Cognitive Loss Research Articles

INCORPORATING SPIRITUALITY INTO COGNITIVE STIMULATION THERAPY GROUPS FOR PERSONS WITH DEMENTIA

Abstract With the rise in Dementia-Related Disorders globally, few non-pharmacological approaches have been developed to effectively target cognitive impairment and memory loss. Cognitive Stimulation Therapy (CST) has shown effectiveness in improving cognition and quality of life of older adults with dementia. To date, no studies have incorporated spirituality into CST for improving the cognition and quality of life of older adults with dementia. This study’s aim is to evaluate the effectiveness of CST with a spirituality component compared to the traditional CST group intervention. Our team grouped participants (Nf34) into either spiritual or traditional groups based on their location of residence and level of cognition. Preliminary results showed that spiritual-themed groups improved in mental health status, mobility, and depression. The spiritual groups had a mean difference of 1.85-points improvement on mental status exam as compared to 0.2-point reduction for the traditional groups. In addition, the spiritual groups had a mean difference of 4.80-points improvement in mobility and 0.6-point improvement on depression as compared to a 5.25-points reduction in mobility and a 2.13-points reduction on depression of the traditional groups respectively. Compared to the traditional CST group, there were no significant differences noted regarding cognition and memory recall. Incorporating spirtiuality and other faith-based themes in groups may provide additional benefit for individuals with memory loss. Both healthcare and long-term care facilities may benefit from incorporating group interventions such as CST into their routine care with older adults.

THE ROLE OF CARE PARTNERS IN SUPPORTING INNER STRENGTH OF PERSONS NEWLY DIAGNOSED WITH MILD COGNITIVE IMPAIRMENT

Abstract Inner strength is one’s internal process of facing challenging circumstances, like receiving a mild cognitive impairment (MCI) diagnosis. However, the role of care partners in this process is unknown. This study explores the role of care partners in supporting inner strength at the time of diagnosis using qualitative methodologies. We interviewed persons diagnosed with MCI (N=5) at a Memory Center within 12 months and their care partners (N=5). We analyzed data in NVivo using reflexive thematic analysis methods. Trustworthiness was maintained through vetted semi-structured interview guides, verbatim transcription, field notes, peer analysis, and audit trails. Care partners supplant cognitive losses (e.g., redistribution of self, organizing and coordinating) to allow the person with MCI to thrive, which is built on a foundation of the care partner’s personal resources and the nature of their relationship with the person with MCI. Implications include incorporating care partners into diagnostic processes and tailoring caregiving supports.

Alzheimer’s disease classification and detection by using AD-3D DCNN model

Deep learning techniques had achieved notability in the healthcare domain and are more specialized in medical imaging. Alzheimer’s disease (AD) enduring nervous system disorder affects elderly senior people with loss of cognitive processes and loss of memory. Early and précised detection of AD is essential for patient medical assistance and potential treatment. Since deep learning algorithms are adequate to analyze the enormous dataset and extract higher-level features from it, unlike traditional machine learning algorithms. This work presents a system-based deep convolutional neural network (DCNN) algorithm to detect AD and its stages. A DCNN and 3D densely connected convolutional neural networks (3D-DCNN) are used to perform the feature analysis and classification task. Finally, the features learned from the DCNN and 3D-DCNN are concatenated to classify disease. Alzheimer's disease neuroimaging initiative (ADNI) dataset is used for experimental analysis. The proposed AD-3DCNN model is compared to existing pre-trained models like Xception, inception V3, mobile Net, and dense Net and has recorded a highest accuracy for predicting different stages of AD. Apart from accuracy, various performance measures are used for evaluating system performance as precision, recall, and F1 score accuracy.

Using exergame-based exercise to prevent and postpone the loss of muscle mass, muscle strength, cognition, and functional performance among elders in rural long-term care facilities: A protocol for a randomized controlled trial.

