The Epidemiology and Pathophysiology of Parkinson’s Disease

The following is an edited excerpt from the book Parkinson’s Disease for the Hospitalist: Managing the Complex Care of a Vulnerable Population by Hooman Azmi and Fiona Gupta.

Parkinson’s disease was first described by an English physician, Dr. James Parkinson, just over 200 years ago. In 1817, Dr. Parkinson published “Essay on the Shaking Palsy,” in which he documented the common symptoms of what he called paralysis agitans. His observations were based on his own patients and also observation on some people he saw on the streets of London. It wasn’t until a century later that the great French neurologist Jean-Martin Charcot named the disease in honor of Dr. Parkinson.

Today, we still diagnose PD much as Dr. Parkinson himself did — with a thorough history and clinical exam. We know much more than he did about the disease, and we have many more tools to treat it, but the diagnosis is still made the same way. No blood test or scan can accurately diagnose PD. Physicians can base their diagnoses only on a careful history and the signs and symptoms revealed by the clinical exam.

Parkinson’s disease is a chronic, progressive neurodegenerative disease in which voluntary movement becomes more and more impaired over time. PD affects voluntary movement and causes stiffness and spasticity, but patients also have a range of nonmotor symptoms, such as sleep issues, constipation, pain, paresthesias, hallucinations, and cognitive impairment.

After Alzheimer’s disease, PD is the most common neurodegenerative disease in America. About five million Americans have Alzheimer’s disease; one million Americans have been diagnosed with PD. Because we now have earlier diagnosis and better treatments, people with PD are living longer, healthier lives.

About 60,000 new cases of PD are diagnosed each year. The number of new patients is expected to double by 2030 and triple by 2050. The chief risk factor for developing Parkinson’s disease is simply getting older. Most people are diagnosed in their sixties or older, so as the population ages, the number of PD cases willrise.

The Pathophysiology Of PD

Parkinson’s disease is a manifestation of dopaminergic neuron depletion over time. Dopamine is a neurotransmitter in the brain. Dopamine is produced in the dopaminergic neurons in the ventral tegmental area (VTA) of the midbrain, the substantia nigra pars compacta, and the arcuate nucleus of the hypothalamus.

By the time the diagnosis of Parkinson’s is finally made, most patients have already lost about 50 to 70 percent of the dopaminergic neurons of the substantia nigra, which is part of a group of nuclei responsible for relaying and refining multiple circuits in the brain, called the basal ganglia. The prodromal stage for PD is lengthy, with nonspecific symptoms such as constipation, depression, and sleep disorders appearing long before motor symptoms arise. The early symptoms of PD are often vague and easily attributed to other causes, however, and PD is not usually diagnosed until motor symptoms become apparent.

The significant neuronal loss of substantia nigra leads to depletion of dopamine production. Recent thinking about PD by Dr. Heiko Braak suggests that Lewy bodies (misfolded clumps or aggregates inside a nerve cell of a protein called alpha-synuclein) may be behind the death of the dopaminergic cells. This hypothesis suggests PD may actually be caused by misfolding of proteins or errors in the cellular “cleanup” mechanism to break down these proteins, similar to the tangled tau proteins seen in Alzheimer’s disease. In PD, the accumulation of Lewy bodies within the neuron damages them, depleting the amount of dopamine that is produced. As this neurotransmitter is depleted, the basal ganglia circuitry, which facilitates normal movement, is disrupted.

Other neurotransmitters are also implicated in Parkinson’s disease. In the pathway of progression proposed by Dr. Braak and his team of neuropathologists, PD begins in the medulla oblongata, where norepinephrine is made. Alpha-synuclein deposition then progressively increases. As the disease progresses, the substantia nigra is affected and dopamine loss occurs. From there, as the cortex gets involved, depletion of acetylcholine and other neurotransmitters occurs.

The progressive depletion of all the neurotransmitters is likely why PD has so many different symptoms. When serotonin is depleted, for example, people with PD develop anxiety, depression, and sleep issues. The lack of norepinephrine accounts for a nonmotor symptom called rapid eye movement behavior disorder (REMBD); the lack of acetylcholine affects cognition.

