PARKINSONISM

DEFINITION:
parkinson’s disease (PD) is a chronic, progressive neurodegenerative disease characterized by at least two of
three cardinal features: resting tremor, bradykinesia, and rigidity. Often, postural instability is seen later in the
disease.
EPIDEOMOLOGY:
PD is recognised as the second-most common neurodegenerative disorder
Approximately 6 million people are diagnosed with Parkinson’s disease (PD) worldwide
PD affects 1–2 per 1,000 of the population
PD affects 1% of the population over the age of 60, but is rare in individuals younger than 50 years
The prevalence of PD rises with age, and in the oldest age groups, PD reaches a prevalence of approximately
4%
Prevalence of Parkinson’s disease by age
• In a meta-analysis of worldwide data, the prevalence of PD increased with age, from 41 per 100,000
people in individuals
40–49 years to 1,903 per 100,000 people in individuals ≥80
• Comparing regions of the world, Asia had a lower prevalence than other areas at all ages studied
• Prevalence of PD by age and geographic location (per 100,000 people)

Age range (years)

Location
50–59 60–69 70–79 80+

South America 228 637 2,180 6,095

Europe/
North America/ 113 540 1,602 2,953
Australia

Asia 88 376 646 1,418

Prevalence of Parkinson’s disease by sex

In a meta-analysis of worldwide data, in the 50–59 age group, males had a significantly increased prevalence of
PD of 134 per 100,000 people relative to females, with a prevalence of PD of 41 per 100,000 people (p<0.05).
The prevalence of PD was greater amongst men than women
A study that combined prevalence data for some of the world’s largest populations predicted that there will be
approximately 8.7 million people living with PD by 2030, with nearly 5 million residing in China.
PATHOPHYSIOLOGY:
No specific, standard criteria exist for the neuropathologic diagnosis of Parkinson disease, as the specificity and
sensitivity of its characteristic findings have not been clearly established. However, the following are the 2
major neuropathologic findings in Parkinson disease:

 Loss of pigmented dopaminergic neurons of the substantia nigra pars compacta

 The presence of Lewy bodies and Lewy neurites. In addition, scattered neurons in basal ganglia,
brainstem, spinal cord, and sympathetic ganglia contain eosinophilic, cytoplasmic inclusion bodies
( Lewy bodies ). These contain fi lamentous aggregates of α-synuclein, along with parkin, synphilin,
neurofi laments, and synaptic vesicle proteins.
The loss of dopamine neurons occurs most prominently in the ventral lateral substantia nigra. Approximately
60-80% of dopaminergic neurons are lost before the motor signs of Parkinson disease emerge.
Some individuals who were thought to be normal neurologically at the time of their deaths are found to have
Lewy bodies on autopsy examination. These incidental Lewy bodies have been hypothesized to represent the
presymptomatic phase of Parkinson disease. The prevalence of incidental Lewy bodies increases with age. Note
that Lewy bodies are not specific to Parkinson disease, as they are found in some cases of atypical
parkinsonism, Hallervorden-Spatz disease, and other disorders. Nonetheless, they are a characteristic pathology
finding of Parkinson disease.

Motor circuit in Parkinson disease

The basal ganglia motor circuit modulates the cortical output necessary for normal movement (see the following
image).
Signals from the cerebral cortex are processed through the basal ganglia-thalamocortical motor circuit and
return to the same area via a feedback pathway. Output from the motor circuit is directed through the internal
segment of the globus pallidus (GPi) and the substantia nigra pars reticulata (SNr). This inhibitory output is
directed to the thalamocortical pathway and suppresses movement.
Two pathways exist within the basal ganglia circuit, the direct and indirect pathways, as follows:

 In the direct pathway, outflow from the striatum directly inhibits the GPi and SNr; striatal neurons
containing D1 receptors constitute the direct pathway and project to the GPi/SNr

