الفهرس يوجد فقط 14 صفحة متاحة للعرض العام
 |  | from | 73 |  |  |
| | | from | 73 | | |
المستخلص
Alzheimer disease (AD) is an irreversible neurodegenerative disease of the brain that slowly destroys memory and the ability to think, eventually debilitating affected patients. A continuous slow decline in cognition is the most characteristic and striking feature of AD. The earliest recognized stage is mild cognitive impairment, in which patients develop amnesia but are not functionally impaired in terms of activities of daily living (ADL).
The etiology of AD is not known but risk factors include: Advancing age, genetics, female sex, lack of education and repeated head trauma.
The pathologic hallmarks of AD include the presence of senile plaques (SPs) and neurofibrillary tangles (NFTs) in the cortex, hippocampus, and other regions of the brain. Senile plaques are primarily composed of insoluble amyloid fibrils containing β amyloid (Aβ peptide). Formation of NFTs is the result of a hyperphosphorylation of the microtubule-associated protein tau. Hyperphosphorylated tau accumulates as tangles of paired helical filaments in neurons undergoing degeneration.
Multiple theories and hypothesis are put to explain how AD occurs, and these include:
Cholinergic and Glutamatergic Involvement: Loss of cholinergic neurons seems to be specifically associated with typical clinical symptoms, like memory deficits, impaired attention, cognitive decline and reduced learning abilities. Although, neuropathologic studies have documented reduced levels of glutamate reuptake in the frontal and temporal cortices of patients with AD.
Tau hypothesis: Hyperphosphorylated and aggregated Tau impairs axonal transport.
Aβ centric theory: The Aβ theory is strongly supported by compelling genetic data. To date only three different genes, all associated with Aβ production, are implicated in the pathophysiology of Alzheimer’s disease, mutations of the amyloid precursor protein gene on chromosome 21, mutations in the presenilin 1 and 2 genes on chromosome 14 and 1, respectively and a polymorphism in the apolipoprotein E gene on chromosome 19.
Vascular theory: Dysfunction of the neurovascular unit, resulting in impaired CBF regulation and BBB transport, could impair Aβ clearance and lead to increased levels of soluble and fibrillary Aβ forms.
Oxidative stress theory: There is increasing evidence that the very earliest neuronal and pathological changes characteristic of AD show evidence of oxidative damage, which indicates that oxidative stress is a very early contributor to the disease.
Nitric oxide: Peroxynitrite formation in AD may be responsible for the observed cytochrome c oxidase deficiency, and it may be relevant for the understanding of the pathogenesis of this disorder.
Neurotrophins: Include Nerve growth factor (NGF), Brain-derived neurotrophic factor, NT-3 and NT-4/5 and Fibroblast growth factor-2.
Mitochondrial involvement: Mitochondrial dysfunction has been widely implicated in the pathogenesis of Alzheimer’s disease.
Cholesterol and amyloid-β production: Levels of total cholesterol and LDL cholesterol in serum have been found to correlate with Aβ load in the brains of patients with AD.
Diagnosis of AD during life is based on medical history, neuropsychological tests, brain imaging studies, and medical tests to rule out any other possible diseases as causes for generalized dementia.
Psychological assessment: Include:
• Cognitive and Functional assessment using multiple tests and scales such as: Disability Assessment for Dementia (DAD) scale and Neuropsychiatric Inventory (NPI).
• Other assessment domains: Nutrition, gait and movement disorders, continence, pressure ulceration, limb contractures, and pain that can be much more difficult to assess.
Laboratory assessment: Include:
• CSF examination:
o An autopsy study demonstrated an inverse correlation between Aβ42 levels in the CSF and the number of plaques.
o There is an increase in the concentration of t-tau in AD patients by approximately 300%
o An increase in p-tau has consistently been found in the CSF of AD patients.
Neuro-Imaging:
Structural MRI
• Hippocampus volumetry: It is the best established structural biomarker for AD.
• Volumetry of the entorhinal cortex:At the MCI stage, it might gradually improve prognostic efficiency by a few percent compared with hippocampal volumetry.
• Voxel-based volumetry:The most commonly investigated method to date is voxel-based volumetry (VBM), as it shows a reduction in the cortical gray matter in the region of the medio-temporal lobes and lateral temporal and parietal association areas in AD patients.
• Analysis of cortical thickness
• Imaging the cholinergic nuclei in the basal forebrain
Functional magnetic resonance imaging: It allows for the measurement of brain activation during cognitive tasks without any radiation exposure to the patient.
Diffusion tensor imaging: It might be useful as a diagnostic tool with measures of regional brain volume.
Magnetic resonance spectroscopy: It provides information on tissue substrate or metabolite concentrations.
SPECT: It can be helpful in diagnosing dementia and differentiating AD from frontotemporal dementia.
Positron Emission Tomography (PET): In AD patients, 18FDG-PET shows a typical pattern of reduced cortical uptake in the region of the temporal and parietal association cortex, particularly in the region of the posterior cingulum; in mild to moderate stages of AD, prefrontal association areas are affected as well.
Treatment of AD: include
• Symptomatic treatment: Many studies indicate that behavioral problems emerge across the course of AD and are most common in the advanced stages. Almost all trials of antipsychotic and mood stabilizing agents have been conducted in patients with moderate to severe AD, reflecting the high prevalence of these disorders in patients with more advanced disease.
• ACE inhibitors: There was little evidence to support a role for ACE in the degradation of Aβ in vivo, by contrast with indications from previous in-vitro studies.
• Disease-modifying trials: The aim of these drugs is to delay progression of the disease by acting on pathophysiological processes. These trials include:
Diet and life style: Cognitively stimulating environments, physical exercise and diets low in calories and ‘bad’ fats (cholesterol and saturated fats) may reduce the risk of AD.
Antioxidant agents: Neuroprotective strategies involving inhibition of free radicals may be effective in delaying disease progression in AD.
• Cholinesterase inhibitors: Donepezil, Rivastigmine, and Galantamine are widely used to treat patients with mild to moder¬ate AD.
• NMDA receptor antagonists:
Memantine: It is NMDA receptor antagonist approved for the treatment of moderate to severe AD.
NitroMemantines: They are second-generation memantine.
• New approaches to the treatment:
1. β secretase inhibitor: It catalyses the first step of Aβ production.
2. γ secretase inhibitor: It is able to reduce Aβ production without affecting Notch signaling.
3. Aβ immunization: One promising approach for preventing and treating AD is based upon stimulating the immune system to remove Aβ from the brain either by active or passive immunization.
4. IVIg: It contains antibodies to amyloid-β, which have been eluted and detected by ELISA.
5. Amyloid anti aggregants.
6. Other amyloid modulating approaches; Tarenflurbil: It is a selective Aβ42 lowering agent (SALA).
7. Metal Chelators (PBT2): The effect of PBT2 is on the putative biomarkers for AD in CSF which means that it has a central effect on Aβ metabolism.
8. Anti-inflammatory: Ibuprofen, indomethacin, celexoxib showed great reduction of Aβ plaques.
9. Cholesterol lowering drugs (STATINS): Statins are clinically safe drugs that pass through the blood–brain barrier, so they could potentially be used as an effective means of reducing Aβ burden