bluuebunny/crossref_metadata_2025 huggingface dataset:
Depression prevalence and sex differences in mild cognitive impairment and mild dementia due to autopsy‐confirmed Alzheimer’s disease or vascular neuropathology
Authors: Tall Sakina Ouedraogo , Yeruva Rajashekar , Chen Maria , Masurkar Arjun V.
Published: December 2023

Background

Depression is increasingly recognized as a modulator of dementia risk and course, and is associated with multiple etiologies of cognitive decline. While it has been studied in clinically diagnosed cohorts, which may suffer from diagnostic error, there is less information in neuropathologically‐defined subjects. We sought to define the depression prevalence and sex difference at mild cognitive impairment (MCI) and mild dementia in an autopsy‐confirmed cohort of Alzheimer’s disease (AD) and vascular neuropathology.

Method

Retrospective data was gathered from the National Alzheimer’s Coordinating Center database on autopsy‐confirmed cases of primary Alzheimer’s disease (AD) and vascular neuropathology. Prevalence of depression was measured by the Geriatric Depression Scale score > = 5 during any visits at MCI (n = 364 AD cases, n = 51 vascular cases) and mild dementia (n = 557 AD cases, n = 24 vascular cases). We excluded those without pathology report, sex data or GDS results. Groups were compared via the chi‐squared test.

Result

Depression prevalence was equal in MCI from AD and vascular neuropathology (27% in each, p = 0.9974). At mild dementia, depression was significantly more prevalent in vascular neuropathology compared to AD (37% versus 20%, p = 0.0363). In AD, at MCI there was no sex difference in depression prevalence (male 28% versus female 27%, p = 0.7560) but at mild dementia there was a female predominance (male 16% versus female 25%, p = 0.0075). In contrast, with vascular neuropathology, at MCI there was a trend for female predominance (male 21% versus female 33%, p = 0.3181) and no sex difference at mild dementia (male 38% versus female 36%, p = 0.9158).

Conclusion

These results demonstrate that the prevalence of depression in cognitive disorders is driven by etiology, stage, and sex, which promotes further mechanistic studies on the interaction of these factors. Moreover, this illustrates the importance of depression screening in dementia, especially in females and those with suspected vascular etiology.
A glioma mimic which almost went under the knife
Authors: Dubey Shubham , P Naveen , Dubey Ayush
Published: December 2023

Background

There are many causes of acute dementia. While on one hand, it is essential to suspect a diagnosis based on clinical symptomatology and examination, radiological findings sometimes pose challenge leading to confusion regarding therapy being offered. An interesting case is discussed here.

Method

A female patient of age 39 years showed up in Neurology OPD with symptoms of forgetfulness, confusion, socially inappropriate behaviour and somnolence for around 15 days. There was no history of seizures, hallucinations or sensory symptoms. With a clinical diagnosis of acute dementia, she was subjected to brain imaging.

Result

Contrast enhanced brain MRI showed ill‐defined non enhancing T2 and FLAIR hyperintense lesion involving bilateral hypothalamus, adjoining antero‐inferior aspect of both thalami, bilateral medial basal ganglia & cavum septum in bilateral symmetrical fashion. There was no evidence of venous thrombosis and on the basis of above findings, a diagnosis of low grade glioma was considered and biopsy was planned. But, before going for invasive procedure, other possibilities were explored. With a suspicion of Wernicke’s encephalopathy, iv thiamine was tried with no benefit. Autoimmune workup showed positive NMDA receptor antibodies and hence, immunotherapy was tried to which, patient responded completely.

Conclusion

NMDA encephalitis can present with variable MRI findings. Thus, a possibility of this entity should always be considered in differentials for young female patients presenting with acute dementia like picture.
Mechanistic Insights of Meglitinides Drug Repurposing and Delivery to Brain for Metabolic Syndrome Linked Neurodegenerative Disease
Authors: Wadhwa Geetika , Taliyan Rajeev
Published: December 2023

Background

Metabolic syndrome (MS) includes clusters of metabolic disorders and type 2 DM (T2DM) is most common MS which cause insulin resistance (IR). The IR mediated dysregulation of signaling cascades in brain increase the production and secretion of Aβ, p‐tau which prompt to Alzheimer’s (AD). Therefore, repaglinide (REP) a meglitinides drug is used, which act by targeting ATP binding cassette and evidence indicated that REP increase neuronal survival via upregulating ATF‐6 gene and blocking the DREAM. Thus, there is huge possibility that REP regulate and modulate the expression of pro‐apoptotic protein, anti‐apoptotic protein, calcium homeostasis and may eventually reduce the neuronal cell death.

Methods

In, in vitro studies, primarily cytotoxicity assay was performed on SHSY‐5Y cells and to mimic the neurodegenerative condition, the cells were treated with streptozotocin (STZ, 2.5mM). Further, to check the efficacy of REP in AD, in vivo studies were performed using HFD fed STZ induced murine model. The HFD was fed for 16 weeks followed by administration of STZ (30mg/kg; i.p) in wistar rats for induction of DM linked AD.

Results

In vitro and in vivo studies were conducted to understand the neuroprotective potential of the REP. It was observed that the REP shows cellular viability of ∼80‐85% and no morphological changes in the cells were identified. Additionally, the results have shown that REP increase the cell viability of STZ treated SHSY‐5Y cells by ∼1.2‐fold and significantly (p<0.01) decreased the oxidative stress in H2O2 treated cells. After treatment of REP (4 mg/kg,p.o) for 4 weeks in DM linked AD wistar rats, a significant (p<0.01) decrement in Aβ, tau proteins, TNF‐α, IL‐6, MDA, NO and increment in BDNF, SOD, GSH level was observed compared to disease control rats. Further, in behavioral studies a significant improvement (p<0.01) in the retention memory and spatial memory was observed after the REP treatment. Additionally, a significant (p<0.05) increase in Bcl‐2, ATF‐6 expression, and decrement in Bax, Caspase‐3 expression indicates reduction in neuronal cell death then the disease rats.

