Deficits In Alzheimer's Disease Research Articles

Monocytes release cystatin F dimer to associate with Aβ and aggravate amyloid pathology and cognitive deficits in Alzheimer’s disease

BackgroundUnderstanding the molecular mechanisms of Alzheimer’s disease (AD) has important clinical implications for guiding therapy. Impaired amyloid beta (Aβ) clearance is critical in the pathogenesis of sporadic AD, and blood monocytes play an important role in Aβ clearance in the periphery. However, the mechanism underlying the defective phagocytosis of Aβ by monocytes in AD remains unclear.MethodsInitially, we collected whole blood samples from sporadic AD patients and isolated the monocytes for RNA sequencing analysis. By establishing APP/PS1 transgenic model mice with monocyte-specific cystatin F overexpression, we assessed the influence of monocyte-derived cystatin F on AD development. We further used a nondenaturing gel to identify the structure of the secreted cystatin F in plasma. Flow cytometry, enzyme-linked immunosorbent assays and laser scanning confocal microscopy were used to analyse the internalization of Aβ by monocytes. Pull down assays, bimolecular fluorescence complementation assays and total internal reflection fluorescence microscopy were used to determine the interactions and potential interactional amino acids between the cystatin F protein and Aβ. Finally, the cystatin F protein was purified and injected via the tail vein into 5XFAD mice to assess AD pathology.ResultsOur results demonstrated that the expression of the cystatin F protein was specifically increased in the monocytes of AD patients. Monocyte-derived cystatin F increased Aβ deposition and exacerbated cognitive deficits in APP/PS1 mice. Furthermore, secreted cystatin F in the plasma of AD patients has a dimeric structure that is closely related to clinical signs of AD. Moreover, we noted that the cystatin F dimer blocks the phagocytosis of Aβ by monocytes. Mechanistically, the cystatin F dimer physically interacts with Aβ to inhibit its recognition and internalization by monocytes through certain amino acid interactions between the cystatin F dimer and Aβ. We found that high levels of the cystatin F dimer protein in blood contributed to amyloid pathology and cognitive deficits as a risk factor in 5XFAD mice.ConclusionsOur findings highlight that the cystatin F dimer plays a crucial role in regulating Aβ metabolism via its peripheral clearance pathway, providing us with a potential biomarker for diagnosis and potential target for therapeutic intervention.

The microtubule-dynamin binding inhibitor peptide PHDP5 rescues spatial learning and memory deficits in Alzheimer’s disease model mice

Dynamin is a microtubule (MT) binding protein playing a key role in vesicle endocytosis. In a brain slice model, tau loaded in presynaptic terminals assembles MTs, thereby impairing vesicle endocytosis via depletion of cytosolic dynamin. The peptide PHDP5, derived from the pleckstrin homology domain of dynamin 1, inhibits dynamin-MT interaction and rescues endocytosis and synaptic transmission impaired by tau when co-loaded in presynaptic terminals. We tested whether in vivo administration of PHDP5 could rescue their learning/memory deficits observed in Alzheimer’s disease (AD) model mice. A modified PHDP5 incorporating a cell-penetrating peptide (CPP) and a FITC fluorescent marker was delivered intranasally to Tau609 transgenic (Tg) and 3xTg-AD mice. FITC-positive puncta were observed in the hippocampus of mice infused with PHDP5 or scrambled (SPHDP5) peptide, but not in saline-infused controls. In the Morris water maze (MWM) test for spatial learning/memory, AD model mice treated with FITC-PHDP5-CPP showed prominent improvements in learning and memory, performing close to the level of saline-infused WT mice control. In contrast, mice treated with a scrambled construct (FITC-SPHDP5-CPP) showed no significant improvement. We conclude that PHDP5 can be a candidate for human AD therapy.

