Parkinson's disease: symptoms, causes and diagnosis
Parkinson’s disease: in 1817, James Parkinson published a monograph entitled ‘Essay on the shaking palsy’
This was the first scientific description of a morbid condition in which the combination of two contradictory phenomena, muscular paralysis and tremor, was emphasised.
Since then, studies on this disease have multiplied to the point of outlining one of the best-known and most in-depth neurological diseases in modern medicine, even though aspects, especially those concerning its causes, remain far from clear.
What is Parkinson’s disease
According to current knowledge, Parkinson’s disease is a primary degenerative nerve disorder, i.e. a process of programmed cell death (apoptosis) that affects a particular type of nerve cell during an individual’s lifetime.
Nerve cells, as most people know, are elements whose reproductive capacity stops at the end of intrauterine development and which remain potentially viable until natural human death. In reality, during a subject’s lifetime, a very large number of nerve cells degenerate, so that the natural course of the ageing process consists of the loss of large populations of neurons, which is countered by the consolidation of the synaptic circuits (i.e. connections between nerve cells) of the surviving cells.
This dual tendency, cell death and synaptic consolidation, is now considered to be the structural basis of the brain’s learning processes during relational life, which is why primary degenerative diseases such as Parkinson’s disease, Alzheimer’s disease or Multisytemic Atrophy are considered to be the effect of an imbalance whereby the rhythm of programmed cell death overrides the harmony of the normal global ageing process of the neuraxis.
The nerve cell most involved in early degeneration during Parkinson’s disease is the dopaminergic cell, i.e. secreting a neurotransmitter called dopamine characterised by a particular blackish pigment.
The highest concentration of dopaminergic cells is found in an area of the lower basal area of the brain (midbrain, in a laminar structure called the black substance) and whose extensions form a circuit with another higher brain area, called the nucleus striatum.
This circuit (nigro-striatal) is part of a more extensive connection between brain structures, collectively known as the ‘basal nuclei’, which in complex ways globally govern the movements of the striated, i.e. ‘voluntary’, muscles.
In reality, there are several variants of primary degenerative diseases that affect dopaminergic cells, with very different mechanisms and with different localisations of neuronal loss.
The reason why Parkinson’s disease is so ‘famous’ stems from the fact that its manifestations are common to several pathological conditions, which is why other degenerative neurological diseases that do not correspond exactly to the classically described disease are also often referred to as ‘Parkinson’s’; secondly, all insults of a different nature, such as inflammation, trauma, intoxication, nutritional deficiencies and, above all, ischaemic damage linked to deterioration of the brain’s vascular tree are potentially able to mimic the signs and symptoms of Parkinson’s disease, simply because they can involve the same brain areas. In this case, we speak of Parkinsonism, i.e. syndromes that partly overlap with those of the degenerative disease, which in these cases is, however, defined as ‘secondary’.
What are the symptoms of Parkinson’s disease
Parkinson’s disease is predominantly a movement disorder. The disease rarely appears before the age of 30.
James Parkinson’s original description includes three basic features, which make up the ‘classic triad’:
- resting tremor of the extremities (typically of the hands, with an involuntary movement reminiscent of the gesture of ‘counting coins’) having a regular rhythm (quite precisely at 3 Hz) and almost always prevailing on one of the sides
- rigidity of the muscle segments, both those of the limbs and those of the trunk; the rigidity is felt by the patient as a ‘clumsiness’ in movements, but more often it is objectively detected by the physician, who assesses the muscle tone at rest during passive mobilisation of the joints, as well as noting the typical posture of the back in hyperflexion (‘camtocormic posture’)
- hypo-akinesia, i.e. the global reduction or loss of the subject’s spontaneous motility, which shows a generalised reduction in accessory movements (e.g. pendular movements of the upper limbs when walking) but above all a clear difficulty in initiating motor sequences aimed at an executive programme, from the simple transition to standing from a seated position to the production of gestures of communicative significance. Hypokinesia is perceived by the observer as slowness of movement (‘bradykinesia’) and as a lack of aptitude for relational gestures.