Conclusion

In summary, it concluded that REP act as a neuroprotective agent which might be used to treat MS linked AD.
An examination of the impact of age and sleep quality on neurocognition within a multi‐ethnic sample
Authors: Slaughter Alexander W. , Arentoft Alyssa , Cham Heining , Oleas Denise S. , Schuck Lauren A , Camuy Alicia M , Breen Elizabeth Anne , Zhu Danqi , Talavera Sandra , Mindt Monica Rivera ,   Study of African‐Americans and Latinas/os for Understanding Dementia (SALUD)
Published: December 2023

Background

Older adults and ethnoracially diverse groups (e.g., non‐Latinx Black (NLB), Latinx) are at higher risk of poor sleep quality. Poor sleep is linked to neurocognitive (NC) decline in middle/older adults, but much of the sleep literature has relied on global NC screening measures. This study examined the effects of age and sleep quality on NC functioning within a multi‐ethnic sample of middle/older adults utilizing a multi‐domain NC battery.

Method

This cross‐sectional study included 119 middle/older adults (M
age = 65.3, SD
age = 6.9; 46% NLB, 31% Latinx, and 23% non‐Latinx White (NLW); 63% female) who completed demographic questionnaires, the Pittsburgh Sleep Quality Index (PSQI), and a comprehensive NC battery. PSQI global and component scores (e.g., Daytime Dysfunction; PSQI‐DD) measured subjective reporting of sleep quality. Demographically‐adjusted NC T‐scores were used to compute 8 NC‐domain and global average T‐scores. Pearson’s correlations, ANOVA, and multiple regressions were used to test hypotheses.

Result

Global NC was not related to any PSQI components, and the PSQI components did not differ across ethnoracial groups (all p’s<.05). However, within‐group correlations revealed that the relationship between PSQI components and NC domains significantly differed across ethnoracial groups. For example, frequency of sleep medication usage was significantly negatively correlated with executive functioning in the NLB group (r = ‐.39, p = .02), but not NLW or Latinx groups. Multiple regressions, including age and the interactions between race/ethnicity and PSQI component scores, significantly predicted 21‐39% of the variance in all NC domains (p’s<.05), except attention/working memory (p = .60). The interaction between PSQI‐DD and ethnoracial status significantly predicted memory (p’s<.05); this relationship was positive in the NLW group (B = 20.20), yet negative in the NLB (B = ‐1.16) and Latinx (B = ‐0.56) groups (ps<.05).

Conclusion

Disordered sleep may have a greater impact on NC functioning, namely memory, among middle/older adults from diverse ethnoracial groups, who are already at heightened risk for NC decline. Importantly, global cognitive screening may be insufficient in examining the effects of sleep quality on NC in middle/older adults. Given the ethnoracial differences in sleep quality, future research should consider culturally‐tailored sleep interventions. Using objective sleep quality measures (e.g., actigraphy) may better quantify sleep components.
GWAS identifies genetic factors associated with severity of cerebral amyloid angiopathy pathology
Authors: Godrich Dana , Pasteris Jeremy , Martin Eden R. , Schellenberg Gerald D. , Pericak‐Vance Margaret A. , Cuccaro Michael L. , Scott William K. , Kukull Walter A. , Montine Thomas J. , Beecham Gary W. ,   the Alzheimer Disease Genetics Consortium
Published: December 2023

Background

Cerebral amyloid angiopathy (CAA) commonly co‐occurs with Alzheimer’s disease (AD) pathologies, leading to an increased risk and severity of cognitive decline. While CAA is known to impact cognitive impairment, the genetics of CAA are not well understood, and most previous sample sizes have been small. To address this gap, we conducted a genome‐wide association study (GWAS) of CAA pathology to identify genetic factors that are associated with this understudied AD‐related amyloidosis.

Method

We utilized data from 6,038 autopsied and genotyped individuals from the National Alzheimer’s Coordinating Centers (NACC) who were evaluated for CAA pathology upon autopsy. Participants were age 50+ at death and non‐Hispanic white. Genetic data were available from SNP arrays imputed to TOPMed and analyses were conducted only on common variants (MAF >0.01). GWAS performed ordinal logistic regression to determine the effects of genetic variants on CAA pathology (coded as 0, none; 1, mild; 2, moderate; 3, severe). Models adjusted for sex, age at death, and the first three genetic principal components (PC‐AiR; GENESIS; R v4.2). We then meta‐analyzed across the cohorts (METAL).

Result

We observed genome‐wide significant associations with CAA severity at established AD loci, including APOE (top SNP: rs429358, MAF = 0.155, P = 1.6E−86) and BIN1 (top SNP: rs6733839, MAF = 0.397, P = 3.9E−08). We observed a novel association with CAA pathology on chromosome 9 (top SNP: rs10908023, MAF = 0.258, P = 4.3E−11).

