Alzheimer’s disease is an irrevocable and progressing neurodegenerative disorder

Alzheimer’s disease is an irrevocable and progressing neurodegenerative disorder

Alzheimer’s disease is an irrevocable and progressing neurodegenerative disorder. Cognitive and non-Cognitive dysfunctions are the main symptoms of Alzheimer’s disease. Noncognitive dysfunction contains psychiatric symptoms as hallucinations and behavioral disorders but cognitive dysfunction comprise executive dysfunction, language complications and memory loss. (Burns A et al., 1990). There are many hypotheses for explaining the pathophysiology of Alzheimer’s disease either still evidenced. The first theory built on cholinergic dysfunction is cholinergic hypothesis. Donepezil is a piperidine derivative and has been accepted as Cholinesterase inhibitor and using as treatment for moderate Alzheimer’s disease.
It can inhibit acetyl cholinesterase, the inhibition is reversibly and non-competitively (Seltzer B 2007)
Neuropathologically, there is another hypothesis known as Tau hypothesis defined by the occurrence of intraneuronal neurofibrillary lesions made up of tau proteins (Trojanowski JQ and Mattson MP 2003).
Genetically, studies support suggestions that the neurodegeneration in Alzheimer’s disease caused by accumulation of amyloid beta (A?) plaques in different areas of the brain. Therefore, accumulation of amyloid-beta (A?) plaques acts as a pathological cascade that includes formation of neurofibrillary tangles via tau protein leads to neuronal dysfunction and cell death in brain. However, some researchers supported that, presenilins 1 and 2 are proteins generally present in neuron determined by PSEN1 and PSEN2 genes.
Nowadays, postmortem diagnosis is the only way to determine Alzheimer’s disease.
Currently, many researchers focus on pathological hallmarks of Alzheimer’s disease. Intracellular neurofibrillary tangles and senile plaque in living brain tissues.
There is extensive variation of technological brain imaging progress of radiolabeled imaging probes for single photon emission computed tomography and positron emission tomography owing to possible quantification of target molecule and real time targeted molecular imaging. (Skovronsky et al., 2000).

Most of the researchers cannot understand the etiology of Alzheimer’s disease, the biochemical signs and backtracking anatomical signs allows to suppose etiology in upstream of the turmoil.
Blood-brain barrier damage, synaptic loss due to neuronal in Alzheimer’s disease brain, there is variety of neurotoxic candidates such as mitochondria dysfunction, increased concentration of aggregated proteins, reduced synthesis of neurotransmitters, inflammation and oxidative stress.
Recently, some investigators think that 10% to 40% of Alzheimer disease cases based on genetic determinates.
Furthermore, the finding that the apolipoprotein E4 allele is a genetic polymorphism that discusses an increased hazard of Alzheimer disease (Selkoe DJ. 2000) shows that genetic factors influencing to the disease do not need to occur in a dominant pattern. Currently, there are four genes have been proved that cause Alzheimer disease (Table 1) and other candidate genes await confirmation.

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Table (1): Genetic Factors Predisposing to Alzheimer’s disease Relationships to ?- Amyloid Phenotype

Chromosome Gene Defect Phenotype
21 ?-amyloid precursor protein mutations Increased production of all ?-amyloid proteins or ?-amyloid protein 42
19 Apolipoprotein E4 Polymorphism Increased density of ?-amyloid plaques and vascular deposits
14 Presenilin 1 mutations Increased production o ?-amyloid protein 42
1 Presenilin 2 mutations Increased production o ?-amyloid protein 42

In Alzheimer’s disease brain, there is variety of neurotoxic candidates such as mitochondria dysfunction, increased concentration of aggregated proteins, reduced synthesis of neurotransmitters, inflammation and oxidative stress. The most dominant etiologic paradigm of Alzheimer’s pathology is ?-amyloid and tau hypotheses. Previous studies showed that the reduction of senile plaques and prevention new deposits of A? (Chang, W.P. et al., 2004) is due to the immunization of amyloid precursor protein in transgenic mice with ?-amyloid.
A safe oral ?-amyloid vaccine has been developed which has shown to elevate antibodies, amyloid precursor protein (APP) transgenic mice and old monkeys have shown significant reduction of amyloid burden without any side-effects, it is supposed that immunization is a hopeful way to cure and prevent Alzheimer’s disease (Tabira, T. 2007).