Typically, the subject also appears reluctant to spontaneous facial expression unless expressly invited to make particular expressions.
The typical hypomimia with automatic-intentional dissociation is expressed in the condition in which the patient does not smile provoked by a witticism but is able to produce a ‘courtesy smile’ on command.
The patient is aware of his difficulty in movement, suffers the consequences both in terms of loss of motor autonomy and in terms of expressive poverty and, in more advanced cases, feels the sensation of being blocked by an irresistible force, especially during bed rest.
Objectively, the patient with untreated Parkinson’s disease, or in the stages of the disease in which treatment loses all or part of its therapeutic effectiveness, is a severe invalid.
In addition to movement disorder, Parkinson’s disease brings with it, to varying degrees, two other pathological conditions
- dysautonomia, i.e. impairment of the nerve activity responsible for controlling vegetative functions (primarily thermoregulation, gastrointestinal activity and control of cardiovascular parameters)
- altered mood resembling, though not coinciding with, a major depressive disorder. In particularly advanced cases, the pathology may come to involve the cortical areas of the brain, inducing states of cognitive impairment.
This is why several authors speak of ‘Parkinson-Dementia’ as a distinct nosological variant.
However, since there are other neurodegenerative diseases that are to some extent ‘related’ to Parkinson’s disease in which the emergence of dementia is much earlier and more pronounced (Lewy Body Dementia, Progressive Supranuclear Palsy, Cortico-Basal Degeneration, etc.), these distinctions tend to appear fragile.
Since it is a chronic disease whose degree of degeneration increases over several years (decades), the above-mentioned signs and symptoms are susceptible to wide variations over time, partly because the inference of drug therapies is currently capable of significantly altering (for better or worse) the course of the pathological manifestations, and partly because each subject tends to manifest the three signs of the classic triad to a different degree.
There are patients who do not develop tremor at all (or develop it only late), just as others manifest tremor as an almost unique sign of the disease (‘tremorigenic variant’).
Muscle rigidity (referred to as ‘plasticity’ by clinicians) and, above all, hypokinesia are more constant features, although they too vary greatly between sufferers.
The causes of Parkinson’s disease
What has been said above about the definition of Parkinson’s disease immediately suggests that the causes of the disease proper are to be sought in the intrinsic biomolecular processes in the cells involved.
Over the decades, numerous possible triggering conditions for selective cell degeneration in the neurons of the sostanza nigra have been invoked.
These include some variants of familial Parkinson’s disease, which can be counted among the genetically determined late-onset diseases, of which rare but definite examples have been found in various populations.
Given their rarity, however, these descriptions have been more useful in the search for particular mutations in the genes involved in the molecular mechanisms of degeneration of the dopaminergic neuron than in explaining the phenomena actually at work in the majority of cases of Parkinson’s disease, the latter being devoid of any recognisable hereditary transmission. In other words, the common disease in humans is, until proven otherwise, sporadic, i.e. without any genetically demonstrable heredity.
The same applies to various other pathogenetic hypotheses, from those based on possible specific toxicities self-induced by the neurons themselves (excitotoxicity), to those involving environmental substances capable of selectively accelerating oxidoreductive phenomena on the neurons’ membrane (oxidative stress), to those that hypothesise inflammatory reactions directed against dopaminergic cells, reactions perhaps triggered by abnormal interactions with the external environment.
Certainly today we have a wealth of information concerning characteristic abnormalities found in cells affected by the disease: certain cell degeneration processes are typical, though not exclusive, of the disease (especially Lewy bodies, particular intracytoplasmic inclusions); furthermore, the dynamic mutations linked to the specific disorder of dopaminergic neurotransmission are at the basis of involutional phenomena also affecting the other neuronal populations involved in the system’s circuitry, to the point of determining structural alterations in the connected cerebral systems (caudate nucleus, globus pallidus, thalamus, motor cortex and associative cortex).