Conclusion

This is the largest study to date aimed at identifying genetics factors associated with CAA pathology. Our findings offer new insights into the genetics of CAA, a common player in the AD landscape. We acknowledge the need for a larger dataset and are now expanding the study by sample size and by including additional ADRD phenotypes to gain a better understanding of the full spectrum AD/ADRD. Continuing to uncover the genetic underpinnings of CAA could potentially help us think about AD treatment in new ways and mitigate the negative side‐effects of brain swelling and bleeding that have been observed in recent clinical trials.
Brain catecholaminergic neurons control monocytes deployment to sites of injury and their loss exacerbate cognitive deterioration in an animal model of Alzheimer’s Disease
Authors: Croese Tommaso , Abellanas Miguel Angel , Ramos Javier Maria Peralta , Arad Michal , Medina Sedi , Castellani Giulia , Schwartz Michal
Published: December 2023

Background

The CNS constantly monitors the organism’s internal state and orchestrates adaptive responses to perturbation of the body’s homeostasis. Emerging evidence revealed that the brain can also instruct immune responses, which in turn can affect the condition of other organs, including the brain itself.

Method

We used neuronal retrograde‐labelling, flow‐cytometry, mass cytometry, scRNAseq and cognitive tests in animal model of Alzheimer’s disease (5xFAD) to study the relevance of the brain Brain‐Immune axis in the context of Alzheimer’s Disease.

Results

We found that catecholaminergic neurons are in direct communication with the spleen, the major secondary lymphoid organ of our body. This connection is impaired in an animal model of neurodegeneration (Alzheimer’s Disease ‐ AD), and undermining this communication at early stage of the disease accelerated disease manifestation. We found that monocytes are the most sensitive cell type to noradrenaline released by the splenic nerve and halting neuronal inputs to the spleen impairs monocytes’ migratory capacity. Monocytes are needed to cope with neurodegenerative diseases and acute CNS damage. Upon splenic denervation, we observed reduced number of monocytes in the brain of AD mice and impaired microglia maturation. Upon denervation of the spleen, reduced number of infiltrating monocytes was also observed in a model of retina excitotoxic damage.

Conclusions

These results highlight a novel pathway through which the CNS can control immune function and therefore trigger tissue repairing processes.
A random population survey of adults aged 65 and over who deny recent cognitive changes asking the question “Do you want to know your risk of developing Alzheimer’s Disease via a simple blood test” after being told that researchers now believe that it is possible detect Alzheimer’s Disease prior to symptoms with a simple blood test
Authors: Curtis Craig T , Meador Jenna
Published: December 2023

Background

Recent advances in blood biomarkers may soon enable clinicians to detect AD many years prior to cognitive decline with great accuracy. This survey address whether older adults would want a blood test to know whether they are at risk of developing AD.

Method

Random subjects who denied recent memory problems were approached on the sidewalk in a 55+ retirement community setting. The following scenario was presented: Scientists have learned that Alzheimer’s Disease starts 10‐20 years before symptoms, such as memory loss, begin. Your doctor can now order a simple blood test that will detect Alzheimer’s Disease before you get symptoms. Knowing that this blood test can show if you will get Alzheimer’s Disease, would you want the blood test?

Result

Data collected from 31 respondents reveal that 29 out of 31 (94%) were “familiar” with AD and 22 (71%) reported they knew someone who had been diagnosed with AD. When given the hypothetical scenario above, 23 (74%) wanted the blood test, 4 (13%) did not want the blood test and 4 (13%) were unsure if they wanted the blood test. Only 12 (39%) stated they received any type of memory testing at their annual doctor’s visit.

Conclusion

A surprisingly large number of respondents in our survey want to know their risk of developing AD. These results indicate a significant portion of the general population do want a simple blood test to know their risk of developing AD and do not seem afraid of knowing their risk of AD.

The survey results also indicated that 94% were familiar with AD, indicating a high level of AD awareness in society. Only 39% reported receiving any type of memory testing at their annual doctor’s visit. Based on these results, clinicians should receive additional AD education so they are better prepared to discuss AD risk factors.

Our survey indicates a large number of older adults are interested in a blood test that determines their risk of AD.

Further work will include increasing the number of participants to 500 to further strengthen the data set.
Slow‐breathing induced hypocapnia mitigates deficit of vasoreactivity measured in patients with cognitive impairment
Authors: Marmarelis Vasilis , Chui Helena C , Billinger Sandra A , Joe Elizabeth B , Shin Dae , Hashem Suhaib , Rizko Jasmin , Aaron Stacey E , Cardim Danilo , Zhang Rong
Published: December 2023

Background

A multi‐center study in Los Angeles (USC), Kansas City (KUMC) and Dallas (UT‐SWMC) has been quantifying the dynamics of CO2 vasoreactivity in MCI/AD patients and cognitively normal controls under spontaneous resting conditions. The goal is to develop effective vasoreactivity physio‐markers for early diagnosis of MCI and pre‐clinical AD, based on previous findings of significantly reduced vasoreactivity in MCI patients [Marmarelis et al., J. Alzh. Dis. 56:89‐105, 2017]. Here, we report on the effects of slow‐paced breathing upon these physio‐markers.

Method

Spontaneous changes in arterial blood pressure (ABP), end‐tidal CO2 (etCO2), and cerebral blood flow velocity (CBFV) in middle cerebral arteries were recorded under resting conditions over two 6‐8 min sessions, separated by session of slow‐paced breathing (6 breaths/minute), in 47 MCI and 25 AD patients and 58 age‐matched cognitively normal controls. Using our novel methodology, we obtained predictive models of the dynamic effects of ABP and etCO2 upon CBFV using the universal convolutional form of linear dynamic models, which are defined by the respective “kernels” estimated from time‐series data. The etCO2‐to‐CBFV kernel is used to compute indices (physio‐markers) that quantify the vasoreactivity in each participant.

