Overview on PD and AD

Parkinson's diseaseParkinson's disease (PD also known as idiopathic or

primary parkinsonism) is a degenerative disorder of the central nervous system.

The motor symptoms of Parkinson's disease result from the death of pigmented dopamine-generating cells in the substantia nigra, a region of the midbrain; the cause of this cell death is unknown.

Early in the course of the disease, the most obvious symptoms are movement-related; these include shaking, rigidity, slowness of movement and difficulty with walking.

Later, thinking and behavioral problems may arise, with dementia commonly occurring in the advanced stages of the disease.

Parkinson's disease: Clinical Overview

Parkinsonism is a clinical syndrome consisting of four cardinal features:

• bradykinesia (slowness and poverty of movement)

• muscular rigidity • resting tremor (which usually abates

during voluntary movement) • an impairment of postural balance leading

to disturbances of gait and falling

The four primary symptoms of PD are tremor, or trembling in hands, arms, legs, jaw, and face; rigidity, or stiffness of the limbs and trunk; bradykinesia, or slowness of movement; and postural instability, or impaired balance and coordination. As these symptoms become more pronounced, patients may have difficulty walking, talking, or completing other simple tasks. PD usually affects people over the age of 50. Early symptoms of PD are subtle and occur gradually.

Parkinson's disease

Clinical features of PDFour cardinal symptoms:• bradykinesia (slowness and poverty

of movement) • muscular rigidity • resting tremor (which usually

abates during voluntary movement)

• an impairment of postural balance leading to disturbances of gait and falling

Parkinson's disease: Clinical Overview

Clinical features of PD

Resting tremor: Most common first symptom, usually asymmetric and most evident in one hand with the arm at rest.

Bradykinesia: Difficulty with daily activities such as writing, shaving, using a knife and fork, and opening buttons; decreased blinking, masked facies, slowed chewing and swallowing.

Rigidity: Muscle tone increased in both flexor and extensor muscles providing a constant resistance to passive movements of the joints; stooped posture, anteroflexed head, and flexed knees and elbows.

Additional clinical features of PD

Postural instability: Due to loss of postural reflexes.

Dysfunction of the autonomic nervous system: Impairedgastrointestinal motility, bladder dysfunction, excessive head and neck sweating, and orthostatic hypotension.

Depression: Mild to moderate depression in 50 % of patients.

Cognitive impairment: Mild cognitive decline including impaired visual-spatial perception and attention, slowness in execution of motor tasks, and impaired concentration in most patients; at least 1/3 become demented during the course of the disease.

Functional neuroanatomy of PD

Substantia nigra: The major origin of the dopaminergic innervation of the striatum.

Part of extrapyramidal system which processes information coming from the cortex to the striatum, returning it back to the cortex through the thalamus.

One major function of the striatum is the regulation of posture and muscle tonus.

Dopamine pathways in human brain

Neurochemistry of PD

PD symptoms become manifest when about 50-60 % of the DA-containing neurons in the substantia nigra and 70-80 % of striatal DA are lost.

The ventral tegmental area (VTA) cells project to limbic (mesolimbic projection) and cortical (mesocortical projection) areas. Neurons of the substantia nigra project to the striatum (nigrostriatal projection). In PD, dopaminergic nerve cells in the substantia nigra nerve cell loss, and its degeneration and the resulting striatal dopamine depletion are responsible for most of the motor abnormalities

Therapy of PD: levodopa

Late 1950s: L-dihydroxyphenylalanine (L-DOPA; levodopa), a precursor of DA that crosses the blood-brain barrier, could restore brain DA levels and motor functions in animals treated with catecholamine depleting drug (reserpine).

First treatment attempts in PD patients with levodopa resulted in dramatic but short-term improvements; took years before it become an established and succesfull treatment.

Still today, levodopa cornerstone of PD treatment; virtually all the patients benefit.

