Alzheimer's disease (AD) is the most prevalent form of dementia, 35 million people live with AD worldwide and a figure expected rise over coming decades is show by current indications. The pathogenesis of familial AD is highly complex, is caused by autosomal dominant mutation in either amyloid precursor protein (APP) or the presenilin (PS1,PS2) genes, the underlying cause of the remaining~98% of sporadic AD (Cole et al ,2007). Recent estimates foresee that more than 100 million individuals will be affected by the disease by 2050 which is a natural consequence of the age - dependent increase in the number of incident cases of AD (Monsuez et al, 2010).Growing prevalence of AD worldwide need the better development of diagnosis tools and more effective therapeutic interventions. The specific degeneration of the neurones involved in the memory consolidation, storage, and retrieval is the common distinctive feature of AD. Understanding the ethology of AD may provide insights into mechanisms of memory and vice versa (Arshavky et al, 2006). Patients suffering from AD forget basic information about their past, loose communication skills, linguistic and calculative abilities. 60% of demented patients manifest the typical pathological findings of Alzheimer's disease - amyloid deposits and neurofibrillary tangles, without any other abnormalities in the brain, while further 15% have these findings accompanied by brain damage of vascular origin. Amyloid plaques and neurofibrillary tangles are the two lesions of AD and they were first describe by Alois Alzheimer in a lecture in Tubingen, Germany, in 1906 (Eschweiller et al, 2010). Amyloid plaques consist of a pathologically processed amyloid protein, the amyloid beta peptide (A β). These abnormalities lead to the activation of neurotoxic cascade and to cytoskeletal change that eventually cause neuronal dysfunction and death (Florenza et al ,2010).
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AD is a severe neurodegenerative disorder of the brain with typically memory loss and cognitive decline. The majority of AD cases are sporadic risk age >60 years, and 2.5% have a genetic disposition. Diagnosis of AD established with a confidence of >90%, based on clinical criteria, including medical history, physical examination, laboratory tests, neuroimaging and neuropsychological evaluation (Humpel et al, 2011).
Diagnosing Alzheimer's disease
The progressive deposition of neurofibrillary tangles has been dived into six stages by Braak and Braak. The clinical diagnosis of AD is usually made when the neuropathological changes have stage III to VI, in the transentorhinal stage (Braak I and II, the depositions still restricted to the entorhinal cortex and parahippocapal cortex, which play a role in the formation of memories and the identification of odors. Disturbed function in these areas underlies early clinical changes of AD, including delayed memory recall and odor identification (Eschweiler et al, 2010). Pre-dementia stage of AD are considered to be mild cognitively impaired(MCI) but do not meet criteria for dementia because their cognitive deficits are limited to memory and/or their everyday abilities are preserved (Nestor et al,2004). Biomarker would distinguish AD from other types of dementia, such MCI, or mixed forms of dementia, such as vascular dementia (VaD), front temporal lobe dementia (FTLD), or Lewy body dementia (LBD). This is important because treatment for this disease might differ. Recent models based on neuropath logical, biochemical and neuroimaging methods have proposed that intracerebral amyloidosis precedes the onset of cognitive symptoms by severe years, if not decades. It is a difficult task to clinically differentiate incipient from cognitive aging from others forms of dementia in the prodromal phases. Clinical abnormalities (depressive episode and impaired identification of odors) may help the clinical detect preclinical AD. Persons aged 50 to 70 with subjective memory impairment have often normal findings, even on highly refined neuropsychological test. Person complains of stress and have more depressive symptoms do not develop dementia after many years' observations, second person over 70 without symptoms of stress or subclinical depression, report a loss of memory despite normal findings on screening tests, and develop dementia in the ensuing years. (Eschweiler et al, 