14 Parkinson's disease as a dopaminergic disorder

Parkinson’s disease (Parkinsonism), like ADHD, is characterized by a disorder of the dopamine system, but it has different neurophysiological causes and must be treated differently than ADHD. Parkinson’s drugs such as L-dopa are not helpful in ADHD, while stimulants such as amphetamine drugs or methylphenidate appear to be effective in Parkinson’s disease.
Although Parkinson’s can be completely differentiated from ADHD, it is helpful to compare the different forms of dopamine system disorders in Parkinson’s and ADHD. There are some points of contact for which the ADHD literature does not yet offer any explanations, such as the increased muscle tone that is also typical of ADHD.

Parkinson’s is a degenerative disease of the extrapyramidal motor system caused by degeneration of the dopaminergic nerve cells in the substantia nigra and VTA. This leads to neurophysiological changes such as a relative excess of acetylcholine, a change in serotonin and noradrenaline.
The symptoms of Parkinson’s include bradykinesia, hypokinesia, akinesia, rigor, resting tremor, postural instability and non-motor neurological symptoms such as depression, irritability and sleep disturbances.
There are different forms of Parkinson’s disease, including idiopathic Parkinson’s disease, monogenetic Parkinson’s disease, atypical Parkinson’s disease and secondary Parkinson’s disease.
The prevalence of Parkinson’s increases with age, and 300,000 to 400,000 people are affected in Germany.
Some of the Parkinson’s symptoms are also present in ADHD, including hypokinesia, increased muscle tension, postural instability, non-motor neurological symptoms and cognitive symptoms. Other Parkinson’s symptoms such as bradykinesia, akinesia, resting tremor and some autonomic symptoms are not present in ADHD.
The treatment of Parkinson’s disease includes various drugs such as dopamine agonists, L-dopa, COMT inhibitors, MAO-B inhibitors, amantadine, anticholinergics, budipine and stimulants. Antioxidants are also discussed for the treatment of Parkinson’s disease.

Earlier names for Parkinson’s were also Parkinson’s disease, paralysis agitans, shaking palsy/shaking paralysis, shaking disease.
Parkinson’s affects around 1% of people over the age of 60.¹

• 1. Neurophysiological correlates of Parkinson’s disease
  • 1.1. Degeneration of dopaminergic nerve cells
  • 1.2. Loss of dopaminergic nerve cells is more serious than just loss of dopamine levels
  • 1.3. Neurophysiological pathways for the loss of dopaminergic neurons
• 2. Symptoms of Parkinson’s disease
  • 2.1. Main symptoms of Parkinson’s disease
  • 2.2. Other possible symptoms of Parkinson’s disease
  • 2.3. Stages of idiopathic Parkinson’s disease
• 3. Forms of Parkinson’s disease
  • 3.1. Idiopathic Parkinson’s syndrome (IPS, Parkinson’s disease, sporadic PD)
  • 3.2. Monogenetic Parkinson’s syndrome
  • 3.3. Atypical Parkinson’s syndrome (Parkinson’s plus syndrome)
  • 3.4. Secondary Parkinson’s 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
  • 4.4. Loss of noradrenergic neurons in the locus coeruleus
  • 4.5. Mitochondrial impairments
• 5. Prevalence of Parkinson’s disease
• 6. Parkinson’s and ADHD
  • 6.1. Parkinson’s symptoms and ADHD symptoms in comparison
    • 6.1.1. Parkinson’s symptoms that also occur with ADHD
    • 6.1.2. Parkinson’s symptoms that do not occur with ADHD
  • 6.2. Comorbidity of Parkinson’s and ADHD
  • 6.3. Stimulants for ADHD and Parkinson’s risk
• 7. Risk factors for Parkinson’s disease
  • 7.1. Gene candidates for Parkinson’s disease
  • 7.2. Age, gender, ethnicity
  • 7.3. Environmental factors that increase the risk of Parkinson’s disease
  • 7.4. Environmental factors that reduce the risk of Parkinson’s disease
• 8. Diagnostics
• 9. Treatment
  • 9.1. Medication for Parkinson’s disease
    • 9.1.1. Dopamine agonists
    • 9.1.2. L-dopa (levodopa)
    • 9.1.3. COMT inhibitors
    • 9.1.4. MAO-B inhibitors
    • 9.1.5. Amantadine
    • 9.1.6. Anticholinergics
    • 9.1.7. Budipin
    • 9.1.8. Stimulants
    • 9.1.9. Antioxidants
  • 9.2. Non-drug treatment of Parkinson’s disease