Result

The vasoreactivity index for each participant is computed from the integrated etCO2‐to‐CBFV kernel as the time‐average over the first 30 sec. The average kernels for patients and controls are shown in Figures 1‐2 for the two sessions respectively. Note the smaller kernel values for patients – while the difference is reduced after slow‐paced breathing. The obtained vasoreactivity indices are significantly smaller for 72 patients (MCI and AD taken together) vs 58 controls for the first session [p = 0.018; mean (SD): 0.057 (0.539) vs 0.424 (1.076)] but NOT for the session after slow‐paced breathing [p = 0.237; mean (SD): 0.193 (0.731) vs 0.361 (0.863)]. Average etCO2 was lower after paced‐breathing [p = 10−6; mean (SD): 36.23 (6.18) vs 33.44 (6.36)].

Conclusion

Quantitative analysis of cerebral CO2 vasoreactivity under resting spontaneous conditions in 72 MCI/AD patients vs 58 age‐matched controls, before and after slow‐paced breathing, revealed that the significant vasoreactivity deficit in MCI/AD patients is mitigated (at least temporarily) after slow‐paced breathing. This effect may be due to observed hypocapnia induced by slow‐paced breathing.
Recruitment and Engagement of LGBTQIA+ Older Adults for The Stonewall Generations Study
Authors: Flatt Jason D. , Tate Jacq , Klenczar Brittany
Published: December 2023

Background

According to the Alzheimer’s Association, approximately 350,000 LGBTQIA+ older adults in the U.S. currently have Alzheimer’s disease and related disorders (ADRD), increasing to over a million by 2030. Our recent research suggests that 1 in 7 LGBTQIA+ older adults report problems with their memory and thinking (subjective cognitive decline), which was much higher than their cisgender (not transgender), heterosexual counterparts. However, very few studies have assessed the cognitive function of LGBTQIA+ older adults.

Methods

We are utilizing tailored recruitment and engagement strategies to recruit a racial/ethnically diverse sample of at least 250 LGBTQIA+ and 250 non‐LGBTQIA+ older adults aged 50+ from the U.S. with a range of cognitive function from healthy to mildly impaired. Our recruitment and engagement approaches are guided by community‐based participatory research approaches that focus on building trust, collaboration, cultural humility, and giving back to the community.

Results

We have been utilizing novel methods to recruit and engage LGBTQIA+ older adults and community organizations across the U.S. into The Stonewall Generations Study. Our current efforts involve a diverse recruitment plan that relies on recruitment via social media (e.g., Facebook, Twitter), referrals from community organizations, local outreach (tabling at community resource fairs, attending Pride and other LGBTQIA+ focused events), presenting to LGBTQIA+ aging service organizations, and developing unique social and educational engagement events.

Conclusions

Our current efforts to recruit and engage LGBTQIA+ older adults are important because they can help to identify ways to improve representation of diverse communities in Alzheimer’s disease and aging research. There is a need for tailoring research and recruiting and engaging diverse older adults, especially LGBTQIA+, into research and finding ways to address the health and Alzheimer’s disease risk of underserved populations. The Stonewall Generations Study aims to increase knowledge of culturally‐relevant recruitment and engagement strategies and identify targets for preventative interventions to decrease ADRD risk among LGBTQIA+ older adults.
Fatigue in vascular cognitive impairment no dementia
Authors: Ciopleias Bogdan , Diaconu Stefania , Irincu Laura , Despa Irina , Opritoiu Bianca , Cusnir Malina , Ungureanu Larisa , Kakucs Cristian , Falup‐Pecurariu Cristian
Published: December 2023

Background

patients with vascular cognitive impairment no dementia (VCI‐ND) may have different complains like sleep disturbancies, fatigue, pain. Fatigue is one of the most common symptoms of these patients. In advanced stages, fatigue is difficult to describe by the patients. Aim of the study: to assess the frequency and risk factors for fatigue in patients with VCI‐ND.

Method

this is a case‐control study, which involved 23 people with VCI‐ND and 23 sex and aged matched controls (with no dementia). A comprehensive neurological assessment in both groups were performed; adittionally we used Hamilton Anxiety and Depression Scale, Epworth Sleepiness Scale, McGill Pain Questionnaire, Fatigue Severity Scale (FSS)

Result

fatigue was described by 7 patients (30.43%) in the study group compared with 2 patients (8.69%) in controls (p<0.05). In the study group, when patients with fatigue were compared with those with no fatigue, the first group had higher Hamilton Anxiety and Depression Rating Scale score and higher Epworth Sleepiness Scale score.

Conclusion

this study suggest that fatigue is quite common among people with vascular cognitive impairment no dementia. Anxiety, depression, excessive daytime sleepiness were independently associated with fatigue.
An exploration of the relationship between financial hardship and cognitive functioning in later life
Authors: Marshall Gillian L. , Stansbury Kim
Published: December 2023

Background

There is a connection between stress and negative health outcomes including cognitive impairment. Few studies have examined the relationship between perceived financial hardship as a secondary stressor and cognitive function. This study aimed to test four indicators of perceived financial hardship and the impact on cognitive function among older adults.

Methods

Using data from four waves of the Health and Retirement Study of persons 65 years and older, we analyzed (N = 6612) across waves 1 and 2 using generalized linear regressions. There were four financial hardship variables (difficulty paying bills, food insecurity, taking less medication due to cost and ongoing financial strain). Cognitive status was conceptualized as a composite variable of episodic memory and mental status.

Results

Results suggests that all four financial hardships were associated with lower mental status scores with food insecurity having the strongest association of the four indicators.