Agomirs upregulating carboxypeptidase E expression rescue hippocampal neurogenesis and memory deficits in Alzheimer’s disease

BackgroundAdult neurogenesis occurs in the subventricular zone (SVZ) and the subgranular zone of the dentate gyrus in the hippocampus. The neuronal stem cells in these two neurogenic niches respond differently to various physiological and pathological stimuli. Recently, we have found that the decrement of carboxypeptidase E (CPE) with aging impairs the maturation of brain-derived neurotrophic factor (BDNF) and neurogenesis in the SVZ. However, it remains unknown whether these events occur in the hippocampus, and what the role of CPE is in the adult hippocampal neurogenesis in the context of Alzheimer’s disease (AD).MethodsIn vivo screening was performed to search for miRNA mimics capable of upregulating CPE expression and promoting neurogenesis in both neurogenic niches. Among these, two agomirs were further assessed for their effects on hippocampal neurogenesis in the context of AD. We also explored whether these two agomirs could ameliorate behavioral symptoms and AD pathology in mice, using direct intracerebroventricular injection or by non-invasive intranasal instillation.ResultsRestoration of CPE expression in the hippocampus improved BDNF maturation and boosted adult hippocampal neurogenesis. By screening the miRNA mimics targeting the 5’UTR region of Cpe gene, we developed two agomirs that were capable of upregulating CPE expression. The two agomirs significantly rescued adult neurogenesis and cognition, showing multiple beneficial effects against the AD-associated pathologies in APP/PS1 mice. Of note, noninvasive approach via intranasal delivery of these agomirs improved the behavioral and neurocognitive functions of APP/PS1 mice.ConclusionsCPE may regulate adult hippocampal neurogenesis via the CPE–BDNF–TrkB signaling pathway. This study supports the prospect of developing miRNA agomirs targeting CPE as biopharmaceuticals to counteract aging- and disease-related neurological decline in human brains.

Early Sensory Deficits in Alzheimer’s Disease: A Review of Potential Integrating Diagnostic Methods

Early Sensory Deficits in Alzheimer’s Disease: A Review of Potential Integrating Diagnostic Methods

Impaired long-range excitatory time scale predicts abnormal neural oscillations and cognitive deficits in Alzheimer’s disease

BackgroundAlzheimer’s disease (AD) is the most common form of dementia, progressively impairing cognitive abilities. While neuroimaging studies have revealed functional abnormalities in AD, how these relate to aberrant neuronal circuit mechanisms remains unclear. Using magnetoencephalography imaging we documented abnormal local neural synchrony patterns in patients with AD. To identify global abnormal biophysical mechanisms underlying the spatial and spectral electrophysiological patterns in AD, we estimated the parameters of a biophysical spectral graph model (SGM).MethodsSGM is an analytic neural mass model that describes how long-range fiber projections in the brain mediate the excitatory and inhibitory activity of local neuronal subpopulations. Unlike other coupled neuronal mass models, the SGM is linear, available in closed-form, and parameterized by a small set of biophysical interpretable global parameters. This facilitates their rapid and unambiguous inference which we performed here on a well-characterized clinical population of patients with AD (N = 88, age = 62.73 +/- 8.64 years) and a cohort of age-matched controls (N = 88, age = 65.07 +/- 9.92 years).ResultsPatients with AD showed significantly elevated long-range excitatory neuronal time scales, local excitatory neuronal time scales and local inhibitory neural synaptic strength. The long-range excitatory time scale had a larger effect size, compared to local excitatory time scale and inhibitory synaptic strength and contributed highest for the accurate classification of patients with AD from controls. Furthermore, increased long-range time scale was associated with greater deficits in global cognition.ConclusionsThese results demonstrate that long-range excitatory time scale of neuronal activity, despite being a global measure, is a key determinant in the local spectral signatures and cognition in the human brain, and how it might be a parsimonious factor underlying altered neuronal activity in AD. Our findings provide new insights into mechanistic links between abnormal local spectral signatures and global connectivity measures in AD.

Synaptic density patterns in early Alzheimer's disease assessed by independent component analysis.

