Cholinesterase inhibitors: beyond Alzheimer’s disease

Cholinesterase inhibitors (ChEIs) are widely licensed for the symptomatic treatment of Alzheimer’s disease, but their use has also been examined in a wide variety of neurological disorders besides Alzheimer’s disease, and this article reviews these uses. The evidence currently available suggests that ChEIs may possibly have a role in the treatment of some patients with dementia with Lewy bodies and Parkinson’s disease dementia, but at this point in time there would seem to be only a limited case for recommending ChEIs in mild cognitive impairment, Down syndrome, progressive supranuclear palsy, pure vascular dementia, frontotemporal lobar degeneration, Huntington’s disease, multiple sclerosis, epilepsy, delirium, traumatic brain injury, sleep-related disorders or certain psychiatric disorders (e.g., schizophrenia and bipolar disorder). Clinical practice with respect to non-Alzheimer’s disease indications for ChEIs may vary according to jurisdiction, specifically with regards to whether national guidelines effectively limit off-licence drug use.     

Iron-chelating backbone coupled with monoamine oxidase inhibitory moiety as novel pluripotential therapeutic agents for Alzheimer’s disease: a tribute to Moussa Youdim

It is for these authors a great privilege to dedicate this review article to Moussa Youdim, who is one of the most imperative pharmacologists and pioneer investigators in the search and development of novel therapeutics for neurodegenerative diseases. 40 years ago, Moussa Youdim has started studying brain iron, catecholamine receptor and monoamine oxidase (MAO)-A and -B functions. Although Moussa Youdim succeeded in exploring the novel anti-Parkinsonian, selective MAO-B inhibitor drug, rasagiline (Azilect, Teva Pharmaceutical Co.), he did not stop searching for superior therapeutic approaches for neurodegenerative disorders. To date, Moussa Youdim and his research group are designing and synthesizing pluripotential drug candidates possessing diverse pharmacological properties that can act on multiple targets and pathological features ascribed to Parkinson’s disease, Alzheimer’s disease (AD) and amyotrophic lateral sclerosis. One such example is the multimodal non-toxic, brain-permeable iron-chelating compound, M30 (5-[N-methyl-N-propargylaminomethyl]-8-hydroxyquinoline), which amalgamates the propargyl moiety of rasagiline with the backbone of the potent iron chelator, VK28. This review discusses the multiple effects of several leading compounds of this series, concerning their neuroprotective/neurorestorative molecular mechanisms in vivo and in vitro, with a special focus on the pathological features ascribed to AD, including antioxidant and iron chelating activities, regulation of amyloid precursor protein and amyloid β peptide expression processing, activation of pro-survival signaling pathways and regulation of cell cycle and neurite outgrowth.     

Alzheimer’s disease

Psychiatric Quarterly - It would appear, on the basis of this study, that Alzheimer’s disease is a distinct clinicopathologic entity which, while not common, is not so rare as commonly...     

Alzheimer’s disease

Conclusions It would appear, on the basis of this study, that Alzheimer's disease is a distinct clinicopathologic entity which, while not common, is not so rare as commonly believed.Finally, it is pertinent to emphasize that familiarity with the clinical picture will show that many more cases exist than have hitherto been suspected.     

Caregivers for persons with Alzheimer’s disease

Families have always cared for relatives with dementia, but scientific advances in diagnosis, management, and treatment will make caring more challenging as more people are diagnosed in early stages and more live longer in severe stages with better health care. This paper discusses the increasing prevalence, the economic value and cost of caregiving, the impact of caregiving in families with and without dementia, the subjective experience of dementia and quality of life, the ethical challenges of clinician-family partnerships, the complexity of family systems and processes that impact care patterns, homicide-suicide in caregiving, long-term care staff training, and theoretic models.     

