The HOPE4MCI study: A randomized double-blind assessment of AGB101 for the treatment of MCI due to AD.

INTRODUCTION: In addition to the accumulation of amyloid plaques and neurofibrillary tangles, the presence of excess neural activity is a pathological hallmark of Alzheimer's disease (AD) and a prognostic indicator for progression of AD pathology and clinical/cognitive worsening in mild cognitive impairment due to Alzheimer's disease (MCI due to AD). The HOPE4MCI clinical study tested the efficacy of a therapeutic with demonstrated ability to normalize heightened neural activity in the hippocampus in a randomized controlled trial of 78 weeks duration in patients with MCI due to AD. METHODS: One hundred and sixty-four participants were randomized to placebo (n = 83) or AGB101 (n = 81), an extended-release formulation of low dose (220 mg) levetiracetam. The primary endpoint was the change in Clinical Dementia Rating Scale Sum of Boxes score (CDR-SB) comparing follow up at 18 months to baseline. The goal of the primary efficacy analysis was to estimate the difference between the AGB101 and placebo arms in the mean change of the primary endpoint. RESULTS: The mean change in CDR-SB was estimated to be 1.12 (95% confidence interval [CI]: 0.66, 1.69) for the AGB101 arm and 1.22 (95% CI: 0.75, 1.78) for the placebo arm. The estimated difference between arms is -0.10 (95% CI: -0.85, 0.58), which was not statistically significant. In a prespecified analysis, the difference was -0.45 (95% CI: -1.43, 0.53) for ApoE-4 noncarriers and -0.10 (95% CI: -0.92, 0.72) for apolipoprotein E (ApoE)-4 carriers. DISCUSSION: The possibility that ApoE-4 carriers and noncarriers will respond differently to therapeutic intervention is consistent with recently reported findings from biologics and the present results show further testing of AGB101 in patients with MCI due to AD who are noncarriers of the ApoeE-4 allele is warranted. Conclusions from the HOPE4MCI study are limited primarily due to the small sample size and results can only be regarded as a guide to future research.

Object-place-context learning impairment correlates with spatial learning impairment in aged Long-Evans rats.

The hippocampal formation is vulnerable to the process of normal aging. In humans, the extent of this age-related deterioration varies among individuals. Long-Evans rats replicate these individual differences as they age, and therefore they serve as a valuable model system to study aging in the absence of neurodegenerative diseases. In the Morris water maze, aged memory-unimpaired (AU) rats navigate to remembered goal locations as effectively as young rats and demonstrate minimal alterations in physiological markers of synaptic plasticity, whereas aged memory-impaired (AI) rats show impairments in both spatial navigation skills and cellular and molecular markers of plasticity. The present study investigates whether another cognitive domain is affected similarly to navigation in aged Long-Evans rats. We tested the ability of young, AU, and AI animals to recognize novel object-place-context (OPC) configurations and found that performance on the novel OPC recognition paradigm was significantly correlated with performance on the Morris water maze. In the first OPC test, young and AU rats, but not AI rats, successfully recognized and preferentially explored objects in novel OPC configurations. In a second test with new OPC configurations, all age groups showed similar OPC associative recognition memory. The results demonstrated similarities in the behavioral expression of associative, episodic-like memory between young and AU rats and revealed age-related, individual differences in functional decline in both navigation and episodic-like memory abilities.

Individual differences in age-related neurocognitive outcomes: within-subject assessment of memory for odors.

Cognitive decline is a common feature of aging, particularly in memory domains supported by the medial temporal lobe (MTL). The ability to identify intervention strategies to treat or prevent this decline is challenging due to substantial variability between adults in terms of age of onset, rate and severity of decline, and many factors that could influence cognitive reserve. These factors can be somewhat mitigated by use of within-subject designs. Aged outbred Long-Evans rats have proven useful for identifying translationally relevant substrates contributing to age-related decline in MTL-dependent memory. In this population, some animals show reliable impairment on MTL-dependent tasks while others perform within the range of young adult rats. However, currently there are relatively few within-subject behavior protocols for assessing MTL function over time, and most require extensive training and appetitive motivation for associative learning. In the current study, we aimed to test whether water maze learning impairments in aged Long-Evans rats would be predictive of delayed recognition memory impairments and whether these odor memory impairments would be stable within subjects over multiple rounds of testing.

mGluR-dependent plasticity in rodent models of Alzheimer's disease.

