I-FP-CIT may be used. .An 18F-DOPA), the PET/CT scan is another way. They are costly and may not be available at all centers

Certainly PET/ SPECT can be used to track PD progression but correlation with clinical scales is rather poor; in fact in certain situations (see ELDOPA study) is even negative. At present functional imaging is not at all the gold standard to track PD (see Ravina), at least clinically. But it is also true that clinical scales have many limitations to study PD evolution, hence other biomarkers are needed. We suggest that timed tests (CAPIT tests quantify age-related motor decline in normal subjects. Journal of Neurological Sciences 2007; 260: 283-285) and ambulatory monitors ( Evaluation of Actitrac -ambulatory activity monitor- in Parkinson disease. Journal of Neurological Sciences 2008; 270: 87-89) could be a valuable and objective aid

Neuromelanin-sensitive MRI seems like an exciting way of tracking changes in brain regions affected in PD (namely the Substantia Nigra and Locus Coeruleus) although the accuracy of this technique may be questionable.

REF: Ohtsuka et al. (2013). Changes in substantia nigra and locus coeruleus in patients with early-stage Parkinson's disease using neuromelanin-sensitive MR imaging. Neurosci Lett. 541: 93-8

The imaging method sounds like a nice idea. While clinical benchmarking is the gold standard today, as Dr. Garcia-Ruiz mentioned, the pharmacological treatment contaminates so many aspects of knowing whether PD progresses. I still return to the original idea from Parkinson that the hallmark feature of this disease is nigral cell loss that is clinically associated with bradykinesia, rigidity and tremor.

Good discussion started.

Dr Konrad is right in mentioning that the key aspect of PD is the loss of SN; that is of course, true; and the typical clinical aspects of PD include bradykinesia, rigidity and tremor. The problem is that we are facing with clinical aspect only and rarely we confirm the clinical points with pathology (certainly brain banks such as British Brain Bank are necessary).

Another practical issue is that clinical-pathological correlation in PD is not as all perfect, Hughes and Lees already showed that many patients with idiopatic PD (defined by the presence of Lewy bodies and loss of SN) did not have tremor (about 40%), or had only a poor response to levodopa....and on the other hand same holds true for atypical PD...many patients with MSA or PSP have a very similar clinical picture compared with PD

and finally...Lewy body disease can be present in ¨normal¨ controls....up to 30% of normal elder controls could be classified as PD...pathologically (same holds true for Alzheimer disease)

But what do we have in clinical practice ? We have only clinical aspects... What can we measure with precission ?....motor performance... hence we should rely, besides clinical scales, on precise motor aspects (such as timed tests and ambulatory monitors) unless we had a clear signature of PD (and we don´t have, for the moment)

Of ourse, this is only my personal view (In this interesting and never lasting issue)

Transcranial sonography of the substantia nigra would be another possibility. However, sensitivity in early stages has shown to be insufficient.

http://www.ncbi.nlm.nih.gov/pubmed/23550093

I was getting excited reading the TCS paper and then the final conclusion, deflated my optimism.... Such is the value of prospective, randomized trials..... they give a hard reality check in the face of hopeful retrospective results.

Thanks for sharing though.

Non-responsive to dopamine replacement therapy, non-motor symptoms such as those emerging from cognitive or autonomic dysfunction, assesed by certain valitated scales, could possible help towards clinical monitoring disease progression. This could be a way to avoid the clinical improvement of dopamine-depended symptoms which masks disease severity in a patient normaly taking his dopaminergic medication

Peter Konrad - Can you give me the references to evidence for the death of dopaminergic neurons in the substantia nigra as the prime cause of PD? I know that postmortem brains of PD patients show shrinkage of the SN but these are usually in the late stage of PD. A recent publication, http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0061786, reported no shrinkage of any part of the brain in 23 symptomatic patients. Free dopamine has a very short half-life and must be synthesised from l-dopa very close to where it is needed.

It is therefore reasonable to infer that patients who respond to l-dopa are unable to make sufficient l dopa themselves but can nevertheless complete the decarboxylation of l-dopa to make dopamine. If the 80% of the SN neurones are dead, where is the l-dopa decarboxylated?

I should admit that I am a 74 year old once biochemist who was diagnosed with the on-tremulious form of PD in 2010. I have agreed to write a layman's summary of what is known about the science of PD. Since nearly every patients' guide quotes the 80% death figure I don;t want to challenge it unless In have thoroughly dug over the ground first.

As a PD patient, knowing how variable the symptoms can be, I would mistrust any judgement based on clinical assessment of symptoms. I am amazed at the projects that aim to measure the effectiveness of interventions on progression of PD without first determining the standard deviation of the method of assessment and the number of replicate measurements and the number of subjects needed to detect a change of specified magnitude in a given period of time with a specified confidence level. We had to do this in 1983 to determine the effect of acid deposition on the pH of surface waters.

It took a very good statistician to do it and the result was sobering!

No one knows with certainty the "cause" of idiopathic Parkinson's. There are various factors which may increase the risk--multiple head injuries, genetics, exposure to toxic agricultural and industrial chemicals, infections, and contributing factors may include increased oxidative stress, inflammation and other mechanisms.

