Parkinson's disease reference

Parkinson's disease (also known as Parkinson disease or PD) is a degenerative disorder of the central nervous system that often impairs the sufferer's motor skills and speech, as well as other functions.[1]

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). 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 subtle language problems. PD is both chronic and progressive.

PD is the most common cause of chronic progressive parkinsonism, a term which refers to the syndrome of tremor, rigidity, bradykinesia and postural instability. PD is also called "primary parkinsonism" or "idiopathic PD" (classically meaning having no known cause although this term is not strictly true in light of the plethora of newly discovered genetic mutations). 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).

Signs and symptoms

Parkinson disease affects movement (motor symptoms). Typical other 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.

Motor symptoms

The cardinal symptoms are (mnemonic "TRAP"):[1]

* Tremor: normally 4-6 Hz 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; these are classified as akinetic-rigid.
* Rigidity: stiffness; increased muscle tone. In combination with a resting tremor, this produces a ratchety, "cogwheel" rigidity when the limb is passively moved.
* bradykinesia/Akinesia: respectively, slowness or absence of movement. Rapid, repetitive movements produce a dysrhythmic and decremental loss of amplitude.
* Postural instability: failure of postural reflexes, which leads to impaired balance and falls.

Other motor symptoms include:

* Gait and posture disturbances:
o 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.
o Decreased arm-swing.
o 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.
o Stooped, forward-flexed posture. In severe forms, the head and upper shoulders may be bent at a right angle relative to the trunk (camptocormia). [2]
o Festination: a combination of stooped posture, imbalance, and short steps. It leads to a gait that gets progressively faster and faster, often ending in a fall.
o Gait freezing: "freezing" is a manifestation of akinesia (an inability to move). Gait freezing is characterized by an inability to move the feet which may worsen in tight, cluttered spaces or when attempting to initiate gait.
o 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.
* Speech and swallowing disturbances.
o 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.[3]
o Monotonic speech.
o Festinating speech: excessively rapid, soft, poorly-intelligible speech.
o Drooling: most likely caused by a weak, infrequent swallow and stooped posture.
o 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.[4]
o Dysphagia: impaired ability to swallow. Can lead to aspiration, pneumonia.
* Other motor symptoms:
o Fatigue (up to 50% of cases);
o Masked faces (a mask-like face also known as hypomimia), with infrequent blinking;[5]
o Difficulty rolling in bed or rising from a seated position;
o Micrographia (small, cramped handwriting);
o Impaired fine motor dexterity and motor coordination;
o Impaired gross motor coordination;
o Poverty of movement: overall loss of accessory movements, such as decreased arm swing when walking, as well as spontaneous movement;
o Akathisia.

Non-motor symptoms

Mood disturbances

Estimated prevalence rates of depression vary widely according to the population sampled and methodology used. Reviews of depression estimate its occurrence in anywhere from 20-80% of cases.[6] Estimates from community samples tend to find lower rates than from specialist centres. Most studies use self-report questionnaires such as the Beck Depression Inventory, which may overinflate scores due to physical symptoms. Studies using diagnostic interviews by trained psychiatrists also report lower rates of depression. More generally, there is an increased risk for any individual with depression to go on to develop Parkinson's disease at a later date.[7] Seventy percent of individuals with Parkinson's disease diagnosed with pre-existing depression go on to develop anxiety. Ninety percent of Parkinson's disease patients with pre-existing anxiety subsequently develop depression; apathy or abulia.

Cognitive disturbances

* Slowed reaction time; both voluntary and involuntary motor responses are significantly slowed.
* Executive dysfunction, characterized by difficulties in: differential allocation of attention, impulse control, set shifting, prioritizing, evaluating the salience of ambient data, interpreting social cues, and subjective time awareness. This complex 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.
* Short term memory loss; procedural memory is more impaired than declarative memory. Prompting elicits improved recall.
* Medication effects: some of the above cognitive disturbances are improved by dopaminergic medications, while others are actually worsened.[8]

Sleep disturbances

* 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

Sensation disturbances

* Impaired visual contrast sensitivity, spatial reasoning, colour discrimination, convergence insufficiency (characterized by double vision) and oculomotor control
* Dizziness and fainting; usually attributable orthostatic hypotension, a failure of the autonomic nervous system to adjust blood pressure in response to changes in body position
* Impaired proprioception (the awareness of bodily position in three-dimensional space)
* Reduction or loss of sense of smell (microsmia 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 disturbances

* Oily skin and seborrheic dermatitis[9]
* 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. Current data addresses male sexual function almost exclusively.
* Weight loss, which is significant over a period of ten years.
Diagnosis
18F PET scan shows decreased dopamine activity in the basal ganglia, a pattern which aids in diagnosing Parkinson's disease.
18F PET scan shows decreased dopamine activity in the basal ganglia, a pattern which aids in diagnosing Parkinson's disease.

