Medical hypotheses
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Clinical Trial Controlled Clinical Trial
Is pigment epithelium-derived factor level in cerebrospinal fluid a promising biomarker for early diagnosis of Alzheimer's disease?
Alzheimer's disease (AD) is the most common cause of dementia in Western countries and in Japan. Early diagnosis and treatment is needed to slow down the degenerative process and dementia in AD. The main histopathological characteristics of AD are senile plaques and neurofibrillary tangles. ⋯ These results suggest that PEDF overexpression may indicate a compensation mechanism to fight against neuronal cell injury in AD. Our present observations suggest that PEDF in CSF might reflect cerebral PEDF turnover and provide a means for monitoring neuronal perturbation induced by oxidative stress in the early stage of AD. Clinical use of CSF-PEDF as a biomarker for AD might enable more effective diagnosis and treatment of patients with this disorder.
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The exacerbation of symptoms after exercise differentiates Chronic fatigue syndrome (CFS) from several other fatigue-associated disorders. Research data point to an abnormal response to exercise in patients with CFS compared to healthy sedentary controls, and to an increasing amount of evidence pointing to severe intracellular immune deregulations in CFS patients. This manuscript explores the hypothetical interactions between these two separately reported observations. ⋯ Second, the activation of the protein kinase R enzyme, a characteristic feature in atleast subsets of CFS patients, might account for the observed excessive nitric oxide (NO) production in patients with CFS. Elevated NO is known to induce vasidilation, which may limit CFS patients to increase blood flow during exercise, and may even cause and enhanced postexercise hypotension. Finally, it is explored how several types of infections, frequently identified in CFS patients, fit into these hypothetical pathophysiological interactions.
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The three common forms of dementias in the elderly include Alzheimer's disease (AD), vascular dementia (VD) and normal pressure hydrocephalus (NPH). These disorders are distinguished by their specific pathological features. However, overlapping clinical and imaging features in a given case are not too uncommon. ⋯ The defective clearance of amyloid may also lead to amyloid angiopathy perpetuating hypoperfusion. Hypoperfusion may also affect formation as well as absorption of CSF altering clearance of amyloid and promoting vascular and parenchymal deposition. Thus the pathologies of AD, VaD and NPH get interrelated.
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Over a decade ago, I formulated the hypothesis that cumulative effects of exposure to high intracranial pressure (ICP) may contribute to the development of Alzheimer's disease (AD), though not necessarily in an exclusive way. In addition to individual ICP characteristics (high 'physiological' ICP) and diseases causing ICP elevation, various activities with significant Valsalva effort, such as weightlifting and wind instrument playing, can generate very high ICPs. Recent studies of normal-pressure hydrocephalus (NPH), glaucoma and Alzheimer's disease provide supportive evidence for this hypothesis. ⋯ Recently, similarities in pathophysiology between glaucoma and AD have been noted, with increased processing of amyloid precursor protein (APP) and up-regulation of beta-amyloid protein expression in retinal ganglion cells (RGCs). Given this link between AD and glaucoma, evidence for a causal relationship between repetitive intermittent ICP elevations and AD is gained from research indicating that high resistance wind instrument playing raises IOP and may result in glaucomatous damage. To test the validity of the hypothesis that exposure to repetitive but nonsustained ICP elevations may predispose to AD a non-invasive, epidemiological study is proposed in this paper.
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Chronic fatigue syndrome is a disorder characterised by prolonged fatigue and debility and is mostly associated with post-infection sequelae although ongoing infection is unproven. Immunological aberration is likely and this may prove to be associated with an expanding group of vasoactive neuropeptides in the context of molecular mimicry and inappropriate immunological memory. Vasoactive neuropeptides including vasoactive intestinal peptide (VIP) and pituitary adenylate activating polypeptide (PACAP) belong to the secretin/glucagon superfamily and act as hormones, neurotransmitters, immune modulators and neurotrophes. ⋯ Perverse immunological memory established against these substances or their receptors may be the reason for the protracted nature of this condition. The novel status of these substances together with their extremely small concentrations in blood and tissues means that clinical research into them is still in its infancy. A biologically plausible theory of CFS causation associated with vasoactive neuropeptide dysfunction would promote a coherent and systematic approach to research into this and other possibly associated disabling conditions.