Basal Ganglia

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Basal Ganglia and PARKINSONISM-Paralysis Agitans:

Basal Ganglia and PARKINSONISM-Paralysis Agitans Dr.Sumangala.M.Patil Associate professor Dept. of Physiology B.L.D.E.A’s Shri.B.M.Patil MC. Bijapur .

Basal Ganglia:

Basal Ganglia Anatomic considerations- Group of subcortical Grey nuclear masses at base of cerebral hemisphere, on each side of brain. play an essential role in control of movements. These ganglias consists of- 5 nuclei. Caudate nucleus, Putamin , Globus pallidus -large nuclear masses. Substantia nigra of midbrain, Subthalamic nucleus(body of luys )of diencephalone - functionally related. Located mainly lateral to, surrounding Thalamus. Inhibitory BG loop involved in modulating cortical acyivity .

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Caudate nucleus + putamen =Neo Striatum(major input center). Putamen + Globus pallidus = Lenticular nucleus. Caudate nucleus - comma shaped band of gray matter, head , body & tail .Head continuous with putamin , tail ends with close relation of amygdaloid body. Putamen - outer part of lenticular nucleus, seperated from pallidum by white fibrous band, it is dark in color compared to pale pallidum . Globus pallidus - Inner region of lenticular nucleus, divided into GP externa & GP interna by internal lamina of white matter.

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Subthalamic body of Luys - biconvex mass of grey matter located in midbrain, just below the thalamus. Substantia nigra - sheet of neurons containing dark pigment neoromelanin present ventral to the crus cerebri in midbrain,divided into – Pars compacta - dopaminergic and cholinergic neurons. Pars reticulata GABAergic neurons. Globus pallidus referred as- palaeostriatum , Caudate N & Putamin - neostriatum . Claustrum and amygdaloid body initially included under BG, not now, they don’t have motor activity. These nuclei are seperated by ant. Limb of internal capsule. Cellular bridges that exist between the nuclei give- structure, a striated appearance.

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Basal ganglia nucleus formed from- central gray matter of the Telencephalon . The internal capsule lies within borders formed by the thalamus, caudate N & lenticular nucleus(P+G.P=lens shaped) . This is a crucial area for passage way for all nerve fibers connecting cerebrum with rest of CNS. Caudate & lenticular N. with adjacent part of internal capsule- corpus striatum .


Connections BG has multiple connections with other parts of CNS- cerebral cortex, cerebellum, thalamus,reticular formation, vision. They are imp. Centres of coordination, in control of automatic associated movements. Corpus striatum(C+P) is responsible for initiation and inhibition of gross intentinal body movements that are unconsciously performed in normal person. Also provide muscle tone – so that exact movements can be performed,hand work- requiring coordinated effort of entire arm & trunk for hand to be able to perform.

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A feedback system operates via circular pathways from motor cortex to BG, thalamus, motor cortex. BG signals also pass through VL.VA nucleus of thalamus to cerebellum. It is hypothesized that BG & cerebellum feedback signals could be integrated in VL nucleus of THALAMUS. Thus BG involved in – 2 general activations- Control of body’s motor tone. Gross intentional movements. The inhibitory loop regulates stereotyped movement patterns that add gracefulness to precise,delicate cortically controlled movements.

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The general effect of BG excitation is of inhibitory (-) signals to bulboreticular facilitatory (+), and excitatory(+) signals to bulboreticular inhibitory(-) areas. When BG are not functioning adequately- Facilitatory areas(+) become overactive . Inhibitory areas(-) become underactive . Resulting in Rigidity throughout body.

Connections and operation of BG-Berne,Levy:

Connections and operation of BG- Berne,Levy Circuitry of BG is complex & its operation is still unknown. The neurons of striatum don’t discharge before neurons of motorcortex are activated by sensory input. Hence these neurons don’t appear to be involved in initiation of stimulus- triggried movements. All the areas of cortex are topographically projected to Striatum .

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The corticostriatal projections arise from neurons from in layer V of cortex& appear to use glutamate as its excitatory NT. The striatum then influences neurons in VL, VA nucleui of thalamus by- 2 pathways. Direct and Indirect- fig . In direct pathway- striatum projects- i segment of GP & pars R of SN. This projection is inhibitory, NT are GABA,subatance P. Gpi + SNr project to VA/VL of thalamus, this is also inhibitory(GABA). The VA /VL send excitatory connection to prefronatal , premotor & supplementary area of cortex.

