13. Parkinson's disease - another disorder of the dopamine system

Parkinson’s disease (Parkinsonism), like ADHD, is characterized by a dysfunction of the dopamine system, but it has different neurophysiological causes and must be treated differently than ADHD. Parkinson’s medications such as L-dopa are not helpful in ADHD, while stimulants such as amphetamine medications or methylphenidate appear to be effective in Parkinson’s.

Although Parkinson’s disease can be completely differentiated from ADHD, it is helpful to compare the different forms of dopamine system disorders in Parkinson’s disease and ADHD. Some points of contact arise for which the ADHD literature has not yet offered any explanatory approaches, such as the increased muscle tone that is also typical in ADHD.

Earlier names of Parkinson’s disease were also Parkinson’s disease, paralysis agitans, shaking paralysis/shaking palsy, shaking disease.

• 1. Neurophysiological correlates of Parkinson’s disease
• 2. Parkinson symptoms
  • 2.1. Main symptoms of Parkinson’s disease
  • 2.2. Possible other symptoms of Parkinson’s
  • 2.3. Stages of idiopathic Parkinson’s disease
• 3. Forms of Parkinson
  • 3.1. Idiopathic Parkinson’s syndrome (IPS, Parkinson’s disease, sporadic PD)
  • 3.2. Monogenetic Parkinson Syndrome
  • 3.3. Atypical Parkinson’s syndrome (Parkinson’s plus syndrome)
  • 3.4. Secondary Parkinson syndromes
• 4. Individual causes of Parkinson’s disease
  • 4.1. Oxidative stress
  • 4.2. Aggregation of alpha-synuclein
  • 4.3. Glucocorticoids and inflammation in Parkinson’s disease
• 5. Prevalence of Parkinson’s disease
• 6. Parkinson’s symptoms and ADHD symptoms in comparison
  • 6.1. Parkinson’s symptoms that also occur with ADHD
  • 6.2. Parkinsonian symptoms that do not occur in ADHD
• 7. Treatment
  • 7.1. Medication of Parkinson
    • 7.1.1. Dopamine agonists
    • 7.1.2. L-dopa (levodopa)
    • 7.1.3. COMT inhibitors
    • 7.1.4. MAO-B inhibitors
    • 7.1.5. Amantadine
    • 7.1.6. Anticholinergics
    • 7.1.7. Budipin
    • 7.1.8. Stimulants
    • 7.1.8. Antioxidants
  • 7.2. Non-drug treatment of Parkinson’s disease

1. Neurophysiological correlates of Parkinson’s disease¶

Parkinson’s disease is the result of degeneration of the dopaminergic nerve cells in

• Substantia Nigra¹²
  • particularly with regard to melanin-containing neurons in the substantia nigra.
    • These inhibit cholinergic neurons in the striatum. This in turn causes bradykinesis.
    • The lack of dopamine in the basal ganglia causes
      • relative excess of acetylcholine
      • Change in serotonin
      • Change in norepinephrine
• VTA¹
  • VTA neurons project in
    • ventral striatum
    • Amygdala
    • prefrontal amygdala
    • PFC
    • other basal forebrain areas involved in cognitive and affective functions.

REM sleep is significantly reduced in Parkinson’s disease. This is (co-)regulated by dopamine.¹

Oxidative stress plays a key role in the loss of dopaminergic neurons. Dopamine metabolism is closely associated with oxidative stress. Dopamine degradation:²

• generates reactive oxygen species (ROS)
• can lead to endogenous neurotoxins
• some DA derivatives show antioxidant effects

Another major cause of neurodegeneration is mitochondrial impairment³

Somatodendritic release of dopamine (which occurs from dendrites alone) causes delayed onset of PD symptoms by compensating for extensive axonal degeneration of SNc dopamine neurons.⁴

2. Parkinson symptoms¶

Parkinson’s is

• a degenerative disease of the extrapyramidal motor system
• a syndrome of hypertonic-hypokinetic movement disorders.⁵