2010). The patient who report impaired memory psychological testing need to be performed to objective and quantitative findings can be compared with those normal individuals of the same age education status. In Peterson criteria 2004 poor test performance in the absence of the explanatory factors an attention deficit iatrogenic ally induced by use of drugs antihistiamic or anticholinerigic an amnestic MCI (Eschweiler et al, 2010). Drug benzodiazepines and alcohol also progress symptoms of dementia. The development of biomarker research in AD is a good example of the successful effort to translate the knowledge of key pathophysiological mechanism of the disease into clinical applications (Forlenza et al, 2010). The measured and evaluated marker for AD is ideal diagnostic in at least three basic requirements: * reflect core neurobiological changes,*assuming that the neuropath logical findings are gold standards off abnormalities affecting the same cascade,*early measure in the disease ideally at presymptomatic stages (Forlenza et al, 2010). Three biomarkers have been discovered and using to well validated and well established to diagnose AD in cerebrospinal fluid (CSF) with ELSAs. Aβ peptide (Aβ 42), total Tau (T-Tau) and phosphorylated Tau (P-Tau) increased level of three biomarkers significantly valid diagnostic for sporadic AD, a combined sensitivity of >95% and specificity of >85% (Humpel et al, 2011). Senile plaques are composed of aggregation of small peptides β-amyloid (Aβ) and evidence demonstrate that overproduction/aggregation of Aβ in the brain is a primary cause of AD inhibition of Aβ generation. The understanding the metabolism /processing of APP is crucial for AD therapeutics (Zhang et al, 2011). Analysis of CSF Aβ a highly significant reduction in AD patients suggested that reduced levels of Aβ(1-42) in the CSF are caused by reduced clearance of Aβ from brain to the blood/CS. Changes in CSF Aβ differ based on the disease (Humpel et al ,2011). The determination of the quotient of A β42 Aβ40, and the finding of an elevated of overall tau protein or phospo-tau, have been found to have more than 85% sensitivity. Aβ and high phosphor-tau are 17 times as likely to progress to ad as are MCI patents without CSF profile (Eschweiler et al, 2010). Blood and urine analysis for biomarkers is also can be used to diagnose AD.
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F2-isoprostane-recently mitochondrial dysfunction has also been speculated as one of the pathogenic process occurring in patient with AD. It is hypothesized that Aβ peptide after entering in mitochondria can induce generation of reactive oxygen species leading to mitochondria dysfunction. Currently there is not CSF marker directly reflecting mitochondrial dysfunction, but measurement of F2- isoprostane (F2-iP), a product of lipid peroxidation reflects oxidative stress in AD, and shown to be elevated in patient with AD and MCI.
Metabolic markers molecular imaging by PET and single photoemission computed tomography (SPECT) with radiopharmaceutical agents are routinely used as measure of metabolic activity in varions parts of brain.
Genetic markers genetic defects occurring to AD were found in mutation in gene APP in early onset familial AD .Also mutations in another 2 gen perslin1 and 2 (PSEN1, PSEN2) were reported as novel too. Mutation in APP and PSEN2 increased level Aβ42 - the primary component of amyloid plaques (Wattamawar et al, 2010).
The Mini -Mental State Examination (MMSE) is a short test that takes 10-15 minutes. The patient is asking to memorise 3 words and repeat them few minutes later. This test can be used to prevalence of mild dementia of different types, but cannot be used to diagnose MCI.
Dem Tect test - the patient read 10 words list in 8 to 12minutes and avoids direct question regarding place and time. This test is 85% sensitivity good for mild cognitive impairment and 83% sensitivity for AD. Test is very well established in Germany, but hardly used in other countries.
The clock drawing test - requited the patient to draw a clock in order, an individual intact sematic memory, visuoconstructive skills, spatial perception and executive functions. 90% sensitivity of this test is not useful for differentiating between MCI and AD dementia. The study shows that only patients with progressed AD have problems drawing the clock face (Eschweiler et al, 2010).