Conclusion

These findings highlight the negative effects of stress in later life. Even secondary stressors such as financial hardships do in fact tax the mental status of older persons. There are higher risks for cognitive impairments in older adults with financial hardships than those without financial hardships This study underlines the importance of interventions to reduce stress while also creating greater access to food and medications specifically.
Association between glial and synaptic fluid biomarkers and brain [18F]FDG‐PET signal
Authors: Machado Luiza Santos , da Rocha Andreia Silva , Antônio De Bastiani Marco , Bellaver Bruna , Soares Carolina , Lazzarotto Gabriela , Vidor Pedro , Schlickmann Thomas , Rahmouni Nesrine , Siebert Marina , Ferreira Pamela C.L. , Pascoal Tharick A. , Souza Diogo O. , Rosa‐Neto Pedro , Benedet Andrea Lessa , Blennow Kaj , Zetterberg Henrik , Ashton Nicholas J. , Zimmer Eduardo R.
Published: December 2023

Background

Beyond the hypometabolic signature, indexed by [18F]FDG‐PET imaging, seen in the brain of Alzheimer’s disease (AD) patients, a transient brain glucose hypermetabolism has been recently identified in the early stages of AD. The cellular source of this dual metabolic response remains controversial, with glial cells gaining a lot of attention. In light of this, whether glial and synaptic fluid biomarkers are associated with [18F]FDG‐PET signal in the early stages of AD remains debatable. Thus, we evaluated the association of astrocyte, microglial and synaptic fluid biomarkers with [18F]FDG‐PET signal in an AD rat model.

Method

[18F]FDG‐PET imaging was conducted in ten‐month‐old (early amyloid stage) APP/PS1 (TgF344‐AD, n = 8‐17) and wild‐type (WT, n = 8‐15) rats. Glial (GFAP and sTREM2), synaptic (neurogranin), and amyloid biomarkers (Aβ1‐40 and Aβ1‐42) were quantified in the cerebrospinal fluid (CSF) and plasma through a multiplex immunoassay. T‐statistical maps of brain [18F]FDG‐PET and those fluid biomarkers were conducted at the voxel level using RMINC. Differences were considered statistically significant at p<0.05 (t>2).

Result

A large hypermetabolic cluster was identified in ten‐month‐old TgF344‐AD (Fig. 1AB, local maxima, t(13) = 4.28). We found positive correlations between CSF TREM2 and brain [18F]FDG‐PET signal (Fig. 2AC, local maxima, t(13) = 4.12). In addition, we identified a positive correlation between plasma GFAP and brain [18F]FDG‐PET signal (Fig. 2BC, local maxima, t(13) = 10.62). Plasma TREM2, CSF GFAP, and plasma neurogranin did not associate with brain glucose metabolism.

Conclusion

Our findings suggest that CSF TREM2 and plasma GFAP are associated with brain metabolism before amyloid load reaches a plateau. Stronger association of plasma GFAP, rather than CSF GFAP, with brain pathology corroborates cross‐sectional human studies. One could argue that [18F]FDG‐PET hypermetabolism identified is likely a response to astrocyte and microglial changes.
Development of a selective estrogen β‐receptor phytoestrogen formulation – PhytoSERM – for the reduction of Alzheimer’s risk and relief of menopausal symptoms in women: a phase 2 randomized clinical trial framework
Authors: Hernandez Gerson D , Lopez Claudia M , Raikes Adam C. , Matthews Dawn C , Mosconi Lisa , Brinton Roberta Diaz
Published: December 2023

Background

The greatest risk factors for Alzheimer’s disease (AD) are age, APOɛ4 allele and female sex. The estimated lifetime risk for AD is 19.5% for women compared to 10.3% in men. Accumulating evidence points to life‐time estrogen exposure as a protective factor against cognitive decline and AD in women, and to the menopause transition as a trigger for an existing AD predisposition. Estrogen replacement therapy (ERT) is effective for sustaining neurological health, but fear of breast cancer is the principal reason menopausal women reject it. Instead, women utilize over the counter products labeled as natural and considered to be safer. Thus, to attain brain protection and address breast protection we developed a rationally designed combination of select ERβ‐selective phytoestrogens that promote brain health to reduce AD risk without increasing breast cell proliferation.

Method

A total of 100 participants, 50 per treatment arm, will be enrolled. Eligible participants are woman, 45‐60 years, peri or post‐menopausal (last menstrual period completed ≥ 60 days and ≤ 4 years), MoCA≥22, and experiencing ≥7 hot flashes per day. Participants will be randomized to 50 mg of PhytoSERM or placebo (orally, once‐per‐day) for a 24‐week period. FDG‐PET scans will be conducted at baseline and 24 weeks. Cognitive measures and clinical ratings will be assessed. Hot flashes will be measured both subjectively with a diary and objectively with a digital wristband measuring electrodermal activity.

Result

Primary endpoint is change from baseline to 24 weeks in regional brain glucose metabolism standardized uptake value ratio (SUVR). Secondary outcome measures include cognitive test battery scores, hot flash score and clinical ratings scores. Exploratory measures will include MRI brain volumes, fractional anisotropy, quantitative anisotropy, functional connectivity, and cerebral blood perfusion.

Conclusion

Herein we present a phase 2 proof‐of‐concept framework to assess the efficacy of PhytoSERM as a potential non‐pharmacologic therapeutic to improve cognitive health and reduce menopausal symptoms. Results from this study will validate previous findings that indicate that PhytoSERM is a safe alternative to hormone therapy and has the potential to sustain neurological health during the menopausal transition.
Association of MRI markers of vascular injury and neurodegeneration and cognitive decline in diverse cohorts: Findings from KHANDLE and STAR
Authors: Lor Yi , Decarli Charles , Peterson Rachel , George Kristen M , Gilsanz Paola , Mungas Dan M. , Mayeda Elizabeth Rose , Barnes Lisa L. , Whitmer Rachel A.
Published: December 2023

Background

MRI biomarkers of vascular injury and neurodegeneration are associated with cognitive decline, but relatively little is known about cognitive change in diverse populations. Our objective is to examine associations of hippocampal volume and white matter integrity on cognitive change over 3 years.