2.1. Main symptoms of Parkinson’s disease¶

• Bradykinesis, hypokinesia, akinesia
  • Bradykinesis:
    • Slowed voluntary motor activity
  • Hypokinesia
    • Reduced mobility, lack of movement, lack of spontaneous motor skills
    • Early signs:
      • Slackening pace in everyday activities
      • Reduced joint movements (arms when walking)
        • Often one-sided at first
      • Restricted facial expression, mask-like face (hypomimia).
      • Font becomes smaller
      • “out-of-round” movement when walking for a longer period of time (tighten up a bit)
      • Soft, monotone, slurred speech
  • Akinesia
    • Rigidity of movement (extreme form)
• Rigor
  • Increased muscle tone
    • Muscle stiffness
      • Involuntary tension of the entire striated musculature
      • Often with muscle pain
      • Slight bending of elbow joint, trunk, neck, later also knee joints
      • Neck/shoulder tension (painful)
      • Muscle groups close to the body (axial) more frequently affected
    • Independent of the speed of the joint movement
    • Gear phenomenon during passive movement of an extremity
      • Jerky yielding of passively moved limb
    • Often (initially) one-sided
      • One arm swings less when walking
      • Early form
• Rest tremor
  • Rhythmic trembling of the extremities during physical rest
  • Frequency approx. 4-6 Hz, rarely up to 9 Hz
  • Reduction through targeted movements
  • Activability through mental occupation or emotions
  • Typical in idiopathic Parkinson’s disease, less frequent in atypical Parkinson’s disease
• Postural instability
  • Gait Insecurity
  • Stance uncertainty
  • Postural instability
  • Consequence of the disturbance of the position reflexes
• Non-motor neurological symptoms
  • Consequence of impairment of other neurotransmitter systems
    • Serotonin
    • Norepinephrine

2.2. Possible other symptoms of Parkinson’s¶

• Sensory symptoms
  • Dysesthesias
    • Tactile hypersensitivity (also in ADHD: increased sensitivity)
  • Pain
    • Especially joints and muscles
  • Hyposmia (reduced perception of smell)
    • Early symptom, occurs years earlier
• Vegetative symptoms
  • Temperature regulation disorder (also in ADHD: increased sensitivity)
    • Reduced heat tolerance
      • Reflex sweating and reflex vasodilatation disturbed during heat
      • In advanced disease up to life-threatening high fever
      • Heavy sweating, esp. at night
  • Bladder dysfunction
  • Gastrointestinal dysfunction
    • Slowed gastric emptying
    • Constipation
  • Sexual dysfunction
    • Libido impaired
  • Increased sebum secretion (ointment face)
• Psychological symptoms
  • Especially depression
    • Dysphoria in 40% of affected persons already years before (frequency increased in ADHD; there also dysphoria with inactivity)
    • Apathy (apathy)
  • Increased irritability (also in ADHD)
  • Bradyphrenia
    • Slowed thought processes
    • Content unaffected
    • Expression of general drive disorder
• Sleep disorders (likewise with ADHD: chronorhythm shifted backwards there)
  • Disturbance of dream sleep / REM sleep
    • Atypical strong movements
    • Healthy REM sleep is usually motionless
    • To the point of screaming or lashing out
    • Often also Restless Legs
• Cognitive symptoms
  • Concentration disorders (also in ADHD)
  • Frontal brain disorders
    • Visuospatial attention impaired (estimation of distances and speeds)
  • In advanced stages dementia
    • Lewy body dementia
• Pseudohypersalivation
  • Saliva swallowing disorder
• Variations in the effect of the selected medication
• Freezing
• Hyperkinesias (over-movements) (similar to ADHD: hyperactivity there)
• Dystonias
  • Prolonged, involuntary contractions of the skeletal muscles
  • Leads to abnormal postures and malpositions of the body or body parts (camptocoria)
• Orthostatic dysregulation
  • Regulatory disturbance of blood pressure when changing to upright body position (orthostasis)
• Psychoses
• Impulse control disorders (as well as ADHD)
• Akinetic crisis
  • Sudden, acute deterioration of motor symptoms (extreme rigor)
    • Up to complete immobility (akinesia)
    • Swallowing difficult (dysphagia)
    • Speech difficult
    • Hyperthermia frequent

