Rapid Cognitive Decline Research Articles

Mapping brain metabolism, connectivity and neurotransmitters topography in early and late onset dementia with lewy bodies

IntroductionEarly-onset dementia with Lewy bodies (EO-DLB) is associated with rapid cognitive decline and severe neuropsychiatric symptoms at onset. MethodsUsing FDG-PET imaging for 62 patients (21 EO-DLB, 41 LO (late-onset)-DLB), we explored brain hypometabolism, and metabolic connectivity in the whole-brain network and resting-state networks (RSNs). We also evaluated the spatial association between brain hypometabolism and neurotransmitter pathways topography. ResultsDirect comparisons between the two clinical subgroups showed that EO-DLB was characterized by a lower metabolism in posterior cingulate/precuneus and occipital cortex. Metabolic connectivity analysis revealed significant alterations in posterior regions in both EO-DLB and LO-DLB. The EO-DLB, however, showed more severe loss of connectivity between occipital and parietal nodes and hyperconnectivity between frontal and cerebellar nodes. Spatial topography association analysis indicated significant correlations between neurotransmitter maps (i.e. acetylcholine, GABA, serotonin, dopamine) and brain hypometabolism in both EO and LO-DLB, with significantly higher metabolic correlation in the presynaptic serotonergic system for EO-DLB, supporting its major dysfunction. ConclusionsOur study revealed greater brain hypometabolism and loss of connectivity in posterior brain region in EO- than LO-DLB. Serotonergic mapping emerges as a relevant factor for further investigation addressing clinical differences between DLB subtypes.

Characteristics of discordance between amyloid positron emission tomography and plasma amyloid-β 42/40 positivity

Various plasma biomarkers for amyloid-β (Aβ) have shown high predictability of amyloid PET positivity. However, the characteristics of discordance between amyloid PET and plasma Aβ42/40 positivity are poorly understood. Thorough interpretation of discordant cases is vital as Aβ plasma biomarker is imminent to integrate into clinical guidelines. We aimed to determine the characteristics of discordant groups between amyloid PET and plasma Aβ42/40 positivity, and inter-assays variability depending on plasma assays. We compared tau burden measured by PET, brain volume assessed by MRI, cross-sectional cognitive function, longitudinal cognitive decline and polygenic risk score (PRS) between PET/plasma groups (PET−/plasma−, PET−/plasma+, PET+/plasma−, PET+/plasma+) using Alzheimer’s Disease Neuroimaging Initiative database. Additionally, we investigated inter-assays variability between immunoprecipitation followed by mass spectrometry method developed at Washington University (IP-MS-WashU) and Elecsys immunoassay from Roche (IA-Elc). PET+/plasma+ was significantly associated with higher tau burden assessed by PET in entorhinal, Braak III/IV, and Braak V/VI regions, and with decreased volume of hippocampal and precuneus regions compared to PET−/plasma-. PET+/plasma+ showed poor performances in global cognition, memory, executive and daily-life function, and rapid cognitive decline. PET+/plasma+ was related to high PRS. The PET−/plasma+ showed intermediate changes between PET−/plasma− and PET+/plasma+ in terms of tau burden, hippocampal and precuneus volume, cross-sectional and longitudinal cognition, and PRS. PET+/plasma− represented heterogeneous characteristics with most prominent variability depending on plasma assays. Moreover, IP-MS-WashU showed more linear association between amyloid PET standardized uptake value ratio and plasma Aβ42/40 than IA-Elc. IA-Elc showed more plasma Aβ42/40 positivity in the amyloid PET-negative stage than IP-MS-WashU. Characteristics of PET−/plasma+ support plasma biomarkers as early biomarker of amyloidopathy prior to amyloid PET. Various plasma biomarker assays might be applied distinctively to detect different target subjects or disease stages.

