Current Alzheimer Research - Volume 11, Issue 3, 2014

A surfeit of errors and an absence of sufficiently rigorous neuroscience theory have led to failures of neuroscience drug developments and to less effective patient care. Alzheimer’s disease (AD) requires systematic grounding of drug developments with mechanistic explanations to replace current trial and error approaches to the development of potential drug products. We foresee the need for regulatory revisions that will provide better balanced supports for advancing the AD scientific knowledge required to more effectively develop clinically useful drugs and for provisions to patients of drug candidates soundly predicted, based on documented effects on AD neuropathologies and safety, to slow or arrest the progression of persons at-risk to AD dementia. We propose that investigators and regulators focus AD clinical research on understanding the inductions of reversible and irreversible neuropathologies and their roles in generating clinical dementia. In support of this, we foresee the need for regulatory changes to create a vehicle for these clinical studies; for example, conditional drug approvals based on drug induced neuropathological changes.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive decline in multiple cognitive domains and it becomes the most common cause of dementia in the elderly. There is an urgent need for the early diagnosis and treatment of AD to ease caregiver burden and medical costs, as well as improve patients’ living activities associated with the dramatic increasing number of affected individuals. Molecular imaging with target-specific probes is contributing to identify the underlying biology in AD, which benefits to the early diagnosis of AD and the evaluation of anti-AD therapy. Molecular imaging probes, such as 11C-PIB, 11C-MP4A, 18F-AV-45, and 11F-FDG, can selectively bind to special bimolecular of AD or accurately accumulate at the location of damage areas, thus become an edge tool for a better management of the diseases in the clinical practice and new drug development. In the past decades, a large variety of probes is being developed and tested to be useful for the early and accurate diagnosis of Alzheimer's disease, patient selection for disease-modifying therapeutic trials and monitoring the effect of anti-amyloid therapy. Since imaging probes may also help to guide physicians to identify those patients that could best benefit from a given therapeutic regimen, dose, or duration of drug, this paper is to present a perspective of the available imaging probes for AD, classified on different modalities. Meanwhile, recent advances of those probes that have been selected for clinical trials and are at the different stages of the US Food and Drugs Administration (FDA) approval are outlined. Additionally, future directions and specific application of imaging strategies designed for both diagnosis and treatment for AD are discussed.

Objective: Myelin disruption is an important feature of Alzheimer’s disease (AD) that contributes to impairment of neuronal circuitry and cognition. In this study we characterize myelin degradation in the brains of patients with Alzheimer’s disease compared with normal aged controls. Methods: Myelin from patients with AD (n=13) was compared to matched controls (n=6). Myelin degradation was examined by immunohistochemistry in frontal white matter (WM) for intact myelin basic protein (MBP), degraded MBP, the presence of myelin lipid and for PAS staining. The relationship of myelin degradation and axonal injury was also assessed. Results: Brains from patients with AD had significant loss of intact MBP, and an increase in degraded MBP in periventricular WM adjacent to a denuded ependymal layer. In regions of myelin degradation, vesicles were identified that stained positive for degraded MBP, myelin lipid, and neurofilament but not for intact MBP. Most vesicles stained for PAS, a corpora amylacea marker. The vesicles were significantly more abundant in the periventricular WM of AD patients compared to controls (44.5±11.0 versus 1.7±1.1, p=0.02). Conclusion: In AD patients degraded MBP is associated in part with vesicles particularly in periventricular WM that is adjacent to areas of ependymal injury.

Current research suggests that amygdalar volumes in patients with Alzheimer’s disease (AD) may be a relevant measure for its early diagnosis. However, findings are still inconclusive and controversial, partly because studies did not focus on the earliest stage of the disease. In this study, we measured amygdalar atrophy in 48 AD patients and 82 healthy controls (HC) by using a multi-atlas procedure, MAPER. Both hippocampal and amygdalar volumes, normalized by intracranial volume, were significantly reduced in AD compared with HC. The volume loss in the two structures was of similar magnitude (~24%). Amygdalar volume loss in AD predicted memory impairment after we controlled for age, gender, education, and, more important, hippocampal volume, indicating that memory decline correlates with amygdalar atrophy over and above hippocampal atrophy. Amygdalar volume may thus be as useful as hippocampal volume for the diagnosis of early AD. In addition, it could be an independent marker of cognitive decline. The role of the amygdala in AD should be reconsidered to guide further research and clinical practice.