1. Neurophysiological correlates of Parkinson’s disease¶

1.1. Degeneration of dopaminergic nerve cells¶

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

• Substantia Nigra²³
  • particularly with regard to the melanin-containing neurons in the substantia nigra.
    • These inhibit cholinergic neurons in the striatum. This causes bradykinesia.
    • The lack of dopamine in the basal ganglia causes
      • relative excess of acetylcholine
      • Change in serotonin
      • Change in noradrenaline
• VTA²
  • VTA neurons project into
    • ventral striatum
    • Amygdala
    • prefrontal amygdala
    • PFC
    • other basal forebrain areas involved in cognitive and affective functions.

A slow loss of dopaminergic cells with age is normal. Using the example of the dopaminergic neurons of the substantia nigra pars compacta:⁴

• 20-year-olds approx. 423,000
• 40-50 year olds approx. 380,000
• over 80-year-olds approx. 305,000
  Post-mortem studies in humans showed that Parkinson’s symptoms only develop when at least 60 %⁴ to 70 % of the dopaminergic neurons in the substantia nigra and 70 % of the dopamine in the striatum have been lost ^{5 67}
  Parkinson’s patients aged between 68 and 85 at the time of death only had around 83,000 neurons left ⁴

The causes of dopaminergic degeneration are thought to be a combination of several factors:⁸

• high dopamine transporter (DAT) expression density per neuron
  • causes excessive dopamine levels in the neuron
• Excess dopamine causes dopamine oxidation, which has a neurotoxic effect
• Dysfunction of the autophagy-lysosome pathway

However, those affected by genetic DAT dysfunction (dysfunctional DAT) also develop Parkinson’s symptoms.⁹

The somatodendritic release of dopamine (from dendrites alone) delays the onset of Parkinson’s symptoms by compensating for the extensive axonal degeneration of SNc dopamine neurons.¹⁰

REM sleep is significantly reduced in Parkinson’s disease. This is (co-)regulated by dopamine.²

1.2. Loss of dopaminergic nerve cells is more serious than just loss of dopamine levels¶

The loss of dopamine neurons has more far-reaching effects than a mere equally severe reduction in dopamine signaling. One study compared genetic mouse models with equally severe chronic dopamine loss. One mouse line had extensive ablation of DA neurons, while the other had only inactivation of DA synthesis with dopamine neurons still intact:¹¹

DA signals reduced to the same extent	DA neuron loss	DA signal inactivation only
Hyperactivity in a new environment	none	none
Motor skills	impaired	impaired
Cognition	more impaired	impaired
Learning	clear deficits	clear deficits
Cue discrimination learning	more serious deficits	significant deficits
spatial learning	drastic deficits	unchanged
spatial memory	drastic deficits	unchanged
Object memory	drastic deficits	unchanged

1.3. Neurophysiological pathways for the loss of dopaminergic neurons¶

Various pathways can lead to the loss of dopaminergic nerve cells:¹

• direct injections of
  • Dopamine (up to 1 μmol) in the striatum
    • alleviated by simultaneous administration of glutathione or ascorbate
  • Aminochrome (a cyclic DAQ) in the substantia nigra
  • DOPAL in the substantia nigra
• Deregulation of endogenous DA synthesis, storage, transport and metabolism by pharmacological and genetic approaches
  • TH overexpression
  • VMAT2 switch-off
  • DAT overexpression
  • Disorders of ALDH-catalyzed detoxification of DOPAL (a reactive dopamine metabolite)
    • environmental exposure to benomyl, a strong ALDH inhibitor, increases the risk of Parkinson’s disease

