PARKINSON'S DISEASE

          ⭐ PARKINSON'S DISEASE ⭐

1) DEFINITION of Parkinson's disease -

     Parkinson's disease is a chronic and progressive disease of nervous system which is characterized by features like tremor , rigidity , akinesia (or bradykinesia) and postural instability .

( The pneumonic for these features is TRAP i.e tremor, rigidity, akinesia, postural instability )

   

2) ETIOLOGY of Parkinson's disease -

     (a) Primary causes - These include

                  Idiopathic parkinsonism

                  Parkinson's disease

                  Paralysis agitans 

          ( Primary causes have origin of their own ... There is absence of any underlying 

factor or cause ) 

      (b) Secondary causes - Here, there are some underlying factors present .

             (I) Infections - HIV , influenza

                 (Infections lead to inflammation

                 which causes release of

                 different cytokines and 

                 mediators. Signalling pathways

                 of apoptosis are also activated.

                 All this leads to neuronal 

                 damage.)

             (II) Tumor of basal ganglia - 

                   ( It may lead to compression 

                    and damage to neurons or it 

                    also cause inflammation) 

            (III) Post encephalitic parkinsonism

                  ( due to encephalitis i.e 

                     inflammation)

             (IV) Toxins - Manganese, Carbon

                   monoxide (CO), MPTP i.e 

                 methyl phenyl tetrahydropyridine

                   (These toxins cause neuronal

                    damage)

             (V) Vascular ischemia - leads to

                   neuronal damage.

             (VI) Drugs - Reserpine, 

                  phenothiazine, metoclopramide

             (VII) Punch drunk syndrome -

                  It is seen mainly in boxers due

                  to injury to head)

     (c) Parkinsonism plus - This includes

           Parkinson's symptoms as well as

          other neurological symptoms.

          E.g - Wilson's disease, progressive

          supranuclear palsy, multiple system

          atrophy (MSA).

3) PATHOPHYSIOLOGY of Parkinson's disease

     

    (a) Alpha synuclein accumulation - 

        # Alpha synuclein is a protein present 

            in presynaptic terminal of neuron.

            It helps and regulates the release 

            of neurotransmitters from the

            presynaptic vesicles.

       # In case of Parkinson's disease, there 

          is mutation of gene coding for alpha

          synuclein. Lewy bodies are formed in

          neurons. These Lewy bodies contain

          mutated and defective alpha 

          synuclein.

       # This causes decreased release of 

          neurotransmitter dopamine from

          neurons and also causes 

          degeneration of neurons in 

          substantia nigra because free 

          dopamine in cytosol can oxidize to

          form aminochrome. Oxidative stress 

          causes neuronal damage.

      # It affects dopaminergic neurons as 

          well as some non dopaminergic 

          neurons which can give rise to non

          motor symptoms.

      # Main symptom are due to deficiency 

          of dopamine which helps in carrying

         out smooth and purposeful 

         movements.

    

    NOTE* - Substantia nigra is a part of

                   Basal ganglia. Dopamine

                   maintains communication

                   across neurons in the parts of 

                   basal ganglia to maintain motor

                   control normally. These 

                   neuronal circuits and motor 

                   control are disrupted in 

                   Parkinson's disease.

       

OTHER FACTORS CONTRIBUTING IN

PATHOGENESIS ARE : 

   (b) Oxidative stress

   (c) Neuroinflammation

   (d) Impaired protein degradation

   (e) Mitochondrial dysfunction

                          ⭐⭐⭐⭐

# It is necessary to understand about direct and indirect pathways in brain when we talk about Parkinson's disease. These are neuronal circuits in brain.

     Motor cortex in frontal lobe is not connected directly to the muscles of body.

It is connected to basal ganglia and then to the muscles. Basal ganglia selects which instructions from cortex are to be

executed and which instructions are to be

inhibited.

  

   ⭐ DIRECT PATHWAY ⭐- 

(A) The neuronal connections are as follows :- 

  # Cortex is connected to striatum . Excitatory neurotransmission via glutamate is present from cortex to striatum.

  # Striatum is connected to two nuclei i.e

GPi (globus pallidus internus) and SNr

(Substantia nigra pars reticulata).

Inhibitory neurotransmission is present between them i.e striatum has tendency to inhibit GPi and SNr .

  # GPi and SNr is further connected to thalamus . Inhibitory neurotransmission indicates that GPi and SNr have tendency to inhibit thalamus when they are stimulated.

