How FINDcures can help
FINDcures specializes in providing help in areas that other foundations often miss or leave unaddressed. When a family member is diagnosed with Parkinson’s Disease, a cascade of questions and concerns materialize that can easily overwhelm a family. Most often the issues of on-going therapy and education on how family members can be an effective caregivers will be need to be addressed.
Beyond the issues of therapy and caregiver education there are other adjustments that need to be considered. Specific concerns, that most often arise in a progression of unanswered questions, can have an overwhelming impact on a family’s sense of security and self-worth. FINDcures has developed a service model (shown at right) called the “Perimeter of Hope” which is designed to provide solutions and answers to the myriad questions that arise when a neurological diagnosis occurs.
The most common questions that come up are these:
- Why is this happening? What caused this? How difficult is this going to be? How is this going to impact my family? Who can I turn to when I start to feel overwhelmed? How do I deal with all of the emotions I’m feeling? (Mental Health & Well-Being Services)
- How will I be able to provide for my family in the future? (Financial Planning & Retirement Services)
- How can I protect my assets so that they will be available as a resource for my family when I am unable to do so? (Legal Assistance & Estate Planning Services)
- If our family needs to relocate to receive better care or to reduce expenses who can I turn to for help? (Housing, Relocation & Real Estate Services)
- Will I be able to help with my children’s education expenses in the future? (Education Planning & Tuition Assistance)
- When will they find a cure? What health steps can we take in the meantime? (Medical Research & Information Services)
When an impacted individual or family is faced with making these decisions on their own and without help from qualified individuals familiar with the impact of neurological diseases, the task list can be overwhelming. Why make things more difficult by going it alone when you can contact an experienced FINDcures representative and allow them to assist you? Our services are free of charge. The consultation costs you nothing and should you choose a service we offer, the cost, if any, is subsidized by the donations we receive.
Parkinson’s Disease – An Overview
Parkinson’s disease (PD) is one of the most common neurodegenerative diseases. Parkinson’s disease (PD) is as synucleinopathy (or) (neurodegenerative) disease. That is represented by an unusually large accumulation of alpha-syncline proteins in the body’s neurons, nerve fibers and glial cells.
P.D is most common in men above 70 years old. About 4% of the world’s population beyond age 80 have Parkinson’s. Only 4% of those living with PD contract the disease prior to age 50. The youngest known male to be diagnosed with the disease was 14 years old, the youngest female was 15 years of age. Our understanding of the pathogenesis of P.D has been improved over the past decade, with several key gene mutations revealing various mechanism’s of pathogenesis in various cases of PD.
The primary pathological standard is dopamine producing cell loss within the substantia nigra region of the brain. At the passing of most Parkinson’s patients, 50–70% of the individual’s dopamine producing cells are dead. The earliest recorded pathological changes in PD. (Ref. 3) was observed in the medulla oblongata/pontine tegmentum and olfactory bulb. In the early stages of the disease (Stage 1 & 2) individuals are pre-symptomatic. As the disease advances to Braak stages 3 and 4—the substantia nigra, midbrain and basal forebrain become involved. Finally, the disease progresses to the neocortex.
The speed of this progression is based on the distribution of Lewy bodies (The Hallmark of P.D). Lewy bodies are α-synuclein-immune-reactive inclusions that consist of an elevated number of neuro-filament proteins. These Lewy bodies include ubiquitin, (a heat shock protein) that targets other proteins for breakdown. Mutations in the α-synuclein gene have been linked to forms of PD. Lewy bodies exist as a hallmark of PD and Dementia, but are not found as consistently or pathologically in any other known neurodegenerative diseases.
Ubiquitin-proteasome system (UPS) is a potential cause in the development of cell death. (5) The UPS is important for intracellular processes that maintain cell viability. It accomplishes this by removing undesirable proteins that are no longer useful to cell function. When UPS stops functioning, proteins accumulate including α-syncline, a major component of Lewy bodies. The Olfactory Bulb is one of the first sites of LB deposits. The Olfactory bulb is responsible for smell and taste, therefore a disturbance in these two senses are often a result LB buildup. This early buildup could be a pathway that eventually leads to neuronal dysfunction and eventual death.
PD is classified as a sporadic disease, however there have been a growing number of single gene mutations identified. At least 10 genes have been Identified that map linkage with six genes. These are: Ubiquitin C-terminal Hydrolase like 1 (UCH-L1), parkin (PRKN), LRRK 2, PINK 1, DJ-1 genes and o-syncline (SNCA).
These single gene defects, with the exception of LRRK 2, are responsible for only a small number of patients with PD. SNCA gene mutation is the catalyst for early onset of PD.
The LRRK 2 gene the common cause of familial or sporadic PD. Genetics appear to play an insignificant role in contracting (P.D). When one family member tests positive with P.D, there is only a 5% chance of other family members contracting the disease.
The LRRK2 gene encodes itself for a protein named Dardarin (The Basque word for tremor) Symptoms at onset are typical of idiopathic PD, namely unilateral bradykinesia rigidity and tremor in some cases.