2. Symptoms of Parkinson’s disease¶

Parkinson’s is

• a degenerative disease of the extrapyramidal motor system
• a syndrome of hypertonic-hypokinetic movement disorders.¹²

2.1. Main symptoms of Parkinson’s disease¶

• Bradykinesia, hypokinesia, akinesia
  • Bradykinesia:
    • Slowed voluntary motor skills
  • Hypokinesia
    • Reduced mobility, lack of movement, lack of spontaneous motor skills
    • Early signs:
      • Slowing down during everyday activities
      • Reduced movement (arms when walking)
        • Often initially one-sided
      • Restricted facial expressions, mask-like face (hypomimia).
      • Font gets smaller
      • “Inconsistent” movement when running for long periods of time (pull back a little)
      • Quiet, monotonous, indistinct 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 flexion of elbow joint, trunk, neck, later also knee joints
      • Neck/shoulder tension (painful)
      • Muscle groups close to the body (axial) are more frequently affected
    • Independent of the speed of the joint movement
    • Cogwheel phenomenon with passive movement of an extremity
      • Jerky yielding of passively moved limb
    • Often (initially) one-sided
      • One arm swings less when walking
      • Early form
• Resting tremor
  • Rhythmic trembling of the extremities during physical rest
  • Frequency approx. 4-6 Hz, rarely up to 9 Hz
  • Reduction through targeted movements
  • Activation through mental activity or emotions
  • Typical in idiopathic Parkinson’s, less common in atypical Parkinson’s
• Postural instability
  • Disturbance of the upright posture
  • Gait instability
  • Stability
  • Postural instability
  • Consequence of the disturbance of the positioning reflexes
• Non-motor neurological symptoms
  • Consequence of the impairment of other neurotransmitter systems
    • Serotonin
    • Noradrenaline

2.2. Other possible symptoms of Parkinson’s disease¶

• Sensory symptoms
  • Dysesthesias
    • Tactile hypersensitivity (also with ADHD: increased sensitivity)
  • Pain
    • Especially joints and muscles
  • Hyposmia (reduced odor perception)
    • Early symptom, occurs years earlier
• Vegetative symptoms
  • Temperature regulation disorder (also with ADHD: increased sensitivity)
    • Reduced heat tolerance
      • Reflective sweating and reflex vasodilation disturbed by heat
      • For advanced disease up to life-threatening high fever
      • Heavy sweating, especially 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 those affected years earlier (frequency increased in ADHD; also dysphoria with inactivity)
    • Apathy (apathy)
  • Increased irritability (also with ADHD)
  • Bradyphrenia
    • Slowed thought processes
    • Content unaffected
    • Expression of general drive disorder
• Sleep disorders (also with ADHD: chronorhythm shifted backwards)
  • Disturbance of dream sleep / REM sleep
    • Atypical strong movements
    • Healthy REM sleep is normally motionless
    • To the point of screaming or lashing out
    • Often also restless legs
• Cognitive symptoms
  • Concentration disorders (also with ADHD)
  • Disorders of the frontal brain
    • Visuospatial attention impaired (estimation of distances and speeds)
  • In advanced stages of dementia
    • Lewy body dementia
• Pseudohypersalivation
  • Saliva swallowing disorder
• Fluctuations in the effect of the selected medication
• Freezing
• Hyperkinesia (excessive movements) (similar to ADHD: hyperactivity there)
• Dystonia
  • Long-lasting, involuntary contractions of the skeletal muscles
  • Leads to abnormal postures and malpositions of the body or body parts (camptocormia)
• Orthostatic dysregulation
  • Disturbance of blood pressure regulation when changing to an upright body position (orthostasis)
• Psychoses
• Impulse control disorders (also with ADHD)
• Akinetic crisis
  • Sudden, acute deterioration of motor symptoms (extreme rigor)
    • Up to complete immobility (akinesia)
    • Difficulty swallowing (dysphagia)
    • Difficult to speak
    • Hyperthermia frequent