2.3. Stages of idiopathic Parkinson’s disease¶

There are six stages of PD⁶, each associated with a specific area of the CNS⁷

• Stage 1 (presymptomatic)
  • Pathology limited to
    • Lesions/dysfunctions in the inferior medulla oblongata⁷
    • Olfactory bulb/anterior olfactory nucleus
  • Disease is diagnosed very rarely
  • Symptoms are subtii:
    • Mainly non-motor symptoms
      • E.g. loss of odor
      • Depressive symptoms
      • Unilateral rest tremor
      • Changes in facial expression.
• Stage 2 (presymptomatic)
  • Damage to the lower raphe nuclei
  • Motor symptoms affecting walking and posture
• Stage 3 (symptomatic)
  • Substantia nigra damaged
  • Motor symptoms such as balance disorders
• Stage 4 (symptomatic)
  • Temporal mesocortex and other gray nuclei of midbrain and forebrain show increasing pathological changes
  • Symptoms are diagnosed more strongly and more frequently
  • Lesions in the nervous system no longer respond to the drugs administered;
• The 5 (final stage 1)
  • Neocortical temporal fields
  • Many everyday activities are no longer possible, and even walking may require assistance
• Stage 6 (final stage 2)
  • Pathological changes of the mature neocortex
  • Parkinson’s manifests in all clinical dimensions
  • Motor difficulties so pronounced that affected persons lose their independence
  • Patients are almost completely immobile and may have mental symptoms such as hallucinations

3. Forms of Parkinson¶

3.1. Idiopathic Parkinson’s syndrome (IPS, Parkinson’s disease, sporadic PD)¶

Affects 3/4 of all Parkinson’s cases.⁵
Subtypes:

• akinetic-rigid type
• Tremordominant type
• Equivalence type
• monosymptomatic rest tremor

Often begins unilaterally,

3.2. Monogenetic Parkinson Syndrome¶

Affects 5 to 10% of all Parkinson’s cases. Gene candidates are PARK 1 to PARK 16.

3.3. Atypical Parkinson’s syndrome (Parkinson’s plus syndrome)¶

Atypical Parkinson’s syndromes arise comorbid with other neurodegenerative diseases such as:

• Multisystem atrophy (MSA)
  • Striatonigral degeneration (MSA-P, SND)
  • Olivopontocerebellar atrophy (MSA-C, OPCA)
• Primary orthostatic hypotension (Shy-Drager syndrome)
• Progressive supranuclear gaze palsy (PSP, Steele-Richardson-Olszewski syndrome)
• Lewy body dementia (LBD)
• Corticobasal degeneration (CBD)

3.4. Secondary Parkinson syndromes¶

Symptomatic/secondary parkinsonian syndromes are a consequence of identifiable primary factors:⁵

• Medication
  • Classic neuroleptics
  • Lithium
  • Valproic acid
  • Antiemetics
    • Metoclopramide
  • Calcium antagonists
    • Cinnarizine
    • Flunarizine
• Poisonings
  • Carbon monoxide
  • Manganese
  • MPTP
  • Paraquat (herbicide)
  • Rotenone (insecticide)
  • Lindane
  • Trichloroethylene- or perchloroethylene-based degreasing and cleaning agents
  • Octenol (a toxin of molds)
• Traumatic brain injury
  • So far, no robust evidence for concussions as a cause of Parkinson’s disease
• Brain tumors
• Inflammations
  • Encephalitis
  • HIV encephalopathy
• Metabolic disorders
  • Wilson’s disease
  • Hypoparathyroidism

4. Individual causes of Parkinson’s disease¶

4.1. Oxidative stress¶

Oxidative stress is considered the most plausible cause of Parkinson’s, leading to dysfunction of dopaminergic neurons in the substantia nigra. Reactive oxygen species (ROS) can activate the caspase cascade in mitochondria, leading to cell death. The presence of ROS appears to increase the risk of Parkinson’s disease.⁸

Cytochrome P450 2D6 deficiency doubles the likelihood of developing Parkinson’s disease when contaminated with pesticides. Normally, CPY2D6 degrades pesticides. The degradation deficiency leads to toxin accumulation. Heavy metal poisoning often leads to accumulation of these toxins in the nigra material, triggering reactive oxidative damage.⁸

4.2. Aggregation of alpha-synuclein¶

Aggregation of alpha-synuclein is a common finding in Parkinson’s disease. These aggregates are detrimental to dopaminergic neurons and can cause Lewy body formation and eventually necrosis. The formation of Lewy bodies can trigger a cascade of events. In a nonpathologic state, Lewy body aggregates are usually flushed by a proteasome complex or lysosome. However, in Parkinson’s disease, defects in these interceptor pathways are common, leading to further propagation of the aggregates. Lewy bodies are considered a defining pathological feature of PD and are also common in dementia. Presumably, the original alpha-synuclein is transported from the enteric nervous system (gut) via the vagus nerve, the major parasympathetic unit.⁸

4.3. Glucocorticoids and inflammation in Parkinson’s disease¶

Chronic inflammation is a characteristic feature of Parkinson’s disease. Parkinson’s correlates with elevated levels of potent pro-inflammatory molecules such as

• TNF-α
• iNOS
• IL-1β.