Elderly individuals in long-term care facilities (LTCFs) have a higher prevalence of sarcopenia than those in the community. Exercise is the gold standard for preventing and treating sarcopenia. Regarding exercise, multicomponent exercises, including progressive resistance training (PRT), are beneficial. However, developing routine, structured exercise programs for the elderly in LTCFs is difficult because of a shortage of healthcare providers, particularly in rural regions. Exergame-based exercises can increase a player's motivation and reduce staff time for an intervention. Nintendo Switch RingFit Adventure (RFA) is a novel exergame that combines resistance, aerobic, and balance exercises. In this study, we aim to investigate the clinical effectiveness of RFA on muscle and functional performance parameters among the elderly in LTCFs. The EXPPLORE (using EXergame to Prevent and Postpone the LOss of muscle mass, muscle strength, and functional performance in Rural Elders) trial is a single-center randomized controlled trial involving elderly individuals (≥60 years) living in LTCFs in rural southern Taiwan. The participants will be equally randomized to the intervention group (exergame-based exercise plus standard care) or the control group (standard care alone). Both groups will receive standard care except that the intervention group will receive exergame-based exercises at the time previously scheduled for sedentary activities in the LTCFs. The exergame-based exercise will be performed using RFA in the sitting position with a specialized design, including arm fit skills and knee assist mode. Each session of the exercise lasts 30 mins and will be performed two times per week for 12 weeks. The primary outcomes will be the osteoporotic fracture index, appendicular skeletal muscle mass index, dominant handgrip strength, and gait speed. Meanwhile, the secondary outcomes will be the dexterity and agility, muscle strength and thickness, range of motion of the joints of the dominant upper extremity, Kihon checklist, Medical Outcomes Study 36-Item Short-Form Health Survey, and Brain Health Test. This trial will provide valuable knowledge on whether exergames using RFA can counteract physical decline and improve quality of life and cognition among the elderly in LTCFs. [www.ClinicalTrials.gov], identifier [NCT05360667].

Moringa oleifera extract and neostigmine confer neuroprotection on aluminium chloride -induced Alzheimer’s disease: Antioxidant and acetylcholinesterase inhibitory activities

Alzheimer’s disease (AD) is a neurological episode associated with the senescence process characterized by neuronal cell death in brain regions and loss of cognition. The study investigate the neuroprotective potentials of Moringa oleifera leaf extract and Neostigmine in a rat model of Alzheimer’s disease induced by Aluminium chloride (AlCl3). A total number of 20 rats weighing 180-240 kg were used for this study and they were grouped into 5 with 4 rats in each group (n=4) labelled A-E. Group A control, received 0.1 mL normal saline (placebo), Group B, received 100 mg/kg of Aluminium chloride, Group C was given Aluminium chloride 100 mg/kg and 200 mg/kg, Group D experimental animals received Aluminium chloride 100 mg/kg and were treated with 400 mg/kg of the extract orally for 21 days, while Group E received the same dose of Alcl3 and 2 mg/kg Neostigmine given intraperitoneal (IP). Thereafter, the rats were sacrificed, and the hippocampi were harvested for histology and histochemical analysis. Our findings revealed visible protective changes in the group treated with the M. oleifera and Neostigmine as the pyramidal cells of CA3 and neurofibrillary tangles which were prominent in the positive control group were resolved. At the end of this study, it was proven that the toxicity induced by Aluminium chloride was reduced by M. oleifera leaf extract and Neostigmine. M. oleifera is a commonly consumed plant therefore the intake should be encouraged.

Targeting neuroinflammation reduces synaptic, neuronal and cognitive loss in 5xFAD Alzheimer mice.

AbstractBackgroundNeuroinflammation is a consistent characteristic of Alzheimer’s disease (AD); however, whether its development drives disease progression or is an epiphenomenon remains unknown (Gyengesy et al., 2020). In this study, we evaluated how treatment with the Immunomodulatory imide drugs (IMiDs) Pomalidomide (Pom) and more potent novel analog 3,6’‐dithioPomalidomide (3,6’‐DP) affects neuronal and synaptic loss as well as cognitive impairment in a 5xFAD transgenic mouse model of AD, by targeting neuroinflammation. These mice are known to develop neuroinflammation consequent to excessive amyloid‐b (Ab) peptide generation.MethodAs a first step, Pom and 3,6’‐DP neuroprotective and anti‐inflammatory potential were characterized on primary cell cultures challenged with Ab. 5xFAD mice were evaluated over a 4‐month period, during which cognitive deficits develop. Behavioral tests were performed to establish whether selective resolution of neuroinflammation could mitigate cognitive impairment. Pom and 3,6’‐DP effects were assessed on markers of neuronal death, microglial activation, astrogliosis, and expression of PSD‐95 post‐synaptic protein. Changes in levels of inflammatory cytokines and Ab in hippocampus and cortex 5xFAD mice were also measured. Lastly, the teratogenic potential of both compounds was appraised by a cereblon/BRD3 binding FRET assay.ResultPom and 3,6’‐DP reduced neuronal and neurite network loss, as well as microglial cell activation in primary cortical cultures challenged with Ab. In hippocampus and cerebral cortex of 5xFAD mice, 3,6’‐DP, in particular, mitigated elevated expression of Iba1, TNF‐a and GFAP proteins, markers of microglial and astrocyte activation. This was accompanied by reductions in synaptic and neuronal cell loss as well as mitigation of behavioral impairment but, notably, no alteration in either Ab plaque or peptide generation. Both 3,6’‐DP and Pom bound cereblon; however, 3,6’‐DP did not lower Ikaros, Aiolos or SALL4, which are key downstream neo‐substrates involved in the anticancer and teratogenic actions of the IMiD drug class. Hence, 3,6’‐DP could represent a potentially safer drug to lower TNF‐a levels.ConclusionMitigating neuroinflammation in the absence of actions on Ab generation to alleviate neurodegeneration and behavioral impairment indicates that neuroinflammation is a primary causative event in the Ab‐mediated pathological cascade leading to neuronal loss/cognitive impairment. Targeting neuroinflammatory mediators with IMiDs represent a promising AD therapeutic strategy.

