Neurodegenerative Disease is a condition which affects the brain function. It results from the deterioration of neurons. These are two types :
Ø Conditions causing’s problems with Movements.
Ø Conditions affecting memory and conditions related to dementia.
Parkinson's disease.
Parkinson's disease (also known as Parkinson disease or PD) is a degenerative disorder of the central nervous system that often impairs the sufferer's motor skills and speech.
Parkinson's disease belongs to a group of conditions called movement disorders. It is characterized by muscle rigidity, tremor, a slowing of physical movement (bradykinesia), and in extreme cases, a loss of physical movement (akinesia). The primary symptoms are the results of decreased stimulation of the motor cortex by the basal ganglia, normally caused by the insufficient formation and action of dopamine, which is produced in the dopaminergic neurons of the brain. Secondary symptoms may include high level cognitive dysfunction and subtle language problems. PD is both chronic and progressive.
PD is the most common cause of “Parkinsonism”, a group of similar symptoms. PD is also called "primary parkinsonism" or "idiopathic PD" ("idiopathic" meaning of no known cause). While most forms of Parkinsonism are idiopathic, there are some cases where the symptoms may result from toxicity, drugs, genetic mutation, head trauma, or other medical disorders.
This disease was first recognized and its symptoms were documented by the British physician James Parkinson. Parkinson's disease was then known as paralysis agitans, the term "Parkinson's disease" being coined later by Jean-Martin Charcot. The underlying biochemical changes in the brain were identified in the 1950s due largely to the work of Swedish scientist Arvid Carlsson, who later went on to win a Nobel Prize. L-dopa entered clinical practice in 1967, and the first study reporting improvements in patients with Parkinson's disease resulting from treatment with L-dopa was published in 1968.
Symptoms
Parkinson disease affects movement (motor symptoms). Typical other symptoms include disorders of mood, behavior, thinking, and sensation (non-motor symptoms). Individual patients' symptoms may be quite dissimilar and progression of the disease is also distinctly individual.
How Parkinson disease occur?
Its occurs when a group of cells in an area of the brain called the Substantia nigra begin to malfunction and die. Substantia nigra produces a neuro transmitter called DOPAMINE which controls movement and co-ordination. When a person has PD there Dopamine producing cells begin to die and the amount of Dopamine produced in the brain decreases. Thus it will cause the movement disorders.
Motor symptoms
Ø Tremor: normally 4-7Hz tremor, maximal when the limb is at rest, and decreased with voluntary movement. It is typically unilateral at onset. This is the most apparent and well-known symptom, though an estimated 30% of patients have little perceptible tremor; these are classified as akinetic-rigid.
Ø Rigidity: stiffness; increased muscle tone. In combination with a resting tremor, this produces a ratchety, "cogwheel" rigidity when the limb is passively moved.
Ø Bradykinesia/akinesia: respectively, slowness or absence of movement. Rapid, repetitive movements produce a dysrhythmic and decremental loss of amplitude. Also "dysdiadokinesia", which is the loss of ability to perform rapid alternating movements
Ø Postural instability: failure of postural reflexes, which leads to impaired balance and falls.
Other motor symptoms include:
Ø Gait and posture disturbances:
Ø Shuffling: gait is characterized by short steps, with feet barely leaving the ground, producing an audible shuffling noise. Small obstacles tend to trip the patient
Ø Decreased arm swing: a form of bradykinesia
Ø Turning "en bloc": rather than the usual twisting of the neck and trunk and pivoting on the toes, PD patients keep their neck and trunk rigid, requiring multiple small steps to accomplish a turn.
Ø Stooped, forward-flexed posture. In severe forms, the head and upper shoulders may be bent at a right angle relative to the trunk (camptocormia).
Ø Festination: a combination of stooped posture, imbalance, and short steps. It leads to a gait that gets progressively faster and faster, often ending in a fall.
Ø Gait freezing: "freezing" is another word for akinesia, the inability to move. Gait freezing is characterized by inability to move the feet, especially in tight, cluttered spaces or when initiating gait.
Ø Dystonia (in about 20% of cases): abnormal, sustained, painful twisting muscle contractions, usually affecting the foot and ankle, characterized by toe flexion and foot inversion, interfering with gait. However, dystonia can be quite generalized, involving a majority of skeletal muscles; such episodes are acutely painful and completely disabling.