There has been extensive research into mitochondrial genetics and function in PD. Abnormalities in the oxidative phosphorylation enzyme pathway has consistently been detected in PD brains, blood platelets and skeletal muscle. Defects in other complexes have also been reported.
Mitochondrial DNA studies have been unable to identify a consistent gene mutation to explain the oxidative phosphorylation defects in PD.
Environmental factors may possibly uncover a predispose to P.D, yet to date findings are inconclusive. Those individuals that live in a rural environment seem to have an increased risk of PD. Epidemiological studies have shown some evidence that exposure to pesticide use and wood preservatives may be a causal factor. It’s possible that mitochondrial dysfunction in PD could be triggered by one or more environmental toxins.
The characteristic features of PD include bradykinesia, rigidity and resting tremor. Postural instability is often the result of Parkinson’s progression.
It is noteworthy that an alternative diagnosis in up to a quarter of patients with PD diagnosed by general neurologists. Misdiagnosis is far less prevalent in patients diagnosed in expert movement disorder clinics. This supports the argument supporting the argument for early referral of patients to specialist experts in movement disorders.
In addition to the symptoms previously mentioned, there are other signs that support proper diagnosis; these include:
- A change of handwriting
- Reduced facial expression.
- Facial Flaking
- A loss of arm swing on one side.
- A reduced sense of smell.
- Reduced Swallowing
- Impaired Reflexes
- Impaired Vision (Less Blinking Occurs, Eyes Dry Out)
- Depression (40% of P.D patients)
- Head or voice tremor
Diagnosis & Technology
Although P.D Diagnosis is clinical, conventional brain imaging with MRI or CT is sometimes used when hydrocephalus or vascular parkinsonism is suspected
Single photon emission computerized tomography (or) (SPECT) imaging uses a dopamine transporter (DAT) to distinguish PD from other conditions with similar symptoms such as; Essential Tremor and Dystonic Tremor, Neuroleptic-Induced Parkinsonism and Psychogenic Parkinsonism.
After establishing a clinical diagnosis, it is vital to take time to explain the condition and its implications to the patient and relatives. It may take some patient’s time to come to terms with and accept the diagnosis. Linking patients with PD nurse specialists and PD charitable organizations, if available locally, can be extremely helpful.
The timing on when to start drug treatment for PD, particularly in an early stage, is up to the individual, especially when a functional deficit does not yet exist. The degree of physical impairment when measured by complications associated with taking a particular prescription drug treatment can be a difficult decision. The bigger picture is whether these treatments show potential for neuroprotection. At present, there are no proven or reliable neuroprotective therapies. Relief at this point is strictly symptomatic.
Treatments vary based on the age of the patient, his or her compliance, cognitive impairment, added medical conditions and the patients willingness to move forward. Initially, treatment is to alleviate symptoms and allow the individual to complete normal daily activities.
Over the past 40 years, levodopa, and a peripheral decarboxylase inhibitor, has been the standard for the treatment of PD. It continues to be the most efficacious drug treatment, but the benefits come with a cost. Long-term levodopa therapy can have disabling side effects. Levodopa-induced dyskinesia’s can accelerate by as much as 10% per annum after commencing levodopa. This figure is even higher in younger onset patients. Levodopa introduced to the blood stream is only effective for 60–90 minutes. The greater the severity of the Nigral neuronal loss at the introduction of levodopa, the more pronounced adverse features will be. Some experts have questioned whether levodopa could have a neurotoxic effect, there is no evidence as of yet that supports this concern. Given the risk of motor complications, treating the individual with small doses of levodopa, tailored to the patient’s needs is still the preferred practice.
Dopamine – Agonist Treatment
There are currently six orally acting dopamine agonists being used in the UK. Rotigotine is administered using a transdermal patch. These dopamine agonists were initially licensed for use in conjunction with levodopa in patients with advanced PD. Monotherapy trials have been undertaken comparing dopamine agonists with levodopa.
Commonly used non-ergot-derived dopamine agonists include ropinirole, pramipexole and rotigotine. There is evidence supporting one side effect of using pramipexole. The individual has an increased risk of pathological gambling.
MAO-B inhibitors effectiveness was recently tested through a meta-analysis of 17 random trials involving 3525 patients. The results suggested that MAO-B inhibitors reduced disability, reliance on levodopa and helped mitigate motor fluctuations. There were no substantial side effects and mortality was neutral.
Research findings now support the likeliness that MAO-B inhibitors do provide first-line monotherapy in PD patients. Selegiline and Rasagiline, both MAO-B inhibitors, have demonstrated efficacy in early and advanced P.D.
After several years of sustained response to levodopa therapy, individuals find fluctuation in motor performance. Levodopa’s effectiveness begins to wane. Periods of immobility unrelated to levodopa dosage begin to take effect.
Levodopa-induced dyskinesia usually occurs following prolonged therapy with 50% of patients developing motor fluctuations and dyskinesia around 5 to 10 years following treatment with levodopa and 20 to 30% developing dyskinesia after 2 years.