Synaptic loss is a primary pathology in Alzheimer's disease and correlates best with cognitive impairment as found in post-mortem studies. Previously, we observed in vivo reductions of synaptic density with [11C]UCB-J PET (radiotracer for synaptic vesicle protein 2A) throughout the neocortex and medial temporal brain regions in early Alzheimer's disease. In this study, we applied independent component analysis to synaptic vesicle protein 2A-PET data to identify brain networks associated with cognitive deficits in Alzheimer's disease in a blinded data-driven manner. [11C]UCB-J binding to synaptic vesicle protein 2A was measured in 38 Alzheimer's disease (24 mild Alzheimer's disease dementia and 14 mild cognitive impairment) and 19 cognitively normal participants. [11C]UCB-J distribution volume ratio values were calculated with a whole cerebellum reference region. Principal components analysis was first used to extract 18 independent components to which independent component analysis was then applied. Subject loading weights per pattern were compared between groups using Kruskal-Wallis tests. Spearman's rank correlations were used to assess relationships between loading weights and measures of cognitive and functional performance: Logical Memory II, Rey Auditory Verbal Learning Test-long delay, Clinical Dementia Rating sum of boxes and Mini-Mental State Examination. We observed significant differences in loading weights among cognitively normal, mild cognitive impairment and mild Alzheimer's disease dementia groups in 5 of the 18 independent components, as determined by Kruskal-Wallis tests. Only Patterns 1 and 2 demonstrated significant differences in group loading weights after correction for multiple comparisons. Excluding the cognitively normal group, we observed significant correlations between the loading weights for Pattern 1 (left temporal cortex and the cingulate gyrus) and Clinical Dementia Rating sum of boxes (r = -0.54, P = 0.0019), Mini-Mental State Examination (r = 0.48, P = 0.0055) and Logical Memory II score (r = 0.44, P = 0.013). For Pattern 2 (temporal cortices), significant associations were demonstrated between its loading weights and Logical Memory II score (r = 0.34, P = 0.0384). Following false discovery rate correction, only the relationship between the Pattern 1 loading weights with Clinical Dementia Rating sum of boxes (r = -0.54, P = 0.0019) and Mini-Mental State Examination (r = 0.48, P = 0.0055) remained statistically significant. We demonstrated that independent component analysis could define coherent spatial patterns of synaptic density. Furthermore, commonly used measures of cognitive performance correlated significantly with loading weights for two patterns within only the mild cognitive impairment/mild Alzheimer's disease dementia group. This study leverages data-centric approaches to augment the conventional region-of-interest-based methods, revealing distinct patterns that differentiate between mild cognitive impairment and mild Alzheimer's disease dementia, marking a significant advancement in the field.

Novel Social Stimulation Ameliorates Memory Deficit in Alzheimer's Disease Model through Activating α-Secretase.

As the most common form of dementia in the world, Alzheimer's disease (AD) is a progressive neurological disorder marked by cognitive and behavioral impairment. According to previous researches, abundant social connections shield against dementia. However, it is still unclear how exactly social interactions benefit cognitive abilities in people with AD and how this process is used to increase their general cognitive performance. In this study, we found that single novel social (SNS) stimulation promoted c-Fos expression and increased the protein levels of mature ADAM10/17 and sAPPα in the ventral hippocampus (vHPC) of wild-type (WT) mice, which are hippocampal dorsal CA2 (dCA2) neuron activity and vHPC NMDAR dependent. Additionally, we discovered that SNS caused similar changes in an AD model, FAD4T mice, and these alterations could be reversed by α-secretase inhibitor. Furthermore, we also found that multiple novel social (MNS) stimulation improved synaptic plasticity and memory impairments in both male and female FAD4T mice, accompanied by α-secretase activation and Aβ reduction. These findings provide insight into the process underpinning how social interaction helps AD patients who are experiencing cognitive decline, and we also imply that novel social interaction and activation of the α-secretase may be preventative and therapeutic in the early stages of AD.