Cell‐type specific alterations in intrinsic excitability and neurotransmission in short‐term virally induced model of Alzheimer’s Disease

AbstractBackgroundAlzheimer’s Disease (AD) is a neurodegenerative cascade resulting in neuronal dysfunction and memory loss, classically characterized by the deposition of amyloid plaques throughout the brain. Although deposition of these proteins correlates with cognitive loss in AD, these aggregates may not be causally related to initial neuronal and circuit pathology in AD. Interestingly, evidence in AD patients and mouse models has reported cortical circuit hyperexcitability prior to plaque pathology. The cell and molecular mechanisms underlying hyperexcitability in early‐stage AD remain unclear. In healthy brains, normal circuit operations are maintained through a fine‐tuned balance between excitatory (pyramidal) and inhibitory neuron activity. In several APP‐expressing mouse models, pyramidal and inhibitory neuron physiology are differentially affected and also evolve with disease severity. However, these parameters have not been explored in an adult‐onset APP model.MethodWe examined rapidly emerging physiological changes in cortical PV interneurons and neighboring pyramidal neurons in an adult‐onset AD model. We analyzed contributions of overexpressed wild‐type human amyloid precursor protein (WT hAPP) using an AAV viral approach. We fluorescently targeted cell types for whole‐cell patch‐clamp electrophysiology using a PV‐specific enhancer labeling technique or an excitatory neuron‐specific AAV. Lastly, we optogenetically stimulated PV interneurons to assess neurotransmission onto neighboring pyramidal cells.ResultWe report alterations in cortical PV interneuron and pyramidal neuron intrinsic excitability, as well as PV‐to‐pyramidal neurotransmission, after short‐term induction of hAPP virally. Interestingly, each of these two neuronal subtypes displayed unique changes suggesting different cell‐type‐specific molecular alterations.ConclusionThis breakdown of APP processing and its effects on PV interneuron and pyramidal neurons provides potential insights into early cell‐type‐specific mechanisms of the pathogenesis of Alzheimer’s Disease, thus providing specific interventions to ameliorate early symptoms and potentially slow the progression towards severe disease.

Identification of circRNAs linked to Alzheimer’s disease and related dementias

AbstractBackgroundAlthough linear mRNA transcriptome study has been well performed for Alzheimer’s disease (AD), little is known for the non‐coding RNA. Circular RNAs(circRNAs) are particularly notable because of their selective expression in the brain and differential regulation in neurological disease conditions, including AD. CircRNAs are formed from back‐splicing events, and they majorly function as sponges for microRNA and RNA‐binding proteins. Our study examines circRNA expression patterns associated with AD and related dementias in different brain regions.MethodTo detect and quantify cortical circRNAs, we used Mount Sinai Brain Bank (MSBB) rRNA‐depleted RNA sequencing(RNAseq) data derived from inferior frontal gyrus tissue of 278 subjects(216 AD cases, 62 controls) by applying DCC and Circexplor3. To detect hippocampal circRNAs, we generated rRNA‐depleted RNAseq data from 207 human postmortem hippocampal region samples(186 AD, 21 controls) obtained from the BU Alzheimer Disease Research Center. Differentially expressed circRNAs were identified using limma and DESeq2. Both cortical and hippocampal circRNA candidates were further validated using RT‐qPCR in a smaller independent cohort of patients.ResultWe identified over 300 circRNA significantly associated with AD condition (FDR<0.05). Interestingly, a major fraction of these circRNAs are derived from genes involved in excitatory synaptic transmission, axon guidance, and calcium signaling pathways. CircRNA from AD‐linked genes, including APP, PICALM and PSEN1, were identified as top candidates associated with AD in cortex. In the hippocampus, we find circSLC8A1 and circHOMER1 among the top differentially regulated circRNAs. We also find expression of circHOMER1, circMLIP, circATRNL1 among others to be correlated with AD traits of clinical dementia, BRAAK pathology, and amyloid plaque. Our analysis of AD‐only patients and AD patients with vascular or Lewy body dementia revealed differential expression of 39 circRNAs common among all three disease conditions.ConclusionCircRNAs are a novel class of regulatory RNAs but their role in AD pathogenesis is just beginning to be explored. Our study identified circRNA whose expression is linked to AD and are correlated with indices of tauopathy and cognitive loss in cortex and hippocampus. Furthermore, particular circRNAs were differentially expressed among patients with AD or other dementias, suggesting that circRNA might be useful disease biomarkers or targets for disease intervention.