Overview of Parkinson’s disease
Parkinson’s disease considered the second common neurodegenerative diseases after Alzheimer’s disease. Etiology of Parkinson’s disease is still being researched with few theories. The world frequency of Parkinson’s disease is approximately 150 individuals per 100 000 and increasing rapidly. Risk factors include age and geographical location. Older people in industrialized regions are at a greater risk of Parkinson’s disease than those in less industrial regions.
Exposure to doses of methylphenyltetrahydropyridine (MPTP), and former exposure to viral encephalitis lethargica also present a risk.
So far, research has focused on endogenous toxins genetics, viral infection and environmental toxins.
The features of Parkinson’s disease are bradykinesia, muscular rigidity, tremor, micrographia and postural instability (Conley, S.C. 1999).
Atypical and Typical usual parkinsonian diseases are characterized according to the neuronal loss caused and the resulting clinical symptoms as labelled in (Table 2).

Neuropathological hallmarks of Parkinson’s disease is the degeneration of dopaminergic neurons in the substantia nigra pars compacta of the brain in addition to astrocytic gliosis and the presence of numerous other neuronal systems, linked with widespread occurrence of intracytoplasmic ?- synuclein positive inclusions known as Lewy bodies and Lewy neurites of neuronal cells (Goedert, M. 2001).
The pathogenesis of Parkinson’s disease includes ubiquitous protein ?-synuclein, aggregation of this protein binds the proteasome and strongly inhibits proteasomal activity. (Hashimoto, M. et al., 2004), there is a correlation between ?-synuclein and dopaminergic neurotransmission (Schultz, et al., 2001).
The genetic involvement in Parkinson’s disease is still a debatable issue. Three genes named ?-synuclein, a pre-synaptic terminal central nervous system lipophilic protein comprised of 140-amino acids, parkin and ubiquitin Cterminal hyrolase L1 have been recognized as the potential cause of hereditary Parkinson’s disease.
Although rare families have mutations of these genes, tau has been recognized as a causative gene for frontotemporal dementia and Parkinsonism (Nobutaka, N. and Yoshikun, M. 2001).
Some cases of Parkinson’s disease have been observed early (20-40 years) is termed juvenile Parkinsonism.
In addition, studies showed the onset of injuries in the dorsal motor vagals nucleus and linked medullary nuclei, instituting the “gain setting system” of the lower brainstem and the olfactory system. The initial lesions in the lower brainstem and olfactory system may clarify early autonomic and olfactory injury that may precede the somato-motor dysfunctions. The initial lesions in the lower brainstem and olfactory system may clarify initial autonomic and olfactory impairment that may precede the somato-motor dysfunctions. Clinical subtypes of Parkinson’s disease revealed specific lesion patterns with neuropathophysiological and therapeutic relevance.
Oxidative stress also play an important role in Parkinson disease Oxidative stress happens when an imbalance is formed between production of reactive oxygen species and cellular antioxidant activity. The cellular dysfunction and demise in Parkinson disease is due to mechanism of oxidative stress (Andersen, 2004).
Many risk factors like oxidative stress are associated with Parkinson disease includes formation of free radicals and a number of environmental toxins (Logroscino G. 2005) (Table 1).
Limited data support genetic relations with Parkinson disease, with some gene mutations identified (Spatola M. and Wider C. 2014) (Table 2).
Although amyloid beta 1–42 is associated with Alzheimer’s disease (AD) and its pathology, recent data suggest that cerebral spinal fluid containing this biomarker may predict cognitive decline in Parkinson’s disease as well. These data are consistent with previous research, which reported that the pathology of Alzheimer’s disease contributes to cognitive impairment in Parkinson’s disease and may have relevance in predicting the cognitive decline associated with Parkinson’s disease (Siderowf A. et al., 2010).
The involvement of inflammation in the pathogenesis of Parkinson’s disease is also being studied, especially the role of cytokines and other mediators. Inflammatory responses secondary to the degeneration of dopaminergic neurons may play a role in PARKINSON’S DISEASE and contribute to its pathogenesis. In vitro data have supported the activation of microglia and astrocytes secondary to injured dopaminergic neurons.
In summary, Parkinson’s disease is a complex neurodegenerative disease involving an array of molecular pathways, all of which may be implicated in the neuropathophysiology of the disease.


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