Reduced Prefrontal-Thalamic Theta Flow During Working Memory Retrieval in APP/PS1 Mice.

Working memory deficits in Alzheimer's disease (AD) are linked to impairments in the retrieval of stored memory information. However, research on the mechanism of impaired working memory retrieval in Alzheimer's disease is still lacking. The medial prefrontal cortex (mPFC) and mediodorsal thalamus (MD) are involved in memory retrieval. The purpose of this study is to investigate the functional interactions and information transmission between mPFC and MD in the AD model. We recorded local field potentials from mPFC and MD while the mice (APP/PS1 transgenic model and control) performed a T-maze spatial working memory task. The temporal dynamics of oscillatory activity and bidirectional information flow between mPFC and MD were assessed during the task phases. We mainly found a significant decrease in theta flow from mPFC to MD in APP/PS1 mice during retrieval. Our results indicate an important role of the mPFC-MD input for retrieval and the disrupted information transfer from mPFC to MD may be the underlying mechanism of working memory deficits in APP/PS1 mice.

Synaptic adhesion molecule protocadherin-γC5 mediates β-amyloid-induced neuronal hyperactivity and cognitive deficits in Alzheimer's disease.

Neuronal hyperactivity induced by β-amyloid (Aβ) is an early pathological feature in Alzheimer's disease (AD) and contributes to cognitive decline in AD progression. However, the underlying mechanisms are still unclear. Here, we revealed that Aβ increased the expression level of synaptic adhesion molecule protocadherin-γC5 (Pcdh-γC5) in a Ca2+ -dependent manner, associated with aberrant elevation of synapses in both Aβ-treated neurons invitro and the cortex of APP/PS1 mice invivo. By using Pcdhgc5 gene knockout mice, we demonstrated the critical function of Pcdh-γC5 in regulating neuronal synapse formation, synaptic transmission, and cognition. To further investigate the role of Pcdh-γC5 in AD pathogenesis, the aberrantly enhanced expression of Pcdh-γC5 in the brain of APP/PS1 mice was knocked down by shRNA. Downregulation of Pcdh-γC5 efficiently rescued neuronal hyperactivity and impaired cognition in APP/PS1 mice. Our findings revealed the pathophysiological role of Pcdh-γC5 in mediating Aβ-induced neuronal hyperactivity and cognitive deficits in AD and identified a novel mechanism underlying AD pathogenesis.

Human transdifferentiated neurons reveal lysosomal repair deficits in Alzheimer's disease

Human transdifferentiated neurons reveal lysosomal repair deficits in Alzheimer's disease

Activation of autophagy by Citri Reticulatae Semen extract ameliorates amyloid-beta-induced cell death and cognition deficits in Alzheimer's disease.

JOURNAL/nrgr/04.03/01300535-202419110-00027/figure1/v/2024-03-08T184507Z/r/image-tiff Amyloid-beta-induced neuronal cell death contributes to cognitive decline in Alzheimer's disease. Citri Reticulatae Semen has diverse beneficial effects on neurodegenerative diseases, including Parkinson's and Huntington's diseases, however, the effect of Citri Reticulatae Semen on Alzheimer's disease remains unelucidated. In the current study, the anti-apoptotic and autophagic roles of Citri Reticulatae Semen extract on amyloid-beta-induced apoptosis in PC12 cells were first investigated. Citri Reticulatae Semen extract protected PC12 cells from amyloid-beta-induced apoptosis by attenuating the Bax/Bcl-2 ratio via activation of autophagy. In addition, Citri Reticulatae Semen extract was confirmed to bind amyloid-beta as revealed by biolayer interferometry in vitro, and suppress amyloid-beta-induced pathology such as paralysis, in a transgenic Caenorhabditis elegans in vivo model. Moreover, genetically defective Caenorhabditis elegans further confirmed that the neuroprotective effect of Citri Reticulatae Semen extract was autophagy-dependent. Most importantly, Citri Reticulatae Semen extract was confirmed to improve cognitive impairment, neuronal injury and amyloid-beta burden in 3×Tg Alzheimer's disease mice. As revealed by both in vitro and in vivo models, these results suggest that Citri Reticulatae Semen extract is a potential natural therapeutic agent for Alzheimer's disease via its neuroprotective autophagic effects.

