Present and prospective clinical therapeutic regimens for Alzheimer’s disease

Alzheimer’s disease (AD) is an incurable neurodegenerative disorder that produces cognitive impairments that increase in severity as the disease progresses. The clinical symptoms are related to the presence of neuritic plaques and neurofibrillary tangles in the cerebral cortex which represent the pathophysiological hallmarks of AD. The debilitating nature of the disease can result in clinical burden for the patient, emotional strain for those that care for patients with Alzheimer’s, and significant financial burden to society. The goals of current treatments, such as cholinesterase inhibitors and N-methyl-D-aspartate receptor antagonist, are to reduce the severity or slow the progression of cognitive symptoms. Although these treatments have demonstrated modest clinical benefit, they are unable to prevent, prohibit, or reverse the underlying pathophysiology of AD. Considerable progress has been made toward the development of disease-modifying treatments. Treatments currently under development mainly target the production, aggregation, and removal of existing amyloid β-peptide aggregates which are believed to instigate the overall development of the neuropathology. Additional strategies that target tau pathology are being studied to promote neural protection against AD pathology. The current research has continued to expand our knowledge toward the development of disease modifying Alzheimer’s therapies; however, no specific treatment strategy capable of demonstrating empirical efficacy and safety has yet to emerge.     

Cognitive impairment and Alzheimer’s disease: Links with oxidative stress and cholesterol metabolism

Oxidative stress has been implicated in the progression of a number of neurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s disease and amyotrophic lateral sclerosis. We carried out an in-depth study of cognitive impairment and its relationships with oxidative stress markers such as ferric-reducing ability of plasma (FRAP), plasma malondialdehyde and total antioxidative capacity (TAC), as well as cholesterol parameters, in two subsets of subjects, AD patients (n = 59) and a control group of neurologically normal subjects (n = 29), attending the University Hospital Salvador in Santiago, Chile. Cognitive impairment was assessed by a set of neuropsychological tests (Mini-Mental State Examination, Boston Naming Test, Ideomotor Praxia by imitation, Semantic Verbal Fluency of animals or words with initial A, Test of Memory Alteration, Frontal Assessment Battery), while the levels of those oxidative stress markers and cholesterol metabolism parameters were determined according with standard bioassays in fresh plasma samples of the two subgroups of patients. No significant differences were observed when the cholesterol parameters (low-, high-density lipoprotein, total cholesterol) of the AD group were compared with normal controls. Interestingly, a correlation was evidenced when the levels of cognitive impairment were analyzed with respect to the plasma antioxidant capacity (AOC) of patients. In this context, the subset of subjects exhibiting cognitive impairment were divided into two subgroups according with their Global Dementia Scale performance: a subgroup with mild AD and a subgroup with moderate to severe AD. Significant differences in AOC were found between subgroups. The different correlations between cognitive impairment of subgroups of subjects with the oxidative stress profile are discussed in the context of AD pathogenesis.     

CSF tau protein and FDG PET in patients with aging-associated cognitive decline and Alzheimer’s disease

Introduction

In Alzheimer’s disease (AD), accelerated neurofibrillary tangle formation occurs which is associated with increased tau protein release into the cerebrospinal fluid (CSF). Recent studies found significantly increased CSF tau already in patients at risk of developing AD, indicating its potential as a biochemical marker of AD. Cerebral glucose metabolism is reduced in frontotemporoparietal and cingulate cortices in patients with mild AD. However, few studies have investigated CSF tau protein and cerebral glucose metabolism changes in patients at risk to develop AD.

Methods

48 patients with AD, 88 patients with aging-associated cognitive decline (AACD), and 39 healthy controls were included. In all participants, CSF levels of tau were determined by ELISA at baseline and compared between the diagnostic groups. 14 AACD patients and 14 controls underwent ¹⁸F-fluorodeoxyglucose positron emission tomography (FDG PET).

Results

AD patients showed the highest CSF tau levels compared with AACD patients and controls. AACD patients had significantly higher tau levels than the controls but lower than the AD patients. AACD patients were characterized by reduced glucose metabolism in bilateral middle temporal cortex, left posterior cingulate cortex, right angular gyrus, and right precuneus compared with controls.