2.3. Stages of idiopathic Parkinson’s disease¶

There are six stages of Parkinson’s disease¹³, each of which is associated with a specific area of the CNS¹⁴

• Stage 1 (pre-symptomatic)
  • Pathology limited to
    • Lesions/dysfunctions in the lower medulla oblongata¹⁴
    • Olfactory bulb/anterior olfactory nucleus
  • Disease is very rarely diagnosed
  • Symptoms are subtii:⁴
    • Mainly non-motor symptoms
      • Disorders of the sense of smell (e.g. loss of smell)
      • Disorders of visual perception
      • Depressive symptoms
      • States of anxiety
      • One-sided rest tremor
      • Changes in facial expression
      • Concentration disorders
      • Tiredness
      • Sleep problems
      • Circulatory and digestive problems
      • Erectile dysfunction
      • Increased sweat, saliva and sebum production
• Stage 2 (pre-symptomatic)
  • Damage to the lower raphe nuclei
  • Motor symptoms that affect walking and posture
  • First disorders of fine motor skills
    • Small typeface (micrography)
    • Quiet, monotonous speech (microphony)
    • Sudden, brief freezing during movement (approx. 1/3 of those affected)
• Stage 3 (symptomatic)
  • Substantia nigra damaged
  • Motor symptoms such as balance disorders
  • Progressive disease
    • Rigid mimic muscles (mask face)
    • Vegetative complaints (swallowing problems, constipation, urinary incontinence, increased salivation)
    • Mental health problems (depression and dementia) increase
• Stage 4 (symptomatic)
  • Temporal mesocortex and other gray nuclei of the 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 medication administered;
• Stage 5 (end stage 1)
  • Neocortical temporal fields
  • Many everyday activities are no longer possible, and even walking may require assistance
• Stage 6 (end stage 2)
  • Pathological changes in the mature neocortex
  • Parkinson’s disease manifests itself in all clinical dimensions
  • Motor difficulties so pronounced that those affected lose their independence
  • Patients are almost completely immobile and may have mental symptoms such as hallucinations

3. Forms of Parkinson’s disease¶

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

Affects 3/4 of all Parkinson’s cases.¹²
The joint occurrence of the Parkinson’s triad of hypokinesia, rigor and tremor is no longer a mandatory requirement for a Parkinson’s diagnosis.
Parkinson’s subtypes:⁴

• akinetic-rigid type
  • dominating:
    • Movement slowdown
    • unstable posture
    • Rigor
• Tremor dominance type
  • Resting tremor dominates
  • other motor symptoms are less pronounced or absent (monosymptomatic resting tremor)
  • relatively slow progression of the disease with fewer functional limitations
• Equivalent type
  • equal severity of all main symptoms

Start often one-sided.

3.2. Monogenetic Parkinson’s syndrome¶

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

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

Atypical Parkinson’s syndromes develop comorbidly with other neurodegenerative diseases, e.g:

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

3.4. Secondary Parkinson’s syndromes¶

Symptomatic/secondary Parkinson’s syndromes are a consequence of identifiable primary factors:¹²

• 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 poison from molds)
• Craniocerebral trauma
  • So far no reliable 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¶

The most plausible cause of Parkinson’s is oxidative stress, which leads to dysfunction of the dopaminergic neurons in the substantia nigra. Reactive oxygen species (ROS) can activate the caspase cascade in the mitochondria, which leads to cell death. The presence of ROS appears to increase the risk of Parkinson’s disease.¹⁵

Dopamine metabolism is closely linked to oxidative stress. Dopamine degradation:³
- generates reactive oxygen species (ROS)
- can lead to endogenous neurotoxins.
- Some dopamine derivatives show antioxidant effects

