Parkinson Disease

Etiology

The etiology of PD is multifactorial and still poorly understood. Numerous studies point to environmental poisons, such as synthetic toxins, pesticides, and heavy metals, as potential risk factors. The environmental hypothesis of PD was born in the early to mid-1980s, when Langston and colleagues discovered that the toxin, 1-methyl 4-phenyl 1,2,3,6-tetrahydropyridine (MPTP) could cause parkinsonism. 1-methyl-4-phenylpyridinium (MPP+) accumulates in mitochondria and interferes with the function of complex I of the respiratory chain. A chemical resemblance between MPTP and some herbicides and pesticides suggested that an MPTP-like environmental toxin might be a cause of PD, but no specific agent has been identified. Nonetheless, mitochondrial complex I activity is reduced in PD, suggesting a common pathway with MPTP-induced parkinsonism. The oxidation hypothesis suggests that free radical damage, resulting from dopamine's oxidative metabolism, plays a role in the development or progression of PD. The oxidative metabolism of dopamine by monoamine oxidase (MAO) leads to the formation of hydrogen peroxide, which may lead to the formation of highly reactive hydroxyl radicals that can react with cell membrane lipids to cause lipid peroxidation and cell damage.

Humans are exposed to numerous pesticides and toxins in nature, yet not everyone develops PD, suggesting that the factors required for disease development are more complex. Many studies, using animal models or patients, point to interactions between an individual's genetic background and exposure to environmental toxins, which has led to the multiple hit hypothesis of PD (i.e., more than one risk factor contributes to disease development and progression). In addition, oxidative stress, protein mishandling, and inflammation are recognized as important features that may contribute to the neurodegenerative process.

Genes for Parkinson Disease

A genetic predisposition has been recognized in PD in the past 20 years. Since the discovery of the first disease-causing mutation in the SNCA gene, investigations into the role of genetics in PD have grown exponentially. Presently known mendelian forms of PD with autosomal dominant and recessive inheritance account for less than 10% of PD cases ( Table 28.1 ). A 2014 meta-analysis of genome-wide association studies, with data from more than 13,700 PD cases and 95,000 controls, identified and replicated 28 independent risk variants for PD across 24 loci.

• Autosomal dominant and autosomal recessive: SNCA and LRRK2 are the two dominantly inherited genes that have been studied most in depth. A base pair change in the SNCA gene was the first mutation identified as causing PD in 1997. Subsequently multiplication mutations in the SNCA gene were described, with the number of copies of the SNCA gene appearing to correlate with disease severity. The significance of the SNCA gene is related to the subsequent discovery of the encoded protein alpha-synuclein (α-Syn), which is the major component of Lewy bodies. Mutations in LRRK2 are the most frequent cause of dominantly inherited PD. It accounts for 2% of all PD and 5% of familial cases. The clinical presentation of the parkinsonian phenotype caused by LRRK2 is often indistinguishable from sporadic PD. Mutations in Parkin, PINK1, and DJ-1 have been identified to cause autosomal recessive forms of PD, characterized by pure parkinsonism, early onset, slow progression, and good response to levodopa. Other genes (PARK9, PARK14, PARK15) with autosomal recessive inheritance have been associated with more complex phenotypes and additional neurologic findings such as hyperreflexia, spasticity, dystonia, and dementia.

• Glucocerebrosidase (GBA) mutations: Clinical observations of frequent occurrence of PD in relatives of patients with Gaucher disease, an autosomal recessive lysosomal storage disorder, led to the discovery that heterozygous mutations in GBA gene increase PD risk by fivefold.

• Mitochondrial mutations: Mitochondrial dysfunction has been recognized as a part of PD pathogenesis. Frequent mitochondrial DNA mutations and reduced mitochondrial function in complex I of the respiratory chain have been detected in the SN pars compacta (SNc) of PD brains.

Pathology/Pathophysiology

The pathologic hallmark of PD is degeneration of the SNc. Neurons within the SN synthesize the neurotransmitter dopamine ( Figs. 28.2 and 28.4 ). These cells contain a dark pigment called neuromelanin. Parkinson symptoms develop when approximately 60% of these cells die. Concomitantly, direct inspection of the SN in PD demonstrates an abnormal pallor when compared with that characteristically seen with the normal hyperpigmented melanin-containing cells.

Microscopically, the SNc and other regions of the central and peripheral nervous system (PNS) in PD patients contain intraneuronal protein accumulation in the form of Lewy bodies and Lewy neurites. α-Syn is the principal component of Lewy pathology and thought to play an important role in PD pathogenesis. The significance of α-Syn in PD originates from discovery of rare mendelian forms of PD caused by mutations in SNCA. Genetic variations in SNCA are linked to an increased risk for sporadic PD. With advances in immunostaining, the extent of Lewy pathology in PD is now known to be more widespread than originally thought. Neurodegeneration with Lewy pathology is also found in the nucleus basalis of Meynert, locus coeruleus (LC), median raphe, and nerve cells in the olfactory system, upper and lower brain-stem, cerebral cortex, spinal cord, and peripheral autonomic system. Perhaps one of the greatest pathologic advancements in PD was when Braak and colleagues examined α-Syn distribution in brains of PD patients and controls ( Fig. 28.5 ). They proposed a sequential pattern of Lewy pathology distribution, beginning in the olfactory system and dorsal motor nucleus of the vagus, progressing to involve the peripheral autonomic nervous system, extending to involve SNc in the mid-stage of the disease, later involving the upper brainstem, and finally affecting the cerebral hemispheres. The findings of Lewy bodies in the olfactory cells and autonomic nerves of the heart and gastrointestinal tract prior to neurodegeneration in SNc and the development of classic motor symptoms of PD support the concept of a prodromal (premotor) phase of PD.

