Current Alzheimer Research - Volume 15, Issue 6, 2018

Objectives: Epidemiological data suggest that non-steroidal anti-inflammatory drugs (NSAIDs) may protect against Alzheimer's disease (AD). Unfortunately, recent trials have failed in providing compelling evidence of neuroprotection. Discussion as to why NSAIDs effectivity is uncertain is ongoing. Possible explanations include the view that NSAIDs and other possible disease-modifying drugs should be provided before the patients develop symptoms of AD or cognitive decline. In addition, NSAID targets for neuroprotection are unclear. Both COX-dependent and independent mechanisms have been proposed, including γ-secretase that cleaves the amyloid precursor protein (APP) and yields amyloid β peptide (Aβ). Methods: We have proposed a neuroprotection mechanism for NSAIDs based on inhibition of mitochondrial Ca²⁺ overload. Aβ oligomers promote Ca²⁺ influx and mitochondrial Ca²⁺ overload leading to neuron cell death. Several non-specific NSAIDs including ibuprofen, sulindac, indomethacin and Rflurbiprofen depolarize mitochondria in the low μM range and prevent mitochondrial Ca²⁺ overload induced by Aβ oligomers and/or N-methyl-D-aspartate (NMDA). However, at larger concentrations, NSAIDs may collapse mitochondrial potential (ΔΨ) leading to cell death. Results: Accordingly, this mechanism may explain neuroprotection at low concentrations and damage at larger doses, thus providing clues on the failure of promising trials. Perhaps lower NSAID concentrations and/or alternative compounds with larger dynamic ranges should be considered for future trials to provide definitive evidence of neuroprotection against AD.

Background: Frontotemporal Dementia (FTD) is a heterogeneous group of disorders and the second most frequent cause of early onset dementia making it the highest number of inherited cases. Review Summary: FTD is characterized by considerable variability in clinical, genetic and histopathologic features. Patients may present symptoms ranging from behavioural disturbances to different language disorders, with or without motor neuron disorders or associated parkinsonism. Atrophy in frontal and temporal lobes is the most relevant radiological finding. In the last 10 years, the knowledge of this clinical entity has undergone remarkable changes both genetically and histopathologically, which have served to establish more consistent clinical criteria. Until now, 10 genes causative of FTLD have been described and up to four different proteins causative of atrophy have been detected in aggregates. Conclusion: This review is mostly addressed to clinicians and aims to provide basic knowledge of these neurodegenerative disorders and clarify the complex FTD scenario.

Numerous authors have provided evidence regarding the beneficial effects of phenolic acids and their derivatives against Alzheimer's disease (AD). In this review, the role of phenolic acids as inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) is discussed, including the structure-activity relationship. In addition, the inhibitory effect of phenolic acids on the formation of amyloid β-peptide (Aβ) fibrils is presented. We also cover the in vitro, ex vivo, and in vivo studies concerning the prevention and treatment of the cognitive enhancement.

Objective: Centrifuges are the principal means of generating physiological hypergravity and have been used for many medical purposes, including the therapy of psychiatric diseases and evaluation of vestibular system in the pilots. In particular, modern centrifuges have evolved into mechanically sophisticated precision instruments compared to primitive ones in old times, indicating that centrifuges might possess great potential in modern medicine. Indeed, studies are in progress to apply centrifuges to musculoskeletal degenerative diseases, such as osteoporosis and sarcopenia. Given that the agingrelated diseases are manifested under microgravity conditions, including astronauts and the bed-ridden elderly, it is reasonable to speculate that centrifuge-induced hypergravity may counteract the progression of these diseases. Such a view may also be important for neurodegenerative diseases for which the radical treatments are yet to be established. Therefore, the main objective of this paper is to discuss a potential therapeutic use of centrifuges for protection against the central nervous system (CNS) disorders, both in space and on Earth. Mechanistically hypergravity may exert stimulatory effects on preconditioning, chaperone expression, synapse plasticity, and growth and differentiation in the nervous system. Furthermore, hypergravity may suppress the progress of type II diabetes mellitus (T2DM), leading to inhibition of T2DM–triggered CNS disorders, including neurodegenerative diseases, ischemia and depression. Conclusion: Moreover, it is possible that hypergravity may counteract the neurodegeneration in hippocampus induced by the microgravity conditions and psychiatric diseases. Collectively, further investigations are warranted to demonstrate that centrifuge-induced hypergravity may be beneficial for the therapy of the CNS disorders.

