The Essentials of Parkinson’s Disease

Parkinson’s disease (PD) is the second most common degenerative disease of the nervous system (NS) after Alzheimer’s disease. The fundamental pillars of its clinical picture were already described by the Briton James Parkinson two centuries ago, based on the mere observation of half a dozen cases.

The prevalence of this disease increases almost exponentially with age: it goes from affecting 1% of those over 60 to 15-20% of those over 80.

What are the causes of PD?

With regard to the causes of PD, we have to say that it is far from being completely clarified. More than twenty genes whose mutations can cause it are currently known, but it is still thought that 70-80% of cases are sporadic in nature. The most common genetic cause of dominantly inherited PD is mutations in the LRKK1 gene (also dardarin-dominant, because it is frequent in the Basque Country, where tremor is called dardar in the vernacular); as for recessive forms, the mutated parkin gene is the most common cause.

Regarding sporadic PD, the disease has been related to toxins such as Mn, consumption of well water and repeated contact with pesticides and insecticides. It should be noted that certain medications (neuroleptics, substituted benzamides, serotonin reuptake inhibitors, calcium antagonists…), all of them potential dopamine receptor blockers, can cause parkinsonism similar to PD, but potentially reversible after cessation of their intake. The progressive loss of the neuronal population of a midbrain nucleus called substantia nigra is the pathological basis of PD; in many cases the surviving neurons have special inclusions called Lewy bodies, which contain alpha-synuclein. Such inclusions are not only found in this nucleus but can also be found in other nuclei and in areas related to sleep, olfaction, and various autonomic functions. The primary biochemical marker of PD is dopamine depletion, primarily in the pathway from the substantia nigra to the striatum, which plays an important role in the regulation of movement patterns.

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What are the most recognizable symptoms of PD?

The clinical picture of PD is characterized by four main symptoms:

  1. Bradykinesia or slowness of movement.
  2. Resting tremor, which usually begins in one limb and generalizes as the disease progresses.
  3. Increased muscle tone in the form of “cogwheel stiffness”, perceived as jumping or intermittent, when attempting passive mobilization of a limb.
  4. Impaired reflexes for straightening and maintenance and control of upright posture.

Before the primary symptoms of PD begin to manifest, patients often present with complaints such as constipation, joint pain (particularly frequent is shoulder pain), depressed mood and sleep disturbances. With regard to sleep, we should underline that the so-called REM sleep disorder often precedes the motor symptoms of PD by several years and is characterized by vocalizations and profuse motor gestures: it is a special theatrical dream experience of the aforementioned rapid-wave sleep phase.

The presence of cognitive impairment is detected in one third of patients with PD; it is usually a mild-moderate cognitive dysfunction, characterized by apathy, attention deficit and planning difficulties. However, some patients develop dementia with significant behavioral disturbances and hallucinations in the early years of their disease, which are known as diffuse Lewy body dementia (DLBD), i.e., the synucleinopathy extends to the cerebral cortex, especially the posterior areas. It may also happen that in DLBD dementia occurs first, followed by the motor symptoms of parkinsonism.

Rivers of ink have been poured to describe the particular features of the personality and character of the parkinsonian patient, especially because of the notoriety of some characters who have suffered PD and who have had, for better or worse, important influence in history (Adolf Hitler, John Paul II, Francisco Franco). Mental rigidity, undaunted fidelity to an ideology, permanent willingness to work despite physical incapacity… are some of the traits to which we alluded. There are many who attribute the proven history of abhorrence of smoking by the majority of PD patients to this debated question of the Parkinsonian personality.

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How can PD be diagnosed?

The diagnosis of PD disease is still based on the clinical picture; imaging techniques are reserved to exclude other entities (tumors, hydrocephalus, cerebrovascular pathology…) that may mimic it. However, it should be emphasized that the contribution of nuclear medicine, in particular the so-called DAT-scan (DAT marks the density of the nigrostriatal dopaminergic neuronal population), is important especially when differentiating PD from drug-induced parkinsonism; the latter usually reverts when the triggering medication is withdrawn.

A particular issue of special relevance is constituted by several nosological entities called parkinson-plus: apart from the aforementioned DCLD, we must mention progressive supranuclear palsy (PSP), corticobasal degeneration (CBD) and multiple system atrophy (MSA). The precise diagnosis of each of these entities, which in some particular cases may respond temporarily to dopaminergic substitution therapy, is of great importance especially because of the prognosis (much worse in all of them than in PD) and because of the need for adequate management and prevention of its complications, such as falls in PSP and syncope in MSA. Nature intended that dopamine, a neurotransmitter involved not only in motor control but also in falling in love, addictive behavior, enjoyment and even breastfeeding, should not cross the blood-brain barrier. In PD, in order to increase striatal dopamine, we have to resort to levodopa; this, through a process of decarboxylation, will be transformed into dopamine already inside the brain.

Levodopa is the basis of PD medical therapy, which is complemented with dopaminergic receptor agonists and other drugs that prevent/difficult the metabolization of dopamine itself. In advanced cases, with motor complications-fluctuations resistant to standard medical therapy, deep brain stimulation surgery, direct infusion of dopa into the duodenum and continuous administration of subcutaneous apomorphine are used.

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Regular physical exercise, physiotherapy and speech therapy are also important therapeutic measures in PD, a disease that we can diagnose in its early stages, but for which, at the moment, we do not have any therapeutic resource to slow down and interrupt its progression.