Ø Speech and swallowing disturbances
Ø Hypophonia: soft speech. Speech quality tends to be soft, hoarse, and monotonous. Some people with Parkinson's disease claim that their tongue is "heavy".
Ø Festinating speech: excessively rapid, soft, poorly-intelligible speech.
Ø Drooling: most likely caused by a weak, infrequent swallow and stooped posture.
Ø Non-motor causes of speech/language disturbance in both expressive and receptive language: these include decreased verbal fluency and cognitive disturbance especially related to comprehension of emotional content of speech and of facial expression[5]
Ø Dysphagia: impaired ability to swallow. Can lead to aspiration, pneumonia, and ultimately death.
Ø fatigue (up to 50% of cases);
Ø masked faces (a mask-like face also known as hypomimia), with infrequent blinking;[6]
Ø difficulty rolling in bed or rising from a seated position;
Ø micrographia (small, cramped handwriting);
Ø impaired fine motor dexterity and coordination;
Ø impaired gross motor coordination;
Ø Poverty of movement: overall loss of accessory movements, such as decreased arm swing when walking, as well as spontaneous movement.
Non-motor symptoms
More generally, there is an increased risk for any individual with depression to go on to develop Parkinson's disease at a later date. 70% of individuals with Parkinson's disease diagnosed with pre-existing depression go on to develop anxiety. 90% of Parkinson's disease patients with pre-existing anxiety subsequently develop depression.
Ø Cognitive disturbances
• slowed reaction time; both voluntary and involuntary motor responses are significantly slowed.
• executive dysfunction, characterized by difficulties in: differential allocation of attention, impulse control, set shifting, prioritizing, evaluating the salience of ambient data, interpreting social cues, and subjective time awareness. This complex is present to some degree in most Parkinson's patients; it may progress to:
• dementia: a later development in approximately 20-40% of all patients, typically starting with slowing of thought and progressing to difficulties with abstract thought, memory, and behavioral regulation. Hallucinations, delusions and paranoia may develop.
• short term memory loss; procedural memory is more impaired than declarative memory. Prompting elicits improved recall.
• medication effects: some of the above cognitive disturbances are improved by dopaminergic medications, while others are actually worsened[9]
Ø Sleep disturbances
• Excessive daytime somnolence
• Initial, intermediate, and terminal insomnia
• Disturbances in REM sleep: disturbingly vivid dreams, and REM Sleep Disorder, characterized by acting out of dream content - can occur years prior to diagnosis
Ø Sensation disturbances
• impaired visual contrast sensitivity, spatial reasoning, colour discrimination, convergence insufficiency (characterized by double vision) and oculomotor control
• dizziness and fainting; usually attributable orthostatic hypotension, a failure of the autonomous nervous system to adjust blood pressure in response to changes in body position
• impaired proprioception (the awareness of bodily position in three-dimensional space)
• reduction or loss of sense of smell (microsmia or anosmia) - can occur years prior to diagnosis,
• pain: neuropathic, muscle, joints, and tendons, attributable to tension, dystonia, rigidity, joint stiffness, and injuries associated with attempts at accommodation
Ø Autonomic disturbances
• oily skin and seborrheic dermatitis
• urinary incontinence, typically in later disease progression
• nocturia (getting up in the night to pass urine) - up to 60% of cases
• constipation and gastric dysmotility that is severe enough to endanger comfort and even health
• altered sexual function: characterized by profound impairment of sexual arousal, behavior, orgasm, and drive is found in mid and late Parkinson disease. Current data addresses male sexual function almost exclusively
• weight loss, which is significant over a period of ten years - 8% of body weight lost compared with 1% in a control group.
Diagnosis.
There are currently no blood or laboratory tests that have been proven to help in diagnosing PD. Therefore the diagnosis is based on medical history and a neurological examination. The disease can be difficult to diagnose accurately. The Unified Parkinson's Disease Rating Scale is the primary clinical tool used to assist in diagnosis and determine severity of PD. Indeed, only 75% of clinical diagnoses of PD are confirmed at autopsy. The physician may need to observe the person for some time until it is apparent that the symptoms are consistently present. Usually doctors look for shuffling of feet and lack of swing in the arms. Doctors may sometimes request brain scans or laboratory tests in order to rule out other diseases. However, CT and MRI brain scans of people with PD usually appear normal.