Conclusion

In conclusion, our findings reflect and confirm the clinical judgment of an incipient neurodegenerative disorder in a considerable portion of AACD patients. In patients with AACD, CSF tau levels and cerebral glucose metabolism show an altered pattern comparable with that found in AD and thus may facilitate early diagnosis.     

Diffusion tensor imaging investigations in Alzheimer’s disease: the resurgence of white matter compromise in the cortical dysfunction of the aging brain

Diffusion tensor imaging (DTI) is a sophisticated MRI-based neuroimaging technique that enables in vivo quantification of differences in molecular diffusion at the cellular level. Owing to the highly directional architecture of white matter (WM), DTI is providing important clues of the structure and geometric organization of this neural compartment. Since DTI can detect changes even in the case of radiologically “normal” appearing WM, researchers are using the technique for the study of WM integrity at the initial stages of the most common neurodegenerative disorders. Along with a well characterized cortical pathology (neuritic plaques and intracellular neurofibrillary tangles), WM changes have been also demonstrated in Alzheimer’s disease (AD). However, these changes had been for years found nonliable in the onset and progress of AD, basically due to lack of incriminatory evidence. The use of novel tools such as DTI has enabled the anatomical distribution of WM microstructural damage in the prodromal stages of AD to be gauged and determined, granting a long-delayed protagonic role to WM in the natural history of this highly prevalent neurodegenerative condition.     

Cerebrovascular phenotypes in mouse models of Alzheimer’s disease

Alzheimer’s disease (AD) is a devastating neurological degenerative disorder and is the most common cause of dementia in the elderly. Clinically, AD manifests with memory and cognitive decline associated with deposition of hallmark amyloid beta (Aβ) plaques and neurofibrillary tangles (NFTs). Although the mechanisms underlying AD remains unclear, two hypotheses have been proposed. The established amyloid hypothesis states that Aβ accumulation is the basis of AD and leads to formation of NFTs. In contrast, the two-hit vascular hypothesis suggests that early vascular damage leads to increased accumulation of Aβ deposits in the brain. Multiple studies have reported significant morphological changes of the cerebrovasculature which can result in severe functional deficits. In this review, we delve into known structural and functional vascular alterations in various mouse models of AD and the cellular and molecular constituents that influence these changes to further disease progression. Many studies shed light on the direct impact of Aβ on the cerebrovasculature and how it is disrupted during the progression of AD. However, more research directed towards an improved understanding of how the cerebrovasculature is modified over the time course of AD is needed prior to developing future interventional strategies.     

Changes in caregiver burden among informal caregivers of stroke patients in Mongolia

Background: Modern therapeutics and health care improvements prolong stroke patients’ survival; however, the degree of disability remains high. Stroke survivors often require caregivers, particularly in the first year after the onset of the stroke. Longitudinal assessment of and factors associated with caregiver burden (CGB) among caregivers of stroke patients has been scarcely discussed. This study aimed to define the changes in CGB in the first year of caregiving among the caregivers of stroke patients and to identify associated factors.

Methods: A prospective, multi-centered observational study was conducted in nine public hospitals in Mongolia. We used the Montgomery CGB Scale for assessing CGB, and repeated the assessment after 1 year. Stroke patient characteristics were included in the analyses. Multinomial logistic regressions were conducted to analyze changes in CGB.

Results: A paired t-test analysis revealed that demand burden increased (from 12.61 to 11.50, p = 0.034), whereas stress burden decreased (from 10.69 to 11.60, p = 0.016). Although objective burden decreased, the difference was not significant. Factors associated with these changes in CGB were the caregiver’s marital status, the caregiver’s relationship with the patient, financial difficulties, and the patient’s sex and dependency.

Discussion: The information on factors predicting changes in CGB in the first year of caregiving provided in this study suggests that social or financial support can assist in reducing CGB among the caregivers of post-stroke patients.     