Method

KHANDLE (age 65+) and STAR (age 50+) are harmonized cohorts of racially/ethnically diverse long‐term members of Kaiser Permanente Northern California. A random sub‐sample of participants received neuroimaging with 3T MRI to measure regional brain volumes and white matter integrity. Hippocampal volume (cm3), log white matter hyperintensities (log‐WMH) (cm3), free water (FW) (cm3), and fractional anisotropy (FA) MRI measures were normalized on intracranial volume and age at scan. Cognitive decline was assessed across three waves using the Spanish English Neuropsychological Assessment Scale measuring executive function (EF) and verbal episodic memory (VEM). Linear mixed models allowing for random intercept and slope estimated the associations of MRI metrics and cognition adjusting for baseline age, education, gender/sex, interview mode (in‐person vs phone), and interactions of these covariates with time from baseline, to adjust for effects of covariates on both baseline cognition and cognitive change.

Result

Among 592 participants with neuroimaging, 59% were women, 47% were college educated, and 52% were Black adults (Table 1). Hippocampal volume was positively associated with baseline VEM (β = 0.268; CI = 0.153, 0.383) and EF change (β = 0.051; CI = 0.009, 0.094) (Table 2, Plot 1). FW was negatively associated with baseline EF (β = ‐6.561; CI = ‐10.758, ‐2.364), baseline VEM (β = ‐5.557; CI = ‐10.03, ‐1.084) and EF decline (β = ‐1.667; CI = ‐3.268, ‐0.066). FA was positively associated with baseline EF (β = 6.222; CI = 3.217, 9.228) and baseline VEM (β = 6.944; CI = 3.768, 10.119). Log‐WMH was negatively associated with baseline EF (β = ‐0.068; CI = ‐0.116, ‐0.020) and VEM (β = ‐0.082; CI = ‐0.132, ‐0.032).

Conclusion

All MRI markers were associated with baseline cognition, but only hippocampal volume and FW were associated with cognitive change. MRI measures of neurodegeneration and white matter integrity may be predictive of cognition and short‐term decline in diverse groups of older adults. Future analyses will examine associations with cognitive impairment.
Neighborhood problems and sleep difficulties predict subjective cognitive decline in Black American men living in urban areas
Authors: Egwuonwu Joshua , Esiaka Darlingtina
Published: December 2023

Background

The impact of the residential neighborhood on health and aging is being increasingly recognized in medical and health sciences. Specifically, research suggests that the neighborhood where people live can be a risk or protective factor for various health outcomes, including brain health. Similar to the impact of neighborhood on health and aging, sleep has been linked to subjective cognitive decline (SCD) in older adults, which may signal a cognitive trajectory to Alzheimer’s disease and related dementia (ADRD). This study aims to evaluate whether neighborhood problems and sleep difficulties predict subjective cognitive decline in Black men living in urban areas and, thus, may be related to elevated risks for ADRD.

Method

Black American men (N = 117), age 40 – 70 years, were recruited through a targeted advert on Amazon Mechanical Turk (MTURK) over a 3‐week period. The participants responded to a survey assessing neighborhood problems, bodily symptoms, length of residence, sleep difficulties, self‐rated health, sociodemographic characteristics, and subjective cognitive decline.

Result

We performed hierarchical regression. In Model 1, only education was a significant predictor of SCD (F (3,113) = 8.52, p<.001), accounting for 18% of the variation in SCD. In Model 2, socioeconomic status, education, and bodily symptoms were significant predictors of SCD (F (5,111) = 13.99, p<.001) and explained 39% of the variation in SCD. In Model 3, neighborhood problems, length of residence added, socioeconomic status, education, and bodily symptoms were significant predictors and contributed 44% of the total variance in SCD (F (7,109) = 12.10, p<.001). In Model 4, sleep difficulties, length of residence, bodily symptoms, socioeconomic status, and education were significant predictors of SCD (F (9,107) = 13.59, p<.001), and accounted for 50% of the variation in SCD.

Conclusion

Given that Black Americans have been found to have a higher prevalence of sleep disturbances compared to white Americans, our findings could add to inform future health interventions and policy recommendations that can address modifiable sources of poorer brain health in Black men.
Cerebral systems underlying anosognosia for memory loss in aging and Alzheimer’s disease
Authors: Mimmack Kayden J. , Qiao Krystal , Gagliardi Geoffroy Pierre , Bueichekú Elisenda , Cacciamani Federica , Wang Sharon , Udeogu Onyinye , Marshall Gad A , Sepulcre Jorge , Vannini Patrizia
Published: December 2023

Background

Loss of awareness of cognitive decline (a.k.a. anosognosia) is a common symptom of Alzheimer’s disease (AD) dementia and has also been observed in its predementia stages. Anosognosia is thought to be related not only to functional changes in individual brain regions, but also to a disturbance in functional connectivity (FC) between or within networks. This study aimed to investigate how memory awareness relates to resting‐state fMRI segregation (within‐network connectivity) and integration (between‐network connectivity) maps across the AD spectrum.

Method

We included 66 older adults divided in two groups: cognitively normal (CN, n = 49), and symptomatic (mild cognitive impairment or mild AD; n = 17). Memory awareness was measured as the discrepancy between the participant’s and study partner’s scores on the Cognitive Function Instrument. Positive values indicated heightened awareness and negative values indicated unawareness. We assessed whole‐brain connectivity with resting‐state fMRI and computed voxel‐level maps of segregation and integration. General linear models were used to relate the integration or segregation of each voxel to memory awareness (in the total sample and in the two groups separately), adjusted for age, sex, and education. Multiple comparison correction was performed using cluster‐wise Monte Carlo simulations.