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This input to cortex influences motor planning, affects discharge of corticospinal , corticobulbar neurons. Pars reticulata also influences eye movementsby projection to superior colliculus . Direct pathway appears to function as follows- Neurons in striatum have little background activity,activated from input of cortex. In contrast Gpi has high level of background activity. Striatum is inhibitory to Gpi , but pallidial neurons themselves are inhibitory to VA,VL N , therefore activation of striatum disinhibits the thalamus- i.e excites these neurons and their target neurons in MOTOR CORTEX .

Indirect pathway:

Indirect pathway Striatum –to exter . Segment of GP which projects to SN- this inturn projects back to Gpi . In this pathway pallidial neurons in Gpe are inhibited by- GABA& enkephalin . GABA & enkephalin disinhibit neurons neurons of SN. The SN neurons become more active as disinhibition . Release Glutamate in int. seg of GP. This transmitter excites neurons of VA/VL Thalamic N. The pallidal action is inhibitory, activity of thalamic N decreases, as does that of cortical neurons.

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Thus the direct & indirect pathways have opposing actions. An increase in either one of these pathways – leads to imbalance in motor control. It influences increase/ decrease in motor output of cortex. Neurons of SN (pc)- project to striatum (3 rd circuit)Dopamine is the neurotransmitter. This has an excitatory effect on Direct and Inhibitory action on indirect pathway. Both actions facilitate activity in C.Cortex . This circuit is imp. Functionally.

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The patient with an extrapyramidal disorder- Great difficulty in maintaining equilibrium in standing. Posture while sitting& rolling from supine to prone position and walking. The righting reflex, vestibular reflex, proprioception are all disturbed. If spinalcord is transected at level of mesencephalone a decerebrate rigidity occurs- indicating the major effect of BG is inhibition. Disorder of BG- Involuntary movements Alteration in muscle tone Disturbance in body posture

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Tremor observed in extrapyramidal disorder is a result of- excess neural activity in one area of the brain from unapposed activity in another area. This characteristic is called- RELEASE phenomenon, is common with tissue destruction in nervous system. Lesion in A removes the regulatory control over B, and B becomes overactive. Both corpus striatum & motor cortex are instrumental in the control of- gross intentional movements(unconscious).

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Control is accomplished through 2 pathways- GP- Thalamus-to the Cortex & downward via Corticospinal pathways – to Spinal cord. GP – to substantia nigra - to reticular formation- and reticulospinal tracts to- spinal cord. GP provides background muscletone necessary for performing exacting movements(hands)- stimulation of GP will stop the movement at any point & keep it locked at that point.


connections The main afferent to BG terminate in – striatum(fig. ganong ). They include corticostriate projections from all parts of cerebral cortex(pre frontal,premotor , associated areas). There is also projection from centromedian nucleus of Thalamus to striatum. The connections between parts of BG include Dopaminergic nigrostriatal projection from PC of substantianigra to striatum, GABAergic from straitum to PR of SN.

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The caudate & putamen project both segments of Globus Pallidus . The external segment of GP projects to subthalamic N, which inturn projects to – both segments of GP & substantia nigra (indirect). The principal output from the BG is from- internal segment of GP via Thalamic fasciculus to Ventra L,.anterior , centromedian nuclei of thalamus. From thalamic N, fibers project to prefrontal & premotor cortex. Substantianigra also projects to thalamus. Aditional projections to habenula,superior colliculus .

Direct and indirect paths :

Direct and indirect paths

Putamin circuit-execution of movements:

Putamin circuit-execution of movements Principal role of BG in motor activity is skilled movements performed subconsciously- Writing letters of alphabet Cutting paper with scissor Hammering nails, shooting basketball. Passing throwball , shoveling dirt Vocalisation , controlled movements of eyes. Damage in putamin circuit- Damage in GP-ATHETOSIS(writhing movements). Lesion in subthalamus - HEMIBALLISMUS( flialing of whole limb) Lesion in putamin - CHOREA(flicking movmet in hand,face ) Damage in SN- PARKINSONISM(TRA/D).

