1. Overview on PD and AD

2. Parkinson's disease
Parkinson'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.

3. 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

4. Parkinson's disease
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. 

5. Clinical features of PD
Parkinson's disease: Clinical Overview
Clinical features of PD
Four 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
Clinically, PD is characterized by three cardinal symptoms: resting tremor, bradykinesia (generalized slowness of movements) and muscle rigidity.

6. 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.
The most common first symptom is resting tremor, which is usually asymmetric and most evident in one hand with the arm at rest. It is the most easily recognized sign of the disease. The frequency of parkinsonian tremor is low, typically in the 3-6 Hz range. The alternating contraction of agonist and antagonist muscles of the forearm results in a "pill-rolling" tremor. Bradykinesia is the central motor abnormality in PD. Difficulties with daily activities such as writing, shaving, cutting food with a knife and fork and opening or buttoning buttons, as well as decreased blinking, masked facies, slowed chewing and swallowing and drooling reflect bradykinesia. Muscle tone is increased in both flexor and extensor muscles providing a constant resistance to passive movements of the joints (a "cog-wheel" rigidity can be felt during passive movements of joints). Rigidity underlies the chracteristic stooped posture, anteroflexed head, and flexed knees and elbows in the patients. The symptoms typically start asymmetrically from one side spreading from one affected limb on one side to the other limb on the same side (e.g. from hand to leg), and later also to contralateral side.
Koller, WC and Minagan, A. Treatment strategies for the management of Parkinson’s disease. In: Parkinson’s disease management guide, Medical economics Company Inc. at Montvale NJ, pp , 2001

7. Additional clinical features of PD
Postural instability: Due to loss of postural reflexes.
Dysfunction of the autonomic nervous system: Impaired
gastrointestinal 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.
In addition to these three cardinal features, postural instability, dysfunction of the autonomic nervous system, depression and cognitive impairment are common. Loss of postural reflexes causes balance difficulties and the body can move or fall into the direction of the center of gravity. Therefore, turning or bending forward may be associated with involuntary steps. Autonomic dysfunction can result into impaired gastrointestinal motility causing sense of fulness and constipation. Furthermore, bladder dysfunction (urinary frequency, urgency and urge incontinence), sialorrhea (due to excessive saliva production and decreased frequency of swallowing), excessive head and neck sweating (resulting from altered thermoregulation), and orthostatic hypotension result from autonomic dysfunction. Approximately 50 % of patients show mild to moderate depression. Many patients show mild cognitive decline including impaired visual-spatial perception and attention, slowness in execution of motor tasks and impaired concentration. At least 1/3 of the patients become demented during the course of the disease.
Koller, WC and Minagan, A. Treatment strategies for the management of Parkinson’s disease. In: Parkinson’s disease management guide, Medical economics Company Inc. at Montvale NJ, pp , 2001

8. 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.
Substantia nigra is the major origin of the dopaminergic innervation of the striatum and is part of so called extrapyramidal system which processes information coming from the cortex to the striatum, and returns it back to the cortex through the thalamus. One major function of the striatum, which is under the control of substantia nigra, is the regulation of posture and muscle tonus.
Source: Marsden, C. D. Parkinson's disease. Lancet 335, , 1990

9. Dopamine pathways in human brain
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 develop nerve cell loss, and its degeneration and the resulting striatal dopamine depletion are responsible for most of the motor abnormalities.

10. Neurochemistry of PD
PD symptoms become manifest when about % of the DA-containing neurons in the substantia nigra and % 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
In late 1950s, it was shown that dopamine is present in mammalian brain, and that the levels are highest within the striatum. In 1960, Ehringer and Hornykiewicz showed that the levels of dopamine are severely reduced in the striatum of patients with PD. Degeneration of the nigrostriatal dopaminergic neurons causes symptoms of PD: symptoms become manifest when about % of the dopamine-containing neurons in the substantia nigra and % of striatal dopamine are lost.
Carlsson, A. The occurrence, distribution and physiological role of catecholamines in the nervous system. Pharmacol. Rev. 11, , 1959
Sano, I. et al. Distribution of catechol compounds in human brain. Biochim. Biophys. Acta 32, , 1959
Ehringer, H. & Hornykiewicz, O. Verteilung von Noradrenalin und Dopamin (3-Hydroxytyramin) im Gehirn des Menschen und ihr Verhalten bei Ekrankungen des extrapyramidalen Systems. Klin. Wschr. 38, (1960)
Marsden, C. D. Parkinson's disease. Lancet 335, , 1990
Forno, L. S. Neuropathology of Parkinson's disease. J. Neuropathol. Exp. Neurol. 55, , 1996
Koller, WC and Minagan, A. Treatment strategies for the management of Parkinson’s disease. In: Parkinson’s disease management guide, Medical economics Company Inc. at Montvale NJ, pp , 2001.