Treatment with C5aR1 antagonist attenuates short‐term hippocampal memory decline and prevents DAM signature in Arctic mice.

AbstractBackgroundUpregulation of complement genes in Alzheimer’s disease (AD) mouse models is associated with inflammation and cognitive decline. Genetic ablation of C5aR1 reduces loss of neuronal complexity and cognition in the Arctic mouse model. Inhibition of C5aR1 with PMX205 has shown success in preclinical studies of AD, reducing recruitment of reactive glia and amyloid deposition in the Tg2576 AD model. However, the molecular and cellular mechanisms underlying this neuroprotection are unclear. Thus, we used single cell RNA‐seq to interrogate gene pathways involved in C5aR1‐mediated deficits in the Arctic mouse model.MethodWT and Arctic mice were treated with PMX205 or vehicle via drinking water (20 µg/mL, equivalent to ∼5 mg/kg/day, consistent with previous studies) from 7.5 to 10 months of age. Effects of PMX205 on long‐ and short‐term memory were tested with object location memory (OLM) with a 24hr inter‐trial interval (ITI) and y‐maze spatial reference memory test with a 1hr ITI, respectively. Hippocampi were dissected and immediately prepared for microglial isolation and fixation. The single cell whole transcriptome kit (Parse Biosciences) was used to prepare single cell microglia libraries for RNA‐seq. Libraries were sequenced using NextSeq 2000. Parse Bioscience split‐pipe v0.7.6 was used to demultiplex reads into single‐cells, Scrublets to remove doublets, and Seurat for quality control, normalization, and clustering.ResultPMX205 protected against short‐, but not long‐, term memory deficits. Arctic‐PMX205 mice spent more time in the novel arm (44%) than Arctic‐vehicle mice (30%) in Y‐maze. Microglial single cell RNA‐seq identified 7 microglial clusters. Within these clusters, we probed for genes previously described as homeostatic, DAM1, and DAM2. DAM1 (Tyrobp, Apoe, Trem2) and DAM2 (Cst7, Itgax) genes were enriched in Arctic‐vehicle mice compared to WT mice, and expression was downregulated with PMX205 treatment in Arctic mice, most notably in DAM1 genes.ConclusionPharmacological C5aR1 inhibition confers some protective function even when treatment is initiated months after amyloid pathology onset in this aggressive mouse model of AD, and alters microglial polarization, suppressing detrimental inflammation. These findings complement previous data from genetic ablation of C5aR1, and suggest that C5aR1 may be a viable therapeutic target for individuals with an AD diagnosis.

Sex education for patients with severe mental illness in Iran: A qualitative study.

Patients with severe mental illness may experience cognitive deficits, impaired judgment or loss of skills. Therefore, they are prone to sexual health complications. Sex education can promote sexual health, and in many countries, it is integrated into other domains of education. The educational contents taught in western countries are not necessarily appropriate for developing countries.This study aims to address sex educational content for these patients in Iran. We have conducted twenty-three face-to-face, deep and semi-structured interviews with patients, family members, psychiatrists, general practitioners, nurses and psychologists. We used the strategy of maximum diversity in selecting the participants. "Improving basic knowledge," "decreasing the risk of unsafe sex", "empowerment" and "persuading to ask for help" should be covered in the education. Sexuality is not considered a priority for these patients. It is necessary to develop a training program with simple educational content for this high-risk group. Raising awareness and knowledge about the possible risks of social media on high-risk behaviours, developing social and behavioural skills, and encouraging patients to talk about their new challenges in sexual life is recommended. Cultural, spiritual and personal beliefs should be considered in designing the educational program.