Development and evaluation of multi-functionalized sialic acid conjugated asiatic acid nanoconstruct to mitigate cognitive deficits in Alzheimer's disease.

Sialic acid (SA) serves a critical role in neuronal repair and cognitive functions. SA is a nine-carbon carboxylated sugar with a glycoconjugate cap that acts as a ligand and surface decoration with SA facilitates delivery to the target site. The present research aimed to develop SA surface modified AA nanostructured lipid carrier (NLCs) with carbodiimide conjugation method. Sterylamine, poloxamer 188 and tween 80 were used as surfactants and several characterization studies including, differential scanning calorimetry, fourier transform infrared spectroscopy and x-ray photon spectroscopy were analyzed. Further, in vitro, neuroprotective efficiency was evaluated in SH-SY5Y cells and hCMEC/D3 cells and found significant potential effects with the treatments of developed NLCs. Pharmacodynamics studies were also assessed in beta-amyloid-injected rats following quantification of Alzheimer's disease (AD) hallmarks like, Aβ(1-42), tau-protein, glycogen synthase kinase-3β levels, interleukin-6 and tumor necrosis factor-α for neuroinflammatory responses. Characterization studies revealed the conjugation on developed NLCs. The in vitro and in vivo results showed significant effects of SA decorated NLCs in reversing the damage by toxicant which was further characterized by the levels of neurotransmitters like acetylcholinesterase, butyrylcholinesterase. The results revealed significant (p < .05) refurbishment of cholinergic functions after 28 days of treatment of developed NLCs. These preclinical findings support the use of SA as a ligand to deliver the AA at targeted site as well as to mitigate the cognitive deficits in AD.

Selective induction of Rab9-dependent alternative mitophagy using a synthetic derivative of isoquinoline alleviates mitochondrial dysfunction and cognitive deficits in Alzheimer's disease models.

Rationale: Promotion of mitophagy is considered a promising strategy for the treatment of neurodegenerative diseases including Alzheimer's disease (AD). The development of mitophagy-specific inducers with low toxicity and defined molecular mechanisms is essential for the clinical application of mitophagy-based therapy. The aim of this study was to investigate the potential of a novel small-molecule mitophagy inducer, ALT001, as a treatment for AD. Methods: ALT001 was developed through chemical optimization of an isoquinolium scaffold, which was identified from a chemical library screening using a mitophagy reporter system. In vitro and in vivo experiments were conducted to evaluate the potential of ALT001 as a mitophagy-targeting therapeutic agent and to investigate the molecular mechanisms underlying ALT001-induced mitophagy. The therapeutic effect of ALT001 was assessed in SH-SY5Y cells expressing mutant APP and mouse models of AD (5×FAD and PS2APP) by analyzing mitochondrial dysfunction and cognitive defects. Results: ALT001 specifically induces mitophagy both in vitro and in vivo but is nontoxic to mitochondria. Interestingly, we found that ALT001 induces mitophagy through the ULK1-Rab9-dependent alternative mitophagy pathway independent of canonical mitophagy pathway regulators such as ATG7 and PINK1. Importantly, ALT001 reverses mitochondrial dysfunction in SH-SY5Y cells expressing mutant APP in a mitophagy-dependent manner. ALT001 induces alternative mitophagy in mice and restores the decreased mitophagy level in a 5×FAD AD model mouse. In addition, ALT001 reverses mitochondrial dysfunction and cognitive defects in the PS2APP and 5×FAD AD mouse models. AAV-mediated silencing of Rab9 in the hippocampus further confirmed that ALT001 exerts its therapeutic effect through alternative mitophagy. Conclusion: Our results highlight the therapeutic potential of ALT001 for AD via alleviation of mitochondrial dysfunction and indicate the usefulness of the ULK1-Rab9 alternative mitophagy pathway as a therapeutic target.