Estrogen receptor-mediated neuroprotection: The role of the Alzheimer’s disease-related gene seladin-1

Experimental evidence supports a protective role of estrogen in the brain. According to the fact that Alzheimer’s disease (AD) is more common in postmenopausal women, estrogen treatment has been proposed. However, there is no general consensus on the beneficial effect of estrogen or selective estrogen receptor modulators in preventing or treating AD. It has to be said that several factors may markedly affect the efficacy of the treatment. A few years ago, the seladin-1 gene (for selective Alzheimer’s disease indicator-1) has been isolated and found to be down-regulated in brain regions affected by AD. Seladin-1 has been found to be identical to the gene encoding the enzyme 3-beta-hydroxysterol delta-24-reductase, involved in the cholesterol biosynthetic pathway, which confers protection against β-amyloid-mediated toxicity and from oxidative stress, and is an effective inhibitor of caspase-3 activity, a key mediator of apoptosis. Interestingly, we found earlier that the expression of this gene is up-regulated by estrogen. Furthermore, our very recent data support the hypothesis that seladin-1 is a mediator of the neuroprotective effects of estrogen. This review will summarize the current knowledge regarding the neuroprotective effects of seladin-1 and the relationship between this protein and estrogen.     

Illuminating Neural Circuits in Alzheimer’s Disease

Alzheimer’s disease (AD) is the most common neurodegenerative disorder and there is currently no cure. Neural circuit dysfunction is the fundamental mechanism underlying the learning and memory deficits in patients with AD. Therefore, it is important to understand the structural features and mechanisms underlying the deregulated circuits during AD progression, by which new tools for intervention can be developed. Here, we briefly summarize the most recently established cutting-edge experimental approaches and key techniques that enable neural circuit tracing and manipulation of their activity. We also discuss the advantages and limitations of these approaches. Finally, we review the applications of these techniques in the discovery of circuit mechanisms underlying β-amyloid and tau pathologies during AD progression, and as well as the strategies for targeted AD treatments.     

Microvessel occlusions alter amyloid-beta plaque morphology in a mouse model of Alzheimer’s disease

Vascular dysfunction is correlated to the incidence and severity of Alzheimer’s disease. In a mouse model of Alzheimer’s disease (APP/PS1) using in vivo, time-lapse, multiphoton microscopy, we found that occlusions of the microvasculature alter amyloid-beta (Aβ) plaques. We used several models of vascular injury that varied in severity. Femtosecond laser-induced occlusions in single capillaries generated a transient increase in small, cell-sized, Aβ deposits visualized with methoxy-X04, a label of fibrillar Aβ. After occlusions of penetrating arterioles, some plaques changed morphology, while others disappeared, and some new plaques appeared within a week after the lesion. Antibody labeling of Aβ revealed a transient increase in non-fibrillar Aβ one day after the occlusion that coincided with the disappearance of methoxy-X04-labeled plaques. Four days after the lesion, anti-Aβ labeling decreased and only remained in patches unlabeled by methoxy-X04 near microglia. Histology in two additional models, sparse embolic occlusions from intracarotid injections of beads and infarction from photothrombosis, demonstrated increased labeling intensity in plaques after injury. These results suggest that microvascular lesions can alter the deposition and clearance of Aβ and confirm that Aβ plaques are dynamic structures, complicating the interpretation of plaque burden as a marker of Alzheimer’s disease progression.     

Neuropsychiatric symptoms in Alzheimer’s disease

Neuropsychiatric symptoms (NPS) are core features of Alzheimer’s disease and related dementias. Once thought to emerge primarily in people with late-stage disease, these symptoms are currently known to manifest commonly in very early disease and in prodromal phases, such as mild cognitive impairment. Despite decades of research, reliable treatments for dementia-associated NPS have not been found, and those that are in widespread use present notable risks for people using these medications. An Alzheimer’s Association Research Roundtable was convened in the spring of 2010 to review what is known about NPS in Alzheimer’s disease, to discuss classification and underlying neuropathogenesis and vulnerabilities, and to formulate recommendations for new approaches to tailored therapeutics.     