  # Thalamus is then again connected to cortex. It has tendency to excite the cortex via excitatory neurotransmission.

(B) In normal person , following events take place

    # Increased activity of cortex leads to excitation of striatum

    # excitation of striatum leads to inhibition of GPi and SNr because of inhibitory neurotransmission.

    # Now, as GPi and SNr are themselves inhibited, they cannot inhibit thalamus. 

Hence, thalamus is excited .

    # Therefore, thalamus sends excitatory impulses to cortex. This causes promotion of movement.

 Thus , DIRECT PATHWAY PROMOTES MOVEMENT.

(C) Direct pathway mainly has D1 dopaminergic receptors.

     D1 receptors are excitatory i.e they cause depolarisation and facilitates neurotransmission in direct pathway.

    # In normal person , dopamine is released in adequate quantities. It binds to D1 receptors in direct pathway and hence 

direct pathway functions properly . Thus, movement is promoted.

   ⭐ # In patients with Parkinson's, dopamine is less. Hence, D1 receptor stimulation is also decreased. Therefore promotion of movement is decreased ( and movements decrease).⭐

       ⭐ INDIRECT PATHWAY ⭐

(A) The neuronal connections are as follows:-

# Cortex is connected to Striatum via excitatory neurotransmission.

# Striatum is connected to GPe (globus pallidus externus) via inhibitory neurotransmission.i.e striatum when stimulated has the tendency to inhibit GPe 

# GPe is connected to STN ( subthalamic nucleus) via inhibitory neurotransmission.

# STN is further connected to GPi and SNr via excitatory neurotransmission i.e STN when stimulated, has the tendency to excite SNr and GPi.

# SNr and GPi are connected to thalamus via inhibitory neurotransmission.

# Thalamus is finally connected to cortex   via excitatory neurotransmission.

(B) In normal person, following events take place:-

    # Increased activity of cortex excites striatum.

    # Stimulated striatum inhibits GPe.

    # As GPe is itself inhibited, it cannot inhibit STN. Hence, STN is excited.

    # Excited STN further excites SNr and GPi via excitatory neurotransmission.

    # SNr and GPi inhibit thalamus via inhibitory neurotransmission.

    # As the thalamus is inhibited, cortex cannot be excited and thus movement is decreased.

Thus, INDIRECT PATHWAY DECREASES MOVEMENT

(C) Indirect pathway mainly has D2 dopaminergic receptors.

    D2 receptors are inhibitory in nature. (They cause hyperpolarization of neurons and stop impulse transmission)Hence, D2 receptors have tendency to decrease neurotransmission in indirect pathway.

    # In normal person, dopamine is released in adequate quantities. It binds to D2 receptors in indirect pathway and hence decreases the functioning of indirect pathway. Hence, movement is promoted.( because indirect pathway has tendency to decrease movement but activation of D2 receptors causes decreased functioning of this pathway)

    ⭐# In patients with Parkinson's, dopamine is decreased. Hence D2 receptor stimulation is also decreased.

Thus indirect pathway functioning increases because there is no much D2 activation and hyperpolarization.

Increased functioning of indirect pathway causes decreased movement. ⭐

🌟✨THUS, IN CASE OF PARKINSON'S DISEASE, IN BOTH THE CASES (direct and indirect pathway) , MOVEMENT IS DECREASED.✨🌟

4) CLINICAL FEATURES of Parkinson's disease:-

    (a)It usually occurs in 6th decade of life.

    (b) Initially - muscle weakness and pain

         (Due to decreased movement due to 

         improper functioning of direct and

         indirect pathway as explained above)

    (c) Tremor - Pill rolling tremor is present 

          at rest. It decreases with action or 

          when the body part is moving.

         ( Tremor is rhythmical involuntary 

          oscillatory movement of a body part 

          that is produced by alternating 

          contractions of reciprocally

          innervated muscles.

          It occurs due to faulty electrical

          signals in deep parts of brain that 

          control movements.

          Cause of tremor in this case may be 

          alteration in activity of substantia 

          nigra, thalamus and changes in 

          levels of dopamine.)

    (d) Rigidity - Lead pipe rigidity (i.e 

          throughout movement rigidity is 

          present) and cogwheel rigidity 

          ( i.e there is alternating rigidity and

           decreased tone during movement)

         #Possible causes :- 

           (I) Improper functioning of direct

              and indirect pathway leads to

              decreased movement leading to

              rigidity.

          (II) Decreased dopamine disrupts the

                balance between muscles which

                contract and relax for each 

                movement.