The observations obtained from the rare cases of genetically transmitted disease, together with the findings obtained on lower vertebrates, have certainly helped to outline plausible models of ‘native’ disease production, leading to the identification of protein molecules specifically implicated in the production of neuronal damage (e.g. the alpha-synucleins within Lewy bodies).
Unfortunately, at present, this does not yet make it possible to outline a clear and incontrovertible causal pathway explaining the causes of Parkinson’s disease induction in individual patients, at least not in the terms that we use, for example, to explain the relationship between Treponema Pallidum infection and the development of syphilis.
Worldwide, the disease is the most frequent primary neurodegenerative disease after Alzheimer’s
There are currently around 230,000 people suffering from Parkinson’s disease in Italy; the prevalence (number of people affected compared to the rest of the population in the current year) of the disease is 1-2% of the population over 60 years of age and 3-5% of the population over 85 years of age.
Out of every 100,000 people in the world, 20 individuals fall ill with Parkinson’s disease every year.
The average age of onset of symptoms is around 60 years, but 5% of patients may present with an early-onset form, with onset before the age of 50.
According to epidemiological studies conducted in Europe and the US, the disease affects men 1.5-2 times more frequently than women.
The duration of the disease, which basically coincides with life expectancy (survival), has undergone a drastic improvement coinciding with the use of L-dopa-based drugs (the precursor to dopamine synthesis, which is lacking in the brain of the sufferer).
In fact, in the pre-L-dopa era, some clinical studies (1967) reported reduced survival in Parkinson’s disease sufferers compared to the general population, up to a 3-fold relative risk of death.
After the introduction of L-dopa and up to the mid-1980s, however, there was a reversal of this trend with numerous clinical studies reporting survival even comparable to the general population.
The Diagnosis
The “combination” of an average age of onset around 60 years, in which an individual is often already the carrier of a variable accumulation of pathological conditions that tend to damage the central nervous system (comorbidity), coupled with the microscopic dimension (invisible even to neuroradiological examinations) of the primary neurodegenerative damage means that the diagnosis of Parkinson’s disease remains one of the most difficult tests for the physician.
Physicians trained to recognise disorders of the nervous system, i.e. neurologists, must bear in mind that it is their responsibility to recognise those clinical aspects (first and foremost the aforementioned classic Parkinsonian triad, sometimes blurred by other movement disorders) that, through diagnostic formulation will lead them to drastically influence the patient’s life, with the imposition of a complex regimen of pharmacological prescriptions, dietary shrewdness and a new existential perspective, sooner or later heralding the need to provide for one’s motor autonomy with ever greater organisational and economic efforts.
Despite the enormous development of diagnostic tools aimed at diseases of the nervous system over the last 20 years (from clinical neurophysiology to iconographic and functional neuroimaging), a procedure for the instrumental objectification of Parkinson’s disease in the living has not yet emerged.
More recently, a selectively sensitive brain scintigraphy test for the activity of dopaminergic neurons of the basal nuclei (DaTSCAN) has been proposed but this, as well as other advanced neuroradiological approaches (Positron Emission Tomography PET, Magnetic Resonance Imaging MRI, etc.), has proved more useful in differentiating individual clinical aspects within limited diagnostic hypotheses (e.g. whether tremor is ascribable to Parkinson’s disease or other neurodegenerative pathologies) rather than in producing the diagnostic act itself.
Put simply, to date it is not possible to replace the clinical neurologist with a machine capable of issuing a diagnosis.
Instead, instrumental examinations are extremely important for the development of knowledge about the pathological phenomena that develop during the course of the disease, both in qualitative terms, i.e. the ways in which the pathology infers on the mechanisms of the nervous system, and in quantitative terms, i.e. the degree of pathological impairment that can be expressed through mathematical observation parameters.
The formulation of a correct diagnosis is, on the other hand, a fundamental condition, especially if it is carried out in the early stages of the disease.
Indeed, we know that patients who are treated appropriately from the outset with the best therapeutic approach are those who will have a better quality of life in the future, both because they will have an overall better response to the drugs active in facilitating general motility and because many of the pharmacological, dietary and occupational therapeutic aids used have been recognised as partly capable of slowing down the processes of degeneration of dopaminergic neurons.
