About Parkinson’s disease

Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized primarily by loss of dopaminergic neurons in the susbtantia nigra.1 Although the underlying cause of PD remains unclear, evidence from several studies has attributed dopaminergic cell death to the toxic effects of Lewy bodies, which are formed by the aggregation of the presynaptic protein, α-synuclein.2

Morning OFF

Etiology

PD is a diffuse neurodegenerative disorder that impacts multiple CNS regions

Etiology of Parkinson's Disease (PD)

Langston JW. Ann Neurol. 2006;59:591-596. © 2006 American Neurological Association. Published by Wiley-Liss, Inc., through Wiley Subscription Services. Adapted with permission.

  • PD was originally viewed primarily as a movement disorder related to nigrostriatal dopamine degeneration3
  • It is now clear that neuropathological progression of PD affects many CNS areas3
  • Extranigral pathology produces many of the clinical motor and non-motor symptoms of PD3

Pathologic progression

The pathologic progression of PD is hypothesized to follow a predetermined sequence that was described by Braak and colleagues in a study evaluating Lewy body pathology in patients with and without clinical symptoms of PD.4

Progression of Parkinson's disease-related pathology4,5

Braak Stages 1 and 2

Autonomic and olfactory disturbances

Braak Stages 1 & 2
Via olfactory
bulb
Via vagus nerve
Premotor symptoms

Believed originate as a synucleinopathy in lower brainstem structures

Braak Stages 3 and 4

Motor disturbance

Braak Stages 3 & 4
Motor symptoms

Pathology spreads to
the midbrain, basal prosencephalon, and mesocortex

Braak Stages 5 and 6

Neuropsychiatric disturbance

Braak Stages 5 & 6

In advanced stages, lesions can be detected in the neocortex

Halliday G, Lees A, Stern M. Mov Disord. 2011;26:1015-1021. © 2011 Movement Disorder Society. Adapted with permission.

Progressive loss of dopaminergic neurons: a pathological hallmark of PD

In a postmortem study, tissue sections of the substantia nigra were taken from the brains of 28 patients with PD and 9 age-matched controls with no clinical or pathologic evidence of disease. Patients ranged in age from 43 to 91 years, with disease duration of 1 to 27 years.6

Tissue sections were immunostained for tyrosine hydroxylase to visualize the dopaminergic neuronal population of the substantia nigra.6

Tyrosine hydroxylase immunoreactivity in the substania nigra in control subjects and patients with PD6

  • Control
    Tyrosine hydroxylase in substantia nigra; Control
  • 1 year PD
    Tyrosine hydroxylase in substantia nigra; One-year Parkinson's Disease (PD)
  • 5 years PD
    Tyrosine hydroxylase in substantia nigra; Five-years Parkinson's Disease (PD)
  • 15 years PD
    Tyrosine hydroxylase in substantia nigra; Fifteen-years Parkinson's Disease (PD)

The number of dopaminergic neurons in the substantia nigra in patients with PD were substantially, although variably, reduced from 50%-90% at all postdiagnosis time points compared to controls.6

Motor features of PD may become recognizable after 50% to 80% of dopaminergic neurons have been lost.7

PD prevalence/incidence

US Prevalence; 1 million

US prevalence: approximately 1.5 million8

  • Approximately 1% aged 60 years and older7
  • 1% to 3% aged 80 years and older7
  • US incidence: approximately 20 cases per 100,000 people per year (60,000 per year)7
  • Mean age of onset: close to 60 years7

Parkinsonism diagnostic criteria9

  1. Tremor-at-rest
  2. Bradykinesia
  3. Rigidity
  4. Loss of postural reflexes
  5. Flexed posture
  6. Freezing (motor blocks)

Definite

At least two of these features must be present, one of them being 1 or 2.

Probable

Feature 1 or 2 alone is present.

Possible

At least two of features 3 to 6 must be present.