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The main feature of the connections ofBGis - Cerebrum projects to striatum-to internal segment of GP-to thalamus. Thalamus back to the cortex, completing the loop. The putput from GP toThalamus is Inhibitory(-) Output from Thalamus to cortex is excitatory(+) Striatum is made up of unique mosaic of patches/ striosomes composed of nerve endings in a matrix receiving other endings. Corticostriate projections originate from deep portion of layer5of cortex terminate in patches( dopaminergic ).where as that origin from layer2 and 3 end primarily in matrix(cell bodies project to GABAergic neurons).

Caudate circuit-cognitive control :

Caudate circuit-cognitive control Thinking process using sensory input & memory in information (stored). Motor activity occur as result of – thoughts generated. Efferents end in accessory motor regions in premotor & supplementary areas-concerned in putting together sequential patterns of movement lasting for seconds/ don’t excite muscle movements. For e.g person seeing a lion. Without thinking for long, respond immediately to achieve complex goal.

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Another imp. Function is change timing & scale the intensity of movements. How rapidly movement is to be performed. How large the movement will be. In patients of severe lesion in BG- timing & scaling is lost. Example is – writing alphabet ‘a’. This is function of BG along with cerebral cortex. In lesion of post. Parietal cortex- Centre for spatial coordination for motor control of all parts of body & relation of body its parts with surrounding.

Fig showsperson lacking cortex draw the face of human being, proper proportion for rt. Side ignoring lt. side(rt. Field of vision), avoid using rt.hand, arm not aware of existance.:

Fig showsperson lacking cortex draw the face of human being, proper proportion for rt. Side ignoring lt. side(rt. Field of vision), avoid using rt.hand , arm not aware of existance .

Metabolic considerations:

Metabolic considerations Metabolism is unique. The structures have a high O2 consumption . Copper content of substantia nigra & locus ceruleus is particularly High. In Wilson’s disease, genetic autosomal recessive disorder, plasma level of copper binding protein ceruloplasmin is- LOW. Chronic copper intoxication and severe degeneration of Lenticular nucleus take place.

Differences between BG& cerebellar motor loops-:

Differences between BG& cerebellar motor loops- BG- receive input from all areas of Ccortex,to cerebellum is more restricted. BG- out put is more widespread, prefrontal, premotor areas, Cerebellar influences only premotor . BG- donot receive somatosensory information from ascending pathways in spinalcord , few connections with brainstem. Cerebellum has rich connection with both.


PARKINSONISM Parkinson's disease is a degenerative disease of the brain that often impairs motor skills , speech, and other functions. 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 ).

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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 language problems. PD is both chronic and progressive.

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PD is also called "primary parkinsonism" or " idiopathic PD" (classically meaning having no known cause although many genetic mutations associated with PD have been discovered). While many forms of parkinsonism are "idiopathic", "secondary" cases may result from toxicity most notably of drugs, head trauma, or other medical disorders. The disease is named after English physician James Parkinson , who made a detailed description of the disease in his essay: "An Essay on the Shaking Palsy" (1817).

Other causes of parkinsonism-:

Other causes of parkinsonism- Postencephalitic Severe carbon monoxide poisoining . Toxic agentsin well water, agricultural pesticides- oxidative metabolities released affect dopamine neurons. Drug induced- Antipsychotic: phenothiazines {post synaptic dopamine receptor blocker}. Antihypertensive: Reserpine [pre synaptic dopamine receptor blocker]. Symptoms of parkinsonism accompany- cerebrovascular diseases, Brain tumors, repeated headtrauma .

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The primary parkinsonism is due to genetic mutations(early onset 45yrs). There are other disorders that are called Parkinson-plus diseases . These include: multiple system atrophy (MSA) , progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). Some include dementia with Lewy bodies (DLB). while idiopathic Parkinson's disease patients also have Lewy bodies — abnormal aggregates of protein that develop inside nerve cells — in their brain tissue, the distribution is denser and more widespread in DLB.