Frequency of TAR DNA‐binding protein 43 (TDP‐43) increases linearly with age in the demented and non‐demented elderly population

AbstractBackgroundTDP‐43 is a nuclear RNA‐binding protein involved in various neurodegenerative diseases, including Alzheimer’s Disease (AD), and normal aging. It strongly affects cognition and memory loss in AD. Concomitant TDP‐43 pathology increases the likelihood of being cognitively impaired at death.MethodMayo Clinic has amassed a large database with 1072 study participants with known TDP‐43 pathology status, who were prospectively recruited and followed in the Mayo Clinic Alzheimer’s Disease Research Center, Mayo Clinic Study of Aging, and Neurodegenerative Research Group. All underwent neurologic, genetic, and neuropathologic evaluations. Amygdala sections immunostained with antibodies against TDP‐43 were screened for TDP‐43‐immunoreactive inclusions and successively staged using the Josephs staging scheme. The frequency of TDP‐43 pathology by age at death was estimated using logistic regression with age modelled using a restricted cubic spline. Models were fit for all cases including the subset of 581 cases with dementia.ResultOur cohort was predominantly White (99%) with median age at death of 87 years (IQR: 80‐92) and relatively even sex distribution (52% female). About 55% had Braak stage V‐VI and 61% had Thal amyloid phase ≥3. Fifty‐two percent met criteria for intermediate‐high probability AD. TDP‐43‐immunoreactivity (TDP‐43+) was detected in 44% with median TDP‐43 stage of 3 (IQR: 1‐5), and in 54% with a median stage of 3 (IQR: 2‐5) in those with dementia. TDP‐43+ frequency increased approximately linearly with age at death. At 70 years at death, an estimated 30% (95% CI: 25–35) of the cohort was TDP‐43+ versus 33% (CI: 27–40) of those with dementia. By 90 years at death, 49% (CI: 45–52) of the overall cohort and 68% (CI:62‐73) of those with dementia were TDP‐43+.ConclusionThe results from our large cohort confirm that TDP‐43 pathology frequency increases in elderly White study participants with age of death, independent of cognitive status. Furthermore, TDP‐43 pathology frequency increases to a greater degree with age in those with dementia. Given the clear links between TDP‐43 and impaired cognition, the contribution of TDP‐43 to an individual’s cognitive impairment is likely to increase with age; a dynamic with significant public health consequences given our aging population.

Synaptic oligomeric Tau is an early event in tau‐affected brain regions in Alzheimer’s disease.

AbstractBackgroundDeposition of fibrillar forms of tau‐neurofibrillary tangles (NFT) and neuropil threads (NT) follow a progressive pattern across brain regions as reflected by Braak stages. However, oligomeric forms of tau have been proposed to precede the appearance of fibrillar forms. Synapses are the earliest structure linked to Azheimer’s Disease cognitive loss, but whether tau pathology, fibrillar or oligomeric affects early this structure in each region remains unclear. This is mainly explained by the technical limitations to study oligomeric forms of tau and the visualization of synaptic terminals. We aim to investigate the presence of oligomeric tau at synapses of human AD cases and its relation to the presence of fibrillar forms of tau in different brain regions.MethodWe used array tomography microscopy to visualize single synaptic terminals on postmortem human samples from BA20/21 and BA17 brain regions of 10 AD and 10 controls with diverse Braak stages. Pre‐ and post‐synaptic terminals (synaptophysin and PSD95) and oligomeric tau (T22 antibody) were labelled. To compare synaptic tau with total fibrillar tau burden, NFTs and NTs were quantified from immunohistochemical sections (AT8 antibody) of the same cases and areas. We also studied the presence of tau in synapses using Western Blot experiments in synaptoneurosomes enriched fractions from the same cases and areas (Tau5 antibody). Finally, the presence at synapses of oligomeric and fibrillar tau was confirmed with other superresolution techniques such as electron microscopy, STORM and DNA‐PAINT.ResultWe found that 1) Oligomeric tau was found in both pre‐ and postsynaptic terminals, in a higher proportion of presynaptic terminals. 2) Oligomeric tau at synapses was found in areas without abundant fibrillar forms of tau. 3) A higher proportion of oligomeric tau when compared to phosphorylated tau was found at synaptic terminals in early affected cases. 4) Early synaptic oligomeric tau was found also by western blot of synaptoneurosomes, electron microscopy and STORM.ConclusionOur results suggest that synaptic oligomeric tau may be an early event at tau‐affected brain regions, preceding the phosphorylation of tau and the formation of fibrillar forms. Also, the findings may support the transsynaptic spreading of tau at early stages.