A cytochrome P450 2D6 deficiency doubles the likelihood of developing Parkinson’s disease when contaminated with pesticides. Normally, CPY2D6 breaks down pesticides. The degradation deficiency leads to an accumulation of toxins. Heavy metal poisoning often leads to an accumulation of these toxins in the nigra material, which triggers reactive oxidative damage.¹⁵

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 the formation of Lewy bodies and eventually necrosis. The formation of Lewy bodies can trigger a cascade of events. In a non-pathologic state, Lewy body aggregates are usually flushed by a proteasome complex or a lysosome. However, in Parkinson’s disease, defects in these scavenging pathways often occur, leading to further proliferation of the aggregates. Lewy bodies are considered a defining pathological feature of Parkinson’s and are also frequently found in dementia. The original alpha-synuclein is probably transported from the enteric nervous system (intestine) via the vagus nerve, the most important parasympathetic unit.¹⁵

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 susceptible to activated glia that release 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 last stage of the HPA axis, the adrenal cortex, activate the glucocorticoid receptor (GR). This mediates the deactivation of the first stages of the HPA axis and regulates inflammation both through direct transcriptional effects on target genes and through indirect inhibition of the transcriptional activities of transcription factors such as NF-κB, AP-1 or interferon regulatory factors. The HPA axis is imbalanced in Parkinson’s disease. Cortisol levels are significantly elevated, which indicates a deregulation of GR function in immune cells. Furthermore, activation of the microglial GR contributes to the deactivation of microglial cells and reduces dopaminergic degeneration. Glucocorticoids also regulate the blood vessels of the human brain and the permeability of the blood-brain barrier (BBB). Disruption of glucocorticoid action may affect the infiltration of cytotoxic molecules, leading to increased vulnerability of dopamine neurons in Parkinson’s disease. Overall, deregulation of glucocorticoid receptor action is likely important for the degeneration of dopamine neurons through the development of chronic inflammation.¹⁶

4.4. Loss of noradrenergic neurons in the locus coeruleus¶

In the late stages of Parkinson’s (and Alzheimer’s), there is also a loss of noradrenergic cells in the nucleus coeruleus.¹⁷ This is responsible for 95% of the brain’s noradrenaline release.

4.5. Mitochondrial impairments¶

Mitochondrial impairments play a key role in the loss of dopaminergic neurons.³

5. Prevalence of Parkinson’s disease¶

The prevalence is strongly age-dependent.¹⁸

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.

Estimated crude prevalence for all age groups depending on the study:¹⁹

• Europe, North America and South America:
  • 66-1,500 / 111-329 / 31-470 per 100,000
• Africa, Asia, Arabia
  • 10-43 / 15-119 / 27-43 per 100,000

6. Parkinson’s and ADHD¶

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

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

Neuropsychological studies on ADHD in adults, Parkinson’s in the prodromal stage and Parkinson’s in the early stages show similar deficits in

• Executive functions
• Memory
• Attention
• Pulse inhibition

These symptoms are mediated by similar neuronal substrates.²⁰

The following Parkinson’s symptoms also occur with ADHD:

• Hypokinesia
  • (only) similar in ADHD: disorders of gross motor skills and fine motor skills
    * Many bruises
    * Font is unattractive to illegible
• Increased muscle tension
  • Parkinson’s disease: 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 disease:
    • Gait instability
    • Stability
    • Postural instability
    • Consequence of the disturbance of the positioning reflexes
  • ADHD shows increased postural instability²¹ in medication-naïve patients²²
• Non-motor neurological symptoms as a result of the impairment of other neurotransmitter systems
  • Noradrenaline
    • Also for ADHD
  • Serotonin
    • Also for ADHD, but only slightly
• Sensory symptoms
  • Dysesthesias
    • Tactile hypersensitivity (also with ADHD: increased sensitivity)
  • Pain
    • Especially joints and muscles
    • With ADHD: increased sensitivity to pain
• Vegetative symptoms
  • Temperature regulation disorder
    • Reduced heat tolerance
      • Reflective sweating and reflex vasodilation disturbed by heat
      • In advanced disease up to life-threatening high fever
      • Heavy sweating, especially at night
    • With ADHD: slightly increased sensitivity to temperature
• Psychological symptoms
  • Especially depression
    • Parkinson’s disease:
      • Dysphoria in 40 % of those affected years earlier
      • Fear
    • ADHD:
      • Depression and anxiety common
      • Also dysphoria during inactivity
  • Drive problems
    • Parkinson’s disease
      • Apathy (apathy)
    • ADHD
      • Weak drive (significantly weaker form): Increased frequency
  • Irritability
    • Parkinson’s disease: increased
    • ADHD: increased
  • Bradyphrenia
    • Parkinson’s disease:
      • 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 disease
    • Disturbance of dream sleep / REM sleep
      • Atypical strong movements
      • Healthy REM sleep is normally motionless
      • To the point of screaming or lashing out
    • Often also restless legs
  • ADHD:
    • Chronorhythm shifted backwards
    • Problems falling asleep
    • Restless legs frequent
• Cognitive symptoms
  • Concentration disorders
    • Parkinson’s disease: frequent
    • ADHD: one of the core symptoms
  • Disorders of the frontal brain
    • Parkinson’s: visuospatial attention impaired (estimation of distances and speeds)
    • ADHD: visuospatial working memory is impaired
• Hyperkinesia (excessive movements)
  • Parkinson’s disease: frequent
  • ADHD: here hyperactivity
• Impulse control disorders
  • Parkinson’s disease: frequent
  • ADHD: frequent

6.1.2. Parkinson’s symptoms that do not occur with ADHD¶

The following Parkinson’s symptoms do not occur with ADHD:

• Bradykinesia, akinesia
  • Bradykinesia:
    • Slowed voluntary motor skills
  • Hypokinesia
    • Reduced mobility, lack of movement, lack of spontaneous motor skills
  • Akinesia
    • Rigidity of movement (extreme form)
• Rigor:
  * Cogwheel phenomenon with passive movement of an extremity
  * Jerky yielding of passively moved limb
  * Often (initially) one-sided
  * One arm swings less when walking
  * Early form
• Resting tremor
  • Rhythmic trembling of the extremities during physical rest
  • Frequency approx. 4-6 Hz, rarely up to 9 Hz
  • Reduction through targeted movements
  • Activation through mental activity or emotions
  • Typical in idiopathic Parkinson’s, less common in atypical Parkinson’s
• Non-motor neurological symptoms
  • Consequence of the impairment of other neurotransmitter systems
    • Serotonin
    • Noradrenaline
  • Hyposmia (reduced odor perception)
    • Early symptom, occurs years earlier
• Vegetative symptoms
  • Temperature regulation disorder
    * For advanced disease up to life-threatening, highly febrile conditions
    * Heavy sweating, especially 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 normally motionless
    • To the point of screaming or lashing out
• Pseudohypersalivation
  • Saliva swallowing disorder
• Fluctuations in the effect of the selected medication
• Freezing
• Dystonia
  • Long-lasting, involuntary contractions of the skeletal muscles
  • Leads to abnormal postures and malpositions of the body or body parts (camptocormia)
• Orthostatic dysregulation
  • Disturbance of blood pressure regulation when changing to an upright body position (orthostasis)
• Psychoses
• Akinetic crisis
  • Sudden, acute deterioration of motor symptoms (extreme rigor)
    • Up to complete immobility (akinesia)
    • Difficulty swallowing (dysphagia)
    • Difficult to speak
    • Hyperthermia frequent

6.2. Comorbidity of Parkinson’s and ADHD¶

There could be a pathophysiological link between ADHD (dopamine deficiency) and Lewy body disease, in particular Parkinson’s disease (dopamine neuron degeneration).²³ Low dopamine levels and abnormal maturation of the dopaminergic system could increase the risk of Parkinson’s disease in ADHD sufferers.²⁴ However, genetic studies found neither causality nor association between Parkinson’s and ADHD²⁵ with regard to the gene candidates SNAP25, SLC6A3 (DAT1), DRD4, HTR1B, TPH2, SLC6A2 (NET) and three SNPs in CDH13²⁶.