Therapy of PD: levodopa

In clinical practice, levodopa is almost always administered in combination with a peripherally acting inhibitor of aromatic L-amino acid decarboxylase, such as carbidopa.

If levodopa is administered alone, the drug is largely decarboxylated by enzymes in the intestinal mucosa and other peripheral sites so that relatively little unchanged drug reaches the cerebral circulation and probably <1% penetrates the CNS

Levodopa: Pharmacokinetics

Therapeutic and adverse effects result from the decarboxylation of levo-dopa to DA.

When administered orally, levodopa is absorbed rapidly from the small bowel by the transport system for aromatic amino acids.

drug in plasma usually peak between 0.5 and 2 hours after an oral dose.

The t1/2 in plasma is short (1-3 hours). The rate and extent of absorption depends on the rate of gastric emptying, the pH of gastric juice, and the length of time the drug is exposed to the degradative enzymes of the gastric and intestinal mucosa.

Administration of levodopa with high-protein meals delays absorption. WHY?

Levodopa: Pharmacokinetics

Inhibition of peripheral COMT by entacapone increases the amount of L-DOPA and dopamine in the brain and improves the alleviation of PD symptoms.

Competition for absorption sites in the small bowel from dietary amino acids also may have a marked effect on the absorption of levodopa.

Entry of the drug into the CNS across the blood-brain barrier also is mediated by a membrane transporter for aromatic amino acids, and competition between dietary protein and levodopa may occur at this level.

In the brain, levodopa is converted to DA by decarboxylation primarily within the presynaptic terminals of dopaminergic neurons in the stratium. The DA produced is responsible for the therapeutic effectiveness of the drug in PD; after release, it is either transported back into dopaminergic terminals by the presynaptic uptake mechanism or metabolized by the actions of MAO and catechol-O-methyltransferase (COMT)

Levodopa: Pharmacokinetics

Therapy of PD: limitations of levodopa

Efficacy tends to decrease as the disease progresses.

Chronic treatment associated with adverse events (motor fluctuations, dyskinesias and neuropsychiatric problems).

Therapy of PD: limitations of levodopa

Does not prevent the continuous degeneration of nerve cells in the subtantia nigra, the treatment being therefore symptomatic.

Therapy of PD: Other treatments

DA receptor agonists (bromocriptine, pergolide, pramipexole, ropinirole, cabergoline)

Amantadine Anticholinergics

What is Alzheimer’s ? Alzheimer's disease (AD), also known as Senile Dementia of the

Alzheimer Type (SDAT) or simply Alzheimer’s is the most common form of dementia.

This incurable, degenerative, terminal disease was first described by a German psychiatrist and neuropathologist Alois Alzheimer in 1906 and was named after him.

Alzheimer's disease (AD) is a slowly progressive disease of the brain that is characterized by impairment of memory and eventually by disturbances in reasoning, planning, language, and perception.

Many scientists believe that Alzheimer's disease results from an increase in the production or accumulation of a specific protein (beta-amyloid protein) in the brain that leads to nerve cell death.

• Generally, it is diagnosed in people over 65 years of age, although the less-prevalent early onset of Alzheimer’s can occur much earlier.

• In 2006, there were 26.6 million sufferers worldwide.

• Alzheimer’s is predicted to affect 1 in 85 people globally by 2050.

Alzheimer’s disease

Stages of Alzheimer’s Disease

1) Early StageDuration period is 2-4 years. Frequent recent memory loss, particularly of

recent conversations and events. Repeated questions, some problems expressing

and understanding language. Writing and using objects become difficult and

depression and apathy can occur. Need reminders for daily activities.

Symptoms of Developing A.D

2) Second stage Duration is 2-10 years. Pervasive and persistent memory loss impacts life

across settings. Rambling speech, unusual reasoning, confusion about

current events, time, and place. Slowness, rigidity, tremors, and gait problems impact

mobility and coordination. Need structure, reminders, and assistance with

activities of daily living.