Parkinson’s disease: prevention
For the sake of brevity and conciseness, here is a brief excerpt from the definitions of Parkinson’s disease prevention available on the Italian Ministry of Health website: ‘Primary Prevention has its field of action on the healthy subject and aims to maintain conditions of well-being and avoid the appearance of disease (…).
Secondary Prevention relates to a later stage than Primary Prevention, intervening on subjects who are already ill, even if at an early stage (…).
Tertiary Prevention refers to all actions aimed at controlling and containing the more complex outcomes of a disease (…)”.
From these statements, in the light of what has already been said about the nature and modalities of contraction (‘etiopathogenesis’) and the course of Parkinson’s disease, it is clear that the more limited the scope of Primary Prevention remains, since it is a disease whose cause is not yet known, the more useful the cues for Secondary and Tertiary Prevention will be.
We have alluded to particular and unusual conditions in which Parkinson’s disease occurs as an outcome determined by certain causes: the most important is the possibility of Parkinson’s disease being genetically transmitted, a rather rare circumstance limited to geographically isolated families characterised by a fair degree of intra-family sexual promiscuity.
A second causal condition, with a similarly circumscribed diffusion and limited by successive socio-healthcare interventions, has been recognised as a consequence of environmental exposure to particular toxins, mostly used in industry and agriculture (paraquat, rotenone, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine MPTP and related substances), i.e. capable of reproducing almost faithfully the pathological pattern of usual Parkinson’s disease, i.e. sporadic.
The other theoretical mechanisms that have emerged on the pathogenesis of the disease are rich in detail and references to well-studied molecular phenomena: the regulation processes of the oxidoreductive balances occurring during neuronal activity, the role of the modulation of various neurotransmitters, inflammation mediators and the very mechanisms of apoptosis (programmed cell death) identified in the action of molecular factors (alpha-synuclein) are all hints for a possible future ‘breakthrough’ in the preventive treatment not only of Parkinson’s disease but also of many other primary degenerative diseases of the nervous system.
To date, we are limited to trying out various preventive treatment hypotheses (antioxidants, ‘cytoprotectors’, modulators of microglia inflammation, etc.), the clinical results of which unfortunately still appear too weak, if not at times questionable.
Quite different prospects of success derive from the field of Secondary Prevention: sixty years of clinical experience and pharmacological research have produced, as already mentioned, a notable refinement of the patients’ ability to care for themselves, at least on the motor (i.e. predominant) manifestations of the disease.
Today, the combined use of different ‘points of attack’ on the synaptic processes underlying neurotransmitter dysfunction (dopamine, but also drugs active on circuits collateral to the nigro-striatal tract) makes it possible to ‘carry on’ patients with disease ages of over 20 years; The variability of the response to treatment today still appears to be partly linked to individual biological factors that are more or less permissive (intermediate metabolism, comorbidity), much more often the result of the therapist’s greater or lesser skill in dosing and choosing the most useful drug combinations in the succession of clinical phenomena (which are very heterogeneous) that characterise the course of the disease in the individual patient.
In this regard, other aspects that are not directly pharmacological, such as diet, physical activity and social recreation, in which the physician can rise to the role of ‘director’, achieving sometimes impressive therapeutic successes, are becoming increasingly important.
The depressive syndromes associated with Parkinson’s disease require further personalised treatment, often necessitating consultation between different specialists (neurologists and psychiatrists), dysautonomia poses problems that are difficult to resolve, in turn involving other specialist spheres (cardiology, gastroenterology, endocrinology), and possible cognitive deterioration can be a dramatic outcome, unfortunately irreversible.
These latter elements, which can be framed within the sphere of interest of Tertiary Prevention, are intertwined with the various combinations of age-related pathologies, first and foremost vascular degenerative diseases.
On this subject, it is even obvious to reiterate the fact that the more medical skill is able to pay attention to the patient as a whole, the greater will be his or her potential to alleviate suffering.
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