Intranasal CEPO-FC prevents attention deficits in streptozotocin-induced rat model of Alzheimer's disease: Focus on synaptic plasticity-related factors.

Alzheimer's disease remains an issue of great controversy due to its pathology. It is characterized by cognitive impairments and neuropsychiatric symptoms. The FDA approved medications for this disease, can only mitigate the symptoms. One reason for the lack of effective medications is the inaccessibility of the brain which is encompassed by the blood-brain barrier, making intranasal (IN) route of administration potentially advantageous. Male Wistar rats underwent stereotaxic surgery to induce an Alzheimer's disease model via intracerebroventricular (ICV) streptozotocin injection, and Carbamylated Erythropoietin-Fc (CEPO-FC), a derivative of Erythropoietin without its harmful characteristics, was administered intranasally for ten consecutive days. Cognition performance for memory and attention was assessed using the Novel Object Recognition Test and the Object-Based Attention Test respectively. Depression like behavior was evaluated using the Forced Swim Test. Western blotting was done on the extracted hippocampus to quantify STIM proteins. Calbindin, PSD-95, Neuroplastin, Synaptophysin and GAP-43 genes were assessed by Realtime PCR. Behavioral tests demonstrated that IN CEPO-FC could halt cognition deficits and molecular investigations showed that, STIM proteins were decreased in Alzheimer's model, and increased after IN CEPO-FC treatment. Calbindin and PSD-95 were downregulated in our disease model and upregulated when treated with IN CEPO-FC. While Neuroplastin, and GAP-43 expressions remained unchanged. This study suggests that IN CEPO-FC in low doses could be promising for improving cognition and synaptic plasticity deficits in Alzheimer's disease and since IN route of administration is a convenient way, choosing IN CEPO-FC for clinical trial might worth consideration. See also the graphical abstract(Fig. 1).

A ratiometric fluorescent probe revealing the abnormality of acetylated tau by visualizing polarity in Alzheimer's disease.

Abnormal neuronal polarity leads to early deficits in Alzheimer's disease (AD) by affecting the function of axons. Precise and rapid evaluation of polarity changes is very important for the early prevention and diagnosis of AD. However, due to the limitations of existing detection methods, the mechanism related to how neuronal polarity changes in AD is unclear. Herein, we reported a ratiometric fluorescent probe characterized by neutral molecule to disclose the polarity changes in nerve cells and the brain of APP/PS1 mice. Cy7-K showed a sensitive and selective ratiometric fluorescence response to polarity. Remarkably, unlike conventional intramolecular charge transfer fluorescent probes, the fluorescence quantum yield of Cy7-K in highly polar solvents is higher than that in low polar solvents due to the transition of neutral quinones to aromatic zwitterions. Using the ratiometric fluorescence imaging, we found that beta-amyloid protein (Aβ) inhibits the expression of histone deacetylase 6, thereby increasing the amount of acetylated Tau protein (AC-Tau) and ultimately enhancing cell polarity. There was a high correlation between polarity and AC-Tau. Furthermore, Cy7-K penetrated the blood-brain barrier to image the polarity of different brain regions and confirmed that APP/PS1 mice had higher polarity than Wild-type mice. The probe Cy7-K will be a promising tool for assessing the progression of AD development by monitoring polarity.