Some common clinical features

In addition to the cardinal motor manifestations of PD, a majority of patients have non-motor symptoms.9,11

Motor Symptoms9

Motor symptoms; Parkinson's Disease (PD)
Cardinal motor
  • Tremor
  • Bradykinesia
  • Rigidity
  • Loss of postural reflexes
Other motor
  • Flexed posture
  • Freezing
  • Gait changes
  • Masked face
  • Reduced blink rate
  • Microphagia
  • Changes in dexterity10
  • Hypokinetic dysarthria
  • Hypophonia
  • Dysphagia
  • Difficulty turning in bed

Non-motor Symptoms9,12,13

Non-motor symptoms; Parkinson's Disease (PD)
Autonomic
  • Lightheadedness/dizziness (orthostasis)
  • Constipation
  • Bladder dysfunction
  • Drenching sweats
  • Shortness of breath
Neuropsychiatric/cognitive
  • Depression/sadness
  • Apathy/dysphoria
  • Fatigue
  • Anxiety/panic attacks
  • Slowness of thinking
  • Memory difficulties
Sensory
  • Pain
  • Akathisia
  • Burning sensations
  • Restless legs

PD symptoms involve multiple neurotransmitter systems

  • Motor symptoms: dysregulation of the dopaminergic system by other neurotransmitter systems may contribute to motor symptoms14
  • Non-motor symptoms: deficits in cholinergic, serotonergic, glutamatergic, and noradrenergic neurotransmitter systems all play a role in non-motor symptoms14

Effects of neurotransmitter modulation on non-motor symptoms of PD.14

Non-motor symptom Cholinergic Serotonergic Adrenergic Glutamatergic GABAergic Adenosine-mediated
st in st in st in st in st in st in

st = stimulation; in = inhibition.

Anxiety Down No change  Down No change  Down Down Down No change  Down Up No change  No change 
Apathy Down No change  No change  No change  No change  No change  No change  No change  No change  No change  No change  No change 
Attention dysfunction Down Down No change  No change  Down No change  No change  No change  No change  No change  No change  No change 
Autonomic dysfunction                        
Orthostatic hypotension Down No change  No change  No change  Down No change  No change  No change  No change  No change  No change  No change 
Constipation Down No change  Down No change  No change  No change  No change  No change  No change  No change  No change  No change 
Cognitive impairment Down Up No change  Up No change  Down Up Down No change  No change  No change  Down
Depression No change  No change  Down No change  Down Up No change  No change  Down No change  No change  No change 
Executive dysfunction No change  Up No change  Up Down No change  No change  Up No change  No change  No change  No change 
Fatigue No change  No change  No change  Up No change  Up No change  Up No change  No change  No change  No change 
Olfactory dysfunction No change  No change  No change  No change  Down No change  No change  No change  No change  No change  No change  No change 
Pain No change  No change  Down No change  Down No change  Down No change  Down No change  Down No change 
Sleep disorders Down No change  No change  No change  No change  No change  Down No change  Down Down No change  Down

Cholinergic

Non-motor symptom Cholinergic
st in

st, stimulation; in, inhibition.

Anxiety Down No change 
Apathy Down No change 
Attention dysfunction Down Down
Autonomic dysfunction    
Orthostatic hypotension Down No change 
Constipation Down No change 
Cognitive impairment Down Up
Depression No change  No change 
Executive dysfunction No change  Up
Fatigue No change  No change 
Olfactory dysfunction No change  No change 
Pain No change  No change 
Sleep disorders Down No change 

Serotonergic

Non-motor symptom Serotonergic
st in

st, stimulation; in, inhibition.

Anxiety Down No change 
Apathy No change  No change 
Attention dysfunction No change  No change 
Autonomic dysfunction    
Orthostatic hypotension No change  No change 
Constipation Down No change 
Cognitive impairment No change  Up
Depression Down No change 
Executive dysfunction No change  Up
Fatigue No change  Up
Olfactory dysfunction No change  No change 
Pain Down No change 
Sleep disorders No change  No change 

Adrenergic

Non-motor symptom Adrenergic
st in

st, stimulation; in, inhibition.

Anxiety Down Down
Apathy No change  No change 
Attention dysfunction Down No change 
Autonomic dysfunction    
Orthostatic hypotension Down No change 
Constipation No change  No change 
Cognitive impairment No change  Down
Depression Down Up
Executive dysfunction Down No change 
Fatigue No change  Up
Olfactory dysfunction Down No change 
Pain Down No change 
Sleep disorders No change  No change 

Glutamatergic

Non-motor symptom Glutamatergic
st in

st, stimulation; in, inhibition.

