In 2003, Heiko Braak identified a pattern of Lewy body deposition, in the synucleinopathies (the term that is given to any disease that results in the accumulation of alpha-synuclein proteins), which include Parkinson's Disease (PD), Multiple Systems Atrophy (MSA), Progressive Supranuclear Palsy (PSP) and Dementia (LBD). The pattern that he identified has been termed the Braak Staging of Lewy Body inclusions. More current research shows that Lewy Body pathology can spread from one area of the nervous system to another, and it's conceivable that this happens in a prion-like fashion. There are also some studies that show alpha-synuclein is not only just an intracellular protein but is extracellular as well, which could explain to some degree, the progression to other areas of the brain. The first three stages of Braak's staging, are largely "asymptomatic" to the uninformed individual.

In stage 1, inclusion bodies begin accumulating in the olfactory bulb (which is the first step of the smell pathway) and a part of our brainstem called the Vagus Nucleus. Symptoms at this point may include a change in the ability to smell and taste, as well as a constellation of symptoms we call autonomic symptoms, which are often casually related to "aging". The symptoms may, or may not include: constipation, sexual dysfunction, dry eyes, dry skin, light-headedness, high blood pressure, insulin resistance, swelling of the hands and feet, bladder dysfunction, an increase in heart rate or arrhythmia, dizziness when getting out of a chair or bed, etc. In stage 2, inclusion bodies begin to form in a part of our brain stem called the locus ceruleous, and vestibular gain setting nuclei. The result of inclusion body formation in these areas leads to difficulty with arousal, wakefulness, and excessive sleepiness. The vestibular gain setting nuclei participate in the maintenance of balance, posture, motion tolerance, as well as eye movement. The involvement of a large brainstem nucleus called the nucleus gigantocellularis can begin to cause tightening and decreased mobility of the neck. In stage 3, as alpha-synuclein ubiquitinates and deposits in the midbrain substantia nigra, some of the classical symptoms associated with Parkinson's disease begin to emerge. The compacted portion of the midbrain produces dopamine to facilitate motor function, while the net-like, or reticular portion of the midbrain produces an inhibitory neurotransmitter called GABA, which has a role in both body movement, and fast eye movements. Typical symptoms at this point time are slowness of movement, usually on one side of the body first, a decrease in motivation, changes in sleep patterns and dreams/hallucinations, smaller handwriting, slowing of walking speed, difficulty walking down stairs, blurred vision, joint stiffness, and more. It is around this time that a Parkinson's expert often first identifies a possibility of the PD diagnosis, which is usually about 7 years after stage 1. At the first appearance of motor signs, it is estimated that about 30%-50% of dopamine neurons have been lost. When the mesocortex, which is a part of the brain between the midbrain and the forebrain, is affected, an individual will begin having changes in emotion. Often this results in a lack of impulse control, anxiety, depression, slowing of speech, avolition (lack of motivation), and flat affect. These are all signs of stage 4. Often in stage four, a tremor may emerge in one hand. It is in stage 4, usually about 10 years after stage 1, that general practitioners start to recognize the signs of Parkinson's disease in their patients. In the final two stages of Parkinson's disease, proteins begin depositing in the sensory association areas of the brain (Stage 5), followed by the supplementary and primary motor areas (Stage 6), leading to slowness, of movement, rigidity, stooped posture (termed camptocormia) slowness of movement (bradykinesia), freezing (akinesia), tremor, slowness of thought (bradyphrenia), difficulty or slowness in swallowing (dysphagia), weakness of voice (hypophonia), and eventually dementia.

Although Parkinson's Disease is not a fatal disease, meaning that individuals do not die of Parkinson's Disease, the effects of the disease can lead to morbidity and mortality, with falls being the number one most common (68.3%) and preventable cause of death in Parkinson's afflicted individuals. There is no standard imaging for Parkinson's Disease, although DaTscan, a variation of SPECT scan that can observe dopamine transport, has shown to be promising. The diagnosis of Parkinson's Disease currently lies in the clinical examination. Authors have indicated that the sensitivity and specificity of accurate diagnosis by a trained and experienced clinician is (Jenkins 2012) 95% and 98% respectively. At this point in time, DaTscan can confirm or at least increase the confidence of an accurate diagnosis. Identifying a problem without suggesting a solution is almost as bad as not knowing about the problem at all.

Since 1978, the Carrick Institute for Graduate Studies has been training doctors around the world to be able to identify Parkinson's Disease quickly, effectively, and early, so that various non-pharmaceutical interventions can improve the quality of life, safety, and well-being of individuals developing, or with Parkinson's Disease. You can contact the Carrick Institute to locate a Functional Neurologist near you.

In the upcoming articles, we will discuss a clinical grading scale termed the UPDRS (or United Parkinson's Disease Rating Scale) that has been developed to measure the progression or regression of Parkinson's Disease. We will also discuss non-pharmaceutical individualized patient-centered applications for Parkinson's Disease, and other neurological conditions.

Further Reading and Reference:

In a past post on the history of Parkinson's disease, I discussed a little bit about how we have arrived at our current understanding of this very prevalent neurodegenerative condition. In this blog post, we will discuss how Parkinson's Disease develops on a cellular level.