Finding subtypes of nonlinear patterns in longitudinal cognition decline

AbstractBackgroundTo characterize subtypes of longitudinal cognition decline considering the possible nonlinear patterns.MethodOlder persons without dementia at study enrollment (n = 1,010) had annual cognitive testing for up to 24 years (mean = 9.9 years, SD = 5.0), died, and underwent a neuropathologic examination to quantify 9 postmortem markers of common neurodegenerative and cerebrovascular conditions. To accommodate the heterogeneity in cognitive trajectories and control for neuropathologic burden, we used a novel latent class functional mixed‐effects model which allows individuals to have different nonlinear patterns of cognitive decline under a unified model structure.ResultIn the latent class functional mixed‐effects model, postmortem markers (AD pathology, Lewy bodies, transactive response DNA‐binding protein 43 (TDP‐43) pathology, hippocampal sclerosis, atherosclerosis, gross infarcts) were associated with global cognitive decline. We found four subtypes of longitudinal cognition decline after adjustment for neuropathologic burden. The residual decline after adjustment was weakly related to age at death; it occurred in only about one third of participants, mostly proximate to death. Results were comparable after eliminating the initial cognitive assessments to minimize retest learning or controlling for frailty proximate to death. Analyses were also conducted with composite measures of episodic memory and perceptual speed. Residual decline not attributable to neuropathologic burden was confined to a subset for each outcome and was most evident proximate to death.ConclusionLate‐life cognitive loss involves heterogenous nonlinear patterns. It mainly reflects non‐normative pathologic and mortality‐related processes rather than normative age‐related processes.

Benzodiazepines in Alzheimer's disease: beneficial or detrimental effects.

Dementia is considered a clinical syndrome characterized by cognitive dysfunction and memory loss. Alzheimer's disease (AD) is the most common type of dementia. AD is linked with the turbulence of diverse neurotransmitters including gamma-aminobutyric acid (GABA). Notably, GABA in the brain and cerebrospinal fluid was reduced in AD. Thus, allosteric modulation of the GABA effect by benzodiazepines (BDZs) may improve the clinical outcomes of AD patients. Therefore, the objective of the present review was to reveal the possible role of BDZs on the pathogenesis and clinical outcomes in AD patients. Though BDZs may adversely affect cognitive functions mainly in elderly patients, herein it was postulated that BDZs may have beneficial, neutral, or detrimental effects in AD. Taken together, there is strong controversy regarding the use of BDZs and the risk for the development of AD. Therefore, experimental, preclinical and clinical studies are critical to determine the potential protective or detrimental effects of BDZs on AD neuropathology.

The effect of combination pretreatment of donepezil and environmental enrichment on memory deficits in amyloid-beta-induced Alzheimer-like rat model

Alzheimer's disease (AD) is progressive neurodegeneration known as the most common cause of dementia, and it is the sixth leading cause of death in older people. Given the promising data on the additive effect of combination therapy with donepezil (Aricept), an acetylcholinesterase inhibitor (AChEI), and regarding the similar neuronal mechanisms through which donepezil (DON) and environmental enrichment (EE) exert their enhancing effects on cognition; we asked whether simultaneous treatment with two paradigms in amyloid-beta-induced AD rats may lead to greater protection against the cognitive impairments than either treatment individually. The experimental groups consisted of Alz, sham-operated, Alz + DON, Alz + EE, and Alz + DON + EE. AD was induced by intrahippocampal injection of amyloid-beta (1–42, 6 μg), and DON was orally administrated (4 mg/kg) for 21 days. Environmental enrichment consisted of housing animals in large cages (50 × 50 × 50 cm) containing a running wheel and differently shaped objects for 21 days. Spatial learning and memory were assessed in the Morris water maze (MWM) and Real-time PCR was performed to assess the expression of brain-derived neurotrophic factor (BDNF) and M1 muscarinic acetylcholine receptor (AchM1R) within the hippocampus. Spatial memory was impaired in Alz animals, and while neither pretreatment with DON nor EE alone could significantly restore spatial memory scores in Alz rats, combination therapy was effective. BDNF expression was suppressed in Alz rats and pretreatment with DON plus EE could increase it to the saline levels. The data suggest that a cholinesterase inhibitor and cognitive stimulation can be used effectively in combination to protect cognitive loss in an AD rat model. This additive protective effect may be in part due to the augmented influence of this combination on BDNF levels and cholinergic neuronal system within the hippocampus.

White matter dementia then… and now.