Renal disease is a risk factor for vascular diseases and for dementia, and renal insufficiency can be a feature of Alzheimer’s disease (AD). Evidence has suggested that vascular mechanisms mediate the link between renal disease and dementia. Our study sought to test this hypothesis by examining renal and vascular functioning in AD by investigating estimated glomerular filtration rates (eGFR), calculated from serum creatinine concentrations, and established biomarkers of vascular functioning, asymmetrical dimethylarginine (ADMA) and plasma homocysteine (Hcy), in individuals with mild to moderate AD (n = 34) and a group of older adult controls (n = 34). We found significantly reduced eGFR, indicative of impaired renal functioning, in individuals with AD (M = 62.9, SD = 15.2) compared with controls (M = 73.6, SD = 11.8). However, concentrations of ADMA and Hcy did not differ between patient and control groups (ADMA: M = 0.47; M = 0.50; Hcy: M = 17.2; M = 14.9; patients and controls). The criteria for a mediation analysis were not met, as concentrations of ADMA and Hcy did not predict AD, indicating that these biomarkers of vascular functioning did not mediate a relationship between renal functioning and AD. This study indicated that renal insufficiency may independently contribute to AD pathology, and other vascular mechanisms may influence a relationship between renal impairment and AD.

Changes in retinal nerve fiber layer (RNFL) thickness have been reported in patients with mild cognitive impairment (MCI), the pre-dementia stage of Alzheimer’s disease (AD). However, whether RNFL thickness is associated with specific cognitive impairment of MCI patients remains unknown. Therefore, we set out to investigate the potential association between RNFL thickness and episodic memory in MCI patients. Seventy five older adults (mean age 74 ± 3 years, 55% men) were included in the study. Fifty-two participants had normal cognition (NC), and 23 participants were diagnosed with MCI. RNFL thickness was obtained by optical coherence tomography measurement. Cognitive function was evaluated by the Repeatable Battery for the Assessment of Neuropsychological Status on the same day of the optical examination. We found that nasal quadrant RNFL thickness was positively associated with episodic memory scores in the participants with normal cognition: word list learning (r=0.392, p=0.004) and story recall (r=0.307, p=0.027). In the participants with MCI, however, the inferior quadrant RNFL thickness was inversely associated with the episodic memory score: word list learning (r=-0.652, p=0.001), story memory (r=-0.429, p=0.041), and story recall (r=-0.502, p=0.015,). The findings from this pilot study suggest that the inferior quadrant RNFL thickness was associated with specific episodic memory in MCI patients and could serve as a biomarker of MCI and AD. These findings would promote more studies to determine the potential application of RNFL as an AD biomarker.

Background: Mild Cognitive Impairment (MCI) and REM Behavior Disorder (RBD) are both associated with a degeneration of ponto-medullary cholinergic pathways. Methods: We conducted a placebo-controlled, cross-over pilot trial of Rivastigmine (RVT) in 25 consecutive patients with MCI, who presented RBD refractory to conventional first-line treatments (melatonin up to 5 mg/day and clonazepam up to 2 mg/day). Results: RVT treatment was followed by a significant reduction of RBD episodes when compared with placebo. Conclusions: Our data suggest that, in MCI patients with RBD resistant to conventional therapies (muscle relaxants benzodiazepines or melatonin,) treatment with RVT may induce a reduction in the frequency of RBD episodes compared to placebo.

Alzheimer´s disease (AD) is characterized by mental and cognitive problems, particularly with memory, language, visuospatial skills (VS), and executive functions (EF). Advances in the neuroimaging of AD have highlighted dysfunctions in functional connectivity networks (FCNs), especially in the memory related default mode network (DMN). However, little is known about the integrity and clinical significance of FNCs that process other cognitive functions than memory. We evaluated 22 patients with mild AD and 26 healthy controls through a resting state functional MRI scan. We aimed to identify different FCNs: the DMN, language, EF, and VS. Seed-based functional connectivity was calculated by placing a seed in the DMN (posterior cingulate cortex), language (Broca´s and Wernicke´s areas), EF (right and left dorsolateral prefrontal cortex), and VS networks (right and left associative visual cortex). We also performed regression analyses between individual connectivity maps for the different FCNs and the scores on cognitive tests. We found areas with significant decreases in functional connectivity in patients with mild AD in the DMN and Wernicke´s area compared with controls. Increased connectivity in patients was observed in the EF network. Regarding multiple linear regression analyses, a significant correlation was only observed between the connectivity of the DMN and episodic memory (delayed recall) scores. In conclusion, functional connectivity alterations in mild AD are not restricted to the DMN. Other FCNs related to language and EF may be altered. However, we only found significant correlations between cognition and functional connectivity in the DMN and episodic memory performance.

