“Until we are better informed respecting the nature of the disease, the employment of internal medicine is scarcely warrantable.” – J. Parkinson.
Extensive research has been conducted by scientists on the ontogeny of A9 DA neurons, with the aim of gaining a more in-depth knowledge of the chronic human progressive and neurodegenerative disorder, PD. The majority of PD cases are sporadic (approximately 95%), commonly referred to as idiopathic PD.34 Idiopathic PD is the second most common neurodegenerative disorder worldwide after Alzheimer’s disease, affecting approximately 0.5-1% of the population between the ages of 65-69 years, whilst 1-3% of the population are affected over the age of 80 years35. In 1817, neurologist James Parkinson first detailed the syndrome and neuropathology of PD in his monograph entitled “An Essay on the Shaking Palsy” or “paralysis agitans”. In his work, he described six patients with “involuntary tremulous motion, with lessened muscular power in parts not in action and even when supported; with a propensity to bend the trunk forward, and to pass from walking to a running pace: the senses and intellects being uninjured”36. Despite James Parkinsons’ request for a more comprehensive understanding of the underlying causes of this disorder to be achieved for the development of therapies, it was not until 50 years later that any advancement or additional pathophysiological understanding was accomplished37.
15 Jean-Martin Charcot, a French physician acknowledged the London apothecary’s formal description of PD and established a more elaborated account of the motor abnormities linked to the disease process38 and also proposed in 1888 that the syndrome should be entitled “maladie de Parkinson” (Parkinson’s disease). In the 1950s, Arvid Carlsson and colleagues started to investigate the underlying physiological and anatomical areas of the brain related to the PD process, and found that 80% of DA in the brain is contained within the BG39. In 1960, Ehringer and Hornykiewicz observed that the movement abnormalities associated with PD were due to the degeneration of the nigrostriatal circuit originating from the A9 DA cell group. Hornykiewicz noted a significantly higher concentration of DA in the striatum of the normal human brain in comparison to low levels of DA localised in the nucleus caudatus, putamen, nucleus accumbens, SN and GP of PD post mortem samples40. Shortly after these discoveries, Levodopa (L-Dopa) was introduced as a treatment for the cardinal motor features of PD. The clinical management of PD symptoms has advanced significantly since the 1960s; however, at present it still remains a challenge to halt the progression of the disease or to restore lost functions in the damaged nigrostriatal pathway.
1.2.1 Clinical and neuropathological characteristics of Parkinson’s disease
Deficiencies of nigrostriatal DAergic neurons with a resultant loss of the neurotransmitter DA in the corpus striatum (the brain region controlling movement) underlie the pathology of PD. One of the pathological hallmarks of PD is the presence of Lewy bodies, eosinophilic proteinaceous cytoplasmic inclusions containing alpha (α)-synuclein which are observed in prevailing SNpc neurons41. Heiko Braak proposed that Lewy body (LB) pathological alterations are not restricted to the SNpc, implying that these protein aggregates follow a distinct
16 pattern of pathological change with disease progression. Autopsied brains have shown that pathology commences in the olfactory apparatus and caudal brainstem (dorsal motor nucleus of the vagus in the medulla), before extending rostrally up the brainstem where neuronal cell loss is evident in the SNpc42.
PD can be characterised clinically by the development of three cardinal symptoms namely tremor at rest, rigidity and hypokinesia34. Other motor symptoms include bradykinesia, postural abnormalities and a freezing (sometimes referred to as motor block) phenomenon (Table 1.1).
Table 1.1 Glossary of Parkinson’s Disease Symptoms Akinesia
“Without motion”; inability to initiate movement and is associated with temporary paralysis.
Apathy State of indifference linked to motivation, personality and cognition.
Ataxia Loss of balance and coordination.
Bradykinesia Slowness of movement.
Dyskinesia Abnormal involuntary movements associated with the onset of striatonigral DAergic degeneration and chronic L-Dopa administration.
Dysphagia Difficulty in swallowing.
Freezing Inability to initiate muscular movement in any desired direction.
Masked Facies Facial muscles become immobilized, resulting in the appearance of a “blank expression”
Micrographia Tendency for handwriting to become smaller in size.
On-off phenomenon Alterations between periods of being “on”, which represent the
patients’ ability to control their movements owing to a good responsiveness to medication. "Off" fluctuations develop when the patients experiences symptoms of their underlying parkinsonism, i.e. bradykinesia, rigidity and loss of muscular coordination.
Tremor Tremor, measuring 4-5 Hz at rest, is the first visible clinical feature recognised in 70% of PD patients, but may be absent in 20%.
Pill-rolling Tremor can be classified by “pill-rolling”, a hand action involving
the thumb and forefinger, occurring as a result of involuntary oscillatory movements of agonist and antagonist muscles.
Postural abnormalities Loss of balance or “unsteady feeling”
Rigidity Increased muscular tone resulting in stiffness and resistance of bodily movements
17 Non-motor symptoms occur in over 90% of PD patients and can sometimes be observed as “premotor” phenomena. They include neuropsychiatric symptoms, autonomic disturbances, sensory symptoms such as olfactory impairment, and sleep disorders (Table 1.2)43. The appearance of the clinical symptoms of PD occurs with the loss of approximately 60% of the DA neurons in the SNpc and 80% of striatal DA content. This poses a major problem for the treatment of PD, as patient diagnosis occurs only when this neurodegenerative disorder has already advanced to a serious pathological level.
Cardinal features Tremor at rest, rigidity, bradykinesia/hypokinesia/akinesia, flexed posture/loss of postural reflexes, freezing gait.
Non-motor symptoms Neuropsychiatric
Dementia, depression, anhedonia, apathy, anxiety, slowness of thought, psychosis, sleep disturbances, sexual dysfunction
Craniofacial Hypomimia, impaired accommodation, sialorrhea and dysphagia, olfactory hypofunction, dysarthria
Autonomic dysfunctions
Bladder dysfunction, erectile dysfunction, impaired gastrointestinal dysfunction, constipation, abnormal thermoregulation and increased sweating.
Sensory symptoms Reduced sense of smell, pain, numbness and paresthesiae.
Skin Seborrhoea.
Musculosketal Scoliosis, peripheral oedema.
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