6.3. Stimulants for ADHD and Parkinson’s risk¶

One hypothesis is that stimulants could explain the link between ADHD and Parkinson’s by having toxic effects on dopaminergic neurons and leading to impaired dopamine regulation and dopamine transport²³ A single study found that the overall 2.3-fold risk of Parkinson’s increased 3.9-fold in people with ADHD who took stimulants. The extent to which the severity of the ADHD (which makes stimulant use more likely) played a role is unclear.²⁷
However, this is contradicted by a number of studies:

• no evidence of stimulants as a cause of Parkinson’s disease²⁴
• Taking stimulants did not increase the risk of Parkinson’s disease⁷
• Taking stimulants reduced the risk of Parkinson’s by around 60%²⁸
• no neurodegenerative effects on dopamine neurons due to amphetamines in drug doses (7 studies).⁷

7. Risk factors for Parkinson’s disease¶

7.1. Gene candidates for Parkinson’s disease¶

Various gene variants are considered candidate genes that may increase the risk of Parkinson’s disease.
None of these are also known to us as ADHD candidate genes.

• GBA (OR >5)¹⁹
• GBA1¹
• Parkin¹
• LRRK¹
• LRRK2¹⁹
• DJ-1¹
• PINK1¹
• SNCA¹
• INPP5F¹⁹
• STK39¹⁹
• SIPA1L2¹⁹
• BST1¹⁹
• RAB7L1-NUCKS1¹⁹
• VPS13C¹⁹
• DDRGK1¹⁹
• GPNMB¹⁹
• CCDC62¹⁹
• MIR4697¹⁹
• BCKDK-STX1B¹⁹

The risk of Parkinson’s appears to be reduced in variants of some genes:¹⁹

• SNCA
• MAPT
• TMEM175-GAK-DGKQ
• HLA-DQB1
• MCCC1
• ACMSD-TMEM163

7.2. Age, gender, ethnicity¶

Age, gender and ethnicity are risk factors for Parkinson’s disease.²⁹

• Age
  • biggest risk factor
  • Prevalence and incidence increase almost exponentially with age
  • Peak after the age of 80
• Gender
  • Ratio between men and women almost 2:1
    • Men: 19.9 / 100,000
    • Women: 9.9 / 100,000
• Ethnicity
  • Risk in the USA:
    • hispanic origin: 16.6 / 100,000
    • non-Hispanic whites: 13.6 / 100,000
    • Asians: 11.3 / 100,000
    • Blacks: 10.2 / 100,000

7.3. Environmental factors that increase the risk of Parkinson’s disease¶

Environmental factors that increase the risk of Parkinson’s include:¹⁹⁴

• Pesticides
  • Paraquat
• Carbon monoxide
• Methanol
• Ethylene glycol
• MTPT [1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine]
  • a synthetic heroin from the 80s
  • caused severe Parkinson’s symptoms in consumers
  • Use since then for the generation of Parkinson’s animal models
• Head injuries
• β-Blocker
• agricultural activity
• Drinking water from wells
• Taking certain medications, although the results here still need to be verified:
  • Antipsychotics
    • especially of phenothiazines, benzamides, haloperidol or risperidone by older people
• Solvent,
  • especially trichloroethylene

7.4. Environmental factors that reduce the risk of Parkinson’s disease¶

Factors that significantly reduce the risk of Parkinson’s include:¹⁹

• Cigarettes
  • Parkinson’s sufferers can give up smoking more easily
• Coffee
• Alcohol consumption
• non-steroidal anti-inflammatory drugs
• Ca2+ channel blocker

8. Diagnostics¶

A “Dopamine Transporter Scan” can be used as a supporting instrument for the diagnosis of Parkinson’s disease. This has been approved by the FDA for this purpose since 2011 and enables a simple, rough estimate of the DAT count³⁰

9. Treatment¶

9.1. Medication for Parkinson’s disease¶

9.1.1. Dopamine agonists¶

Dopamine agonists act directly on the dopamine receptors.
Slow dosing required (like stimulants for ADHD).
Less frequent fluctuations in effect or restlessness when taken for many years than L-dopa.
First choice drug. Only if not sufficient, supplement with L-dopa.