Association of retinal neurodegeneration with the progression of cognitive decline in Parkinson’s disease

Retinal thickness may serve as a biomarker in Parkinson’s disease (PD). In this prospective longitudinal study, we aimed to determine if PD patients present accelerated thinning rate in the parafoveal ganglion cell-inner plexiform layer (pfGCIPL) and peripapillary retinal nerve fiber layer (pRNFL) compared to controls. Additionally, we evaluated the relationship between retinal neurodegeneration and clinical progression in PD. A cohort of 156 PD patients and 72 controls underwent retinal optical coherence tomography, visual, and cognitive assessments between February 2015 and December 2021 in two Spanish tertiary hospitals. The pfGCIPL thinning rate was twice as high in PD (β [SE] = −0.58 [0.06]) than in controls (β [SE] = −0.29 [0.06], p < 0.001). In PD, the progression pattern of pfGCIPL atrophy depended on baseline thickness, with slower thinning rates observed in PD patients with pfGCIPL below 89.8 µm. This result was validated with an external dataset from Moorfields Eye Hospital NHS Foundation Trust (AlzEye study). Slow pfGCIPL progressors, characterized by older at baseline, longer disease duration, and worse cognitive and disease stage scores, showed a threefold increase in the rate of cognitive decline (β [SE] = −0.45 [0.19] points/year, p = 0.021) compared to faster progressors. Furthermore, temporal sector pRNFL thinning was accelerated in PD (βtime x group [SE] = −0.67 [0.26] μm/year, p = 0.009), demonstrating a close association with cognitive score changes (β [SE] = 0.11 [0.05], p = 0.052). This study suggests that a slower pattern of pfGCIPL tissue loss in PD is linked to more rapid cognitive decline, whereas changes in temporal pRNFL could track cognitive deterioration.

Incident anti-LGI1 autoimmune encephalitis during dementia with Lewy bodies: When Occam razor is a double-edged sword

In Dementia with Lewy bodies (DLB), rapid cognitive decline and seizures seldom complicate the typical clinical course. Nevertheless, concurrent, treatable conditions may be responsible. We report a case of DLB with superimposed anti-LGI1 encephalitis, emphasizing the importance of thorough diagnostic reasoning beyond the simplest explanation amid distinct clinical cues.

The characteristics of cognitive and daily living functions of neurocognitive disorders with delusions in elderly Alzheimer's disease.

Delusions in neurocognitive disorder due to Alzheimer's disease (AD) worsen patients' cognitive functions and activities of daily living (ADL), increasing caregiver burden and the risk of mortality. AD patients with delusions tend to experience a more rapid decline in cognition and have demonstrated poorer performance on various cognitive function tests. Considering the prognosis of delusion in AD patients, it tends to be more favorable with appropriate treatment. However, there is a lack of neuropsychological research, specifically examining the impact of delusions in AD, characterized by progressive deterioration of cognitive function. This study investigates the impact of delusions on cognitive function and ADL under conditions controlling for disease severity. We compared cognitive function and ADL in AD patients aged 65 years or older according to the presence of delusions. To assess longitudinal change, we analyzed data from patients monitored for an average of 15 to 16 months. We assessed cognitive function and ADL using the Seoul Neuropsychological Screening Battery-Second Edition (SNSB-II) and delusions using the Neuropsychiatric Inventory (NPI). We used IBM SPSS Statistics version 25.0 for all statistical analyses. The analysis was not adjusted for multiple comparisons. We investigated how delusions impact cognitive function and ADL, controlling for age, educational level, and disease severity. The delusions group exhibited poorer immediate recall of verbal memory than the non-delusions group. In the follow-up evaluation, patients who developed delusions had lower baseline cognitive function than those who did not, and their language fluency declined over time. In addition, we found the presence of delusions associated with worse functional impairment in ADL as the disease progressed. While controlling for the severity of AD, we found no significant negative impacts of delusions on most cognitive functions. Nevertheless, it is noteworthy that the immediate recall of verbal memory and the Controlled Oral Word Association Test (COWAT)_animal sensitively detected the negative impact of delusions. Furthermore, since delusions are associated with worsening ADL, we understand that delusion treatment is important for improving the quality of life for patients and caregivers.