 The indirect pathway contains inhibitory connections between the striatum and the external segment of
the globus pallidus (GPe) and between the GPe and the subthalamic nucleus (STN); striatal neurons with
D2 receptors are part of the indirect pathway and project to the GPe.
The STN exerts an excitatory influence on the GPi and SNr. The GPi/SNr sends inhibitory output to the
ventral lateral nucleus (VL) of the thalamus. Dopamine is released from nigrostriatal (substantia nigra
pars compacta [SNpc]) neurons to activate the direct pathway and inhibit the indirect pathway. In
Parkinson disease, decreased striatal dopamine causes increased inhibitory output from the GPi/SNr via
both the direct and indirect pathways (see the following image).
Schematic representation of the basal ganglia - thalamocortical motor circuit and the relative change in neuronal
activity in Parkinson disease.
The increased inhibition of the thalamocortical pathway suppresses movement. Via the direct pathway,
decreased striatal dopamine stimulation causes decreased inhibition of the GPi/SNr. Via the indirect pathway,
decreased dopamine inhibition causes increased inhibition of the GPe, resulting in disinhibition of the STN.
Increased STN output increases GPi/SNr inhibitory output to the thalamus.
Etiology
Although the etiology of Parkinson disease is still unclear, most cases are hypothesized to be due to a
combination of genetic and environmental factors. Currently known genetic causes of Parkinson disease
account for approximately 10% of cases.
MPTP interference with mitochondrial function:
Several individuals were identified who developed parkinsonism after self-injection of 1-methyl-4-phenyl-
1,2,3,6-tetrahydropyridine (MPTP). These patients developed bradykinesia, rigidity, and tremor, which
progressed over several weeks and improved with dopamine replacement therapy. MPTP crosses the blood-
brain barrier and is oxidized to 1-methyl-4-phenylpyridinium (MPP+) by monoamine oxidase (MAO)-B. 

MPP+ accumulates in mitochondria and interferes with the function of complex I of the respiratory chain. A
chemical resemblance between MPTP and some herbicides and pesticides suggested that an MPTP-like
environmental toxin might be a cause of Parkinson disease, but no specific agent has been identified.
Nonetheless, mitochondrial complex I activity is reduced in Parkinson disease, suggesting a common pathway
with MPTP-induced parkinsonism.

Oxidation hypothesis:

The oxidation hypothesis suggests that free radical damage, resulting from dopamine's oxidative
metabolism, plays a role in the development or progression of Parkinson disease. The oxidative
metabolism of dopamine by MAO leads to the formation of hydrogen peroxide. Normally, hydrogen peroxide is
cleared rapidly by glutathione, but if hydrogen peroxide is not cleared adequately, it may lead to the formation
of highly reactive hydroxyl radicals that can react with cell membrane lipids to cause lipid peroxidation and cell
damage. In Parkinson disease, levels of reduced glutathione are decreased, suggesting a loss of protection
against formation of free radicals. Iron is increased in the substantia nigra and may serve as a source of donor
electrons, thereby promoting the formation of free radicals.
Parkinson disease is associated with increased dopamine turnover, decreased protective mechanisms
(glutathione), increased iron (a pro-oxidation molecule), and evidence of increased lipid peroxidation.
This hypothesis has raised concern that increased dopamine turnover due to levodopa administration could
increase oxidative damage and accelerate loss of dopamine neurons. However, there is no clear evidence that
levodopa accelerates disease progression.
Genetic factors