On the left a Lewy body of substantia nigra section from a PD patient labeled with a polyclocal -synuclein antibody . On the right cortical Lewy bodies of cingulate gyrus labelled . Bayer, T. A. et al. -synuclein accumulates in Lewy bodies in Parkinson's disease and dementia but not in Alzheimer's disease -amyloid plaque cores.:

On the left a Lewy body of substantia nigra section from a PD patient labeled with a polyclocal  - synuclein antibody . On the right cortical Lewy bodies of cingulate gyrus labelled . Bayer, T. A. et al.  - synuclein accumulates in Lewy bodies in Parkinson's disease and dementia but not in Alzheimer's disease - amyloid plaque cores.

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Neuropathology of PD Eosinophilic, round intracytoplasmic inclusions called lewy bodies and Lewy neurites. First described in 1912 by a German neuropathologist - Friedrich Lewy. Inclusions particularly numerous in the substantia nigra pars compacta.

Lewy bodies:

Lewy bodies

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These Parkinson-plus diseases may progress more quickly than typical idiopathic Parkinson disease. If cognitive dysfunction occurs before or very early in the course of the movement disorder then DLBD may be suspected. Early postural instability with minimal tremor especially in the context of ophthalmoparesis should suggest PSP. Early autonomic dysfunction including erectile dysfunction and syncope may suggest MSA. The presence of extreme asymmetry with patchy cortical cognitive defects such as dysphasia and apraxias especially with "alien limb" phenomena should suggest CBD.

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The usual anti-Parkinson's medications are typically either less effective or not effective at all in controlling symptoms; patients may be exquisitely sensitive to neuroleptic medications like haloperidol . Additionally, the cholinesterase inhibiting medications have shown preliminary efficacy in treating the cognitive, psychiatric, and behavioral aspects of the disease, so correct differential diagnosis is important.

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Wilson's disease (hereditary copper accumulation) may present with parkinsonian features; young patients presenting with parkinsonism or any other movement disorder are frequently screened for this rare condition, because it may respond to medical treatment. Typical tests are liver function , slit lamp examination for Kayser -Fleischer rings , and serum ceruloplasmin levels. Parkinson disease affects movement (motor symptoms). Other typical symptoms include disorders of mood, behavior, thinking, and sensation (non-motor symptoms). Patients' individual symptoms may be quite dissimilar and progression of the disease is also distinctly individual

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Motor symptoms- The cardinal symptoms are (mnemonic " TRAP "): Tremor : normally 4–6 cps 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; if patient has stroke/ hemeplegia - tremor disappear on that side . Rigidity : stiffness; increased muscle tone. In combination with a resting tremor, this produces a leadpipe , "cogwheel " rigidity when the limb is passively moved. Akinesia / bradykinesia absence of movement and slowness in initiating spontaneous , respectively. Rapid, repetitive movements produce a dysrhythmic and decremental loss of amplitude . Postural instability : failure of postural reflexes , which leads to impaired balance and falls.

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Other motor symptoms include: Gait and posture disturbances: Shuffling: gait is characterized by short steps, with feet barely leaving the ground, producing an audible shuffling noise. Small obstacles tend to cause the patient to trip. Decreased arm-swing, mask face, voice low, monotonus , micrographia . 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.

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Festination : a combination of stooped posture, imbalance, and short steps. It leads to a Stooped, forward-flexed posture . It leads to Gait that gets progressively faster and faster, often ending in a fall. In severe forms, the head and upper shoulders may be bent at a right angle relative to the trunk ( camptocormia ).

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Gait freezing : "freezing" is a manifestation of akinesia (an inability to move). It is characterized by an inability to move the feet which may worsen in tight, cluttered spaces or when attempting to initiate gait. Dystonia (in about 20% of cases): abnormal, sustained, painful twisting muscle contractions, often affecting the foot and ankle (mainly toe flexion and foot inversion) which often interferes with gait .

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Speech and swallowing disturbances. Hypophonia : soft speech. Speech quality tends to be soft, hoarse, and monotonous. Some people with Parkinson's disease claim that their tongue is "heavy" or have cluttered speech . Monotonic speech . Festinating speech: excessively rapid, soft, poorly-intelligible speech. Drooling: most likely caused by a weak, infrequent swallow and stooped posture. Dysphagia : impaired ability to swallow. Can lead to aspiration pneumonia .