Long-term potentiation (LTP) and depression (LTD) are currently the most comprehensive models of synaptic plasticity models to subserve learning and memory. In the CA1 region of the hippocampus LTP and LTD can be induced by the activation of either NMDA receptors or mGluR5 metabotropic glutamate receptors. Alterations in either form of synaptic plasticity, NMDAR-dependent or mGluR-dependent, are attractive candidates to contribute to learning deficits in conditions like Alzheimer's disease (AD) and aging. Research, however, has focused predominantly on NMDAR-dependent forms of LTP and LTD. Here we studied age-associated changes in mGluR-dependent LTP and LTD in the APP/PS1 mouse model of AD and in Octodon degu, a rodent model of aging that exhibits features of AD. At 2 months of age, APP/PS1 mouse exhibited robust mGluR-dependent LTP and LTD that was completely lost by the 8th month of age. The expression of mGluR protein in the hippocampus of APP/PS1 mice was not affected, consistent with previous findings indicating the uncoupling of the plasticity cascade from mGluR5 activation. In O. degu, the average mGluR-LTD magnitude is reduced by half by the 3 rd year of age. In aged O. degu individuals, the reduced mGluR-LTD correlated with reduced performance in a radial arm maze task. Altogether these findings support the idea that the preservation of mGluR-dependent synaptic plasticity is essential for the preservation of learning capacity during aging.

Loss of functional heterogeneity along the CA3 transverse axis in aging.

Age-related deficits in pattern separation have been postulated to bias the output of hippocampal memory processing toward pattern completion, which can cause deficits in accurate memory retrieval. Although the CA3 region of the hippocampus is often conceptualized as a homogeneous network involved in pattern completion, growing evidence demonstrates a functional gradient in CA3 along the transverse axis, as pattern-separated outputs (dominant in the more proximal CA3) transition to pattern-completed outputs (dominant in the more distal CA3). We examined the neural representations along the CA3 transverse axis in young (Y), aged memory-unimpaired (AU), and aged memory-impaired (AI) rats when different changes were made to the environment. Functional heterogeneity in CA3 was observed in Y and AU rats when the environmental similarity was high (altered cues or altered environment shapes in the same room), with more orthogonalized representations in proximal CA3 than in distal CA3. In contrast, AI rats showed reduced orthogonalization in proximal CA3 but showed normal (i.e., generalized) representations in distal CA3, with little evidence of a functional gradient. Under experimental conditions when the environmental similarity was low (different rooms), representations in proximal and distal CA3 remapped in all rats, showing that CA3 of AI rats is able to encode distinctive representations for inputs with greater dissimilarity. These experiments support the hypotheses that the age-related bias toward hippocampal pattern completion is due to the loss in AI rats of the normal transition from pattern separation to pattern completion along the CA3 transverse axis.

Lateral entorhinal cortex dysfunction in amnestic mild cognitive impairment.

The entorhinal cortex is the site of some of the earliest pathological changes in Alzheimer's disease, including neuronal, synaptic and volumetric loss. Specifically, the lateral entorhinal cortex shows significant accumulation of tau neurofibrillary tangles in the amnestic mild cognitive impairment (aMCI) phase of Alzheimer's disease. Although decreased entorhinal cortex activation has been observed in patients with aMCI in the context of impaired memory function, it remains unclear if functional changes in the entorhinal cortex can be localized to the lateral or medial entorhinal cortex. To assess subregion specific changes in the lateral and medial entorhinal cortex, patients with aMCI and healthy aged-matched control participants underwent high-resolution structural and functional magnetic resonance imaging. Patients with aMCI showed significantly reduced volume, and decreased activation localized to the lateral entorhinal cortex but not the medial entorhinal cortex. These results show that structural and functional changes associated with impaired memory function differentially engage the lateral entorhinal cortex in patients with aMCI, consistent with the locus of early disease related pathology.

Individual differences in neurocognitive aging in outbred male and female long-evans rats.

Individual differences in biology as well as experience and exposures throughout life may contribute risk or resilience to neurocognitive decline in aging. To investigate the role of sex as a biological variable in cognitive function due to normal aging, we used substantial cohorts of healthy male and female aged outbred rats maintained under similar conditions throughout life to assess whether both sexes display a similar distribution of individual differences in behavioral performance using a water maze task optimized to assess hippocampal-dependent cognition in aging. We found both aged male and female rats performed poorer than young adults overall, but with no performance differences between sex in either young adults or aged groups in memory probe tests. In addition, aged male and female rats had similar distributions of individual differences such that the same proportion of male and female performed on par with (intact memory) or outside of (impaired memory) the benchmark of young rats of their respective sex. The data support the use of this outbred model with biological diversity to study the neurobiology of aging trajectories for variation in cognitive outcomes in both male and females. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

All-or-none disconnection of pyramidal inputs onto parvalbumin-positive interneurons gates ocular dominance plasticity.