18F PET scan shows decreased dopamine activity in the basal ganglia, a pattern which aids in diagnosing Parkinson's disease.Pathology
The symptoms of Parkinson's disease result from the loss of pigmented dopamine-secreting (dopaminergic) cells and subsequent loss of melanin, secreted by the same cells, in the pars compacta region of the substantia nigra (literally "black substance"). These neurons project to the striatum and their loss leads to alterations in the activity of the neural circuits within the basal ganglia that regulate movement, in essence an inhibition of the direct pathway and excitation of the indirect pathway.
The direct pathway facilitates movement and the indirect pathway inhibits movement, thus the loss of these cells leads to a hypokinetic movement disorder. The lack of dopamine results in increased inhibition of the ventral lateral nucleus of the thalamus, which sends excitatory projections to the motor cortex, thus leading to hypokinesia.
There are four major dopamine pathways in the brain; the nigrostriatal pathway, referred to above, mediates movement and is the most conspicuously affected in early Parkinson's disease. The other pathways are the mesocortical, the mesolimbic, and the tuberoinfundibular. These pathways are associated with, respectively: volition and emotional responsiveness; desire, initiative, and reward; and sensory processes and maternal behavior. Disruption of dopamine along the non-striatal pathways likely explains much of the neuropsychiatric pathology associated with Parkinson's disease.
The mechanism by which the brain cells in Parkinson's are lost may consist of an abnormal accumulation of the protein alpha-synuclein bound to ubiquitin in the damaged cells. The alpha-synuclein-ubiquitin complex cannot be directed to the proteosome. This protein accumulation forms proteinaceous cytoplasmic inclusions called Lewy bodies. Latest research on pathogenesis of disease has shown that the death of dopaminergic neurons by alpha-synuclein is due to a defect in the machinery that transports proteins between two major cellular organelles — the endoplasmic reticulum (ER) and the Golgi apparatus. Certain proteins like Rab1 may reverse this defect caused by alpha-synuclein in animal models.
Excessive accumulations of iron, which are toxic to nerve cells, are also typically observed in conjunction with the protein inclusions. Iron and other transition metals such as copper bind to neuromelanin in the affected neurons of the substantia nigra. So, neuromelanin may be acting as a protective agent. Alternately, neuromelanin (an electronically active semiconductive polymer) may play some other role in neurons. That is, coincidental excessive accumulation of transition metals, etc. on neuromelanin may figure in the differential dropout of pigmented neurons in Parkinsonism. The most likely mechanism is generation of reactive oxygen species.
Iron induces aggregation of synuclein by oxidative mechanisms.Similarly, dopamine and the byproducts of dopamine production enhance alpha-synuclein aggregation. The precise mechanism whereby such aggregates of alpha-synuclein damage the cells is not known. The aggregates may be merely a normal reaction by the cells as part of their effort to correct a different, as-yet unknown, insult. Based on this mechanistic hypothesis, a transgenic mouse model of Parkinson's has been generated by introduction of human wild-type α-synuclein into the mouse genome under control of the platelet-derived-growth factor-β promoter.
Dopaminergic pathways of the human brain in normal condition (left) and Parkinson's disease (right). Red Arrows indicate suppression of the target, blue arrows indicate stimulation of target structure.
Most Striking Gross Pathology Abnormality in PD
Ø Loss of pigmentation in Substantia nigra due to the loss of Neuromelanin containing Dopamine producing neurons.
Ø Lewi bodies are found in the cytoplasm of neurons and are composed of densely aggregated filaments. These filaments contain Ubiquitin and alpha synuclein.
What Happens to this Dopamine Secreting cells?
The symptoms of PD results from the loss of Dopaminergic Cells and subsequent loss of Melanin; secreted by the same cells in the Para compacta region of Substantia nigra. These neurons project to the Striatum and their loss leads to alterations in the activity of the neural circuits within the Basal Ganglia that regulates movement by direct and indirect pathway.
Ø Direct pathway facilitates Movement
Ø Indirect pathway inhibits Movement
Thus loss of these cells leads to hypokinetic movement disorder. The lack of Dopamine results in increased inhibition of the ventral lateral nucleus of the Thalamus, which sends excitatory projections to the motor cortex thus leading to Hypokinesia.
There are four major Dopamine pathways in Brain.
Ø Nigrostriatal Pathway – mediates movement [ most conspicuously affected in early PD ]
Ø Mesocortical pathway – mediates emotional responses.