Dopaminergic neurons are particularly vulnerable to activated glia releasing these toxic factors. Microglia, astrocytes, and infiltrating T cells mediate chronic inflammation. Another important effector system in the regulation of inflammation is the HPA axis. Glucocorticoids, as released by the final stage of the HPA axis, the adrenal cortex, activate the glucocorticoid receptor (GR). This mediates deactivation of the first stages of the HPA axis and regulates inflammation both by direct transcriptional action on target genes and by indirect inhibition of the transcriptional activities of transcription factors such as NF-κB, AP-1, or interferon regulatory factors. In Parkinson’s disease, the HPA axis is imbalanced. Cortisol levels are markedly elevated, suggesting deregulation of GR function in immune cells. Further, activation of microglial GR contributes to deactivation of microglial cells and reduces dopaminergic degeneration. Glucocorticoids further regulate human brain blood vessels as well as blood-brain barrier (BBB) permeability. Disruption of glucocorticoid action may affect the infiltration of cytotoxic molecules, leading to increased vulnerability of dopamine neurons in PD. Overall, deregulation of glucocorticoid receptor action is likely important for the degeneration of dopamine neurons through the development of chronic inflammation.⁹

5. Prevalence of Parkinson’s disease¶

The prevalence is strongly age-dependent.¹⁰

40 to 49 years: 0.041 %
50 to 59 years: 0.107 %
60 to 69 years: 0.428 %
70 to 79 years: 1.087 %
over 80 years: 1.903 %

In Germany, 300,000 to 400,000 people are affected.

There are few differences between genders and ethnicities.

6. Parkinson’s symptoms and ADHD symptoms in comparison¶

6.1. Parkinson’s symptoms that also occur with ADHD¶

Neuropsychological studies of adult ADHD, prodromal Parkinson’s disease, and early Parkinson’s disease show similar deficits in

• Executive functions
• Memory
• Attention
• Pulse inhibition

These symptoms are mediated by similar neuronal substrates.¹¹

In ADHD, the following Parkinson’s symptoms also occur:

• Hypokinesia
  • (only) similar in ADHD: disturbances of gross motor skills and fine motor skills
    * Many bruises
    * Font is unattractive to illegible
• Muscle tension increased
  • Parkinson: Rigor
    • Increased muscle tone
      • Muscle stiffness
      • Neck/shoulder tension (painful)
  • ADHD: Muscle tension
    • Increased muscle tone
      • Neck/shoulder/back tension (painful)
• Postural instability
  • Parkinson’s:
    • Gait Insecurity
    • Stance uncertainty
    • Postural instability
    • Consequence of the disturbance of the position reflexes
  • ADHD shows increased postural instability¹² in medication-naïve sufferers¹³
• Non-motor neurological symptoms as a result of impairment of other neurotransmitter systems
  • Norepinephrine
    • Also for ADHD
  • Serotonin
    • Also in ADHD, but only slightly
• Sensory symptoms
  • Dysesthesias
    • Tactile hypersensitivity (also in ADHD: increased sensitivity)
  • Pain
    • Especially joints and muscles
    • With ADHD: increased sensitivity to pain
• Vegetative symptoms
  • Temperature regulation disorder
    • Reduced heat tolerance
      • Reflex sweating and reflex vasodilatation disturbed during heat
      • In advanced disease up to life-threatening high fever
      • Heavy sweating, esp. at night
    • In ADHD: slightly increased sensitivity to temperature
• Psychological symptoms
  • Especially depression
    • Parkinson’s:
      • Dysphoria in 40% of those affected already years beforehand
      • Fear
    • ADHD:
      • Depression and anxiety common
      • Also dysphoria with inactivity
  • Drive problems
    • Parkinson’s
      • Apathy (listlessness)
    • ADHD
      • Weakness of drive (significantly weaker form): Frequency increased
  • Irritability
    • Parkinson: increased
    • ADHD: increased
  • Bradyphrenia
    • Parkinson’s:
      • Slowed thought processes
      • Content unaffected
      • Expression of general drive disorder
    • Reminiscent of SCT, which used to be considered an ADHD subtype
• Sleep disorders
  • Parkinson’s
    • Disturbance of dream sleep / REM sleep
      • Atypical strong movements
      • Healthy REM sleep is usually motionless
      • To the point of screaming or lashing out
    • Often also Restless Legs
  • ADHD:
    • Chronorhythm shifted backwards
    • Problems falling asleep
    • Restless Legs common
• Cognitive symptoms
  • Concentration disorders
    • Parkinson’s disease: frequent
    • ADHD: one of the core symptoms
  • Frontal brain disorders
    • Parkinson’s disease: visuospatial attention impaired (estimation of distances and speeds)
    • ADHD: visospatial working memory is impaired
• Hyperkinesias (over-movements)
  • Parkinson’s disease: frequent
  • ADHD: here hyperactivity
• Impulse Control Disorders
  • Parkinson’s disease: frequent
  • ADHD: frequent