Anxiety Down No change 
Apathy No change  No change 
Attention dysfunction No change  No change 
Autonomic dysfunction    
Orthostatic hypotension No change  No change 
Constipation No change  No change 
Cognitive impairment Up Down
Depression No change  No change 
Executive dysfunction No change  Up
Fatigue No change  Up
Olfactory dysfunction No change  No change 
Pain Down No change 
Sleep disorders Down No change 

GABAergic

Non-motor symptom GABAergic
st in

st, stimulation; in, inhibition.

Barone P. Eur J Neurol. 2010;17(3):364-376.

Anxiety Down Up
Apathy No change  No change 
Attention dysfunction No change  No change 
Autonomic dysfunction    
Orthostatic hypotension No change  No change 
Constipation No change  No change 
Cognitive impairment No change  No change 
Depression Down No change 
Executive dysfunction No change  No change 
Fatigue No change  No change 
Olfactory dysfunction No change  No change 
Pain Down No change 
Sleep disorders Down Down

Adenosine-mediated

Non-motor symptom Adenosine-mediated
st in

st, stimulation; in, inhibition.

Anxiety No change  No change 
Apathy No change  No change 
Attention dysfunction No change  No change 
Autonomic dysfunction    
Orthostatic hypotension No change  No change 
Constipation No change  No change 
Cognitive impairment No change  Down
Depression No change  No change 
Executive dysfunction No change  No change 
Fatigue No change  No change 
Olfactory dysfunction No change  No change 
Pain Down No change 
Sleep disorders No change  Down

References

  1. Anglade P, Vyas S, Javoy-Agid F, et al. Apoptosis and autophagy in nigral neurons of patients with Parkinson's disease. Histol Histopathol. 1997;12:25-31.
  2. Spillantini MG, Schmidt ML, Lee VM, Trojanowski JQ, Jakes R, Goedert M. Alpha-synuclein in Lewy bodies. Nature. 1997;388:839-840.
  3. Langston JW. The Parkinson's complex: parkinsonism is just the tip of the iceberg. Ann Neurol. 2006;59:591-596.
  4. Braak H, Del Tredici K, Rüb U, de Vos RA, Jansen Steur EN, Braak E. Staging of brain pathology related to sporadic Parkinson's disease. Neurobiol Aging. 2003;24:197-211.
  5. Halliday G, Lees A, Stern M. Milestones in Parkinson's disease⎯clinical and pathologic features. Mov Disord. 2011;26:1015-1021.
  6. Kordower JH, Olanow CW, Dodiya HB, et al. Disease duration and the integrity of the nigrostriatal system in Parkinson’s disease. Brain. 2013;136:2419-2431.
  7. DeMaagd G, Philip A. Parkinson's disease and its management: part 1: disease entity, risk factors, pathophysiology, clinical presentation, and diagnosis. P T. 2015;40:504-532.
  8. Parkinson's disease. American Association of Neurological Surgeons Web site. http://www.aans.org/en/Patients/Neurosurgical-Conditions-and-Treatments/Parkinsons-Disease. Accessed May 7, 2018.
  9. Fahn S. Parkinsonism: clinical features and differential diagnosis. In: Fahn S, Jankovic J, Hallett M, eds. Principles and Practice of Movement Disorders. Amsterdam, Netherlands: Elsevier Ltd Inc, BV; 2011.
  10. Gebhardt A, Vanbellingen T, Baronti F, Kersten B, Bohlhalter S. Poor dopaminergic response of impaired dexterity in Parkinson’s disease: bradykinesia or limb kinetic apraxia? Mov Disord. 2008:23:1701-1706.
  11. Poewe W, Seppi K, Tanne CM, et al. Parkinson disease. Nat Rev Dis Primers. 2017;3:1-21.
  12. Martínez-Fernández R, Schmitt E, Martinez-Martin P, Krack P. The hidden sister of motor fluctuations in Parkinson's disease: a review on nonmotor fluctuations. Mov Disord. 2016;31:1080-1094.
  13. Rizos A, Martinez-Martin P, Odin P, et al. Characterizing motor and non-motor aspects of early-morning off periods in Parkinson's disease: an international multicenter study. Parkinsonism Relat Disord. 2014;20:1231-1235.
  14. Barone P. Neurotransmission in Parkinson's disease: beyond dopamine. Eur J Neurol. 2010;17:364-376.