The association of CSF biomarkers and cognitive decline with choroid plexus volume in early Parkinson's disease

ObjectiveThis study aims to determine the link between choroid plexus (CP) volume and cognitive decline in patients with early-stage Parkinson's disease (PD) and to test whether pathological proteins in the cerebrospinal fluid (CSF) are involved in the modulation of any detrimental effects from CP volume. MethodsData on 95 early-stage PD patients with 5 years of follow-up were collected from the Parkinson's Progression Marker Initiative cohort. The patients were separated into three groups based on tertiles of baseline CP volume. We then used a linear mixed model for longitudinal analysis and conducted path analysis to investigate mediating effects. ResultsAt baseline, the patients in both the upper and middle tertile group were older and had lower concentrations of CSF Aβ1-42 than those in the lowest tertile group. Longitudinal analysis showed that the upper tertile group suffered from a more rapid cognitive decline in the Symbol Digit Modalities test, Hopkins Verbal Learning Test (HVLT)-retention, and HVLT delayed recalled score. Furthermore, path analysis showed that the pathological effects of CP volume on the 5-year decline in memory might be partly mediated by the CSF Aβ1-42/αsyn ratio. ConclusionCP enlargement could be an independent risk factor for decreased cognition in patients with early-stage PD, and this risk may be mediated by CSF pathological proteins.

THE PREVALENCE AND PREDICTORS OF APATHY AMONG CANADIAN LONG-TERM CARE RESIDENTS: A SECONDARY DATA ANALYSIS

Abstract Apathy, defined as a reduction in interest or motivation to engage in goal directed activities, is a frequent and persistent health concern among persons residing in long term care facilities. Research showed that apathy is associated with rapid cognitive decline, impaired functional ability, and increased mortality risk. To prevent or mitigate the negative impacts of apathy on persons living in long term care facilities, there is need for better understanding of the risk factors associated with it. Therefore, the aim of this study was to determine the prevalence of apathy and its risk factors in a large sample of Canadian long-term care residents (N=332,454). We performed cross-sectional analysis of data from MDS 2.0 assessments completed between 2015 and 2019 fiscal year. Results from descriptive and inferential analyses showed that apathy was more prevalent among persons aged 65 or younger and speak English. The strongest predictors of apathy were province of residence (OR 4.09 (CI 2.99-5.59) followed by resistance to care (OR 2.43 CI 2.38-2.49), conflict with family (OR 2.30 CI 2.2-2.4), and insomnia (OR 2.16 CI 2.11-2.2). These findings highlight the important role of environmental contextual factors including the physical and social environment as well as personal factors in the development of or recovery from apathy. Strategies for combating apathy in long term care facilities should take into account the individual, institutional and provincial variances.

Alzheimer's Disease-Related Proteins Targeted by Secondary Metabolite Compounds from Streptomyces: A Scoping Review.

Alzheimer's disease (AD) is a neurodegenerative disease that is characterized as rapid and progressive cognitive decline affecting 26 million people worldwide. Although immunotherapies are ideal, its clinical safety and effectiveness are controversial, hence, treatments are still reliant on symptomatic medications. Concurrently, the Streptomyces genus has attracted attention given its pharmaceutically beneficial secondary metabolites to treat neurodegenerative diseases. To present secondary metabolites from Streptomyces sp. with regulatory effects on proteins and identified prospective target proteins for AD treatment. Research articles published between 2010 and 2021 were collected from five databases and 83 relevant research articles were identified. Post-screening, only 12 research articles on AD-related proteins were selected for further review. Bioinformatics analyses were performed through the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) network, PANTHER Go-Slim classification system (PANTHER17.0), and Kyoto Encyclopedia of Genes and Genomes (KEGG) Mapper. A total of 20 target proteins were identified from the 12 shortlisted articles. Amyloid-β, BACE1, Nrf-2, Beclin-1, and ATG5 were identified as the potential target proteins, given their role in initiating AD, mitigating neuroinflammation, and autophagy. Besides, 10 compounds from Streptomyces sp., including rapamycin, alborixin, enterocin, bonnevillamides D and E, caniferolide A, anhydroexfoliamycin, rhizolutin, streptocyclinone A and B, were identified to exhibit considerable regulatory effects on these target proteins. The review highlights several prospective target proteins that can be regulated through treatments with Streptomyces sp. compounds to prevent AD's early stages and progression. Further identification of Streptomyces sp. compounds with potential anti-AD properties is recommended.