Result

Demographics are presented in Table 1. Segregation maps showed that lower awareness was associated with increased connectivity within the frontoparietal network (FPN) and with decreased connectivity within the medial visual, default mode (DMN), and sensory‐motor networks (Figure 1A(i); Table 2A(i)). The relationship with the FPN persisted in the CN and symptomatic groups separately, and an additional negative association between awareness and FC in the salience network was found in the CN group (Figure 1B‐C(i); Table 2B‐C(i)). In integration maps, lower awareness was associated with increased between‐network connectivity of the dorsal attention and DMN, and decreased connectivity of the salience and sensory‐motor networks (Figure 1A(ii); Table 2A(ii)). In the CN group, the sensory‐motor relationship persisted, while the DMN relationship reversed (Figure 1B‐C(ii); Table 2B‐C(ii)).

Conclusion

Anosognosia is characterized by reduced FC patterns featuring disconnection between self‐referential networks (DMN and salience) to other networks and hyperconnectivity within the FPN. Future studies should investigate the pathological underpinnings for these functional changes.
Bayesian network analysis of BIN1 risk allele and other risk factors and biomarkers of Alzheimer’s disease
Authors: Wang Jian , Rathore Saima , Morris Amanda , Lu Ming , Sabourin Jeremy , Hooli Basavaraj
Published: December 2023

Background

The Bridging Integrator I (BIN1) is a significant genetic risk gene, second only to the established risk gene apolipoprotein E (APOE4), for late‐onset Alzheimer’s disease (LOAD, AD) (Carrasquillo, 2011). BIN1 rs744733 risk allele was shown to affect tau pathology and cognitive decline (Franzmeier, 2021).

In this study, we compared BIN1 risk allele rs6733839 with APOE4 on interdependency among AD risk factors and biomarkers by applying Bayesian Network (BN) modeling (Scutari, 2017) to data from Lilly AD clinical trials.

Method

Data from A05C (n = 142, NCT01565382), A05E (n = 217, NCT02016560), and untreated arms of AZES (n = 206, NCT02245737), LLCF (n = 229, NCT02791191), and LZAX (n = 194, NCT01900665) trial participants were used for the analysis (table 1). We constructed graphs representing the dependencies among the variables, including demographics, genetic risk genes, brain amyloid and tau measured by 18F‐Florbetapir or 18F‐Flortaucipir positron emission tomography (PET) imaging quantified globally and regionally as a standardized uptake value ratio. Longitudinal tau changes from baseline were computed for a sub cohort (n = 234). Conditional Gaussian Bayesian Network (CGBN) was used to model discrete (gender, genotype) and continuous (age, PET quantifications) variables. Directed Acyclic Graphs (DAG) structure was learned using constraint‐based Incremental Association (iamb) algorithm and score‐based Hill‐Climbing (hc) algorithm with one‐sided type I error rate at 10%. The connection strength was estimated by bootstrap resampling and computing the probability of any variable influencing another variable. Model parameters were estimated using the maximum likelihood estimation method.

Result

The result shows that age influences baseline amyloid (Strength s = 1.0) and parietal tau (s = 0.83). APOE4 influences baseline amyloid (s = 0.75) and tau at four lopes with strength ranging from 0.84 to 0.31 in the order of frontal, parietal, occipital, and temporal lobes. BIN1 influences baseline tau at the parietal lobe (s = 0.42) and other lobes with strength below 0.3. We have not observed consistent dependency between variables and change in tau, likely due to the small sample size (n = 234).

Conclusion

Our study result is consistent with current knowledge of APOE4 influencing amyloid and tau. The finding that BIN1 influences tau supports the observation of BIN1 rs744373, in linkage disequilibrium with rs6733839, in ADNI and BioFINDER studies (Franzmeier, 2021).
Challenges in identifying Latinos living with ADRD among newly diagnosed cancer patients
Authors: Schiaffino Melody , Moore Alison A. , Gilbert Paul E , Murphy James D , Marquine María J.
Published: December 2023

Background

Navigating the complex decision‐making and coordination challenges of a cancer diagnosis is difficult for any person diagnosed with cancer. This burden can become untenable for Latinos living with Alzheimer’s and Related Dementias (ADRD). The literature has demonstrated the disproportionate burden of late‐life comorbidities on Latino populations due to a myriad of existing inequities, such as barriers related to patient‐provider communication and language, cultural and other unique needs, and social and economic factors. Identifying ADRD and social correlates of risk for ADRD and cancer in Latino patients is critical to improve treatment planning and outcomes. However, Latinos are critically underrepresented in most population‐based and nationally‐representative databases. We studied a linked claims database and tumor registry to explore variation across tumor prevalence and social correlates of Latinos living with ADRD and cancer.

Methods

This retrospective cohort study examined ADRD and cancer in Latinos using the National Cancer Institute’s SEER‐Medicare database of newly diagnosed cancer patients aged 67+ (N = 337,932). Tumor and claims‐based utilization on Latino and non‐Latino patients with and without ADRD were used to explore variation in prevalence of ADRD, cancer, and social correlates. A non‐cancer 5% sample from the same Medicare cohort was used as a control.

Results

Latinos were widely underrepresented across all tumor sites: breast, cervical, colorectal, oral, lung, and prostate. The prevalence of Latino patients with ADRD and cancer varied significantly compared to White patients. Latinos had a higher prevalence across all cancer sites with the lowest prevalence for Latinos in Prostate cancer (4.63% vs 2.33% for White patients) and the highest in Oral cancer (12.67% vs 7.82%).