11. 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.
In late 1950´s, it was shown that L-dihydroxyphenylalanine (L-DOPA; levodopa), a precursor of dopamine that crosses the blood-brain-barrier, could restore brain dopamine levels and motor functions in animals treated with catecholamine depleting drug, reserpine. The observations about the striatal dopamine depletion in PD were followed by attempts to alleviate the symptoms through the administration of levodopa. First attempts resulted in dramatic but short-term improvements. It took years before this treatment become an established and succesfull treatment for PD. Still today, it continues to be the cornerstone of PD treatment. Virtually all PD patients benefit from levopoda treatment.
Cotzias, G. C. et al. Modification of parkinsonism: chronic treatment with L-DOPA. N. Engl. J. Med. 280, , 1969.
Koller, WC and Minagan, A. Treatment strategies for the management of Parkinson’s disease. In: Parkinson’s disease management guide, Medical economics Company Inc. at Montvale NJ, pp

12. 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
In late 1950´s, it was shown that L-dihydroxyphenylalanine (L-DOPA; levodopa), a precursor of dopamine that crosses the blood-brain-barrier, could restore brain dopamine levels and motor functions in animals treated with catecholamine depleting drug, reserpine. The observations about the striatal dopamine depletion in PD were followed by attempts to alleviate the symptoms through the administration of levodopa. First attempts resulted in dramatic but short-term improvements. It took years before this treatment become an established and succesfull treatment for PD. Still today, it continues to be the cornerstone of PD treatment. Virtually all PD patients benefit from levopoda treatment.
Cotzias, G. C. et al. Modification of parkinsonism: chronic treatment with L-DOPA. N. Engl. J. Med. 280, , 1969.
Koller, WC and Minagan, A. Treatment strategies for the management of Parkinson’s disease. In: Parkinson’s disease management guide, Medical economics Company Inc. at Montvale NJ, pp

13. 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.
Catechol-O-methyl-transferase (COMT) inhibitors, like entacapone, which increase the bioavailability of levodopa by inhibiting COMT enzyme peripherally and thus slow down the breakdown of levodopa, can be used as adjunctive therapy to levodopa to reduce some of the adverse effects related to long-term levodopa treatment (results in smoother levodopa plasma levels, and a decrease in motor fluctuations in patients).

14. Levodopa: Pharmacokinetics
Administration of levodopa with high-protein meals delays absorption. WHY?
Catechol-O-methyl-transferase (COMT) inhibitors, like entacapone, which increase the bioavailability of levodopa by inhibiting COMT enzyme peripherally and thus slow down the breakdown of levodopa, can be used as adjunctive therapy to levodopa to reduce some of the adverse effects related to long-term levodopa treatment (results in smoother levodopa plasma levels, and a decrease in motor fluctuations in patients).

15. 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.
Levodopa: Pharmacokinetics
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)
Catechol-O-methyl-transferase (COMT) inhibitors, like entacapone, which increase the bioavailability of levodopa by inhibiting COMT enzyme peripherally and thus slow down the breakdown of levodopa, can be used as adjunctive therapy to levodopa to reduce some of the adverse effects related to long-term levodopa treatment (results in smoother levodopa plasma levels, and a decrease in motor fluctuations in patients).

16. 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).
Levodopa therapy has, however, its limitations. The efficacy of the therapy is greatest during the early stages of the disease, and tends to decrease as the disease progresses. Chronic levodopa treatment is also associated with the development of adverse events (motor fluctuations, dyskinesias and neuropsychiatric problems) in the majority of patients.

17. Therapy of PD: limitations of levodopa
Does not prevent the continuous degeneration of nerve cells in the subtantia nigra, the treatment being therefore symptomatic.
Levodopa does not however prevent the continuing degeneration of nerve cells in the substantia nigra, the treatment being therefore symptomatic.
Koller, WC and Minagan, A. Treatment strategies for the management of Parkinson’s disease. In: Parkinson’s disease management guide, Medical economics Company Inc. at Montvale NJ, pp

18. Therapy of PD: Other treatments
DA receptor agonists (bromocriptine, pergolide, pramipexole, ropinirole, cabergoline)
Amantadine
Anticholinergics
In addition to levopoda, other drugs increasing dopaminergic activity can be used as symptomatic treatments. These include e.g. dopamine receptor agonists (e.g. bromocriptine, pergolide, pramipexole, ropinirole, cabergoline) which directly stimulate striatal dopamine receptors, and are thus independent of the degenerating dopaminergic projections of the substantia nigra for their mechanism of action. Amantadine is an antiviral agent which also increases dopamine release, blocks dopamine reuptake, and stimulates dopamine receptors. It is also a non-competitive NMDA receptors antagonist. However its mechanism of action at therapeutic doses in PD is still under discussion.
Normally there is a balance between dopaminergic and cholinergic neurotransmission in the striatum, which is disrupted in PD due to dopamine depletion resulting in a state of relative cholinergic sensitivity, so that cholinergic drugs exacerbate and anticholinergic drugs improve parkinsonian symptoms. Anticholinergics can be used in younger PD patients and are useful for treating resting tremor, but adverse effects (such as memory impairments, acute confusion and hallucinations, as well as peripheral side effects) are common are limit their use.
Koller, WC and Minagan, A. Treatment strategies for the management of Parkinson’s disease. In: Parkinson’s disease management guide, Medical economics Company Inc. at Montvale NJ, pp

19. 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.

20. 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

21. Stages of Alzheimer’s Disease

22. Symptoms of Developing A.D
Early Stage
Duration 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.

23. 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.

24. 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

25. 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

26. Diagnosis of Alzheimer’s Disease
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.

27. Causes 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.

28. 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

29. Neuropathology
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.

30. Treatment
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).

31. Treatment of AD

32. Continued
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.

33. Continued 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.

34. Continued
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.