Cerad neurocognitive dementia screening test is used in memory clinics. The result with its current cut - of scores has low sensitivity to MCI, and using it as sole screen cognitive for instrument MCI and preclinical dementia might result in false negative (Karrasch et al,2005).
AD have approximately 60% to70% of all dementia case. Cholinesterase inhibitors (ChEI) are mainly treatment for AD which improves behaviour, activities of daily living, and cognitive functions in patients. However, not every patient benefits from this treatment. To responded positively patients with AD to this treatment there are testing by A Quick Test of cognitive speed (AQT), which is a well - validated ,sensitive screening tool for cognitive impairment and AD .Test takes 3-5 minutes, has no ceiling or floor effect. Is independent of gender, education, and culture. The study shown that the AQT test activates temporoparietal cortical area, which is the major brain regions affected in AD (Palmqvist et al 2010). AQT is a promising test for detecting treatment response in AD. For evaluating treatment ChEI is also recommended MMSE test. AQT is very promising test for detecting treatment response in AD. Study in Sweden enrolled patient with AD for treatment with baseline. After 8 weeks treatment, the AQT improvement and was significantly greater compare of the MMSE. AQT test of cognitive speed and attention, seem to be twice as sensitive as the MMSE in detecting early treatment response to CHEI in AD patients. AQT may be important when evaluating new treatments in early stages of AD, because of its sensitivity and lack of ceiling effect (Palmqvist et al, 2010).
AD is the most prevalent causes of dementia and the last stage clinical can result in substantial clinical burden and a reduction of quality of life. There is a number of effective no pharmacological and symptomatic pharmacological approaches to treat AD. Chollinesterase inhibitors have been the cornerstone of treatment for patients with AD for over a decade. Four drugs in this class, donepezil, galntamine, rivastigmine, and tacrine, are approved for the treatment of mild to moderate AD, and they are recommended by the American Academy of Neurology practice parameter as standard of care for treatment of AD (Gedmacher et al, 2007).These drugs are felt to correct the cholinergic deficit seen with AD where there in the loss of acetycholine producing neurons in the brain (Hogan et al, 2007). Vitamin E, Ginkgo biloba, coenzyme Q10 using like antioxidants in support treatment in AD not be successfully recommended after several tests regarding the group of people with AD .Folic acid, vitamin B6 and B12 have the limited effect and has been in demented individuals. Inflammation is felt to be part of pathological cascade that leads to AD, studies that examined diclofenac, naproxen, celcoxib and rofecoxib have been negative (Hogan et al, 2007). Another promising drug is the T-817 MA, which can fight against Aβ inducted toxicity; and can ameliorate congnitive deficits in animal models. Dimebolin (latreperidine) a retired Russian anti-histiamine drug. Dimebolin was reported to inhibit acetylcholinesterase, to potentiate activities of AMPA receptor and block NMDA receptors, Study enrolled 183 patients with mild-to -moderate AD showed significant benefit in cognitive function after 26-week dimebolin treatment(Fan et al,2010 ).Memantine in studies showed improvement in cognitive function ,and behaviours in people with moderate to severe AD after 6 months also may reduce psychological symptoms and reduce behavioural in dementia(Fan et,al 2010).
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Fig2: Morphological MRI scans subjected to automated image analysis. Colour coding is used to indicate the brain areas that are particularly informative for the computer program with regard to the differential diagnosis of Alzheimer's disease from normal aging. The blue and green areas are mainly in the hippocampus and are reduced in size in the patients with Alzheimer's disease; modified from Reference 20, reproduction rights belong to the author, S. Klöppel
Currently there is no cure for AD , and treatments only manage to slow dawn the progression of AD in some patients. Until now there is still no single treatment that can successfully stop or reverse the progression of AD .We propose that near future therapeutics of various combination of symptomatic treatments (AChEI and memantine) and disease modifying therapies will emerge as the standard regimen of AD treatment which should be able to provide a much better efficacy than all current approaches (Fan et,al 2010),