Ø Mesolimbic pathway – mediates desire, initiative, reward.
Ø Tuberoinfundibular pathway – sensory process & maternal behavior.
Other brain chemicals like GABA , Norepinephrine , Serotonin and Acetyl choline also exhibit damage in PD.
Biochemical findings.
In the brain cells there is an abnormal accumulation of the protein Alpha-synuclein bound to Ubiquitin in the damaged cells. This protein accumulations forms proteinaceous cytoplasmic inclusions called lewy bodies. Excessive accumulations of iron which are toxic to nerve cells are also typically observed in conjugation with the protein inclusions.
Causes of Parkinson's disease
Most people with Parkinson's disease are described as having idiopathic Parkinson's disease (having no specific cause). There are far less common causes of Parkinson's disease including genetic, toxins, head trauma, and drug-induced Parkinson's disease.
Genetic : In recent years, a number of specific genetic mutations causing Parkinson's disease have been discovered. These account for a small minority of cases of Parkinson's disease. Somebody who has Parkinson's disease is more likely to have relatives that also have Parkinson's disease. However, this does not mean that the disorder has been passed on genetically.
Genetic forms that have been identified include:
Ø PARK1, caused by mutations in the SNCA gene, which codes for the protein alpha-synuclein. PARK1 causes autosomal dominant Parkinson disease. So-called PARK4 is probably caused by triplication of SNCA.
Ø PARK2, caused by mutations in protein parkin. Parkin mutations may be one of the most common known genetic causes of early-onset Parkinson disease. Patients with parkin mutations (PARK2) do not have Lewy bodies. Such patients develop a syndrome that closely resembles the sporadic form of PD; however, they tend to develop symptoms at a much younger age.
Ø PARK3 , mapped to 2p, autosomal dominant
Ø PARK5, caused by mutations in the UCHL1 gene which codes for the protein ubiquitin carboxy-terminal hydrolase L1
Ø PARK6 , caused by mutations in PINK1 which codes for the protein PTEN-induced putative kinase 1.
Ø PARK7 , caused by mutations in DJ-1
Ø PARK8 , caused by mutations in LRRK2 which codes for the protein dardarin. In vitro, mutant LRRK2 causes protein aggregation and cell death, possibly through an interaction with parkin.LRRK2 mutations, of which the most common is G2019S, cause autosomal dominant Parkinson disease, with a penetrance of nearly 100% by age 80.
Ø PARK12, maps to the X chromosome.
Toxins : This disease may result in many or even most cases from the combination of a genetically determined vulnerability to environmental toxins along with exposure to those toxins. The toxins most strongly suspected at present are certain pesticides and transition-series metals such as manganese or iron, especially those that generate reactive oxygen species, and or bind to neuromelanin. Other toxin-based models employ PCBs, paraquat (an herbicide) in combination with maneb (a fungicide) rotenone (an insecticide), and specific organochlorine pesticides including dieldrin and lindane.
Head trauma : Past episodes of head trauma are reported more frequently by sufferers than by others in the population. A methodologically strong recent study found that those who have experienced a head injury are four times more likely to develop Parkinson’s disease than those who have never suffered a head injury.
Drug-induced : Antipsychotics, which are used to treat schizophrenia and psychosis, can induce the symptoms of Parkinson's disease by lowering dopaminergic activity. Due to feedback inhibition, L-dopa can also eventually cause the symptoms of Parkinson's disease that it initially relieves. Dopamine agonists can also eventually contribute to Parkinson's disease symptoms by decreasing the sensitivity of dopamine receptors.
Treatment
Parkinson's disease is a chronic disorder that requires broad-based management including patient and family education, support group services, general wellness maintenance, exercise, and nutrition. At present, there is no cure for PD, but medications or surgery can provide relief from the symptoms.
Ø Levodopa : The most widely used form of treatment is L-dopa in various forms. L-dopa is transfomed into dopamine in the dopaminergic neurons by L-aromatic amino acid decarboxylase (often known by its former name dopa-decarboxylase). However, only 1-5% of L-DOPA enters the dopaminergic neurons. The remaining L-DOPA is often metabolised to dopamine elsewhere, causing a wide variety of side effects. Due to feedback inhibition, L-dopa results in a reduction in the endogenous formation of L-dopa, and so eventually becomes counterproductive.