Conclusion

The differential prevalence of ADRD and cancer is significant in massive claims data which is a key source of nationally representative healthcare utilization and care information on older adults. Our cohort excluded dual‐eligible, metastatic, and undocumented patients. Claims and registry data lack context on language proficiency and diagnostic accuracy suggesting our substantial variation may be conservative. Improving methods and data for identifying and addressing social correlates of risk for patients with ADRD and cancer is critical for this rapidly growing and high‐risk population.
Aβ in the Lens of the Eye: A Noninvasively Detectable Early Biomarker of Alzheimer’s Disease β‐Amyloidopathy in Humans and Transgenic Mouse Model
Authors: Goldstein Lee E , Moncaster Juliet A , Moir Robert D , Minaeva Olga , Alvarez Victor E. , Clark John I , McKee Ann C. , Tanzi Rudolph E.
Published: December 2023

Background

Amyloid‐β (Aβ) accumulation in brain is an early hallmark of Alzheimer’s disease (AD). We discovered Aβ deposition, β‐amyloidopathy, and colocalizing supranuclear cataracts (SNC) in lenses from people with AD (Goldstein LE et al., Lancet, 2003) and Down syndrome (DS; Moncaster JA et al., PLoS One, 2010), but not other neurodegenerative diseases or normal aging. These findings spurred development of an investigational drug‐device lens Aβ eye scanner (Sapphire II, Cognoptix) that combines an Aβ‐binding fluorescent ligand (Aftobetin) and specialized laser scanning ophthalmoscope for noninvasive measurement of lens Aβ (FDA Breakthrough Device, 2021). Early clinical results indicate that lens Aβ is an ideal biomarker for early AD detection. Here, we investigated Aβ accumulation and amyloidopathy in lens and brain.

Method

Tg2576 transgenic (Tg+) mice express Swedish mutant human amyloid precursor protein (hAPP‐Swe), human Aβ (hAβ), β‐amyloidopathy, and cognitive deficits (Hsiao et al., Science, 1996). Non‐transgenic (Tg–) littermates were used as controls. Lenses were examined by ex vivo lens stereomicroscopy. Brains and lenses were analyzed by Aβ immunohistochemistry, amyloid histopathology, anti‐Aβ immunogold electron microscopy, tryptic digest mass spectrometry, anti‐hAβ ELISA/immunoblotting. Quasi‐elastic light scattering hAβ‐lens protein aggregation analysis.

Result

Tg2576 Tg+ mice, but not Tg– controls, age‐dependently express hAPP, accumulate hAβ, and develop hAβ molecular pathology in the lens and exhibit age‐dependent Aβ supranuclear opacification that recapitulates lens pathology and SNC phenotype expression in human AD and DS. We detected hAβ in conditioned medium from Tg+ but not Tg– lens explant cultures. hAβ potently promotes mouse lens protein aggregation in vitro.

Conclusion

These results support mechanistic (genotype‐phenotype) linkage between age‐dependent Aβ pathology and AD‐related phenotypes in lens and brain. Collectively, our findings identify Aβ pathology as the shared molecular etiology of age‐dependent supranuclear cataracts associated with two human diseases (AD, DS) and homologous murine cataracts in the Tg2576 transgenic mouse model of AD. These results represent the first evidence of AD‐related Aβ pathology outside the brain and support lens Aβ as an optically‐accessible biomarker for early detection and longitudinal monitoring of AD.
The Role of Socioeconomic Status in Basic Education for Illiterate Adults
Authors: Ruppert Emma Patrice , Faria Rocha João Victor , Lourandes Aida , dos Santos Tomaz Kelle Luisa , Friedlaender Clarisse Vasconcelos , de Castro Magalhães Assenção Joanna , Grinberg Lea T. , Rosen Howard J. , Rincon Luciana Paula , Ribeiro Norton Gray Ferreira , Constantina Dulce , Zacarias Ana Paula , Caramelli Paulo , Maciel Francisca Izabel Pereira , Paula França Resende Elisa
Published: December 2023

Background

The role of education is a well established protective factor regarding dementia but not much is known as to the effect of literacy acquisition in adults. Therefore, our study aims to determine whether adults enrolled in late‐life literacy programs will improve memory and cognitive reserve and the role of socioeconomic status in learning.

Method

108 illiterate adults were enrolled and 77 completed the assessments. For SES, only participants living in Belo Horizonte with a verifiable address were included (68). The intervention group had 34 participants that received intensive literacy training, while the 34 controls attended regular classes for six months. SES was based on the Quality of Urban Living Index (QULI) of 2016 created by the municipal council and the Municipal Human Development Index (MHDI) of 2010 made by Atlas Brasil. The instruments used were Rodrigues et al, 2015 list of words and pseudowords to assess reading and Beta III matrix reasoning for non‐verbal reasoning.

Result

Participants lived in 14 different regions of Belo Horizonte, 32 in areas with a low QULI and 36 within a high QULI. When using the HDI classification, 29 had medium MHDI, 25 had high MHDI and 14 very‐high MHDI. In regards to reading, people from low QULI areas went from reading on average 20.86 to 22.26 words and 4.21 to 5.13 pseudowords. Participants from high QULI regions went from an average of 22.14 to 25.08 words and 5.56 pseudowords to 6.86. One‐way ANOVA showed a significant effect of MHDI on post‐test Beta III scores, F (2, 37.5) = 3.64, p = 0.03. Post Hoc comparisons using Games‐Howell test indicated that the average score in high MHDI (M = 6.24, SD = 2.26) were significantly better than those with medium MHDI (M = 4.63, SD = 2.14), but no significant difference was found between high and very high or very high to medium MHDI.

Conclusion

Participants from all groups improved during the assessments. However, it was also possible to see that SES has a role to play in the extent of this improvement.