Clinical Characteristics and Follow‐up Assessment in Patients Diagnosed with Alzheimer’s Dementia Through Regional Dementia Centers and Conventional Hospital System

AbstractBackgroundThe rapidly increasing socioeconomic burden due to dementia is a significant global public health issue. To address this issue in Korea, regional dementia centers (RDCs) have been established nationwide. This study investigated the clinical features and courses in patients diagnosed with Alzheimer’s dementia(AD) through RDCs or conventional hospital system in the community.MethodThis retrospective cohort study was performed in a single general hospital and included patients newly diagnosed with AD from January 2019 to March 2022. Analysis was conducted to compare two groups of patients: the hospital group, who came directly to the hospital, and the RDC group, who were referred to the hospital from the RDCs in Pohang city. Their clinical courses were followed for a year after AD diagnosis.ResultA total of 1209 study participants were assigned to the hospital (n = 579) or RDC group (n = 630). The RDC group was 80.1 ± 6.6 years old, significantly older than the hospital group (P &lt;0.001). In the linear regression model, the RDC group independently associated the CDR‐SB increment (β = 19.007 and P &lt;0.001). In the multivariable binary logistic regression model, the RDC group showed a significantly lower risk for hospitalization within one year after the diagnosis of AD (odds ratio, 0.54; 95% confidence interval, 0.30–0.98; P = 0.014).ConclusionAD patients in the RDCs were older, diagnosed with more advanced conditions, and were rated as having more rapid cognitive decline than patients diagnosed in the conventional hospital system. RDCs may contribute to the initiation of treatment by discovering AD patients hidden in the community due to limited access to healthcare.

Traumatic Brain Injury and Cognitive Aging Among Older Veteran Men – A Twin Study Accounting for Genetics and Medical Conditions

AbstractBackgroundTraumatic brain injury (TBI) is associated with increased risk of dementia, but whether TBI influences cognitive trajectories in later life is less clear. Identifying those at high‐risk of cognitive decline creates intervention opportunities to delay dementia. Since twins share many genes and environmental factors, we capitalize on the twin‐study design to investigate the association between lifetime TBI and cognitive decline.MethodParticipants (n = 8,662) members of the National Academy of Sciences‐National Research Council’s Twins Registry of World‐War‐II Male Veterans born between 1917‐1927 with self or proxy‐reported history of TBI and from one to four assessments over 12 years using the modified‐Telephone Interview for Cognitive Status (TICS‐m). We used linear random‐effects‐mixed models to examine the association between TBI and TICS‐m in the full sample and among co‐twins discordant for TBI. Additional TBI predictor variables included: number and severity (with/without loss‐of‐consciousness[LOC]) of TBI; and age of first TBI (age &lt;25 vs 25+). Models were adjusted for age (centered‐at‐70‐years), age‐squared, education, wave, twin pairs and for lifestyle behaviors and medical conditions. In a subset, we assessed the impact of APOE on TICS‐m.ResultHistory of any TBI, TBI with LOC, and older age of TBI were associated with lower TICS‐m scores at 70‐years (p‐values&lt;0.001). TBI with LOC, more than one TBI, and older age of TBI were associated with faster cognitive decline (p‐values&lt;0.05). Among monozygotic twin pairs discordant for TBI (589 pairs), a history of TBI and having TBI at older age was associated with lower TICS‐m scores (p‐values&lt;0.01); those with more than one TBI and TBI at older age showed greater cognitive decline (p‐values&lt;0.05) compared to their cotwin without TBI. Across all twins, APOE‐e4 carriers with TBI, more than one TBI, TBI with LOC, and older age of TBI had lower TICS‐m scores and greater cognitive decline compared to APOE‐e4 non‐carriers.ConclusionThese findings support an association between TBI and lower cognitive score and more rapid cognitive decline in later life. The results in the monozygotic pairs, who share all genes and many exposures particularly in early life, provide evidence of a causal relationship between TBI and poorer late life cognitive outcomes.