Ø Carbidopa and benserazide are dopa decarboxylase inhibitors. They help to prevent the metabolism of L-dopa before it reaches the dopaminergic neurons and are generally given as combination preparations of carbidopa/levodopa and benserazide/levodopa .
Ø Tolcapone : inhibits the COMT enzyme, thereby prolonging the effects of L-dopa, and so has been used to complement L-dopa.
Ø Dopamine agonists :The dopamine-agonists bromocriptine, pergolide, pramipexole, ropinirole , cabergoline, apomorphine, and lisuride, are moderately effective. Dopamine agonists can be useful for patients experiencing on-off fluctuations and dyskinesias as a result of high doses of L-dopa.
Ø MAO-B inhibitors :Selegiline and rasagiline reduce the symptoms by inhibiting monoamine oxidase-B (MAO-B), which inhibits the breakdown of dopamine secreted by the dopaminergic neurons.
Ø Surgical interventions : Deep brain stimulation is presently the most used surgical means of treatment, but other surgical therapies that have shown promise include surgical lesion of the subthalamic nucleus and of the internal segment of the globus pallidus, a procedure known as pallidotomy.
Physical exercise: Regular physical exercise and/or therapy, including in forms such as yoga, tai chi, and dance can be beneficial to the patient for maintaining and improving mobility, flexibility, balance and a range of motion.
Methods undergoing evaluation
Ø Gene therapy: Currently under investigation is gene therapy. This involves using a harmless virus to shuttle a gene into a part of the brain called the subthalamic nucleus (STN). The gene used leads to the production of an enzyme called glutamic acid decarboxylase (GAD), which catalyses the production of a neurotransmitter called GABA. GABA acts as a direct inhibitor on the overactive cells in the STN.
Ø GDNF infusion involves the infusion of GDNF (glial-derived neurotrophic factor) into the basal ganglia using surgically implanted catheters. Via a series of biochemical reactions, GDNF stimulates the formation of L-dopa. GDNF therapy is still in development.In the future, implantation of cells genetically engineered to produce dopamine or stem cells that transform into dopamine-producing cells may become available. Even these, however, will not constitute cures because they do not address the considerable loss of activity of the dopaminergic neurons.
Ø Neuroprotective treatments: Neuroprotective treatments includes some neuroprotective agents. These agents could protect neurons from cell death induced by disease presence resulting in a slower pregression of disease. Agents currently under investigation as neuroprotective agents include apoptotic drugs (CEP 1347 and CTCT346), lazaroids, bioenergetics, antiglutamatergic agents and dopamine receptors. Clinically evaluated neuroprotective agents are the monoamine oxidase inhibitors selegiline and rasagiline, dopamine agonists, and the complex I mitochondrial fortifier coenzyme Q10.
Ø Neural transplantation
Ø Nutrients: Nutrients have been used in clinical studies and are widely used by people with Parkinson's disease in order to partially treat Parkinson's disease or slow down its deterioration. The L-dopa precursor L-tyrosine was shown to relieve an average of 70% of symptoms. Ferrous iron, the essential cofactor for L-dopa biosynthesis was shown to relieve between 10% and 60% of symptoms in 110 out of 110 patients. Vitamin C and vitamin E in large doses are commonly used by patients in order to theoretically lessen the cell damage that occurs in Parkinson's disease. This is because the enzymes superoxide dismutase and catalase require these vitamins in order to nullify the superoxide anion, a toxin commonly produced in damaged cells.
Prognosis
PD is not by itself a fatal disease, but it usually gets worse with time. The average life expectancy of a PD patient is generally lower than for people who do not have the disease. In the late stages of the disease, PD may cause complications such as choking, pneumonia, and falls that can lead to death.
The progression of symptoms in PD may take 20 years or more. In some people, however, the disease progresses more quickly.
One commonly used system for describing how the symptoms of PD progress is called the Hoehn and Yahr scale. Another commonly used scale is the Unified Parkinson's Disease Rating Scale (UPDRS).
Notable Parkinson's sufferers
Ø Michael J. Fox , who has written a book about his experience of the disease and established The Michael J. Fox Foundation for Parkinson's Research to develop a cure for Parkinson's disease within this decade.
Ø Pope John Paul II
Ø Eugene O'Neill – playwright
Ø Muhammad Ali - boxer.
Ø Adolf Hitler
Ø Francisco Franco.
Ø Mao Zedong
Ø Yasser Arafat.
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