          (III) Enhancement of stretch evoked

                reflexes from segmental spinal or

                supraspinal activity. There may 

                be increased activity of spinal 

                cord motoneurons in response 

                to peripheral stimulation and 

                there may be increased response

                to muscle stretch.

         (IV) Reduction in opposing inhibition 

                to neurotransmission.

  (e) Hypokinesia / Akinesia / Bradykinesia

         # Hypokinesia - decreased amplitude

             of movement.

        # Akinesia - inability to start 

            movement.

        # Bradykinesia - slowing down of 

            movement ( decreased swinging of

           arms while walking, no facial 

           expression - mask like face )

       ( Cause - decreased movement of

         muscles due to improper functioning

         of motor control pathways )

  (f) Disturbed postural reflexes :- occurs

      late.

       (I) Posture - bent / stooped (due to 

          rigidity) , tendency to fall, difficulty

          in maintaining equilibrium while 

          sitting, standing, walking.

          Shuffling gait - short steps, dragging

          of feet while walking and no 

          swinging of arms, turning around 

          becomes difficult.

      (II) Glabellar tap is positive - 

           When the point between two 

           eyebrows is touched, eyes close.

           It is a primitive reflex.

      (III) Speech - low volume, monotonous

           (in same low tone) - this is due to 

           muscle rigidity.

      (IV) Micrographia - small handwriting

            with tendency to tail towards the

            end.

      (V) Lastly, the body becomes flexed.

           Patient gets curled up in bed. 

           Infections and death may occur.

 (g) Non-motor symptoms - 

      (I) Psychiatric - Depression, anxiety,

          Psychosis, dementia,panic attacks

      (II) Autonomic- Orthostatic 

           hypotension, urinary incontinence,

           constipation, sialorrhea,impotency

      (III) Sensory - decreased smell ,pain,

            Insomnia, day time somnolence.

       (Possible causes of Non-motor 

         symptoms - due to neuronal loss and

         Lewy body deposition in sympathetic

         and parasympathetic ganglia )

5) DIAGNOSIS of Parkinson's disease

       

Diagnosis:

Clinical- 4 symptoms = TRAP

(Tremor, Rigidity, Akinesia/Bradykinesia, Postural disability)

Investigation- MRI, CT (if additional symptoms)

6) TREATMENT of Parkinson's disease-

Treatment:

     (a) Anticholinergics- 

(MOA= Normally Dopamine decreases Ach release from Caudate. In Parkinson, decreased dopamine cause increased Ach which cause increased muscle rigidity. Therefore, Anticholinergic is used in treatment of Parkinson's disease as Anticholinergic decreases action of Ach increasing activity of dopaminergic neurons & thereby decreasing muscle rigidity.)

     (b) Amantidine- antiviral drug

(MOA= blocks NMDA receptors & acts on dopamine neurons increasing dopamine release & decreasing its reuptake thus treating muscle rigidity.)

    (c) Levodopa- 

(MOA= levodopa crosses the Blood Brain Barrier which dopamine alone cannot cross & degrades to form dopamine thus treating Parkinson's symptoms.

However, Peripheral decarboxylation of levodopa causes some loss of dopamine thus decreasing its concentration.

In order to prevent this, Peripheral Decarboxylase Inhibitors are used. eg. Carbidopa/ Benzeseride)

    (d) Dopamine Receptor Agonists:

(MOA= They increase dopamine treating the symptoms.)

   i)Ergot derivatives=

eg. Bromocriptine,  Cabergoline.

ii)Non ergot derivatives=

eg.Rotigotine, Ropinirole, Apomorphine.

NON ERGOTS ARE PREFERRED BECAUSE ERGOT DERIVATIVES CAUSE CARDIAC VALVULOPATHY.

    (e) MAO-B inhibitors:

(MOA=Mono Amino Oxidase-B degrades dopamine. These inhibitors prevent dopamine degradation & thus increasing dopamine & thereby treating symptoms.)

eg. Selegiline, Rasagiline

    (f) COMT inhibitors:

(MOA= COMT enzyme degrades Levodopa to 3-O-Methyl dopa. These inhibitors prevent it.)

eg. Tolcapone, Entacapone

    (g)  Rivastigmine:

(MOA: Anticholinesterase.

Therefore , it has cholinergic action. Ach allows nerve communication & helps to improve symtoms like DEMENTIA)

  

    (h)  Surgery:

Deep brain Stimulation.

                 ⭐⭐⭐⭐⭐⭐⭐⭐