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Other motor symptoms: Fatigue (up to 50% of cases); Masked faces (a mask-like face also known as hypomimia ), with infrequent blinking ; Difficulty rolling in bed or rising from a seated position; Micrographia (small, cramped handwriting); Impaired fine motor dexterity and motor coordination ; Impaired gross motor coordination ; Akathisia , the inability to sit still

Neuropsychiatric :

Neuropsychiatric PD causes cognitive and mood disturbances . Estimated prevalence rates of depression vary widely according to the population sampled reviews of depression estimate its occurrence from 20–80% of cases. Most studies use self-report questionnaires such as the Beck Depression Inventory , Studies using diagnostic interviews by trained psychiatrists report lower rates of depression. There is an increased risk for any individual with depression to develop Parkinson's disease at a later date. 70%go on to develop anxiety. 90% of Parkinson's disease patients with pre-existing anxiety subsequently develop depression; apathy or abulia .

Cognitive disturbances include: :

Cognitive disturbances include: Slowed reaction time ; both voluntary and involuntary motor responses are significantly slowed. Executive dysfunction , characterized by difficulties in: differential allocation of attention, impulse control, prioritizing, evaluating the data, interpreting social clues, and subjective time awareness. This 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.

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Sleep 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

Perception :

Perception Impaired visual contrast sensitivity , spatial reasoning, color discrimination, convergence insufficiency (characterized by double vision ) . Dizziness and fainting; usually attributable orthostatic hypotension , a failure of the autonomic nervous system . Impaired proprioception (the awareness of bodily position in three-dimensional space) Reduction or loss of sense of smell ( hyposmia 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

Autonomic :

Autonomic 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. Weight loss , which is significant over a period of ten years.

Causes :

Causes Most people with Parkinson's disease are described as having idiopathic Parkinson's disease (having no specific known cause). Others including genetic, toxins, head trauma, cerebral anoxia , and drug-induced Parkinson's disease. Genetic In recent years, genetic mutations causing Parkinson's disease have been discovered, certain populations ( Contursi , Italy). In some with autosomal dominent inheritance, mutations in gene for- alpha- synnuclein have been found, precursor for nonamyloid component of plaques, found in inclusion body- Lewy body.

Role of Toxins:

Role of 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 , as originally suggested by G.C. Cotzias . In the Cancer Prevention Study II Nutrition Cohort, a longitudinal investigation, individuals who were exposed to pesticides had a 70% higher incidence of PD than individuals who were not exposed.

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The tragedy of a group of drug addicts in California in the early 1980s who consumed a contaminated and illicitly produced batch of the synthetic opiate MPPP brought to light MPTP (pro-toxin N-methyl-4-phenyl-1,2,3,6-tetrahydropyidine) as a specific cause of Parkinson symptoms. This made it possible to develop the first animal model for Parkinson's. MPTP's toxicity likely comes from the generation of reactive oxygen species through tyrosine hydroxylation . The Case of the Frozen Addicts by J. William Langston (Vintage, New York, June 25, 1996) documents this tragedy and describes the first attempts at fetal brain tissue transplants to treat PD

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Dopamine production/ Metabolism -Dopamine is synthesized from tyrosine, which is first catalysed to L-DOPA by tyrosine hyroxylase . L-DOPA is then decarboxylated to dopamine by dopadecarboxylase , and stored in the vesicles. When released into synaptic cleft, dopamine binds to receptors (D1-D5 in the figure), which activates different second messenger systems inside the cell causing changes in excitability, metabolism and gene expression . Reuptake of dopamine is by dopamine transporter. If unstored in the cytosol , dopamine is oxidized by monoamine oxidase (MAO).

Dopamine pathways in human brain:

Dopamine pathways in human brain

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Dopamine synthesis

Head trauma :

Head trauma Past episodes of head trauma are reported with Parkinson's disease. A recent methodologically retrospective study found that those who have experienced a head injury are 4 times more likely to develop Parkinson’s disease and it increases 11-fold for patients who had experienced severe head injury. recently by Tanner and colleagues,who found a similar risk of 3.8, with increasing risk associated with more severe injury and hospitalization. However, whether the head trauma actually contributed to Parkinson's disease development or the early symptoms of clumsiness associated with Parkinson's causes individuals to have more head trauma is still unknown .