SUMOylation impact on synaptotoxicity of tau oligomers

AbstractBackgroundTau oligomers (oTau) secreted by neurons and astrocytes are linked to the propagation of pathology and negatively affect neuronal activity and viability. oTau‐mediated synaptic loss leads to cognitive deficits and manifests the clinical outcomes of Alzheimer’s disease and related tauopathies. Small Ubiquitin‐like MOdifier (SUMO) proteins regulate multiple cellular events and SUMOylation plays pivotal roles in synaptic biology. Changes in SUMO conjugation and function are also linked to AD and related neurodegenerative disorders such as Huntington’s and Parkinson’s disease. The goal of this investigation is to determine the impact of the two main SUMO isoforms, SUMO1 and SUMO2, on oTau related synaptotoxicity.MethodSUMO1 and SUMO2 transgenic mice were generated with expression regulated by the neuron‐specific prion cos‐tet promoter. These in vivo models were used to generate double transgenic mice expressing human SUMO proteins and P301S mutant Tau. Changes in synaptic density and activity and the effects of oTau pathology were investigated with respect to cognitive deficits and long term potentiation (LTP).ResultElevated expression of human SUMO1 lead to impaired synaptic development and increased tau aggregation. SUMO1 transgenics crossed to Tau mutant mice resulted in an accelerated synaptic loss and a more severe disease phenotype as evidenced by LTP impairments and rapid cognitive decline. Conversely, SUMO2 conjugation levels were decreased in the presence of oTau and phospho‐tau pathology indicating a down‐regulation of its function. Enhanced SUMO2 expression in a mouse model of Tau pathology reversed this process and resulted in a significant reduction in oTau‐mediated synaptotoxicity and the associated LTP and cognitive impairments.ConclusionCumulatively, our findings indicate that SUMO1 negative impacts and exacerbates oTau‐related synaptic dysfunction. In contrast, SUMO2 confers substantial neuroprotection and represents a potential therapeutic avenue to counteract oTau‐induced synaptotoxicity in AD.

Characterization of peripheral immune cell populations in stable and progressive Alzheimer’s disease

AbstractBackgroundAlzheimer’s disease (AD) is the most common type of dementia which results in debilitating memory loss as the disease advances. In addition to the amyloid plaques, tau tangles, and neuronal inflammation characteristic of AD, there is strong evidence of dysregulation in the peripheral immune system, including decreased naïve T cells and increased memory T cells among older adults with AD. However, the involvement of the peripheral immune system in the neurodegenerative cascade leading to AD is poorly understood. Furthermore, among older adults with AD, some may experience rapid cognitive decline while others may maintain a stable cognitive status for years. It is currently unknown whether dysfunction in the peripheral immune system is associated with neuronal inflammation and cognitive decline.MethodIn our ongoing work, we are longitudinally characterizing resting peripheral immune system cells by flow cytometry and here present data from a subset of those with AD (n = 19) or no dementia (ND, n = 93) whom we have followed for &gt;1 year.ResultWe have identified an increase in B cells (percent all lymphocytes, AD 6.4 (SD 8.6) vs ND 4.0 (SD 2.4) p = 0.031) and CD4+/CD62L+ naïve T cells (percent CD4+ lymphocytes, AD 33.4 (SD 18.4) vs ND 25.4 (SD 14.1) p = 0.034) among AD patients. Among the population of AD patients experiencing cognitive decline (n = 4) determined by increasing ADAS‐Cog score &gt;6 points over one year compared to stable scores (n = 11), we have discovered a decrease in CD4+/CD62L+ naïve T cells (percent CD4+ lymphocytes, stable 33.9 (SD 14.5) vs declining 20.5 (SD 16.1) p = 0.049), increase in effector memory CD4+ T cells (percent CD4+ lymphocytes, stable 28.2 (SD 4.8) vs declining 47.0 (SD 6.5) p&lt;0.001), and increase in B cells (percent all lymphocytes, stable 2.6 (SD 1.5) vs declining 5.3 (SD 1.8) p = 0.010), when compared to older adults with AD and stable cognitive status.ConclusionThis longitudinal clinical study identifies changes in resting peripheral B and T cell populations in AD patients and among AD patients with cognitive decline.