Background: 6-chlorotacrine is a cholinesterase inhibitor showing good inhibitory potential, even better than parent compound tacrine, in vitro. Despite tacrine scaffold is broadly used for design and synthesis of novel compounds with anti-Alzheimer's potential, no in vivo effects have been investigated so far. Thus, basic toxicological and behavioural evaluation has been carried out throughout this study. Methods: Maximum tolerated dose (MTD) and median lethal dose (LD50) were assessed in BALB/c mice and Wistar rats. Behavioural effects were observed in rats performing the multiple T-maze test, the water maze test and the step-through passive avoidance test. All outcomes were compared with the effects of parent compound - tacrine. Results: The toxicity of 6-chlorotacrine was increased compared to tacrine with MTD 6.0/5.0 mg.kg-1 (i.m., male/female mice), 6.0/5.0 mg.kg-1 (i.p., male/female rats) and LD50 9.0 mg.kg-1 (male rats). At MTD doses, no histopathological changes and blood biochemistry abnormalities were observed except decreased plasma creatinine levels. 6-chlorotacrine showed good effects in the reversal of quinuclidinyl benzilate-induced amnesia. Best results were achieved at the dose of 1.8 mg.kg-1 (20% LD50) in the water maze test; the pro-cognitive effect was stronger than that of tacrine (5.2 mg.kg-1, 20% LD50). Other doses tested (0.9 mg.kg-1 and 2.7 mg.kg-1) showed similar effects as tacrine in the water maze, multiple T-maze and passive avoidance test. Conclusion: Observed effects predetermined 6-chlorotacrine as a potent parent compound for the synthesis of novel multifactorial drugs intended to the treatment of Alzheimer's disease. Even though 6- chlorotacrine showed in vivo beneficial effect with no signs of toxicity, further tests on the field of biochemistry and pharmacology are essential to disclose the exact mechanism of action, safety evaluation and the metabolic fate of the compound after the repeated administration.

Background: Mild cognitive impairment (MCI) has an increased rate of progression to dementia. Alterations of some metabolic factors, such as deficiency of vitamin D, are a risk factor for cognitive deterioration. Vitamin D is involved in the clearance of β-amyloid (Aβ) from the brain. We have reported that lymphocytes from Alzheimer's disease (AD) patients have an increased susceptibility to oxidative death by H2O2 exposure, but currently it is unknown if this characteristic is modifiable in vivo. Objective: To determine if correction of low vitamin D levels protects lymphocytes from oxidative death and increases Aβ1-40 plasma levels in MCI and very early AD (VEAD) patients. Method: Sixteen MCI, 11 VEAD and 25 healthy control (HC) voluntaries were evaluated with the Clinical Dementia Rating (CDR), Montreal Cognitive assessment (MoCA), and Memory Index score (MIS). Lymphocyte death was measured by flow cytometry after 20h exposure to H2O2. In patients with low levels of vitamin D -11 MCI, 9 VEAD and 20 HC- lymphocyte H2O2-death, plasma Aβ1-40 levels and cognitive status were evaluated pre- and post-vitamin D supplementation for 6 months. Results: Lymphocytes from MCI and VEAD patients showed increased susceptibility to oxidative death at study entry. In MCI, but not VEAD patients, lymphocyte susceptibility to death and Aβ1-40 levels plasma levels improved after 6 months of vitamin D supplementation. In addition, cognitive status on follow-up (18 months) improved in MCI patients after vitamin D supplementation. Conclusion: Vitamin D supplementation may be beneficial in MCI. The lack of effect in VEAD may be due to a more advanced stage or different characteristics of the neurodegenerative process.