There are currently no blood or laboratory tests that have been proven to help in diagnosing PD. Therefore the diagnosis is based on medical history and a neurological examination. The disease can be difficult to diagnose accurately. The Unified Parkinson's Disease Rating Scale is the primary clinical tool used to assist in diagnosis and determine severity of PD. Indeed, only 75% of clinical diagnoses of PD are confirmed at autopsy.[10] Early signs and symptoms of PD may sometimes be dismissed as the effects of normal aging. The physician may need to observe the person for some time until it is apparent that the symptoms are consistently present. Usually doctors look for shuffling of feet and lack of swing in the arms. Doctors may sometimes request brain scans or laboratory tests in order to rule out other diseases. However, CT and MRI brain scans of people with PD usually appear normal.

Clinical practice guidelines introduced in the UK in 2006 state that the diagnosis and follow-up of Parkinson's disease should be done by a specialist in the disease, usually a neurologist with an interest in movement disorders.[11]

Classification

"Parkinson's disease" is the synonym of "primary parkinsonism", i.e. isolated parkinsonism due to a neurodegenerative process without any secondary systemic cause. In some cases, it would be inaccurate to say that the cause is "unknown", because a small proportion is caused by genetic mutations. It is possible for a patient to be initially diagnosed with Parkinson's disease but then to develop additional features, requiring revision of the diagnosis.[11]

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 in their brain tissue, the distribution is denser and more widespread in DLB. Even so, the relationship between Parkinson disease, Parkinson disease with dementia (PDD), and dementia with Lewy bodies (DLB) might be most accurately conceptualized as a spectrum, with a discrete area of overlap between each of the three disorders. The natural history and role of Lewy bodies is little understood.

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 dysphasia and apraxias especially with "alien limb" phenomena should suggest CBD.

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.

Essential tremor may be mistaken for Parkinson's disease but lacks all other features besides tremor, and has particular characteristics distinguishing it from Parkinson's, such as improvement with beta blockers and alcoholic beverages.[1]

Wilson's disease (hereditary copper accumulation) may present with parkinsonistic 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-Fleisher rings, and serum ceruloplasmin levels.

Pathology
Dopaminergic pathways of the human brain in normal condition (left) and Parkinson's disease (right). Red Arrows indicate suppression of the target, blue arrows indicate stimulation of target structure.
Dopaminergic pathways of the human brain in normal condition (left) and Parkinson's disease (right). Red Arrows indicate suppression of the target, blue arrows indicate stimulation of target structure.

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, in essence 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 ventral anterior nucleus of the thalamus, which sends excitatory projections to the motor cortex, thus leading to hypokinesia.

There are four major dopamine pathways in the brain; the nigrostriatal pathway, referred to above, 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 likely explains much of the neuropsychiatric pathology associated with Parkinson's disease.

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. The alpha-synuclein-ubiquitin complex cannot be directed to the proteosome. This protein accumulation forms proteinaceous cytoplasmic inclusions called Lewy bodies. 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 in animal models.[12]

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.[13] Iron also induces aggregation of synuclein by oxidative mechanisms.[14] Similarly, dopamine and the byproducts of dopamine production enhance alpha-synuclein aggregation. The precise mechanism whereby such aggregates of alpha-synuclein damage the cells is not known. The aggregates may be merely a normal reaction by the cells as part of their effort to correct a different, 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.[15]

Causes

Most people with Parkinson's disease are described as having idiopathic Parkinson's disease (having no specific cause). There are far less common causes of Parkinson's disease including genetic, toxins, head trauma, cerebral anoxia, and drug-induced Parkinson's disease.

Genetic

In recent years, a number of specific genetic mutations causing Parkinson's disease have been discovered, including in certain populations (Contursi, Italy). These account for a small minority of cases of Parkinson's disease. Someone who has Parkinson's disease is more likely to have relatives that also have Parkinson's disease. However, this does not mean that the disorder has been passed on genetically.