Acute hemorrhagic leukoencephalitis in a young female with excellent response to corticosteroids

Background: Acute hemorrhagic leukoencephalitis (AHLE) is a rare fulminant entity of acute disseminated leukoencephalitis (ADEM) that has a rapidly progressive polysymptomatology corresponding to areas of brain affected. It’s characterized by rapid cognitive decline, coma or even rapid death. It is postulated to be a post infective immune mediated monophasic demyelinating disease. Diagnosis is clinical supported by CSF and MRI findings. It is challenging to differentiate the disease from MDEM (multiphasic demyelinating encephalomyelitis) and multiple sclerosis during the initial presentation.Case presentation: Here we report a case of a 36-yearold Sri Lankan Sinhalese lady who presented with seizure following febrile illness followed by gross right sided hemiparesis later progressing to mutism and cognitive decline. Her CSF showed pleocytosis 12/cumm with 5% polymorphs, red cells, mildly high proteins with normal glucose and positive oligoclonal bands. MRI showed evidence of multiple focal supra and infratentorial signal abnormalities and gyral thickening with hemorrhages, largest lesions being in left frontal region with mass effect but no herniation. She was diagnosed with AHLE and treated with high dose IV methyl prednisolone later converting to oral prednisolone tapering regime. She was continued on intravenous cefotaxime and acyclovir as per meningoencephalitis. Improvement with steroids was dramatic with complete neurological recovery, minimal sequel and no recurrences at 6 months follow up.Conclusion: The case is a representation of a very rare entity of an infrequently reported disease which needs high degree of clinical suspicion with early imaging for aggressive and early immunosuppressive treatment that may hinder progression to commonly described sequel including coma, death or residual neurology. The predictions on future MDEM or MS on first presentation and overlap are areas that need further exploration.

23 The Utility of Global versus Domain-specific Neuropsychological Test Score Dispersion as Markers of Cognitive Decline

Objective:Higher baseline dispersion (intra-individual variability) across neuropsychological test scores at a single time-point has been associated with more rapid cognitive decline, onset of Mild Cognitive Impairment (MCI) and Alzheimer’s disease (AD), faster rates of hippocampal and entorhinal atrophy, and increased AD neuropathology. Comparison between predictions made from test score dispersion within a cognitive domain versus global, cross-domain dispersion is understudied. Global dispersion may be influenced by ability-and test-specific characteristics. This study examined the performance of global versus domain-specific dispersion metrics to identify which is most predictive of cognitive decline over time.Participants and Methods:Data for baseline and five follow-up visits of 308 participants with normal cognition (Mage=73.90, SD=8.12) were selected from the National Alzheimer’s Coordinating Center (NACC) Dataset. Participants were required to have no focal neurological deficits, or history of depression, stroke, or heart attack. Diagnoses and progression to MCI and/or dementia were determined at each visit through consensus conferences. Raw neuropsychological scores were standardized using NACC norms. Global baseline dispersion was defined as the intraindividual standard deviation (ISD) across the 10 scores in the NACC battery. Domain-specific dispersions were calculated by constructing composites and ISD was computed across tests sampling their respective domains (executive functioning/attention/processing speed [EFAS], language, and memory; see Table 1 for details on these tests). Higher values on each of these metrics reflect greater dispersion. Multinomial logistic regression model fit statistics and parameter estimates were compared across four different models (global, EFAS, Language, and Memory dispersion) covarying for age, years of education, sex, race, ethnicity, and ApoE4 status. Models were compared using the Likelihood Ratio Test (LRT) and the Akaike Information Criteria (AIC) of Models statistics.Results:Of the 308 participants, 70 (22.7%) progressed to MCI, and 82 (26.6%) progressed to dementia. Tables 1 and 2 show the results of the logistic regressions for the four models. All models fit the data well, with statistically significant predictions of conversion. Model 1 (global dispersion) showed a better fit than domain-specific models of dispersion per LRT and AIC values. Consistent with the results from mean differences between groups, parameter estimates showed that only global dispersion and EFAS dispersion significantly predicted conversion to dementia (when included with other covariates in models), with higher dispersion reflecting a greater risk of conversion.Conclusions:In this sample, baseline global and EFAS dispersion measures significantly predicted conversion to dementia. Although global dispersion was a stronger predictor of dementia progression, findings suggest that executive functioning performance may be driving this relationship. A single index of global variability, from the calculation of standard deviation across test scores, may be supplementary for clinicians when distinguishing individuals at risk for dementia progression. None of the models were predictive of conversion to MCI. Further research is required to examine cognitive variability differences among patients who progress to MCI and patient-specific factors that may relate to test score dispersion and its utility in predicting the progression of symptoms.

