An overview of Parkinson’s disease with focus on dementia...

[visionarybear]

hey guys, jus finished writing this essay for a neurobiology assignment, nice n brief on PD, jus thought id post incase anyone was interested.




An overview of Parkinson’s disease with focus on dementia and cognitive aspects

Parkinsons disease (PD) is a progressive neurodegenerative disease characterised pathologically by substantial loss of the dopaminergic neurons of the substantia nigra (SN), with lewy bodies and lewy neutrites present in surviving cells [1]. Clinical symptoms used in a differential diagnosis include: hypokinesia, muscle rigidity, resting tremor, abnormal gait and postural instability. Some patients will also experience a cognitive decline as the disease progresses[1, 2]. PD affects around 1% of the population older than 65 [1]. The majority of motor-deficits are attributed to the loss of dopaminergic neurons, and therefore decrease in striatal dopamine concentrations [2].
   
The etiology of both sporadic and familial PD is still poorly understood. Recent research has identified 5 genes that appear to have mutations leading to a predisposition of PD [1]. These genes are α-Synuclein, Parkin, UCHL1, DJ-1 and PINK-1[1].
Over expression of, or mutations in, α-Synuclein (PARK-1) promotes aggregation into oligomeric species in response to oxidative stress [1,4].
   Parkin (PARK-2) and UCHL-1 (PARK-5) are both part of the Ubiquitin-proteasome system(UPS) [1]. A loss of function will result in  cytotoxic protein build up. Parkin has been associated with autosomal recessive jouvenal parkinsons disease (AR-JPD)[1].
   PINK-1 (PARK-6) phosphorylates mitochondrial proteins to prevent mitochondrial dysfunction in the presence of oxidative stress [1].
DJ-1 (PARK-7) may act as an antioxidant protein or a sensor of oxidative stress[1].

Currently Levadopa (L-dopa) and other dopamine receptor agonists are used to treat early stage PD but is coupled with a many adverse therapy related symptoms [5,6]. Experimentally, the implantation of foetal dopaminergic cells into the SN have shown great promise, with observed regeneration of striatal dopaminergic projections[5].
Dementia assosciated with PD is not uncommon. Estimates put the occurance anywhere between 27-78% and at 6x more common than in control individuals[7].Notably, it has been observed that almost all PD patients will suffer some degree of cognitive decline, but not severe enough to warrant the diagnosis of dementia[2,6,7]. This decline has been shown to be proportional to the motor decline [7]. This link can be either a direct cause of late stage PD or an increased vulnerability to other Neurodegenerative diseases such as Alzheimer’s disease (AD)
Research has started to cast doubt over many neurodegenerative diseases being mutually exclusive [6-9]. The 2 conditions providing the greatest similarity of pathology and clinical symptoms are dementia with lewy bodies (DLB) and PD with dementia (PDD)[6,8,9]. The major clinical differentiation between them is the time of dementia onset. If dementia precedes, or occurs within 1 year of , the onset of parkinsonian symptoms, it is classed as DLB, but if it occurs >1year after initial PD onset then it is termed as PDD[6,9]. Pathologically, there will most often be more cortical lewy bodies in DLB but this can be variable and the 2 pathologies can be indistinguishable unless patient history is available[6,9]. This suggests a common pathological pathway in the Initiated by the disease process with differing start points but similar end points.

It is also interesting that AD type changes were also noted in pathological studies of some of the specimens. Notably the presence of senile plaques (SP) of neurofibrillary tangles (NFTs) [6,8,9]. In DLB and PDD, α-Synuclein positive lewy bodies are the most common pathology. [6,8,9]. This suggest that lewy bodies may play a role in normal cellular function as a protective mechanism. Faulty/misfolded/redundant proteins may aggregate if their accumulation exceeds protein degradation capacity as to remove them from cellular function as not to cause a deleterious effect. In disease states, if cellular mechanisms of degradation are compromised, or if proteins are over expressed, the accumulation of aggregates may itself have a deleterious effect as it can not be broken down or far exceeds breakdown capacity. If this build up is in structures influencing cognitive function, a decrease in functionality could be presumed. This is however an untested hypothesis and more research would be required to asses its validity.