Pathophysiology :

Pathophysiology The symptoms of Parkinson's disease result from the loss of pigmented dopamine -secreting ( dopaminergic ) 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, 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 VAN of the thalamus, which sends excitatory projections to the motor cortex , thus leading to hypokinesia .

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Presumably, loss of Dopamine- overactivity of Indirect pathway from striatum to globus . Therefore disinhibition of neurons in VA/VL N These inturn activate motor cortex. Thus increase discharge of motor neurons, Including gamma- motor neurons . Resulting in increased muscle tone Hyperactivity of BG - inhibition of cortex- akinesia . Hypoactivity of BG- stimulation of cortex- hyperkinesia .

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There are four major dopamine pathways in the brain; the nigrostriatal pathway, mediates movement and is the most conspicuously affected in early Parkinson's disease. The other pathways are the mesocortical , the mesolimbic , and the tuberoinfundibular . Disruption of dopamine along the non- striatal pathways explains much of the neuropsychiatric pathology associated with Parkinson's disease.

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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.. This protein accumulation forms proteinaceous cytoplasmic inclusions called Lewy bodies .

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The 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 animal models.

Recent theories-:

Recent theories- 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 . Neuromelanin may be acting as a protective agent. The most likely mechanism is generation of reactive oxygen species. Iron also induces aggregation of synuclein by oxidative mechanisms. dopamine and the byproducts of dopamine production enhance alpha- synuclein aggregation.

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The precise mechanism by which aggregates of alpha- synuclein damage the cells is not known. The aggregates may be a normal reaction by the cells as part of their effort to correct , 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 alpha- synuclein into the mouse genome under control of the platelet-derived-growth factor -β promoter.

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Short term memory loss ; procedural memory is more impaired than declarative memory . 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. Medication effects: some of the above cognitive disturbances are improved by dopaminergic medications, while others are actually worsened.

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Diagnosis 18F PET scan shows decreased dopamine activity in the basal ganglia , a pattern which aids in diagnosing Parkinson's disease. Typically, the diagnosis is based on medical history and neurological examination conducted by interviewing and observing the patient in person using the Unified Parkinson's Disease Rating Scale .

Treatment :

Treatment Parkinson's disease is a chronic disorder that requires broad-based management including patient and family education, physiotherapy , exercise, and nutrition. At present, there is no cure for PD , but medications or surgery can provide relief from the symptoms.

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The most widely used form of treatment is L-dopa in various forms. L-dopa is transformed into dopamine in the dopaminergic neurons by L-aromatic amino acid decarboxylase (often known by its former name dopa-decarboxylase ),

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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.

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Carbidopa and benserazide are dopa decarboxylase inhibitors. They help to prevent the metabolism of L-dopa before it reaches the dopaminergic neurons generally given as combination preparations of carbidopa / levodopa (co- careldopa ) (e.g. Sinemet , Parcopa ) and (co- beneldopa ) (e.g. Madopar ).

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There are also controlled release versions of Sinemet and Madopar that spread out the effect of the L-dopa. Duodopa is a combination of levodopa and carbidopa , dispersed as a viscous gel. Using a patient-operated portable pump, the drug is continuously delivered via a tube directly into the upper small intestine, where it is rapidly absorbed.

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Tolcapone inhibits the COMT enzyme, thereby prolonging the effects of L-dopa, used to complement L-dopa. Due to its possible side effects such as liver failure, it is limited in its availability. A similar drug, entacapone has not been shown to cause significant alterations of liver function and maintains adequate inhibition of COMT over time.

Dopamine agonists :

Dopamine agonists The dopamine agonists bromocriptine , pergolide , pramipexole , ropinirole , cabergoline , apomorphine , and lisuride are moderately effective. These have their own side effects somnolence, hallucinations insomnia. Dopamine agonists initially act by stimulating some of the dopamine receptors . dopamine receptors to become progressively less sensitive , eventually increasing the symptoms .

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Dopamine agonists can be useful for patients experiencing on-off fluctuations and dyskinesias as a result of high doses of L-dopa. Apomorphine can be administered via subcutaneous injection using a small pump which is carried by the patient .

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A low dose is automatically administered throughout the day, reducing the fluctuations of motor symptoms by providing a steady dose of dopaminergic stimulation. The injection site must be changed daily and rotated around the body to avoid the formation of nodules . Apomorphine is also available in a more acute dose as an autoinjector pen for emergency doses such as after a fall . Nausea and vomiting are common, and may require domperidone (an antiemetic).