The pathologic spreading scheme in the brains of PD raised the possibility of prionlike mechanism of α-Syn in disease progression called the Prion Hypothesis. Autopsy studies in PD patients with fetal brain tissue grafts found Lewy pathology similar to that of PD in the grafted neurons more than 10 years after the transplant procedure, suggesting a possible transmissible nature of α-Syn. Under certain circumstances, α-Syn undergoes conformational change from α-helical structure to β-sheet–rich fibrils, similar to prion proteins. Recent studies using animal models have demonstrated a “seeding” phenomenon of α-Syn fibrils inducing endogenous α-Syn protein to misfold, aggregate, form Lewy body–like inclusions, and cause neuronal death. The prion hypothesis has challenged the traditional way that we view PD.

Human Gut Microbiota (GM) has now been accepted as a potential modulator of cognition, learning, and behavior and can directly or indirectly modify brain neurochemistry. GM can influence dopamine turnover, dopaminergic cell expression, striatal gene expression, etc. The GM's composition is altered in PD, and this dysbiosis has been related to motor fluctuations. More studies are needed to establish a cause and effect relationship between GM and PD.

Anatomy

The pathologic sites responsible for the parkinsonian disorders reside in a group of brain gray matter structures known as the extrapyramidal system or basal ganglia. The prevailing model of basal ganglia function states that two circuits, the direct and indirect pathways, originate from distinct populations of striatal medium spiny neurons (MSNs) and project to different output structures. These circuits are believed to have opposite effects on movement. Specifically, the activity of direct pathway MSNs is postulated to promote movement, whereas the activation of indirect pathway MSNs is hypothesized to inhibit it. An important pathway that modulates the direct and indirect circuits is the dopaminergic nigrostriatal projection from the SNc to the striatum. D1 dopamine receptors are present in the striatal neurons of the direct pathway and are depolarized by dopamine, whereas D2 dopamine receptors predominate in the striatal neurons from the indirect pathway and are inhibited by the presence of dopamine. Therefore, in the presence of dopamine, the cortex is stimulated by both direct and indirect circuits. The loss of dopamine neurons in PD causes impairment of movements due to the development of an imbalance between direct and indirect pathways, in favor of the latter, with consequent inhibition of motor cortex regions ( Fig. 28.6 ).

Diagnosis and Biomarkers

It has been increasingly recognized that PD has a long prodromal phase during which early symptoms can occur years before the appearance of motor symptoms. Our current method of diagnosing PD during life remains clinical, whereas definitive diagnosis is obtained through pathologic confirmation of α-Syn deposition and neurodegeneration in the SNc. Clinical diagnostic accuracy ranges from 75% to 95% depending on disease duration and stage and clinician expertise. In 2015 the International Parkinson and Movement Disorder Society (MDS) created new Clinical Diagnostic Criteria for PD ( Box 28.1 ). The MDS-PD criteria incorporated nonmotor symptoms (NMSs) while retaining the central features of parkinsonism as bradykinesia in combination with either rest tremor, rigidity, or both. MDS-PD criteria proposed a list of absolute exclusions and red flags that argues against the diagnosis of PD, and supportive criteria that argue in favor of PD as the etiology of parkinsonism. Two ancillary diagnostic tests, olfactory loss and metaiodobenzylguanidine (MIBG) scintigraphy, were deemed reliable, with specificity greater than 80%; these can be used as supportive criteria. Two levels of diagnostic certainty based on these positive and negative factors were proposed: clinically established PD and clinically probable PD.

Biomarkers

There is no definitive validated biomarker for PD at this time. A number of candidates are undergoing evaluation, including fluid and tissue analysis, genetic susceptibility, clinical evaluations such as olfactory testing, and neuroimaging. Positron emission tomography (PET) and single-photon emission computed tomography (SPECT) using radiolabeled tracers have allowed functional assessment of the nigrostriatal pathway. Neurodegeneration in the SN leads to decreased striatal density of presynaptic dopaminergic nerve terminals and dopamine transporters (DATs), which can be reflected by reduced ligand binding on DAT SPECT imaging. SPECT with DAT radiotracers can help to distinguish neurodegenerative parkinsonism from nonneurodegenerative parkinsonism ( Fig. 28.7 ). PET imaging measuring cerebral glucose metabolism and cerebral blood flow may have some potential application for the differential diagnosis of parkinsonian syndromes. Transcranial sonography (TCS), a noninvasive and low-cost ultrasound imaging method, has shown potential usefulness in the clinical diagnosis of PD by assessing the echogenicity of the SNc. Novel MRI techniques have been developed to evaluate the SNc in PD.

Clinical Presentation

The clinical course or temporal profile of PD is quite variable. It usually progresses slowly and inexorably ( Fig. 28.8 ). Typically, the illness begins unilaterally with focal tremor or difficulty using one limb. Eventually, the symptoms become more generalized and occur on the contralateral side, interfering with activities of daily living (ADLs). Clinical features can be divided into motor and NMSs.