Disinhibition is an obligatory initial step in the remodeling of cortical circuits by sensory experience. Our investigation on disinhibitory mechanisms in the classical model of ocular dominance plasticity uncovered an unexpected form of experience-dependent circuit plasticity. In the layer 2/3 of mouse visual cortex, monocular deprivation triggers a complete, "all-or-none," elimination of connections from pyramidal cells onto nearby parvalbumin-positive interneurons (Pyr→PV). This binary form of circuit plasticity is unique, as it is transient, local, and discrete. It lasts only 1 d, and it does not manifest as widespread changes in synaptic strength; rather, only about half of local connections are lost, and the remaining ones are not affected in strength. Mechanistically, the deprivation-induced loss of Pyr→PV is contingent on a reduction of the protein neuropentraxin2. Functionally, the loss of Pyr→PV is absolutely necessary for ocular dominance plasticity, a canonical model of deprivation-induced model of cortical remodeling. We surmise, therefore, that this all-or-none loss of local Pyr→PV circuitry gates experience-dependent cortical plasticity.

Effect of aging differs for memory of object identity and object position within a spatial context.

There has been considerable focus on investigating age-related memory changes in cognitively healthy older adults, in the absence of neurodegenerative disorders. Previous studies have reported age-related domain-specific changes in older adults, showing increased difficulty encoding and processing object information but minimal to no impairment in processing spatial information compared with younger adults. However, few of these studies have examined age-related changes in the encoding of concurrently presented object and spatial stimuli, specifically the integration of both spatial and nonspatial (object) information. To more closely resemble real-life memory encoding and the integration of both spatial and nonspatial information, the current study developed a new experimental paradigm with novel environments that allowed for the placement of different objects in different positions within the environment. The results show that older adults have decreased performance in recognizing changes of the object position within the spatial context but no significant differences in recognizing changes in the identity of the object within the spatial context compared with younger adults. These findings suggest there may be potential age-related differences in the mechanisms underlying the representations of complex environments and furthermore, the integration of spatial and nonspatial information may be differentially processed relative to independent and isolated representations of object and spatial information.

Spatial learning in male and female Long-Evans rats.

Male and female Long-Evans rats were tested in the Morris water maze at 6 months of age. A place training procedure, in which rats learned the position of a camouflaged platform, was followed by cue training, in which rats escaped to a visible platform. No sex difference was found in place learning ability. Search accuracy on probe trials, when the platform was unavailable, was also equivalent for the male and female groups. These results contrast with previous studies of rodents at younger ages, which have reported a male advantage in spatial learning. It is suggested that the age at which rats are assessed may be an important factor, possibly reflecting a different course in the relatively protracted maturation of the hippocampus in male and female rats. The results of this investigation are also discussed with reference to studies of sex differences for spatial abilities in humans. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Heterogeneity of Age-Related Neural Hyperactivity along the CA3 Transverse Axis.

Age-related memory deficits are correlated with neural hyperactivity in the CA3 region of the hippocampus. Abnormal CA3 hyperactivity in aged rats has been proposed to contribute to an imbalance between pattern separation and pattern completion, resulting in overly rigid representations. Recent evidence of functional heterogeneity along the CA3 transverse axis suggests that proximal CA3 supports pattern separation while distal CA3 supports pattern completion. It is not known whether age-related CA3 hyperactivity is uniformly represented along the CA3 transverse axis. We examined the firing rates of CA3 neurons from young and aged, male, Long-Evans rats along the CA3 transverse axis. Consistent with prior studies, young CA3 cells showed an increasing gradient in mean firing rate from proximal to distal CA3. However, aged CA3 cells showed an opposite, decreasing trend, in that CA3 cells in aged rats were hyperactive in proximal CA3, but possibly hypoactive in distal CA3, compared with young (Y) rats. We suggest that, in combination with altered inputs from the entorhinal cortex and dentate gyrus (DG), the proximal CA3 region of aged rats may switch from its normal function that reflects the pattern separation output of the DG and instead performs a computation that reflects an abnormal bias toward pattern completion. In parallel, distal CA3 of aged rats may create weaker attractor basins that promote abnormal, bistable representations under certain conditions.SIGNIFICANCE STATEMENT Prior work suggested that age-related CA3 hyperactivity enhances pattern completion, resulting in rigid representations. Implicit in prior studies is the notion that hyperactivity is present throughout a functionally homogeneous CA3 network. However, more recent work has demonstrated functional heterogeneity along the CA3 transverse axis, in that proximal CA3 is involved in pattern separation and distal CA3 is involved in pattern completion. Here, we show that age-related hyperactivity is present only in proximal CA3, with potential hypoactivity in distal CA3. This result provides new insight in the role of CA3 in age-related memory impairments, suggesting that the rigid representations in aging result primarily from dysfunction of computational circuits involving the dentate gyrus (DG) and proximal CA3.