Apolipoprotein E ε4 allele (ApoE4) has been associated with increased risk of sporadic Alzheimer’s disease (AD) and of conversion from mild cognitive impairment to AD. But the underlying mechanism of ApoE4 affecting brain atrophy and cognition is not fully understood. We investigated the effect of ApoE4 on amyloid beta (Aβ) protein burden and its correlation with the structure change of hippocampus and cortex, cognitive and behavioral changes in ApoE4 transgenic mice. Male ApoE4 transgenic mice and age-matched control mice at age 12 months and 24 months were tested in the Morris Water Maze (MWM). Brain volume changes (including whole brain, hippocampus, cortex, total ventricles and caudate putamen) were assessed by using small animal 7T-MRI. Aβ level was assessed by immunohistochemistry (IHC) and immunoprecipitation/western blot. In MWM, escape latency was longer and time spent in the target quadrant was shorter in aged ApoE4 mice (12- and 24-month-old), suggesting age- and ApoE4-dependent visuospatial deficits. Atrophy on MRI was prominent in the hippocampus (p=0.039) and cortex (p=0.013) of ApoE4 mice (24-month-old) as compared to age-matched control mice. IHC revealed elevated Aβ deposition in the hippocampus. Consistently, both soluble and insoluble Aβ aggregates were increased in aged ApoE4 mice. This increase was correlated inversely with hippocampal atrophy and cognitive deficits. These data give further evidence that ApoE4 plays an important role in brain atrophy and memory impairment by modulating amyloid production and deposition.

Background: This retrospective cohort study was designed to assess whether there is an association between newly diagnosed dementia and the risk of stroke. Methods: From Taiwan’s National Health Insurance Research Database of reimbursement claims, we identified 2811 patients with newly diagnosed dementia and 14,055 randomly selected, agematched patients without dementia. A Cox proportional hazards model was constructed to calculate the development of stroke, including ischemic stroke, and intracerebral, or subarachnoid hemorrhage. Results: During the 3-year follow-up period, 339 patients with dementia (12.06%) and 691 patients without dementia (4.92%) developed stroke. The adjusted HRs of developing stroke among newly diagnosed dementia patients were 2.33-times (range, 2.05–2.66), and the incidence of hemorrhagic stroke was higher than that of other stroke types. Patients who had Alzheimer’s disease were at the highest risk of hemorrhagic stroke. Conclusion: Individuals with dementia, especially Alzheimer’s disease, are at greater risk of developing stroke, especially in intracerebral and subarachnoid hemorrhage than patients without dementia. Early mental screening programs and health education should be initiated for dementia patients.

Alzheimer’s disease (AD) is the most common age related human neurodegenerative disorder. The major histopathological characteristics of the AD brain are extracellular amyloid-beta (Aβ) peptide loaded plaques and intraneuronal neurofibrillary tangles made of phosphorylated tau proteins. Amyloid plaques consist primarily of aggregated Aβ 1-42 and Aβ 1-40 peptides. The aim of our current study was to test novel ligands/agents with the potential to disrupt or inhibit the aggregation of Aβ peptide, specifically K114, (trans,trans)-1-bromo-2,5-bis(4-hydroxystyryl)benzene, which was initially developed as a potential positron emission tomography (PET) ligand for the in vivo detection of amyloid plaques. Systemic administration of K114 has been shown in the AD/transgenic (Tg) mouse model to be capable of crossing the blood-brain barrier (BBB) and be colocalized with amyloid plaques. In this study we determined whether K114 has the potential to inhibit Aβ aggregation in vitro in AD/Tg mice and also tested, in vivo, whether chronic daily orally administered K114 has any therapeutic potential as evidenced by inhibition or reduction of the deposits of amyloid aggregates in the brains of AD/Tg mice. Our results demonstrated that K114 strongly blocked, in vitro, the aggregation of Aβ peptide in the amyloid plaques of AD/Tg mouse brain. Systemic treatment with K114 was also effective in significantly reducing the deposits of amyloid plaques in the brains of living transgenic AD mice. Additionally, K114 significantly inhibited the typically observed plaque associated astrocytic activation, as revealed by GFAP immunohistochemistry, suggesting possible anti-inflammatory properties.