The steroid hormone ADIOL promotes learning by reducing neural kynurenic acid levels.

Reductions in brain kynurenic acid levels, a neuroinhibitory metabolite, improve cognitive function in diverse organisms. Thus, modulation of kynurenic acid levels is thought to have therapeutic potential in a range of brain disorders. Here we report that the steroid 5-androstene 3β, 17β-diol (ADIOL) reduces kynurenic acid levels and promotes associative learning in Caenorhabditis elegans We identify the molecular mechanisms through which ADIOL links peripheral metabolic pathways to neural mechanisms of learning capacity. Moreover, we show that in aged animals, which normally experience rapid cognitive decline, ADIOL improves learning capacity. The molecular mechanisms that underlie the biosynthesis of ADIOL as well as those through which it promotes kynurenic acid reduction are conserved in mammals. Thus, rather than a minor intermediate in the production of sex steroids, ADIOL is an endogenous hormone that potently regulates learning capacity by causing reductions in neural kynurenic acid levels.

Levels of plasma brain-derived tau and p-tau181 in Alzheimer's disease and rapidly progressive dementias.

Rapidly progressive dementias (RPDs) are a group of neurological disorders characterized by a rapid cognitive decline. The diagnostic value of blood-based biomarkers for Alzheimer's disease (AD) in RPD has not been fully explored. We measured plasma brain-derived tau (BD-tau) and p-tau181 in 11 controls, 15 AD patients, and 33 with RPD, of which 19 were Creutzfeldt-Jakob disease (CJD). Plasma BD-tau differentiated AD from RPD and controls (p=0.002 and p=0.03, respectively), while plasma and cerebrospinal fluid (CSF) p-tau181 distinguished AD from RPD (p<0.001) but not controls from RPD (p>0.05). The correlation of CSF t-tau with plasma BD-tau was stronger (r=0.78, p<0.001) than the correlation of CSF and plasma p-tau181 (r=0.26, p=0.04). The ratio BD-tau/p-tau181 performed equivalently to the CSF t-tau/p-tau181 ratio, differentiating AD from CJD (p<0.0001). Plasma BD-tau and p-tau181 mimic their corresponding cerebrospinal fluid (CSF) markers. P-tau significantly increased in AD but not in RPD. Plasma BD-tau, like CSF t-tau, increases according to neurodegeneration intensity.

A Study on the Longitudinal Relationship between Changes in Depression and Cognitive Function among Older Adults Living Alone.

As South Korea faces unprecedented population aging, this longitudinal study examined the relationship between depression and cognitive function changes in older individuals living alone. The study used data from the Korean Longitudinal Study of Aging (KLoSA). A total of 1354 participants with data available over a period of at least three years, from 2016 (wave 1) to 2020 (wave 8), were included, and latent growth modeling (LGM) was used for analysis. Depression levels increased gradually among older individuals living alone and cognitive function declined over time among older adults living alone. Moreover, higher initial depression levels were associated with lower initial cognitive function levels and a more rapid cognitive decline over time. Therefore, it is imperative that depression be addressed as a potential cause of cognitive impairment and dementia. Furthermore, rapid increases in depression corresponded to rapid declines in cognitive function, indicating the need for continuous monitoring and intervention in cases of escalating depression, as it may negatively affect cognitive abilities. These findings highlight the complex interplay between depression and cognitive function among older individuals living alone. Policy support to encourage participation in these programs is crucial to enhance the well-being of this vulnerable population.

Sex-dependent alterations in hippocampal connectivity are linked to cerebrovascular and amyloid pathologies in normal aging.