White matter dementia (WMD) is a concept introduced in 1988 to highlight the importance of white matter pathology in producing cognitive dysfunction and dementia. Whereas gray matter, particularly the cerebral cortex, has been primarily investigated in the dementias, subcortical pathology has long been correlated with cognitive loss, and a corticocentric perspective cannot account for the full range of neurobehavioral disorders. Within the subcortical regions, white matter is prominent, accounting for about half the volume of the adult brain, and many white matter diseases, injuries, and intoxications can produce cognitive dysfunction so severe as to justify the term dementia. Recognition of this novel syndrome relied heavily on the introduction of magnetic resonance imaging (MRI) that permitted in vivo visualization of white matter lesions. Neuropsychological studies clarified the clinical presentation of WMD by identifying a profile dominated by cognitive slowing and executive dysfunction, and a precursor syndrome of mild cognitive dysfunction was proposed to identify early cognitive impairment that may later evolve to WMD. As knowledge advanced, the role of white matter in structural connectivity within distributed neural networks was elucidated. In addition, highlighting the frequent commingling of gray and white matter involvement, white matter pathology was associated with neurodegenerative diseases such as Alzheimer's disease and chronic traumatic encephalopathy, with potentially transformative clinical implications. In particular, preventive measures and treatments exploiting white matter restoration and plasticity are gaining much attention. Today, WMD has matured into a concept that not only integrates knowledge from across the spectrum of clinical neuroscience, but also informs new investigations into many perplexing disorders and enables a more complete understanding of brain-behavior relationships.

Role of amyloid beta (25−35) neurotoxicity in the ferroptosis and necroptosis as modalities of regulated cell death in Alzheimer's disease

Neuronal cell death as a prominent pathological feature contributes to cognitive decline and memory loss in Alzheimer’s disease. We investigated the role of two forms of cell death pathways, ferroptosis and necroptosis, and their interactions following entorhinal cortex (EC) amyloidopathy. The Aβ25–35 was bilaterally injected into the rat’s EC, and Morris Water Maze was applied to determine spatial performance one week after Aβ injection. For evaluation of ferroptosis and necroptosis involvement in Aβ induced pathology, ferroptosis inhibitor, Ferrostatin (Fer-1), and necroptosis inhibitor, Necrostatin (Nec-1), were injected into the EC during training days of behavioral test. Our behavioral and histological assessment showed spatial learning and memory impairment, along with neuropathology changes such as cell survival and intracellular Aβ deposits in response to EC amyloidopathy, which were ameliorated by treatment with Fer-1 or Nec-1. The expression of ferroptosis key factors GPX4 and SLC7A11 were decreased and the level of TfR was increased following Aβ toxicity. Also, Necroptosis pathway related factors RIP1, RIP3, and MLKL were modulated by Aβ neurotoxicity. However, application of Fer-1 or Nec-1 could inhibit the hippocampal ferroptosis and necroptosis pathways due to EC amyloidopathy. Our data also demonstrated that Aβ-induced necroptosis suppressed by Fer-1, although Nec-1 had no effect on ferroptosis, indicating that ferroptosis pathway is upstream of necroptosis process in the Aβ neurotoxicity. Moreover, Aβ induced hippocampal mGLUR5 overexpression and reduced level of STIM1/2 recovered by Fer-1 or Nec-1. According to our findings ferroptosis and necroptosis pathways are involved in Aβ neurotoxicity through modulation of mGLUR5 and STIM1/2 signaling.

Ameliorative effect of vanillin on scopolamine-induced dementia-like cognitive impairment in a mouse model.

Alzheimer's disease (AD) is the most common form of dementia, which is among the top five causes of death in the United States. It is a neurodegenerative disorder that causes permanent loss of memory and cognition. The current pharmacotherapy for AD is based on providing symptomatic relief only and has many side effects. There is a need for a safer, disease-modifying drug for the treatment of AD. The PASS online software was used to screen phytoconstituents based on their predicted effects on various AD-related targets. Vanillin was selected as the compound of interest, as it has not been researched elaborately on any animal model of AD. The acetylcholinesterase inhibitory activity of vanillin was established in vitro. Thereafter, ameliorative effect of vanillin was evaluated using the exteroceptive memory model in scopolamine-induced cognitive impairment mice model. Vanillin showed an acetylcholinesterase inhibitory activity in vitro, and the IC50 value was calculated to be 0.033 mM. Vanillin significantly reversed the memory and behavioral deficits caused by scopolamine as demonstrated by significant improvement in memory in negative reinforcement, elevated plus maze, and spatial learning paradigms. Vanillin also proved to have a nootropic effect. Also, vanillin proved to have significantly better antioxidant and acetylcholinesterase inhibitory effects in vivo than donepezil hydrochloride. The potential anti-AD activity of vanillin was also confirmed by the reduction in IL-6 levels and TNF-α levels. Our results suggest that vanillin is a safe and effective natural drug candidate having a great potential for the treatment of AD. However, more research is required to evaluate its effect on A beta plaques and Tau neurofibrillary tangles in vivo.