Some researchers propose the olfactory bulb and gut as initial sites for neurotropic pathogens, as they may be implicated in nonmotor symptoms decades before the motor symptoms appear.

Stephen Warren--if, by 80%, you mean the presumed decline in dopaminergic neurons that supply the BG by the time of diagnosis--I have not found a consensus about that. Here is one article estimating 58-64%: http://www.ncbi.nlm.nih.gov/pubmed/11456307. There are plenty of other views, however, and different estimates each have limitations. I saw one view which proposed a proportion of the neurons as going dormant.

Although most clinicians assume SN neuronal changes as a benchmark, is it possible that is changing? More than just dopamine circuits and motor symptoms, Parkinson’s is considered a multisystem neurodegenerative disorder, with implications for multiple nonmotor and nondopaminergic neural pathways (Alexander, 2004, Olanow et al, 2011).

This doesn't help, however with measuring disease progression. Also, progression is not consistent. Jankovic (2008) indicates that "Studies making use of UPDRS to track the progression of PD suggest that the course of PD is not linear and that the rate of deterioration is variable and more rapid in the early phase of the disease and in patients with the postural instability gait difficulty (PIGD)".

Also, progression as measurement of what issues? Non-motor symptoms are not alleviated as well as motor ones, and have increasing impact on QoL. A non-tremor subtype of PD is more likely to develop dementia. I heard one neurologist state, if you have met one person with Parkinson's, you have met one person with Parkinson's. Each person presents with a different set of symptoms and rate of progression.

Rosi - I think most clinicians are sill wedded to the dopamine story if only because it's an easy explanation for patients. Research has long switched to protein misfolding as the source of all the NDDs and conformational diseases in general. The relative failure, however, of drugs developed to reduce beta amyloid protein tangles to produce any lasting benefit to AD patients has damaged confidence in the (unwarranted) assumption that because all the NDDs are associated with protein tangles then their must be a causative connection. Research continues of course, but more circumspectly than before. There is an excellent review (BBA_Molecular_Basis_Diseases_1822_261.pdf) edited by Vladimir Uversky, that pulls it all together.

Predicting outcomes of PD is notoriously difficult, not least because predictions are based on outcomes in past patients. The attached document is from my blog (stevecience.com) in WordPress and shows the extent to which PD, particularly the non tremulous form, is probably undiagnosed in the elderly in the UK.

Another big topic is why exercise is so effective at reducing (by 48%) the risk of contracting AD. Clinicians end to wave their hands and say it improves the blood supply to the brain but exercise also releases BDNF and proteosomes in the brain, which I think is probably more relevant.

My opinion is that to measure the progression of the disease process one should ideally use imaging of synucleinopathy, perhaps not restricted to the CNS. What would be very valuable is a marker of misfolded synuclein that could be used for PET studies.

As for the clinical progression, I am not convinced that any available scales cut it in terms of actual disease progress. The confounding effects of treatment have already been mentioned. To be fair though it may be more interesting for patients to base studies on the development of handicaps and symptoms. It is most likely that one of the benefits of treatment is that brain plasticity is altered and it is possible (and likely) that this accounts for some of the "disease modifying" effects of treatment with LDOPA and MAOBi. As long as there is no treatment that halts the disease process (and even then) it will be fundamental to judge disease progression from the development of disability

Dr. Konrad,

Nonmotor symptoms/nondopaminergic features are largely unaffected by treatment with L-dopa, and QoL continues to decline, so they are a candidate for a systematic way to track disease progression. Here is a paper along these lines, although I only have access to the abstract, so am not sure if it address all the issues raised by you and others in this discussion:

van der Heeden, JF, et al. Importance of nondopaminergic features in evaluating disease severity of Parkinson disease. http://www.ncbi.nlm.nih.gov/pubmed/24391163

There is some data from PPMI (Parkinson's Progression Markers Initiative) suggesting that dopamine transporter imaging (DAT binding) could be sensitive to disease progression and hence could be potentially used as a biomarker for examining efficacy of disease modifying treatments in development.

dear all, i want to know the best dose of rotenone to induce PD in rats in case of intravenous injection. and better to dissolve rotenone in DMSO:PEG 1:1 or one of them only and what is the best concentration of them to be used if i will use them separately. please urgently

As clinician, the advantages of UPDRS and non-motor scores are that they are closer linked to patient function and quality-of-life but most PD clinicians know that these are imperfect insensitive subjective rating scales and that Parkinson's disease is not a dopamine-only disease.

As there is no non-invasive measure for synuclein which can easily be repeated, the most compelling objective quantitative non-invasive biomarker is likely to be dopamine-transporter-SPECT (DaT-scan) if the PPMI data bears out with follow-up. There will not be consensus on this until PPMI formally publishes. The problem I anticipate with DaT-scans is two-fold:

- it is unlikely to correlate with quality of life and function as many young PD patients and Parkin-mutation patients have very abnormal DaT but better QoL and slower progression than elderly PD.

- there will be a floor effect as many patients have no measurable DaT uptake at diagnosis so will be useless for long-term monitoring.

As such, for now, it is going to have to be a combination of motor and non-motor clinical scales.