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Side effects of Dopamine- Cardiac dysarrythmias,postural hypotension CNS- hallucination, confusion, insomnia, depression. Other drugs used- vitamin E - slows toxic action of oxidative metabolities . Botulism toxin injection- to treate dystonias .

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MAO-B inhibitors Selegiline and rasagiline reduce the symptoms by inhibiting monoamine oxidase -B (MAO-B), thereby inhibiting the breakdown of dopamine secreted by the dopaminergic neurons. Metabolites of selegiline include levoamphetamine / levomethamphetamine . This might result in side effects such as insomnia. A side effect of selegiline in conjunction with L-dopa can be stomatitis .

Surgery and deep brain stimulation :

Surgery and deep brain stimulation Treating Parkinson's disease with surgery was once a common practice, but after the discovery of levodopa , surgery was restricted to only a few cases. surgery is again being used in people with advanced PD for whom drug therapy is no longer sufficient .

Photograph showing an electrode being inserted during deep brain stimulation:

Photograph showing an electrode being inserted during deep brain stimulation 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 .

Neurorehabilitation :

Neurorehabilitation There is partial evidence that speech or mobility problems can improve with rehabilitation Regular physical exercise and/or therapy can be beneficial to the patient for maintaining and improving mobility, flexibility, strength, gait speed, and quality of life; and speech therapy may improve voice. One of the most widely practiced treatment for the speech disorders associated with Parkinson's disease is the Lee Silverman Voice Treatment (LSVT). LSVT focuses on increasing vocal loudness.

Prognosis :

Prognosis PD is not considered to be a fatal disease by itself , but it progresses with time. The average life expectancy of a PD patient is lower 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 to be fatal. In some people, the disease progresses more quickly . people with PD can live productive lives for many years after diagnosis.

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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). This much more complicated scale has multiple ratings that measure motor function, and also mental functioning, behavior, mood, and activities of daily living , how much treatments are helping them. neither scale is specific to Parkinson's disease

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Epidemiology According to some sources, Parkinsons disease is slightly less prevalent in the African-American community. The average crude prevalence is estimated at being from 120-180 out of 100,000 among the Caucasian (white) community. Parsi community in Mumbai, India suffers from particularly high rates of Parkinson's disease.


HISTORY Symptoms of Parkinson's disease have been known and treated However, it was not formally recognized and its symptoms were not documented until 1817 in An Essay on the Shaking Palsy 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 .

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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 from treatment with L-dopa published in 1968.

Gene therapy :

Gene therapy Currently under investigation is gene therapy. This involves using a non-infectious 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.

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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.

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Implantation of stem cells genetically engineered to produce dopamine or stem cells that transform into dopamine-producing cells has already being used. These could not cure because they do not improve the considerable loss of activity of the dopaminergic neurons. Initial results have been unsatisfactory, with patients still retaining their drugs and symptoms.

Neural transplantation :

Neural transplantation The first prospective randomised double-blind sham-placebo controlled trial of dopamine-producing cell transplants failed to show an improvement in quality of life although some significant clinical improvements were seen in patients below the age of 60.

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A significant problem was the excess release of dopamine by the transplanted tissue, leading to dystonias . Research in African green monkeys suggests that the use of stem cells might in future provide a similar benefit without inducing dystonias .

Complementary therapies :

Complementary therapies Nutrients have been used in clinical studies and are used by people with PD in order to partially treat PD 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.

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Vitamin C and vitamin E in large doses are commonly used by patients in order to theoretically lessen the cell damage that occurs in PD. 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. Coenzyme Q10 has more recently been used for similar reasons.

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Mucuna pruriens is plant of the legume family that has been used by Ayurvedic practitioners to treat Parkinson's for more than 4,500 years. Western medicine is now accepting mucuna as an alternative/ complementary therapy with, L-dopa, as study after study is proving its effectiveness.

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Research cited by the National Parkinson Foundation found that "dose for dose, mucuna was two to three times more effective than equivalent amounts of synthetic L-dopa [and] the side effects were minimal.... Further, the cost of the drug was much cheaper compared to the synthetic. THANK- U.

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