The neuroprotective effects of oxygen therapy in Alzheimer’s disease: a narrative review

Alzheimer’s disease (AD) is a degenerative neurological disease that primarily affects the elderly. Drug therapy is the main strategy for AD treatment, but current treatments suffer from poor efficacy and a number of side effects. Non-drug therapy is attracting more attention and may be a better strategy for treatment of AD. Hypoxia is one of the important factors that contribute to the pathogenesis of AD. Multiple cellular processes synergistically promote hypoxia, including aging, hypertension, diabetes, hypoxia/obstructive sleep apnea, obesity, and traumatic brain injury. Increasing evidence has shown that hypoxia may affect multiple pathological aspects of AD, such as amyloid-beta metabolism, tau phosphorylation, autophagy, neuroinflammation, oxidative stress, endoplasmic reticulum stress, and mitochondrial and synaptic dysfunction. Treatments targeting hypoxia may delay or mitigate the progression of AD. Numerous studies have shown that oxygen therapy could improve the risk factors and clinical symptoms of AD. Increasing evidence also suggests that oxygen therapy may improve many pathological aspects of AD including amyloid-beta metabolism, tau phosphorylation, neuroinflammation, neuronal apoptosis, oxidative stress, neurotrophic factors, mitochondrial function, cerebral blood volume, and protein synthesis. In this review, we summarized the effects of oxygen therapy on AD pathogenesis and the mechanisms underlying these alterations. We expect that this review can benefit future clinical applications and therapy strategies on oxygen therapy for AD.     

Extracellular vesicles in Alzheimer’s disease: from pathology to therapeutic approaches

Alzheimer’s disease is a progressive and fatal neurodegenerative disorder that starts many years before the onset of cognitive symptoms. Identifying novel biomarkers for Alzheimer’s disease has the potential for patient risk stratification, early diagnosis, and disease monitoring in response to therapy. A novel class of biomarkers is extracellular vesicles given their sensitivity and specificity to specific diseases. In addition, extracellular vesicles can be used as novel biological therapeutics given their ability to efficiently and functionally deliver therapeutic cargo. This is critical given the huge unmet need for novel treatment strategies for Alzheimer’s disease. This review summarizes and discusses the most recent findings in this field.     

Causes and consequences of baseline cerebral blood flow reductions in Alzheimer’s disease

Reductions of baseline cerebral blood flow (CBF) of ∼10–20% are a common symptom of Alzheimer’s disease (AD) that appear early in disease progression and correlate with the severity of cognitive impairment. These CBF deficits are replicated in mouse models of AD and recent work shows that increasing baseline CBF can rapidly improve the performance of AD mice on short term memory tasks. Despite the potential role these data suggest for CBF reductions in causing cognitive symptoms and contributing to brain pathology in AD, there remains a poor understanding of the molecular and cellular mechanisms causing them. This review compiles data on CBF reductions and on the correlation of AD-related CBF deficits with disease comorbidities (e.g. cardiovascular and genetic risk factors) and outcomes (e.g. cognitive performance and brain pathology) from studies in both patients and mouse models, and discusses several potential mechanisms proposed to contribute to CBF reductions, based primarily on work in AD mouse models. Future research aimed at improving our understanding of the importance of and interplay between different mechanisms for CBF reduction, as well as at determining the role these mechanisms play in AD patients could guide the development of future therapies that target CBF reductions in AD.     

A White Matter Connection of Schizophrenia and Alzheimer’s Disease

Schizophrenia (SZ) is a severe psychiatric illness associated with an elevated risk for developing Alzheimer’s disease (AD). Both SZ and AD have white matter abnormalities and cognitive deficits as core disease features. We hypothesized that aging in SZ patients may be associated with the development of cerebral white matter deficit patterns similar to those observed in AD. We identified and replicated aging-related increases in the similarity between white matter deficit patterns in patients with SZ and AD. The white matter “regional vulnerability index” (RVI) for AD was significantly higher in SZ patients compared with healthy controls in both the independent discovery (Cohen’s d = 0.44, P = 1·10^–5, N = 173 patients/230 control) and replication (Cohen’s d = 0.78, P = 9·10^–7, N = 122 patients/64 controls) samples. The degree of overlap with the AD deficit pattern was significantly correlated with age in patients (r = .21 and .29, P < .01 in discovery and replication cohorts, respectively) but not in controls. Elevated RVI-AD was significantly associated with cognitive measures in both SZ and AD. Disease and cognitive specificities were also tested in patients with mild cognitive impairment and showed intermediate overlap. SZ and AD have diverse etiologies and clinical courses; our findings suggest that white matter deficits may represent a key intersecting point for these 2 otherwise distinct diseases. Identifying mechanisms underlying this white matter deficit pattern may yield preventative and treatment targets for cognitive deficits in both SZ and AD patients.