Previous researchers believed PD originates in the substantia nigra. The Braak hypothesis suggests the disease begins long before it reaches the substantia nigra. This alternative explanation is supported by the chronological appearance of autonomic, motor, and cognitive symptoms as the disease progresses. The Braak hypothesis opens the way for research into earlier detection and possible biomarkers by looking at nonmotor symptoms and alpha-synuclein levels.

Why People Get PD

We’re not exactly sure why people get Parkinson’s disease. The “two-hit” theory suggests the disease is probably caused by a combination of genetic and environmental factors. When an individual who is already genetically predisposed to Parkinson’s is then exposed to something from the environment, the combination starts the cascade that culminates in neurotransmitter loss.

We still don’t know exactly what in the environment triggers PD or how long the exposure needs to be. Pesticides, herbicides, well water, and rural living have all been hypothesized as causes, but solid evidence is lacking.

Some forms of PD have genetic aspects. So far, about 20 to 30 genes related to PD have been mapped, but the research on this is preliminary. True genetic Parkinson’s is rare, however. Most people with Parkinson’s have no family history of the disease.

Simply getting older is the largest risk factor for PD. The average patient is diagnosed in their sixties or seventies, but the age range is varied. We see PD quite often in patients younger than 50 and even sometimes younger than 40. Young-onset Parkinson’s disease (YOPD) is a genetic form that usually occurs in people younger than 40.

Diagnosing PD

Parkinson’s disease is difficult to diagnose and can be challenging to treat. Patients often don’t present in a typical fashion. As there’s still no reliable blood test or scan for PD, diagnosis continues to depend on a good history and a good clinical exam. Often, patients have comorbidities or confounding factors or an unclear history; it is not common to make the diagnosis on a first visit.

We often need to follow up with consecutive visits or try a medication challenge and see how the patient responds. We need to apply clinical judgment to objective and subjective findings and make an accurate diagnosis.

Certain symptoms occur in most PD patients. Known as cardinal features, they aid in making the diagnosis. Cardinal features include:

• Bradykinesia (slowed movement)
• Resting tremor
• Limb rigidity
• Postural instability

To be diagnosed with PD, the person must have bradykinesia and at least one other cardinal feature.

Resting tremor is a high-frequency tremor, with low to moderate amplitude, that occurs when the limb is supported against gravity — when it’s at rest. Resting tremor is commonly seen when the person’s arm and hand rest on their lap and shake. If the patient is distracted, the tremor might get stronger, but if the patient focuses on the tremor, sometimes they’re able to suppress it.

While cardinal features help with the diagnosis of PD, what is challenging about the disorder is how different each patient can be in terms of overall symptoms, response to treatment, and progress of the disease.

PD And Parkinson-Like Syndromes

Idiopathic Parkinson’s disease is the most common type of disorder in this category and what we often mean by the term typical Parkinson’s disease. Parkinson-like syndromes, also called Parkinson-plus syndromes, or atypical Parkinson’s, can easily be confused with true PD. These syndromes include:

• Progressive supranuclear palsy (PSP)
• Multisystem atrophy (MSA)
• Corticobasal ganglionic degeneration (CBGD)
• Lewy body dementia
• Drug-induced Parkinsonism
• Vascular Parkinsonism

All these syndromes are characterized by slow, stiff movement and trouble signaling from the brain to the body, but the progress and pathophysiology for each are very different and they each have a different pattern of symptoms. In Lewy body dementia, for example, patients have cognitive symptoms early on, including profound hallucinations, psychosis, and dementia. Vascular Parkinsonism is caused by multiple strokes or ministrokes that affect the white matter of the brain and can cause difficulty with gait (gait apraxia).

Two factors in general distinguish PD and Parkinson-plus syndromes. The time frame of disease advancement varies between these two categories. The rate of progression is usually significantly more accelerated for the atypical forms. Another distinguishing factor is the response to drug treatment. People with typical or idiopathic PD usually respond well to levodopa therapy, while people with the atypical forms respond only minimally or not at all.

As mentioned previously, because PD can vary so much from person to person, diagnosis can be challenging. It is important to seek the expertise of a movement disorders specialist to be able to arrive at the correct diagnosis and appropriate treatment.

PD Epidemiology And Pathophysiology

To keep reading, pick up Parkinson’s Disease for the Hospitalist: Managing the Complex Care of a Vulnerable Population by Hooman Azmi and Fiona Gupta.