If genetic factors are important in a particular disease, concordance in genetically identical monozygotic (MZ)
twins will be greater than in dizygotic (DZ) twins, who share only about 50% of genes. Early Parkinson disease
twin studies generally found low and similar concordance rates for MZ and DZ pairs.
However, genetic factors in Parkinson disease appear to be very important when the disease begins at or before
age 50 years. In a study of 193 twins, overall concordance for MZ and DZ pairs was similar, but in 16 pairs of
twins in whom Parkinson disease was diagnosed at or before age 50 years, all 4 MZ pairs, but only 2 of 12 DZ
pairs, were concordant. 
The identification of a few families with familial Parkinson disease sparked further interest in the genetics of
the disease. In one large family in Salerno, Italy, 50 of 592 members had Parkinson disease; linkage analysis
incriminated a region in bands 4q21-23, and sequencing revealed an A-for-G substitution at base 209 of the
alpha-synuclein gene.Termed PD-1, this mutation codes for a substitution of threonine for alanine at amino acid
53. These individuals were characterized by early age of disease onset (mean age, 47.5 years), rapid progression
(mean age at death, 56.1 years), lack of tremor, and good response to levodopa therapy. [8] Five small Greek
kindreds were also found to have the PD-1 mutation.
In a German family, a different point mutation in the alpha-synuclein gene (a substitution of C for G at base 88,
producing a substitution of proline for alanine at amino acid 30) confirmed that mutations in the alpha-synuclein
gene can cause Parkinson disease. [9] A few additional familial mutations in the alpha-synuclein gene have been
identified and are collectively called PARK1. It is now clear that these mutations are an exceedingly rare cause
of Parkinson disease.
A total of 18 loci in various genes have now been proposed for Parkinson disease. Mutations within 6 of these
loci (SNCA, LRRK2, PRKN, DJ1, PINK1, and ATP 13A2) are well-validated causes of familial
parkinsonism. [10] Inheritance is autosomal dominant for SNCA and LRRK2 (although LRRK2 mutations exhibit
variable penetrance). Inheritance is autosomal recessive for PRKN, DJ1, PINK1, and ATP13A2. In addition,
polymorphisms within SNCA and LRRK2, as well as variations in MAPT and GBA, are risk factors for
Parkinson disease.
In one study of 953 patients with Parkinson disease with age at onset of 50 years or younger, 64 patients (6.7%)
had a PRKN mutation, 1 patient (0.2%) had a DJ1 mutation, 35 patients (3.6%) had an LRRK2 mutation, and 64
patients (6.7%) had a GBA mutation. Mutations were more common in patients with age at onset of 30 years or
younger (40.6%) than in those with age at onset between 31 and 50 years (14.6%); more common in patients of
Jewish ancestry (32.4%) than in non-Jewish patients (13.7%); and more common in patients reporting a first-
degree family history of Parkinson disease (23.9%) than in those without such a family history (15.1%). 
Although the mechanisms by which genetic mutations cause Parkinson disease is not known, evidence to date
converges on mechanisms related to abnormal protein aggregation, defective ubiquitin-mediated protein
degradation, mitochondrial dysfunction, and oxidative damage.
Alpha-synuclein conformational changes and aggregation:

Abnormally aggregated alpha-synuclein is the major component of Lewy bodies and Lewy neurites, which are
characteristic pathologic findings in Parkinson disease. Missense mutations and multiplications in
the SNCA gene that encodes alpha-synuclein, although rare, cause autosomal dominant Parkinson disease.
However, genome-wide association studies have also demonstrated a link between SNCA and sporadic
Parkinson disease.
Dysfunction of alpha-synuclein appears to play a central role in the pathogenesis of Parkinson disease, and
understanding its relationship to the disease process holds major promise for the development of a cure.
Alpha-synuclein is a 140-amino-acid protein that is unfolded at neutral pH. However, when bound to
membranes or vesicles containing acidic phospholipids, it takes on an alpha-helical structure. Normally, alpha-
synuclein is found mainly in neuronal presynaptic terminals and may play a role in assembly and function of
SNARE (soluble N-ethylmaleimide-sensitive factor activating protein receptor) proteins that are involved in
neurotransmitter release.
Under certain conditions, alpha-synuclein aggregates into oligomers that are gradually converted to the beta–
sheet-rich fibrillary structures that form Lewy bodies and neurites in Parkinson disease. Most evidence currently
suggests that it is the intermediate soluble oligomers that are toxic to neurons.
Multiple mechanisms have been suggested as to how abnormally aggregated alpha-synuclein could exert
neurotoxicity. One hypothesis suggests that oligomeric alpha-synuclein can promote formation of ion-permeable
pores on neuronal membranes, leading to increased calcium influx. Aberrant pore formation could also lead to
neurotransmitter leaks from synaptic vesicles into the cytosol. In addition, overexpression of alpha-synuclein
has been demonstrated to impair mitochondrial complex I activity, and oligomeric alpha-synuclein may have a
direct effect on mitochondrial membranes. Other lines of evidence suggest that oligomerization of alpha-
synuclein could cause cytoskeletal disruption, possibly by an effect on the microtubule-stabilizing protein, tau. 
Elevated levels of alpha-synuclein promote abnormal aggregation. levels are normally regulated by a balance
between synthesis and degradation. SNCA multiplications lead to increased synthesis of alpha-synuclein and can
cause Parkinson disease. Alpha-synuclein appears to be degraded by the ubiquitin proteasome system and the
autophagy-lysosome pathway. Several genetic mutations associated with Parkinson disease may lead to
decreased alpha-synuclein degradation. For example, increased risk of Parkinson disease in carriers
of GBA (beta-glucocerebrosidase gene) mutations, which encode for the lysosomal enzyme glucocerebrosidase,
may be due to lysosomal dysfunction and consequent alpha-synuclein accumulation and oligomerization.
How the Parkinson disease process begins is not known. Once it is initiated, however, it may propagate by a
prionlike process in which misconformed proteins induce the templated misfolding of other protein molecules.
In Parkinson disease, synuclein pathology begins in the lower brainstem and olfactory bulb, ascends up the
midbrain, and eventually affects the neocortex. One set of observations in support of a prionlike process comes
from experience with fetal dopaminergic grafts transplanted into the striata of patients with Parkinson disease,
because these grafts develop Lewy bodies, suggesting host-graft transmission of disease. 
Preventing the propagation of abnormal alpha-synuclein aggregation may be the key to slowing or stopping
Parkinson disease progression.