Background: Alzheimer's disease (AD) is a neurodegenerative disease that gradually induces cognitive deficits in the elderly and working memory impairment is typically observed in AD. Amyloid-β peptide (Aβ) is a causative factor for the cognitive impairments in AD. Gamma oscillations have been recognized to play important roles in various cognitive functions including working memory. Previous study reported that Aβ induces gamma oscillation dysfunction in working memory. Objective: Although repetitive transcranial magnetic stimulation (rTMS) represents a technique for noninvasive stimulation to induce cortical activity and excitability changes and has been accepted for increasing brain excitability and regulating cognitive behavior, the question whether rTMS can reserve the Aβ-induced gamma oscillation dysfunction during working memory remains unclear. The present study aims to investigate the effect of rTMS to the Aβ-induced gamma oscillation dysfunction during working memory. Method: The present study investigates the rTMS-modulated gamma oscillation in Aβ1-42-induced memory deficit. Adult SD rats were divided into four groups: Aβ, Con, Aβ+rTMS and Con+rTMS. 16-channel local field potentials (LFPs) were recorded from rat medial prefrontal cortex while the rats performed a Y-maze working memory task. Gamma oscillation among LFPs was measured by coherence. Results: The results show that rTMS improved the behavior performance and enhanced gamma oscillation for the Aβ-injected subjects. Conclusion: These results indicate that rTMS may reserve the Aβ-induced dysfunction in gamma oscillation during working memory and thus result in potential benefits for working memory.

Background: Previous work designed a network-based protocol of cognitive training. This programme exploits a mechanism of induced task-oriented co-activation of multiple regions that are part of the default mode network (DMN), to induce functional rewiring and increased functional connectivity within this network. Objective: In this study, the programme was administered to patients with a diagnosis of mild cognitive impairment to test its effects in a clinical sample. Method: Twenty-three patients with mild cognitive impairment (mean age: 73.74 years, standard deviation 5.13, female/male ratio 13/10) allocated to the experimental condition, underwent one month of computerised training, while fourteen patients (mean age: 73.14 years, standard deviation 6.16, female/ male ratio 7/7) assigned to the control condition underwent a regime of intense social engagement. Patients were in the prodromal stage of Alzheimer's disease (AD) as confirmed by clinical follow ups for at least two years. The DMN was computed at baseline and retest, together with other, control patterns of connectivity, grey matter maps and neuropsychological profiles. Results: A condition-by-timepoint interaction indicating increased connectivity triggered by the programme was found in left parietal DMN regions. No decreases as well as no changes in the other networks or morphology were found. Although between-condition cognitive changes did not reach statistical significance, they correlated positively with changes in DMN connectivity in the left parietal region, supporting the hypothesis that parietal changes were beneficial. Conclusion: This programme of cognitive training up-regulates a pattern of connectivity which is pathologically down-regulated in AD. We argue that, when cognitive interventions are conceptualised as tools to induce co-activation repeatedly, they can lead to clinically relevant improvements in brain functioning, and can be of aid in support of pharmacological and other interventions in the earliest stages of AD.

Objective: Alzheimer disease is traditionally conceptualized as a disease of brain gray matter, however, studies with diffusion tensor imaging have demonstrated that Alzheimer disease also involves alterations in white matter integrity. We measured number of tracts, tracts length, tract volume, quantitative anisotropy and general fractional anisotropy of neuronal tracts in subcallosal area, paraterminal gyrus and fornix in patients with Alzheimer disease and healthy age-matched controls. Our hypothesis was that patients with Alzheimer disease should exhibit decrease in the integrity of these white matter structures that are crucial for semantic memory function. Methods: For our study were selected 24 patients with confirmed Alzheimer disease diagnosis and 24 healthy controls (AD center, Department of Neurology, Charles University, Prague, Czech Republic). Statistically significant differences between the patients with Alzheimer disease and the control group were found both on the left and right fornices but only concerning the tract numbers and tract length. The subcallosal area and paraterminal gyrus showed statistically significant differences between the patients with Alzheimer disease and the control group, but only on the left side and only associated with the tract volume and quantitative anisotropy. Conclusion: Our explanation for these findings lies in the severe hippocampal atrophy (and subsequent loss of function) with compensatory hypertrophy of the subcallosal area and paraterminal gyrus neuronal fibers that occurs in Alzheimer's disease, as an adaptation to the loss of projection from the hippocampal formation via fornix.