Platelet monoamine oxidase activity in subjects tested for Huntington’s disease gene mutation

Summary. Monoamine oxidase activity (MAO) has been related to neuronal damage, since the oxidative deamination of biogenic amines produces free radicals that may enhance oxidative stress. Elevated enzyme activities in brain (MAO-A and MAO-B forms) and in platelets (MAO-B form) have been reported in several degenerative diseases, indicating that MAO activity may be involved in the disease progression. We estimated platelet MAO activity in a group of 59 patients (34 males) with HD, 20 subjects (7 males) at risk, and 29 (14 males) healthy subjects with positive family history for HD, categorized according to clinical features and the number of CAG repeat units (CAG-RN) at the Huntington gene. A group of 64 subjects (36 males) with negative family history for HD served as controls. In contrast to some previous studies, platelet MAO activities in both male and female patients (CAG-RN 40 to 62) with overt symptomatology, were not different compared to same sex control subjects. Subjects at risk (CAG-RN 39 to 52), though, showed significantly lower activities compared to same sex patients or controls. MAO activities seem to increase with disease progression, and tend to be higher in patients with dementia. The increases may be an epiphenomenon of disease pathology, but the possibility that an increase in the expression of the enzyme precedes the onset of the disease and contributes to enhanced oxidative stress should be considered in future longitudinal studies as a possible mechanism that accelerates disease progression.     

Imaging Alzheimer’s disease

Prior reviews on the topic of imaging and Alzheimer’s disease have focused predominately on the technical features of imaging modalities or have summarized the results of epidemiologic studies. As brain scientists and brain practitioners, our main focus should be on the neurobiologic correlates of imaging, so we can intertwine this knowledge with our understanding of disease pathophysiology. A focus on these two features—the neurobiologic correlates of imaging and the pathophysiology of Alzheimer’s disease—has provided the organizing principle of this review.     

Cholinesterase inhibitors may increase phosphorylated tau in Alzheimer’s disease

Cholinesterase inhibitors (ChEIs) are widely used for the symptomatic treatment of Alzheimer’s disease (AD). In vitro and in animal studies, ChEIs have been shown to influence the processing of Aβ and the phosphorylation of tau, proteins that are the principal constituents of the plaques and neurofibrillary tangles, respectively, in AD brain. However, little is known about the effects of these drugs on Aβ and tau pathology in AD. Using avidin-biotin immunohistochemistry and computer-assisted image analysis, we compared Aβ and tau loads in the frontal and temporal cortices of 72 brains from matched cohorts of AD patients who had or had not received ChEIs. Patients treated with ChEIs had accumulated significantly more phospho-tau in their cerebral cortex than had untreated patients (P = 0.004). Aβ accumulation was reduced but not significantly. These data raise the possibility that increased tau phosphorylation may influence long-term clinical responsiveness to ChEIs.     

β-Carbolines as selective monoamine oxidase inhibitors:In vivo implications

Summary The inhibitory action of a range of-carbolines on human and rat monoamine oxidase (MAO) A and B has been studied. Concentrations of 5-hydroxytryptamine and phenylethylamine, approximately at their K_m values, were used as substrates for MAO A and B respectively. A wide variation in selectivity was found, with harmaline being 10,000 times more potent an inhibitor of A than B whereas, using tetrahydro--carboline and harmane, the difference was nearer to ten-fold. Of the carbolines which have been found endogenously, tetrahydro--carboline, 6-methoxytetrahydro--carboline and harmane are all sufficiently potent inhibitors of human MAO A, with I₅₀ values of 5×10^–6, 10^–6, 5×10^–7M respectively, for this property to be of possible physiological significance. Harmane, with an I₅₀ of 5×10^–6M, might also play a role as an inhibitor of MAO B.     