Symptoms of Developing A.D

3) Moderate stage Increased memory loss and confusion. Problems recognizing family and friends. Inability to learn new things. Difficulty carrying out tasks that involve multiple steps (such

as getting dressed). Problems coping with new situations. Delusions In moderate AD, damage occurs in areas of the brain that

control language, reasoning, sensory processing, and conscious thought

Symptoms of Developing A.D

4) Last stage Duration is 1-3 years. Confused about past and present. Loss of

recognition of familiar people and places Generally incapacitated with severe to total loss

of verbal skills. Unable to care for self. Immobility likely. Patients need total support and care, and often

die from infections or pneumonia

Symptoms of Developing A.D

Alzheimer's disease is usually diagnosed clinically from the patient history, collateral history from relatives, and clinical observations, based on the presence of characteristic neurological and neuropsychological features and the absence of alternative conditions.

Advanced medical imaging with computed tomography (CT) or magnetic resonance imaging (MRI), and with single photon emission computer tomography (SPECT) or positron emission tomography (PET) can be used to help exclude other cerebral pathology or subtypes of dementia.

Diagnosis of Alzheimer’s Disease

Mutations in three genes have been identified as causes of early-onset AD.

i. APP, which encodes amyloid-beta precursor protein Ii. PSEN1 and Iii.PSEN2, encoding presenilin 1 and 2.

All three genes are involved in production of amyloid-beta peptides. Amyloid- peptide is generated by sequential proteolytic cleavage of

APP by two enzymes, beta-secretase and γ –secretase.The presenilins form the catalytic core of γ-secretase. Amyloid –peptide accumulates in the brain in the form of soluble

oligomers and amyloid plaques, which is toxic when to neurons.

Causes of Alzheimer’s Disease

Plaques– deposits of the protein beta-amyloid that accumulate in the spaces between nerve cells

Tangles – deposits of the protein tau that accumulate inside of nerve cells

Causes of Alzheimer’s Disease

Alzheimer's disease is characterised by loss of neurons and synapses in the cerebral cortex and some subcortical regions.

This loss results in gross atrophy: degeneration in the temporal lobe and parietal lobe, parts of the frontal cortex.

Both amyloid plaques and neurofibrillary tangles are clearly visible by microscopy in brains of those afflicted by AD.

Plaques are dense, mostly insoluble deposits of amyloid – beta peptides and cellular material outside and around neurons.

Tangles (neurofibrillary tangles) are aggregates of the microtubule-associated protein tau which accumulate inside the cells themselves.

Neuropathology

Although there is currently no way to cure Alzheimer's disease or stop its progression, researchers are making encouraging advances in Alzheimer's treatment, including medications and non-drug approaches to improve symptom management.

Mild/Moderate AD: Cholinesterase inhibitors increase the levels of acetylcholine

in the brain, which plays a key role in memory and learning. This kind of drug postpones the worsening of symptoms for 6 to 12 months in about half of the people who take it. Cholinesterase inhibitors most commonly prescribed for mild to moderate Alzheimer's disease include Aricept (donezepil HCL), Exelon (rivastigmine), and Razadyne (galantamine).

Treatment

Treatment of AD

• Exelon is a cholinesterase inhibitor that prevents the breakdown of acetylcholine and butyrylcholine in the brain by blocking the activity of two different enzymes. Acetylcholine and butyrylcholine play a key role in memory and learning.

• When given orally, bioavailability is about 40% in the 3 mg dose. The compound can cross the blood-brain barrier.

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Aricept (Donepizel)• One of the most widely used drugs to treat

the symptoms of Alzheimer's disease. Aricept is FDA-approved for mild, moderate, and severe stages of the disease.

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• Memantine (NAMENDA) is used either as an adjunct or an alternative to cholinesterase inhibitors in AD, and is also commonly used to treat other neurodegenerative dementias. Memantine is a noncompetitive antagonist of the NMDA-type glutamate receptor.

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