• Non-ergot dopamine agonists ((modern; selective D2 receptor agonists)
  • Apomorphine
    • D2 agonist
  • Piribedil
  • Pramipexole
  • Ropinirole
    • Selective D2 and D3 agonist
  • Rotigotine
• Ergot dopamine agonists (classic ergot alkaloids)
  • Bromocriptine
  • Cabergoline
  • Dihydroergocryptine
  • Lisuride
  • Pergolide

9.1.2. L-dopa (levodopa)¶

L-dopa is a prodrug of dopamine. L-dopa is the most effective Parkinson’s medication
Rather with older patients.
Initially taken orally, increasing to continuous infusion if necessary
IdR combined with decarboxylase inhibitors. Decarboxylase inhibitors ensure that L-dopa is not converted to dopamine in the blood, but only in the brain:

• Benserazide
• Carbidopa

Time to effect: from first intake to several weeks
L-Dopa is available as an immediately effective or slow-release preparation.

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 through internalization of D2 homomers and A2A-D2 heteromers. As a consequence, 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 primarily due to the increasing dominance of A2A signaling with increased firing, which is why L-dopa fails to silence these neurons and remove the motor brake.³¹.

In some Parkinson’s models L-DOPA showed a protective effect, in others it showed toxicity for neurons and non-neuronal cells.
Autooxidation of L-DOPA produces toxic and reactive ROS and DAQs. In a computer model, L-DOPA showed a loss of dopaminergic neuronal terminals in the substantia nigra, which was alleviated by the simultaneous administration of glutathione. L-DOPA appears to have neurotoxic and neuroprotective effects depending on the oxygen tension. At physiological oxygen levels, L-DOPA inhibits mitochondrial functions, suppresses oxidative phosphorylation and depletes the NADH pool without causing auto-oxidation of L-DOPA and oxidative cell damage.¹

9.1.3. COMT inhibitors¶

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

9.1.4. MAO-B inhibitors¶

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

• Selegiline
  • Degradation to amphetamines
  • Amphetamines can promote sleep disorders
  • In this case, take it at lunchtime at the latest
• Rasagiline

9.1.5. 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 release of dopamine
• Dopamine reuptake inhibition

Symptom effect:

• Tremor reduced
• Akinesia reduced.

Side effects

• Skin changes
• Edema
• Nightmares
• Activating effect
  • do not take later in the afternoon if you have trouble sleeping

9.1.6. Anticholinergics¶

Anticholinergics act as acetylcholine antagonists
Can improve tremor (trembling) if L-dopa or dopamine agonists are not sufficient.

Side effects (significant):

• Dry mouth
• Circulatory disorders
• Urinary retention
• Forgetfulness

9.1.7. Budipin¶

Budipin has various mechanisms of action:

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

Symptom efficacy:

Tremor (trembling) is reduced

Side effects (significant):

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

• Sensory illusions
• Nightmares
• Headache
• Visual disturbances
• Hot flushes
• Loss of appetite
• Akathisia

Contraindications:

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

9.1.8. Stimulants¶

Stimulants, which are also commonly used for ADHD, appear to support the treatment of Parkinson’s disease.

• Amphetamine drugs
• Methylphenidate³²

9.1.9. Antioxidants¶

Due to the role of ROS in the development of Parkinson’s disease, the use of ROS antioxidants is being discussed. Curcumin is a candidate for reducing ROS.¹⁵

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

Non-drug treatment of Parkinson’s disease can be considered:¹²
- deep brain stimulation (brain pacemaker)
- Occupational therapy
- Physiotherapy
- Speech therapy
- Psychoeducation and self-help groups