Compared to males, females have an accelerated trajectory of cognitive decline in Alzheimer's disease (AD). The neurobiological factors underlying the more rapid cognitive decline in AD in females remain unclear. This study explored how sex-dependent alterations in hippocampal connectivity over 2 years are associated with cerebrovascular and amyloid pathologies in normal aging. Thirty-three females and 21 males 65 to 93 years of age with no cognitive impairment performed a face-name associative memory functional magnetic resonance imaging (fMRI) task with a 2-year follow-up. We acquired baseline carbon 11-labeled Pittsburgh compound B ([11 C]PiB) positron emission tomography (PET) and T2-weighted fluid-attenuated inversion recovery (T2-FLAIR) MRI to quantify amyloid β (Aβ) burden and white matter hyperintensity (WMH) volume, respectively. Males had increased hippocampal-prefrontal connectivity over 2 years, associated with greater Aβ burden. Females had increased bilateral hippocampal functional connectivity, associated with greater WMH volume. These findings suggest sex-dependent compensatory mechanisms in the memory network in the presence of cerebrovascular and AD pathologies and may explain the accelerated trajectory of cognitive decline in females.

Type 2 Diabetes Comorbidity and Cognitive Decline in Patients with Alzheimer's Disease.

Although insulin dysregulation and resistance likely participate in Alzheimer's disease (AD) etiologies, little is known about the correlation between type 2 diabetes mellitus (T2DM) and the progression of cognitive decline in patients with AD. To determine whether AD patients with T2DM experience more rapid cognitive decline than those without T2DM. All cognitive performance data and the presence or absence of T2DM comorbidity in patients with AD were derived from the US National Alzheimer's Coordinating Center's (NACC) Uniform Data Set (UDS). A search of the UDS identified 3,055 participants with AD who had more than one epoch completed. The data set culled clinically diagnosed AD dementia patients who were assessed for diabetes type identified during at least 1 visit. These patients were divided into 2 groups based on whether they had a diagnosis of T2DM. The data from these groups were then analyzed for differences in cognitive decline based on neuropsychological test battery scores and a Clinician Dementia Rating using a general linear model. Comparisons of the mean scores for 16 selected tests from the neuropsychological test battery showed no significant differences in baseline scores and scores at subsequent visits between the T2DM and nondiabetic groups. The results revealed no differences in cognitive decline metrics over the course of 5 visits in either study group. These data indicate that the presence of T2DM does not increase the rate of cognitive decline in AD. This finding contradicts expected disease burden and will need to be explored further.

A - 40 Assessment of Dementia with Lewy Bodies in a Patient with both Characteristic and Atypical Features.

Dementia with Lewy Bodies (DLB) is the second most common neurodegenerative dementia after Alzheimer disease (ad). Its heterogeneous presentation and overlapping features with other dementias result in frequent misdiagnosis, which can delay optimal management. The present case illustrates complex symptomology, comprehensive assessment, and diagnostic challenges in a patient with DLB. A 64-year-old female presented to an academic medical center neurology clinic with rapid cognitive deterioration over the past 1.5years accompanied by visual disturbances, psychiatric and behavioral changes, and mild motor symptoms. Initial differential included Creutzfeldt-Jakob disease, atypical parkinsonism, frontotemporal lobar degeneration (FTLD), encephalopathy, and ad. Work-up in included neuropsychological, neuroimaging, cerebral spinal fluid (CSF), electroencephalogram (EEG), and skin biopsy assessments. Neuropsychological interview revealed fluctuating attention/alertness, visual hallucinations, hyposmia, paranoid and repetitive behaviors, and subtle evidence for dream enactment. Her cognitive profile showed global impairment with pronounced visuospatial and executive deficits. Recognition memory, verbal reasoning, and naming were relatively well-preserved. Magnetic resonance imaging showed mild atrophy; fluorodeoxyglucose positron emission tomography (PET) showed hypometabolism in frontal and temporal regions whereas uptake was highest in the occipital lobes and basal ganglia; skin biopsy was positive for synucleinopathy; CSF and EEG were broadly unrevealing. The preponderance of data was consistent with diagnostic criteria for probable DLB. Skin biopsy increased diagnostic confidence. Atypical features included relatively rapid cognitive decline, minimal parkinsonism, and PET imaging suggesting FTLD. The present case highlights the utility of a multidisciplinary approach (e.g., neurological exam, detailed symptom screening, neuropsychological testing, and advanced laboratory assessments) in a complex case of DLB.