In younger patients, the progression is worse, with almost every patient beginning treatment prior to age 40 developing motor complications within 6 years of introduction of levodopa. Treatment of levodopa-induced dyskinesia has drawbacks. Reducing the daily dose often renders patients rigid and immobile.
Peak-dose dyskinesia is related to high-plasma concentrations of levodopa. This condition can be managed by fractionating levodopa dosage. Amantidine has also been effective in reducing peak-dose dyskinesia.
Biphasic dyskinesia occurs when plasma levodopa levels rise or fall. This can affect the lower extremities and is difficult to control.
Off-period dystonia can be caused by periods of inadequate mobility. An understanding of the pathophysiology of motor complications while using levodopa therapy is only is only partially understood.
Several treatments have been used to reduce motor complications. It appears that pramipexole and ropinirole have benefit over bromocriptine by reducing ‘off’ time. Amantadine, an anti-viral agent, was discovered by chance to have a positive influence on reduction of motor complications. Evidence supports that amantadine reduces the frequency of motor complications, including freezing, Amantadine has shown some side effects in elderly patients including; confusion, hallucinations, ankle swelling and livedo reticularis.
Entacapone is a peripheral catechol-O-methyltransferase COMT (In layman terms it’s an enzyme that degrades neurotransmitters, thereby lengthening the effectiveness of Levadopa by 45 to 50%). Entacapone compliments the action of amino acid de-carboxylase (AADC) inhibitors. When entacapone or tolcapone are added to levodopa therapy, they create a more sustained plasma and central nervous system level of dopamine, more than levodopa alone. In essence these two enzymes improve motor function.
Surgery as a means of treating PD dates back more than 50 years. In those days patients with severe tremor would receive ablative surgery on the contralateral thalamus. Levodopa, replaced surgical treatment and ironically regained its popularity as levodopa-induced complications prompted surgeons to revisit surgical intervention. The initial focus was on lesion surgery in the form of pallidotomy
The next chapter in P.D surgery came by way of stimulators. The surgery involved placement of high-frequency deep brain stimulators (DBS) in discrete areas referred to as the basal ganglia of the brain. The operation although technically difficult, is rather low risk in experienced hands, but the infrastructure and support team required limits the availability of this form of treatment. The procedure has its psychiatric side effects, in particularly depression is common following DBS.
Patients having cognitive impairment and significant depression are generally speaking not suitable for the procedure. STN DBS is most often performed in patients under the age of 75, who are free of substantial systemic co-morbidity and without structural abnormality on MR imaging.
Patients should be responsive to levodopa treatment and disabled while off levodopa and independent while on it. Patients will usually have had P.D for at least 5 years to allow for atypical causes of parkinsonism to become evident.
Age appears less critical in DBS performed for disabling tremor. Recent studies show evidence that DBS surgery may be beneficial in improving axial stability. Assessment of whether an individual is a patient for DBS requires assessment by a well experienced multi-disciplinary team.
There are several non-motor complications in PD. They are mostly unrelated to dopaminergic pathways and can be manifest by individuals before the onset of general P.D symptoms appear.
Sleep disorders includes both disturbed nocturnal sleep and excessive daytime somnolence. Nocturnal sleep disturbance is experienced in 60–98% of individuals and correlates with disease severity and levodopa dosages. Rem Behavioral Disturbance (RBD) is increasingly recognized in individuals with neurodegenerative disease, There is evidence that the rate of progression can predict cognitive impairment in PD patients without dementia. A small dosage of clonazepam at night may prove helpful.
Daytime sleep events are more prevalent in individuals with P.D. In extreme cases the individual may experience sudden irresistible sleep attacks without warning. These episodes are more frequent with the use of dopamine agonists, particularly ropinirole and pramipexole.
Patients should be counselled to stop driving and avoid operating machinery should this condition develop. The condition subsides as the offending drug is withdrawn.
Cognitive involvement in PD is common. Many individuals with PD develop dementia, within 10 years or more following the onset of motor symptoms. On average 40% of all P.D patients will experience dementia. Dementia in individuals impacted by PD can be related to a several different pathologies. However, Lewy bodies and/or Alzheimer pathology are most relevant. Cholinesterase inhibitors such as rivastigmine, donepezil and galantamine have shown a modest benefit in cognitive function.
Mood disturbance and PD
Depression is the primary mood disturbance in PD with a prevalence of 50% and can occur at any stage of the illness. Depression, can be treated with antidepressants including tricyclics and serotonin uptake inhibitors (SSRIs). Pramipexole has a significant antidepressant action.
Psychosis and confusion in PD
Psychosis has been found in up to 30% of PD patients. It is often manifest by hallucinations, delusions and sometimes aggression. Patients may become paranoid toward partners and other family members.
The newer ‘atypical’ antipsychotic agents such as quetiapine and clozapine are better tolerated and often effective.
PD is one of the more prevalent neurodegenerative diseases. The causes of P.D are unclear, although genetics and environmental factors may play a role in the individual contracting the disease, each circumstance varys. Diagnosis remains clinical at best. There are many agents and a few surgical interventions to treat P.D complications. Future PD treatments will likely to focus on disease modifying drugs that offer neuroprotection.
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