Alzheimer’s disease,Huntington’s disease and cancer

Neurodegenerative disorders and cancer are two of the most common groups of conditions in our world. Some studies have proposed that neurodegenerative disorders may be protective of the development of cancer.We tested this hypothesis using two neurodegenerative disorders with different molecular pathophysiology – Alzheimer’s disease (AD) and Huntington’s disease (HD) – to see if the inverse relationship between cancer and neurodegeneration was generalizable. Five-year cancer incidence was determined in two large datasets: AD using the C-Path Online Date Repository (CODR) database (n = 6383) and HD using the ENROLL-HD database (n = 2608). Cancer incidence was determined in the populations and compared to normal population data for Australia, United Kingdom and the United States of America. Age-sex standardized rates of cancer were determined and expressed as 95% confidence intervals. We describe an age-sex standardized cancer rate of 1179.6/per 100,000 population to 1253.7/per 100,000 population in normal populations.The rate in AD was 815.2/per 100,000 population (95% CI 813.32–817.5/per 100,000 population) and for HD 1296.6/per 100,000 population (95% CI 1288–1308.2/per 100,000 population).We conclude that patients with AD have a reduced age-sex standardized rate of developing cancer not shared with HD, a finding that hints at different molecular mechanisms.     

Diet and Alzheimer’s disease

Alzheimer’s disease (AD) is increasing in prevalence. There are no known preventive or curative measures. There is evidence that oxidative stress, homocysteinerelated vitamins, fats, and alcohol have a role in the pathogenesis of AD. Some epidemiologic studies suggest that higher dietary intake of antioxidants, vitamins B₆, B₁₂, and folate, unsaturated fatty acids, and fish are related to a lower risk of AD, but reports are inconsistent. Modest to moderate alcohol intake, particularly wine, may be related to a lower risk of AD. The Mediterranean diet may also be related to lower AD risk. However, randomized clinical trials of supplements of vitamins E, B₁₂, B₆, and folate have shown no cognitive benefit, and randomized trials for other nutrients or diets in AD are not available. The existing evidence does not support the recommendation of specific supplements, foods, or diets for the prevention of AD.     

Progress in Alzheimer’s disease

After more than one century from Alois Alzheimer and Gaetano Perusini’s first report, progress has been made in understanding the pathogenic steps of Alzheimer’s disease (AD), as well as in its early diagnosis. This review discusses recent findings leading to the formulation of novel criteria for diagnosis of the disease even in a preclinical phase, by using biological markers. In addition, treatment options will be discussed, with emphasis on new disease-modifying compounds and future trial design suitable to test these drugs in an early phase of the disease.     

Astrocyte and Alzheimer’s disease

The past several decades have given rise to more insights into the role of astrocytes in normal brain function and diseases. Astrocytes elicit an effect which may be neuroprotective or deleterious in the process of Alzheimer’s disease (AD). Impairments in astrocytes and their other functions, as well as physiological reactions of astrocytes to external injury, can trigger or exacerbate hyperphosphorylated tau and amyloid-beta (Aβ) pathologies, leading to the formation of both amyloid plaques and neurofibrillary tangles (NFTs), as well as neuronal dysfunction. This review addresses the involvement of astrocytes in the Aβ pathology, where the main mechanisms include the generation and clearance of Aβ, and the formation of NFTs. It is also discussed that metabolic dysfunction from astrocytes acts as an initiating factor in the pathogenesis of AD and a contributor to the onset and development of clinical presentation in AD.     

Astrocytes in Alzheimer’s disease

The circuitry of the human brain is formed by neuronal networks embedded into astroglial syncytia. The astrocytes perform numerous functions, providing for the overall brain homeostasis, assisting in neurogenesis, determining the micro-architecture of the grey matter, and defending the brain through evolutionary conserved astrogliosis programs.     

Pharmacotheraphy for Alzheimer’s disease

In the past 2 years, substantive advances in therapy for Alzheimer’s disease (AD) have occurred. The nature of the effects of cholinesterase inhibitors has been refined with the publication of several studies that have examined different aspects of the symptomatology of AD. Break-throughs in the basic science of Alzheimer’s disease have led to new insights into potential therapeutic strategies targeted at the secretases involved in the metabolism of the Alzheimer precursor protein. An immunization approach, in which the β-amyloid protein itself was used as the immunizing agent, has also been presented and independently validated. Other areas of investigation with disappointing results, such as estrogen replacement therapy, anti-inflammatory approaches, and several other therapeutic agents, are also reviewed.