Memory encoding and retrieval by retrosplenial parvalbumin interneurons are impaired in Alzheimer’s disease model mice

Memory deficits in Alzheimer's disease (AD) show a strong link with GABAergic interneuron dysfunctions.1,2,3,4,5,6,7 The ensemble dynamics of GABAergic interneurons represent memory encoding and retrieval,8,9,10,11,12 but how GABAergic interneuron dysfunction affects inhibitory ensemble dynamics in AD is unknown. As the retrosplenial cortex (RSC) is critical for episodic memory13,14,15,16 and is affected by β-amyloid accumulation in early AD,17,18,19,20,21 we address this question by performing Ca2+ imaging in RSC parvalbumin (PV)-expressing interneurons during a contextual fear memory task in healthy control mice and the 5XFAD mouse model of AD. We found that populations of PV interneurons responsive to aversive electric foot shocks during contextual fear conditioning (shock-responsive) significantly decreased in the 5XFAD mice, indicating dysfunctions in the recruitment of memory-encoding PV interneurons. In the control mice, ensemble activities of shock-responsive PV interneurons were selectively upregulated during the freezing epoch of the contextual fear memory retrieval, manifested by synaptic potentiation of PV interneuron-mediated inhibition. However, such changes in ensemble dynamics during memory retrieval and synaptic plasticity were both absent in the 5XFAD mice. Optogenetic silencing of PV interneurons during contextual fear conditioning in the control mice mimicked the memory deficits in the 5XFAD mice, while optogenetic activation of PV interneurons in the 5XFAD mice restored memory retrieval. These results demonstrate the critical roles of contextual fear memory-encoding PV interneurons for memory retrieval. Furthermore, synaptic dysfunction of PV interneurons may disrupt the recruitment of PV interneurons and their ensemble dynamics underlying contextual fear memory retrieval, subsequently leading to memory deficits in AD.

Fastball ‐ a new functional biomarker of cognitive impairment

AbstractBackgroundFastball provides a new, rapid, objective EEG method for assessing cognitive function. Fastball is culturally, linguistically and educationally independent. Participants do not need to understand the task, or provide any response, and tasks take just minutes to complete. Fastball has recently been shown to be sensitive to memory deficits in Alzheimer’s disease (Stothart et al., Brain, 2021), and we present the latest findings in Mild Cognitive Impairment (MCI) patients.MethodHealthy older adult controls (n = 56, ACE‐III = 96+‐3) and MCI patients (n = 46, ACE‐III = 82+‐10) completed a Fastball task designed to measure their recognition memory at baseline and at 12 month follow up. All EEG data were collected in patients' homes using low‐cost portable EEG. They also completed the ACE‐III and the Delayed Match to Sample 48, a validated neuropsychological measure of recognition memory.ResultBetween group comparisons, controlling for individual differences in EEG response magnitude, showed amnestic MCI patients had significantly reduced Fastball responses compared to non‐amnestic MCI patients (p = .002) and healthy older adult controls (p = .005). Fastball scores correlated with the ACE‐III memory subscale (r(46) = .44, p = 0.002) and no other ACE‐III subscale, demonstrating sensitivity and specificity to memory dysfunction. Fastball scores also correlated with performance on the Delayed Match to Sample 48 abstract subscale (r(46) = .37, p = .011). 12 month follow up is underway and data will be presented at AAIC 2023.ConclusionFastball is a passive, rapid measure of memory dysfunction in Alzheimer’s disease that we have now demonstrated to be sensitive to early memory dysfunction in Mild Cognitive Impairment. Fastball data can be reliably collected in patients' homes using low‐cost portable EEG, and the approach holds great potential as a future diagnostic tool.