Decreased investigatory head scanning during exploration in learning-impaired, aged rats.

"Head scanning" is an investigatory behavior that has been linked to spatial exploration and the one-trial formation or strengthening of place cells in the hippocampus. Previous studies have demonstrated that a subset of aged rats with normal spatial learning performance show head scanning rates during a novel, local-global cue-mismatch manipulation that are similar to those of young rats. However, these aged rats demonstrated different patterns of expression of neural activity markers in brain regions associated with spatial learning, perhaps suggesting neural mechanisms that compensate for age-related brain changes. These prior studies did not investigate the head scanning properties of aged rats that had spatial learning impairments. The present study analyzed head scanning behavior in young, aged-unimpaired, and aged-impaired Long Evans rats. Aged-impaired rats performed the head scan behavior at a lower rate than the young rats. These results suggest that decreased attention to spatial landmarks may be a contributing factor to the spatial learning deficits shown by the aged-impaired rats.

Using internal memory representations in associative learning to study hallucination-like phenomenon.

Studies of Pavlovian conditioning have enriched our understanding of how relations among events can adaptively guide behavior through the formation and use of internal mental representations. In this review, we illustrate how internal representations flexibly integrate new updated information in reinforcer revaluation to influence relationships to impact actions and outcomes. We highlight representation-mediated learning to show the similarities in properties and functions between internally generated and directly activated representations, and how normal perception of internal representations could contribute to hallucinations. Converging evidence emerges from recent behavioral and neural activation studies using animal models of schizophrenia as well as clinical studies in patients to support increased tendencies in these populations to evoke internal representations from prior associative experience that approximate hallucination-like percepts. The heightened propensity is dependent on dopaminergic activation which is known to be sensitive to hippocampal overexcitability, a condition that has been observed in patients with psychosis. This presents a network that overlaps with cognitive neural circuits and offers a fresh approach for the development of therapeutic interventions targeting psychosis.

Afterhyperpolarization amplitude in CA1 pyramidal cells of aged Long-Evans rats characterized for individual differences.

Altered neural excitability is considered a prominent contributing factor to cognitive decline during aging. A clear example is the excess neural activity observed in several temporal lobe structures of cognitively impaired older individuals in rodents and humans. At a cellular level, aging-related changes in mechanisms regulating intrinsic excitability have been well examined in pyramidal cells of the CA1 hippocampal subfield. Studies in the inbred Fisher 344 rat strain document an age-related increase in the slow afterhyperpolarization (AHP) that normally occurs after a burst of action potentials, and serves to reduce subsequent firing. We evaluated the status of the AHP in the outbred Long-Evans rat, a well-established model for studying individual differences in neurocognitive aging. In contrast to the findings reported in the Fisher 344 rats, in the Long-Evan rats we detected a selective reduction in AHP in cognitively impaired aged individuals. We discuss plausible scenarios to account for these differences and also discuss possible implications of these differences.

Comparison of male and female patients with amnestic mild cognitive impairment: Hippocampal hyperactivity and pattern separation memory performance.

INTRODUCTION: Recent studies have suggested that sex confers a differential risk in the incidence and prevalence of Alzheimer's disease (AD) thought to be the result of the increased lifespan of women compared to men. However, other factors may contribute to risk beyond the effect of increased lifespan. METHODS: This study examined the role of sex in hippocampal hyperactivity localized to the dentate gyrus (DG)/CA3 subregion of the hippocampus and associated episodic memory impairment, considered a characteristic feature of AD in patients with amnestic mild cognitive impairment (aMCI). RESULTS: While participants with aMCI showed decreased memory performance and increased activation in the DG/CA3 when compared to controls, no significant sex-related differences in performance or activation were observed. DISCUSSION: Although other factors may contribute to sex differences in the prevalence of AD these findings show that no sex differences are observed in hippocampal dysfunction characteristic of the aMCI phase of AD.

Engagement of the Lateral Habenula in the Association of a Conditioned Stimulus with the Absence of an Unconditioned Stimulus.