6.2. Parkinsonian symptoms that do not occur in ADHD¶

In ADHD, the following Parkinson’s symptoms do not occur:

• Bradykinesis, akinesia
  • Bradykinesis:
    • Slowed voluntary motor activity
  • Hypokinesia
    • Reduced mobility, lack of movement, lack of spontaneous motor skills
  • Akinesia
    • Rigidity of movement (extreme form)
• Rigor:
  * Gear phenomenon during passive movement of an extremity
  * Jerky yielding of passively moved limb
  * Often (initially) one-sided
  * One arm swings less when walking
  * Early form
• Rest tremor
  • Rhythmic trembling of the extremities during physical rest
  • Frequency approx. 4-6 Hz, rarely up to 9 Hz
  • Reduction through targeted movements
  • Activability through mental occupation or emotions
  • Typical in idiopathic Parkinson’s disease, less frequent in atypical Parkinson’s disease
• Non-motor neurological symptoms
  • Consequence of impairment of other neurotransmitter systems
    • Serotonin
    • Norepinephrine
  • Hyposmia (reduced perception of smell)
    • Early symptom, occurs years earlier
• Vegetative symptoms
  • Temperature regulation disorder
    * In case of advanced disease up to life-threatening, highly febrile conditions
    * Heavy sweating, esp. at night
  • Bladder dysfunction
  • Gastrointestinal dysfunction
    • Slowed gastric emptying
    • Constipation
  • Sexual dysfunction
    • Libido impaired
  • Increased sebum secretion (ointment face)
• Psychological symptoms
  • Bradyphrenia
    • Slowed thought processes
    • Content unaffected
    • Expression of general drive disorder
• Sleep disorders
  • Disturbance of dream sleep / REM sleep
    • Atypical strong movements
    • Healthy REM sleep is usually motionless
    • To the point of screaming or lashing out
• Pseudohypersalivation
  • Saliva swallowing disorder
• Variations in the effect of the selected medication
• Freezing
• Dystonias
  • Prolonged, involuntary contractions of the skeletal muscles
  • Leads to abnormal postures and malpositions of the body or body parts (camptocoria)
• Orthostatic dysregulation
  • Regulatory disturbance of blood pressure when changing to an upright body position (orthostasis)
• Psychoses
• Akinetic crisis
  • Sudden, acute deterioration of motor symptoms (extreme rigor)
    • Up to complete immobility (akinesia)
    • Swallowing difficult (dysphagia)
    • Speech difficult
    • Hyperthermia frequent

7. Treatment¶

7.1. Medication of Parkinson¶

7.1.1. Dopamine agonists¶

Dopamine agonists act directly on dopamine receptors.
Slow dosing required (like stimulants for ADHD).
Less frequent fluctuations in effect or agitation with long-term use than L-dopa.
First-choice drug. Only if not sufficient, supplement with L-dopa.

