenged with Aβ, Hcy, or the combination in the presence or absence of CAi. EC barrier properties and changes in mitochondrial function were assessed.

Result

The presence of Aβ or Hcy independently increased BBB permeability, and, when both present, Hcy worsened Aβ‐induced barrier permeability; these effects were prevented by CAi. Preliminary data suggests that the mitochondrial ATP production is impaired in the presence of Aβ40‐E22Q (Dutch mutant) but not in the presence of Hcy. These results may be a reflection of the observed deficits in mitochondrial oxygen consumption rate (OCR).

Conclusion

The EC barrier is negatively affected by the presence of Aβ, and Hcy aggravates Aβ‐induced BBB permeability. The presence of Aβ40‐E22Q affects mitochondrial OCR and ATP production, indicative of changes in cellular metabolism and mitochondrial dysfunction. These results suggest a central role of the mitochondria as a mediator of vascular dysfunction in the presence of Aβ.
GFAP expression levels are associated with brain glucose metabolism in a rat model of Alzheimer’s disease
Authors: Machado Luiza Santos , da Rocha Andreia Silva , Soares Carolina , de Souza Débora Guerini , Ramos Vanessa G. , Bellaver Bruna , Ferreira Pamela C.L. , Zimmer Eduardo R.
Published: December 2022

Background

Glial Fibrillary Acidic Protein (GFAP) is an intermediate filament expressed almost exclusively in astrocytes, and it is usually overexpressed in reactive astrocytes. We have previously shown that astrocytes play a critical role in brain energy metabolism and are significant contributors to the [18F]FDG‐PET signal. The cortex is majorly composed of glial cells, whereas the cerebellum is predominantly composed of neurons. In light of this, whether GFAP levels in the brain tissue are associated with [18F]FDG‐PET signal remains unknown. Thus, we aimed to investigate the associations between cortical and cerebellar GFAP levels with brain glucose metabolism in a rat model of Alzheimer’s disease.

Methods

Brain metabolism of ten‐month‐old TgF344‐AD (n=8) and wild‐type (WT,n=6) rats was assessed with [18F]FDG‐PET. Then, GFAP RNA levels were quantified in the frontal cortex (CXF), temporoparietal cortex (CXTP), and cerebellum (CB) using qRT‐PCR. The [18F]FDG‐PET standardized uptake ratio (SUVr) was calculated using pons as the reference region. T‐tests were used to assess the differences between groups in GFAP RNA expression levels and regional brain [18F]FDG‐PET. Comparisons were conducted using t‐statistical analyses at voxel level (RMINC). Differences were considered statistically significant at p<0.05 (t>2).

Results

No differences between groups were found in the whole brain FDG metabolism or regions of interest (CXF, CXTP, and CB;t(13)<2). At the voxel level, we identified small cortical hypermetabolic clusters in the TgF344‐AD rats (t(13)=5.55, local maxima). The GFAP RNA was increased in the CXTP of TgF344‐AD rats (p=0.001). No significant differences were found between groups in GFAP RNA levels in other brain regions evaluated. Interestingly, we found positive correlations between [18F]FDG‐PET metabolism and the GFAP RNA expression in the CXTP (local maxima, t(13)=8.33;Fig.1a) and CXF (local maxima, t(13)=4.82;Fig.1b). By contrast, [18F]FDG metabolism did not associate with GFAP RNA expression levels in the CB (t(13)<2;Fig.1c).

Conclusion

GFAP RNA levels were increased in the CXTP of TgF344‐AD rats, which may indicate early astrocyte reactivity. GFAP RNA expression was associated with [18F]FDG metabolism only in cortical regions, suggesting that astrocytes may have major roles in cortical glucose uptake, but not in cerebellum.