Neurons in the lateral habenula (LHb) are activated by reward omission and inhibited by reward delivery-reward processing functions opposite those of midbrain dopaminergic neurons. To further explore this, we examined the role of the LHb in associating a conditioned stimulus (CS) with the absence of an unconditioned stimulus (US) in an appetitive Pavlovian-conditioning paradigm. Rats underwent training in which a CS (light) was either paired (100% CS-US contingency) or unpaired (0% CS-US contiguity and negative contingency) with an US (food). Rats in the paired group exhibited steady acquisition of conditioned food-cup behaviors, while rats in the unpaired group showed low levels of response throughout training. After training, c-Fos levels were measured in the LHb, substantia nigra pars compacta (SNc), and ventral tegmental area (VTA) of rats in all groups. c-Fos levels were higher in the SNc/VTA of the paired group and the LHb of the unpaired group compared with the group with graded excitatory conditioning due to 50% of the CSs paired with USs and a low rate of USs presented during the intertrial interval and control groups for non-associative factors. The number of c-Fos-positive signals in LHb neurons projecting to dopaminergic midbrain neurons was higher in the unpaired group than in the paired group. Excitotoxic LHb lesions did not affect the acquisition of conditioned behaviors in the association of a CS with the presence or absence of an US. Significant increases in the numbers of c-Fos-positive neurons in the unpaired group suggest that LHb neurons engage in the process that associates a CS with the absence of an US.

Significance of inhibitory recruitment in aging with preserved cognition: limiting gamma-aminobutyric acid type A α5 function produces memory impairment.

Numerous aging studies have identified a shift in the excitatory/inhibitory (E/I) balance with heightened hippocampal neural activity associated with age-related memory impairment across species, including rats, monkeys, and humans. Neurobiological investigations directed at the hippocampal formation have demonstrated that unimpaired aged rats performing on par with young adult rats in a spatial memory task exhibit gene expression profiles, mechanisms for plasticity, and altered circuit/network function, which are distinct from younger rats. Particularly striking is a convergence of observational evidence that aged unimpaired rats augment recruitment of mechanisms associated with neural inhibition, a finding that may represent an adaptive homeostatic adjustment necessary to maintain neural plasticity and memory function in aging. In this study, we test the effect of limiting inhibition via administration of TB21007, a negative allosteric modulator of the alpha 5 subtype of gamma-aminobutyric acid type A α5 receptor, on a radial arm maze assessment of memory function. Impaired memory performance produced by this intervention in otherwise high-performing aged rats supports an adaptive role for gamma-aminobutyric acid in the functional maintenance of intact cognition in aging.

What are the threats to successful brain and cognitive aging?

The structure and function of the brain change over the life span. Aged brains often accumulate pathologic lesions, such as amyloid plaques and tau tangles, which lead to diminished cognitive ability in some, but not all, individuals. The basis of this vulnerability and resilience is unclear. Age-related changes can alter neural firing patterns and ability to form new memories. Risk factors for cognitive decline include male sex and apolipoprotein E genotype. Physical activity seems to be protective against cognitive decline. Longitudinal studies have shown that, although the onset of amyloid pathology and associated cognitive decline can vary greatly, once it begins, the rate of deposition is similar among affected individuals. This session of the Cognitive Aging Summit III explored fixed and modifiable factors that can threaten cognitive function in aging adults and approaches to modulate at least some of these risks.

Reduced cognitive performance in aged rats correlates with increased excitation/inhibition ratio in the dentate gyrus in response to lateral entorhinal input.

Aging often impairs cognitive functions associated with the medial temporal lobe (MTL). Anatomical studies identified the layer II pyramidal cells of the lateral entorhinal cortex (LEC) as one of the most vulnerable elements within the MTL. These cells provide a major excitatory input to the dentate gyrus hippocampal subfield through synapses onto granule cells and onto local inhibitory interneurons, and a fraction of these contacts are lost in aged individuals with impaired learning. Using optogenetics, we evaluated the functional status of the remaining inputs in an outbred rat model of aging that distinguishes between learning-impaired and learning-unimpaired individuals. We found that aging affects the presynaptic and postsynaptic strength of the LEC inputs onto granule cells. However, the magnitude of these changes was similar in impaired and unimpaired rats. In contrast, the recruitment of inhibition by LEC activation was selectively reduced in the aged impaired subjects. These findings are consistent with the notion that the preservation of an adequate balance of excitation and inhibition is crucial to maintaining proficient memory performance during aging.