As a quick recap from our previous post, scientists have determined that the main neurological structure involved and Parkinson's disease is a part of the midbrain called the substantia nigra pars compacta; The area involved with producing dopamine, which is a mood, emotion, arousal, and movement neurotransmitter. Scientists have also determined that one of the cellular mechanisms that are associated with Parkinson's disease, is an accumulation of a protein called alpha-synuclein. Alpha-synuclein is an intracellular protein that is found mainly in neurological tissues but is also found in small quantities in heart muscle as well as some skeletal muscle. Despite its diffuse presence in tissue, the function of alpha-synuclein it's still not completely understood. However, leading researchers believe that it is intimately involved with the transport of neurotransmitters, particularly dopamine. Some researchers believe that it functions as a structural protein, called a microtubule-associated protein, or MAP, very similar to the other protein (tau protein) found accumulated in neurodegenerative conditions, such as Alzheimer's disease. The function of these MAP proteins is thought to facilitate the transportation of neurotransmitters from the cell body to the part of the neuron that communicates with other neurons, called the synaptic cleft. These microtubule-associated proteins of tau and alpha-synuclein either maintain the integrity of the transport tubules or facilitate the release of the neurotransmitters, respectively. Some studies have shown that mice lacking alpha-synuclein show an increase in dopamine release in movement-sensitive areas of the brain. Other studies in mice show that decreasing alpha-synuclein is detrimental to neurological functions, particularly with spatial learning, and working memory. Alpha-synuclein has been shown to be involved in calcium regulation, mitochondrial function, and modulation of calcium-gated voltage channels on neurons. Other studies show that alpha-synuclein actually serves to regulate dopamine levels, to protect an individual from dopamine toxicity, by blocking dopamine transporters and re-uptake. So the question becomes, "if these proteins have a purpose for maintaining the proper neurological function, why would they accumulate in individuals with neurological diseases?" In the presence of a couple of different scenarios, these types of proteins begin to accumulate, or clump together and damage the neurons where they accumulate. This process is called ubiquitination.

Ubiquitination is the process by which a polypeptide called ubiquitin (which is found everywhere in our body, as the name would suggest), is attached to a substrate protein, such as alpha-synuclein. Think of this process as Velcro touching your favorite cashmere sweater. In this example, the Velcro would be ubiquitin, and your sweater is alpha-synuclein. When the ubiquitin sticks to alpha-synuclein it causes the protein to fold over and stick to itself, and clump together. Independently, they are not sticky, but when they touch, they join and are difficult to separate. When these proteins begin to accumulate and clump together, they form what are called Lewy Bodies.

Courtesy of the Alzheimers Association (https://www.alz.org/dementia/images/lewy_family.jpg)

Lewy Body disease is named after the neurologist, Dr. Frederick Lewy, who discovered them while working with Dr. Alois Alzheimer in the early 1900s. (Dr. Lewy is standing on the right, with Dr. Alzheimer standing third from the right). Photo courtesy of the Alzheimer's Association. You may be thinking that we need to determine a way to stop ubiquitination. However, this process is very important in certain functions like mitosis, antibody-antigen responses, apoptosis (or programmed cell death of unhealthy cells), the formation of intracellular organelles and ribosomes, synaptic vesicle transportation, etc. In light of its importance, the scientific community is focusing efforts on trying to determine is what causes ubiquitination to become deregulated and target these dopamine-producing neurons. Researchers have identified a number of different situations that seem to promote ubiquitination:

  1. Active or dormant viral presence, particularly Epstein-Barr virus
  2. Inflammation, particularly as a consequence to type two diabetes
  3. Stress
  4. Genetic predisposition to increased production of alpha-synuclein and/or ubiquitination
  5. Neural and muscular degeneration

As alpha-synuclein goes through the ubiquitination process and Lewy bodies begin to form, they render the neurons in that area begin to lose their ability to transmit neurological impulses, decrease their ability to produce neurotransmitters, and dysfunctional. It is estimated that at the time of death, an individual with Parkinson's Disease will have lost approximately 60% of their functional brain tissue to Lewy Body disease. In my next post, we'll discuss the 6 stages of Lewy Body inclusions, termed Braak's Staging.

More reading: Alexander, G. E. (2004, September). Biology of Parkinson's disease: pathogenesis and pathophysiology of a multisystem neurodegenerative disorder. Retrieved June 17, 2017, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3181806/ Greffard S, Verny M, Bonnet AM, et al. Motor score of the Unified Parkinson Disease Rating Scale as a good predictor of Lewy body-associated neuronal loss in the substantia nigra. Arch Neurol. 2006;63:584–588. Retrieved June 17, 2017, from https://www.ncbi.nlm.nih.gov/pubmed/16606773 Olanow CW, Kieburtz K, Schapira AH. Why have we failed to achieve neuroprotection in Parkinson's disease? Ann Neurol. 2008;64 2:S101–S110. Retrieved June 17, 2017, from https://www.ncbi.nlm.nih.gov/pubmed/19127580

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