Melanoma
For years, there has been speculation about a relationship between PD and melanoma. Initially, it was theorized
that the drug levodopa led to an increased risk of skin cancer, but studies did not confirm this. However,
subsequent trials have since found an increased risk for melanoma in patients with PD. One particular study
conducted in 2017 found that Parkinson patients have about a 4-fold increased risk of having preexisting
melanoma.  Another study found the risk to be 7-fold. 
Diabetes
In a large cohort study, researchers found that individuals with type 2 diabetes had a 32% increased risk of
developing later Parkinson's disease than those without diabetes. The study involved 2 million people with type
2 diabetes and compared them to a reference cohort of 6,173,208 people without diabetes and results showed
significantly elevated rates of Parkinson's disease in the type 2 diabetes cohort (hazard ratio [HR], 1.32, 95%
confidence interval [CI], 1.29 - 1.35; P < .001). The relative increase was greater in patients with diabetic
complications and in younger individuals with type 2 diabetes aged 25 to 44 years. 
NON MOTOR SYMPTOMS:
• Mood changes (depression, anxiety, irritability)
• Cognitive changes (memory problems, personality
changes, psychosis/hallucinations)
• Orthostatic hypotension (lightheadedness and low blood pressure when standing)
• Constipation and early satiety (a feeling of fullness after eating small amounts)
• Hyperhidrosis (excessive sweating)
• Seborrhea (oily skin)
• Urinary urgency and incontinence
• Sexual dysfunction
• Loss of sense of smell
• Sleep disorders
• Insomnia, excessive daytime sleepiness (EDS), rapid eye movement behavioral
disorder (RBD) or active dreaming, dream enactment, involuntary movements and
vocalizations during sleep, restless leg syndrome (RLS)/periodic limb movement
disorder (PLMD)
• Fatigue
• Sensory problems (pain, tightness, tingling, burning)

MIXED MOTOR AND NON-MOTOR SYMPTOMS

• Drooling due to slowed swallowing (sialorrhea)
• Speech and swallowing problems.
DIAGNOSIS:
MANAGEMENT:

Goals of Treatment:
The goals of treatment are to minimize symptoms, disability, and side effects while maintaining quality of life.
Education of patients and caregivers, exercise, and proper nutrition are essential.

{Refer above image for non pharmacological management}

It is important for persons with PD to realize that although the underlying disease progresses slowly, the clinical
course over many years varies greatly with each person. Effective management of PD symptoms requires an
experienced and compassionate healthcare provider, the person with PD and his or her care partner to determine
a treatment plan consisting of appropriate medications, regular exercise, a healthy diet, social engagement and
cognitive activities, counseling and other therapies. As the disease progresses and problems accumulate,
deep brain stimulation (DBS) surgery may be a reasonable therapeutic option for some individuals,
although many people with PD do not qualify for DBS for a variety of reasons. However, the majority of
people with PD can lead full and active lives with good symptom control for many years.

PHARMACOLOGICAL TREATMENT:

Treatment of PD can be divided into neuroprotective and symptomatic therapy.

Initiation of symptomatic treatment for a PD patient is determined by the degree to which the patient is
functionally impaired.

NEUROPROTECTIVE THERAPY
Among the compounds that have been investigated as potential neuroprotective agents to slow disease
progression are antioxidants, antiapoptotic agents, glutamate antagonists, intraparenchymally administered
glial-derived neurotrophic factor, and anti-inflammatory drugs. None of these agents has been shown to be
effective in this context, however, and their use for therapeutic purposes is not indicated at this time. Coenzyme
Q10, creatine, pramipexole, and pioglitazone have not been found to be effective despite early hopes to the
contrary. The possibility that rasagiline has a protective effect was discussed earlier. Active and passive
immunization against α-synuclein is being explored.
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