The psychological changes seen are not thought to be only due to the loss of dopaminergic neurons of the SN, but also due to the less substantial loss of serotinergic neurons of the raphe nucleus, the loss of adrenergic neurons in the locus coeruleus and the loss of cholinergic neurons of the basal nucleus of Meynert [2]. The main cognitive deficit thought to be attributable to dopaminergic neuron loss is dysexecutive syndrome due to loss of neurons in the medial SN [2]. Noradrenergic neuron loss correlates to a decrease in alertness and attention to a task [2]. Serotinergic neuron depletion has been thought to possibly play some role in depressive states observed in some PD and PDD patients [2]. This notion of the involvement of other systems is strengthened by the findings that cognitive impairment does not respond to l-dopa treatment, leading to a non-dopamine hypothesis [2]. With the involvement of non-dopaminergic systems, new pharmacological treatments for non-motor PD symptoms can be developed. Several studies have found Acetylcholine-esterase inhibitors effective in improving cognitive and behavioural symptoms such as apathy, hallucinations, confusion, psychosis and anxiety with minimal worsening of motor symptoms [2]. This hypothesis is also strengthened by experiments showing hyoscine to cause memory impairment in no demented PD patients but not in healthy subjects, suggesting that there is a decrease in Ach in PD, but not below the threshold as seen in PDD [2]. With further understanding of how these other neural systems are affected by the progression of PD, a better understanding of the complete spectrum of the disease course can be obtained and with this new treatments can be devised. PDD patients as well as PD patients may benefit from treatments to help correct these neuro-chemical deficits. Drugs such as bupropion HCL, a weak noradrenaline and dopamine uptake inhibitor, may hold some therapeutic value. The interactions and effect in PD patients would need to be assessed, but it could also help to alleviate some of the negative symptoms of  l-dopa therapy currently used, allowing for a lower dosage for the same effect when used in combination therapy. The development of pharmacological treatments for the symptoms of PDD and PD in general will be reliant on development of more selective drugs as well as better vehicles of administration to maximise positive effect and minimise negative effects of treatment. The greatest prospects seem to be a tailored combination therapy, allowing for better management of PD symptoms and thus an increase in the quality of life for sufferers.


References

[1]    Moore D.J., West A.B., Dawson V.L., Dawson T.M. .Molecular Pathophysiology of Parkinson’s Disease. Annual Review of Neuroscience.2005.28:57-87
[2]   Emre M. Dementia associated with Parkinson’s disease. Lancet Neurology. 2003.2(4):229-237
[3]    Cookson  M.R. The biochemistry of Parkinson’s Disease. Annual Revue of Biochemistry. 2005.74:29-52
[4]   Maguire-Zeiss. K.A., Short. D.W., Federoff. H.J. Synuclein, dopamine and oxidative stress: co-conspirators in Parkinson’s Disease?. Molecular Brain Research. 2005.134:18-23
[5]    Winkler. C., Kirik. D., Björklund. A. Cell transplantation in parkinson’s disease: how can we make it work?. Trends in neuroscience. 2005.28(2)
[6]   Mori. H. Pathological substrate of dementia in Parkinson’s diseaseâ€"Its relation to DLB and DLBD. Parkinsonism and related disorders, 2005.11:41-45
[7]   Sabbagh M.N., Silverberg N., Bircea S., Majeed B., Samant S. Caviness J.N., Reisberg B., Adler C.H., Is the functional decline of Parkinson’s disease similar to functional decline of Alzheimer’s disease?. Parkinsonism and related disorders.2005.11:311-315
[8]   Tsuboi Y.,Dickson D.W. Dementia with lewy bodies and Parkinson’s disease with dementia: Are they different?. Parkinsonism and related disorders.2005.11:47-51
[9] Guo L., Itaya M., Takanashi M., Mizuno Y., Mori H. Relationship between Parkinson’s disease with dementia and dementia with lewy bodies. Parkinsonism and related disorders.2005.11:305-309

[neonaut]

thank you my gfriends grandfather suffers from this, keep up the ggod work.

[rhodopsin]

...

[visionarybear]

yes, i actually stumbled across l-selegiline whilst showing a friend how to use the article database/e-journals, didnt have time to read it tho, am planning on looking into it when uni dies down abit..

vb~

[Green2Herman]

The same kind of food that keep the heart nice and clean will also make parkinsons less likely.

Some more articles:
http://www.helpguide.org/elder/alzheimers_dementias.htm
http://www.mindtools.com/memory.html
http://www.ec-online.net/Knowledge/Arti ... ement.html
http://memory.ucsf.edu/Education/Treatm ... ments.html
http://www.helpguide.org/elder/alzheime ... atment.htm