Interpretable deep learning translation of GWAS and multi-omics findings to identify pathobiology and drug repurposing in Alzheimer's disease.

Translating human genetic findings (genome-wide association studies [GWAS]) to pathobiology and therapeutic discovery remains a major challenge for Alzheimer's disease (AD). We present a network topology-based deep learning framework to identify disease-associated genes (NETTAG). We leverage non-coding GWAS loci effects on quantitative trait loci, enhancers and CpG islands, promoter regions, open chromatin, and promoter flanking regions under the protein-protein interactome. Via NETTAG, we identified 156 AD-risk genes enriched in druggable targets. Combining network-based prediction and retrospective case-control observations with 10 million individuals, we identified that usage of four drugs (ibuprofen, gemfibrozil, cholecalciferol, and ceftriaxone) is associated with reduced likelihood of AD incidence. Gemfibrozil (an approved lipid regulator) is significantly associated with 43% reduced risk of AD compared with simvastatin using an active-comparator design (95% confidence interval 0.51-0.63, p<0.0001). In summary, NETTAG offers a deep learning methodology that utilizes GWAS and multi-genomic findings to identify pathobiology and drug repurposing in AD.

ODP202 Geriatric Type 1 Diabetes- unique management challenge

Abstract Case Presentation A 87 year old female with a past medical history of Type 1 Diabetes Mellitus (DM), Parkinson's disease and osteoporosis was sent from an assisted living facility to the emergency department for evaluation of elevated blood glucose levels. She had a long standing history of type 1 DM and further review revealed that she had extremely labile (brittle) blood sugars, with multiple prior hospitalizations for both hypoglycemia and hyperglycemia. Assisted living facility staff reported that her blood sugars were persistently elevated despite receiving scheduled insulin doses. On presentation, she did not have any specific complaints except for polydipsia and polyuria. She was hemodynamically stable, alert and oriented to time, place and person. Initial lab work included serum glucose 754 (70-79 mg/dL), bicarbonate 25 (21-31 mmol/L), anion gap 10 (6-14 mmol/L), ketone 0.9 (&amp;lt; 0.6 mmol/L), leukocyte count 4.7 (4-11 k/mm u) and creatinine 1. 06 (0.6-1.2 mg/dL). Urinalysis showed glycosuria and proteinuria but no evidence of infection. IVF and insulin were started. Extensive infectious work-up was negative. Her blood glucose levels stabilized with basal-bolus regimen and correctional doses of insulin. Tight glycemic control was avoided due to her history of hypoglycemic unawareness and multiple previous episodes for severe and recurrent hypoglycemia. Discussion Brittle diabetes is a disorder commonly seen in patients with Type 1 DM and is characterized by extreme swings in blood glucose levels (severe recurrent hypoglycemic and hyperglycemic episodes) without a clear cut precipitating cause requiring hospitalizations. It has been linked to autonomic dysfunction, hormonal imbalance, psychological issues, nutrient malabsorption and autoimmune conditions. Geriatric Type 1 DM presents great challenges in management as it combines micro and macro vascular complications of long standing DM with geriatric syndrome - concurrent comorbidities, cognitive losses of various degrees, vision and hearing loss, loss autonomic and hormonal counter-regulation, and progressive frailty leading to severe glycemic instability makes self management of DM near impossible. Our patient was an elderly female with osteoporosis, Parkinson's and hypoglycemic unawareness. Great care was taken to maintain her blood glucose levels in the optimal range both during and after hospitalization. Daily insulin was being administered by staff after checking blood glucose levels, avoiding the possibility of dose omission or errors. Detailed instructions on administration of the correct dose of insulin according to caloric consumption and physical activity were provided. With this case, we wish to highlight the unique challenge Brittle Diabetes in geriatric presents, and as this sector of population is growing owing to better treatment options for diabetics and longer life expectancy, there is a growing need to recognize this entity, adopt a multi-disciplinary patient centered approach and prioritize prevention of both hypoglycemia and extreme hyperglycemia over tight glycemic control. Presentation: No date and time listed