• Nonergot dopamine agonists ((modern; selective D2 receptor agonists)
  • Apomorphine
    • D2 agonist
  • Piribedil
  • Pramipexole
  • Ropinirole
    • Selective D2 and D3 agonist
  • Rotigotine
• Ergot dopamine agonists (classical ergot alkaloids)
  • Bromocriptine
  • Cabergoline
  • Dihydroergocryptin
  • Lisuride
  • Pergolide

7.1.2. L-dopa (levodopa)¶

L-dopa is a prodrug of dopamine. L-dopa is the most effective Parkinson’s drug
More likely in older affected individuals.
Initially oral intake, increasing if necessary up to continuous infusion
IdR combined with decarboxylase inhibitors. Decarboxylase inhibitors cause L-dopa to be converted to dopamine not already in the blood, but only in the brain:

• Benserazide
• Carbidopa

Time to effect: from first intake to several weeks
L-dopa is available as immediate-release or sustained-release preparations.

The close connection between the adenosine system and the dopamine system is also important in Parkinson’s disease.
Chronic administration of L-dopa leads to downregulation by internalization of D2 homers and A2A-D2 heteromers. Subsequently, D2 activation can increase phospho-CREB formation, which can stimulate an atypical cAMP response element (CRE) in the A2A protomer. This, in turn, causes upregulation of A2A homomers, leading to an increase in protein phosphorylation that can stabilize pathological receptor mosaics, resulting in abnormal motor function and dyskinesias. The loss of therapeutic effect of L-dopa may be mainly due to the increasing dominance of A2A signaling with increased firing, therefore L-dopa fails to silence these neurons and remove the motor brake.¹⁴.

7.1.3. COMT inhibitors¶

• Entacapon
  • alone or in combination with L-dopa
• Tolcapon
  • only if entacapone is not effective.
  • Requires monitoring of liver values

7.1.4. MAO-B inhibitors¶

MAO-B inhibitors inhibit the breakdown of dopamine by MAO-B.
Use as an early medication for mild form or adjunctive to other medications for more severe form.

• Selegiline
  • Degradation to amphetamines
  • Amphetamines can promote sleep disorders
  • In this case, taking therefore no later than lunchtime
• Rasagiline

7.1.5. Amantadine¶

Mechanisms of action:

• Inhibition of the NMDA receptor
  • thereby reducing the overactivity of glutaminergic interneurons in the striatum
• Indirect dopamine receptor agonist in the striatum.
  • increased dopamine release
• Dopamine reuptake inhibition

Symptom effect:

• Tremor reduced
• Akinesia reduced.

Side effects

• Skin lesions
• Edema
• Nightmares
• Activating effect
  • do not take later in the afternoon in case of sleep disturbance

7.1.6. Anticholinergics¶

Anticholinergics act as acetylcholine antagonists
Can improve tremor (shaking) when L-dopa or dopamine agonists are insufficient for this purpose.

Side effects (significant):

• Dry mouth
• Circulatory disorders
• Urinary retention
• Forgetfulness

7.1.7. Budipin¶

Budipin has several mechanisms of action:

• Dopamine agonist
• Glutamate NMDA receptor antagonist
• Dopamine reuptake inhibitor
• Monoamine oxidase inhibitors

Symptom efficacy:

Tremor (shaking) is reduced

Side effects (significant):

• Cardiac arrhythmias
  • prolonged QT time
  • regular ECG checks are required.
• Dry mouth
• Circulatory disorders
• Urinary retention
• Forgetfulness

• Sensory illusions
• Nightmares
• Headache
• Visual disturbances
• Hot flashes
• Loss of appetite
• Akathisie

Contraindications:

• Myasthenia gravis
• Heart failure
• Cardiomyopathies
• AV Block
• Bradycardia
• Ventricular arrhythmias
• Hypokalemia
• Hypomagnesemia

7.1.8. Stimulants¶

Stimulants, such as those commonly used for ADHD, appear to help treat PD.

• Amphetamine drugs
• Methylphenidate¹⁵

7.1.8. Antioxidants¶

Because of the contributions of ROS to the development of PD, the use of ROS antioxidants is being discussed. Curcumin is a candidate to reduce ROS.⁸

7.2. Non-drug treatment of Parkinson’s disease¶

Non-drug treatments for Parkinson’s include:⁵
- deep brain stimulation (brain pacemaker)
- Occupational Therapy
- Physiotherapy
- Speech therapy
- Psychoeducation and self-help groups