Fastball ‐ a new functional biomarker of cognitive impairment

AbstractBackgroundFastball provides a new, rapid, objective EEG method for assessing cognitive function. Fastball is culturally, linguistically and educationally independent. Participants do not need to understand the task, or provide any response, and tasks take just minutes to complete. Fastball has recently been shown to be sensitive to memory deficits in Alzheimer’s disease (Stothart et al., Brain, 2021), and we present the latest findings in Mild Cognitive Impairment (MCI) patients.MethodHealthy older adult controls (n = 56, ACE‐III = 96+‐3) and MCI patients (n = 46, ACE‐III = 82+‐10) completed a Fastball task designed to measure their recognition memory at baseline and at 12 month follow up. All EEG data were collected in patients' homes using low‐cost portable EEG. They also completed the ACE‐III and the Delayed Match to Sample 48, a validated neuropsychological measure of recognition memory.ResultBetween group comparisons, controlling for individual differences in EEG response magnitude, showed amnestic MCI patients had significantly reduced Fastball responses compared to non‐amnestic MCI patients (p = .002) and healthy older adult controls (p = .005). Fastball scores correlated with the ACE‐III memory subscale (r(46) = .44, p = 0.002) and no other ACE‐III subscale, demonstrating sensitivity and specificity to memory dysfunction. Fastball scores also correlated with performance on the Delayed Match to Sample 48 abstract subscale (r(46) = .37, p = .011). 12 month follow up is underway and data will be presented at AAIC 2023.ConclusionFastball is a passive, rapid measure of memory dysfunction in Alzheimer’s disease that we have now demonstrated to be sensitive to early memory dysfunction in Mild Cognitive Impairment. Fastball data can be reliably collected in patients' homes using low‐cost portable EEG, and the approach holds great potential as a future diagnostic tool.

Restoring Synaptic Function: How Intranasal Delivery of 3D-Cultured hUSSC Exosomes Improve Learning and Memory Deficits in Alzheimer's Disease.

Memory problems are often the first signs of cognitive impairment related to Alzheimer's disease (AD), and stem cells and stem cell-derived exosomes (EXOs) have been studied for their therapeutic potential to improve the disease signs. While many studies have shown the anti-inflammatory and immunomodulatory effects of stem cells and exosomes on improving memory in different AD models, there is still insufficient data to determine how they modulate neural plasticity to enhance spatial memory and learning ability. Therefore, we conducted a study to investigate the effects of exosomes derived from 3D-cultured human Unrestricted Somatic Stem Cells (hUSSCs) on spatial memory and neuroplasticity markers in a sporadic rat model of AD. Using male Wistar rats induced by intracerebral ventricle injection of streptozotocin, we demonstrated that intranasal administration of hUSSC-derived exosomes could decrease Aβ accumulation and improve learning and memory in the Morris water maze test. We also observed an increase in the expression of pre-synaptic and post-synaptic molecules involved in neuronal plasticity, including NMDAR1, integrin β1, synaptophysin, pPKCα, and GAP-43, in the hippocampus. Our findings suggest that intranasal administration of exosomes can ameliorate spatial learning and memory deficits in rats, at least in part, by increasing the expression of neuroplasticity proteins. These results may encourage researchers to further investigate the molecular pathways involved in memory improvement after stem cell and exosome therapy, with the goal of increasing the efficacy and safety of exosome-based treatments for AD.

Targeting dopamine transporter to ameliorate cognitive deficits in Alzheimer's disease.

Alzheimer's disease (AD) is characterized by the pathologic deposition of amyloid and neurofibrillary tangles in the brain, leading to neuronal damage and defective synapses. These changes manifest as abnormalities in cognition and behavior. The functional deficits are also attributed to abnormalities in multiple neurotransmitter systems contributing to neuronal dysfunction. One such important system is the dopaminergic system. It plays a crucial role in modulating movement, cognition, and behavior while connecting various brain areas and influencing other neurotransmitter systems, making it relevant in neurodegenerative disorders like AD and Parkinson's disease (PD). Considering its significance, the dopaminergic system has emerged as a promising target for alleviating movement and cognitive deficits in PD and AD, respectively. Extensive research has been conducted on dopaminergic neurons, receptors, and dopamine levels as critical factors in cognition and memory in AD. However, the exact nature of movement abnormalities and other features of extrapyramidal symptoms are not fully understood yet in AD. Recently, a previously overlooked element of the dopaminergic system, the dopamine transporter, has shown significant promise as a more effective target for enhancing cognition while addressing dopaminergic system dysfunction in AD.