Mild Parkinsonian Signs in a Community Population

One question that many of the PREDICT-PD participants ask me is “I am slower than I used to be, does it mean that I am getting Parkinson’s?”

I am interested in the early motor phases of Parkinson’s disease. They are subtle in appearance and usually start before the classical symptoms of Parkinson’s arise, which are slowness of movement, stiffness and tremor. 

When studying subtle abnormalities it is important to know the full range of normal amongst older people. It can be difficult to establish the boundaries between what is normal and abnormal, especially at very early stages of Parkinson’s and in older people.

What it is known is that mild parkinsonian signs or subtle motor symptoms are quite common in the elderly population (ranging from 15% to 50%). The question of whether their presence occurs as part of normal aging or as the result of neurodegeneration has not been clearly answered. 

Here I share a paper that tries to address the issue mentioned above. 

https://www.ncbi.nlm.nih.gov/pubmed/32310187?dopt=Abstract

Abstract.

Background: Mild parkinsonian signs (MPS) are common in the older adult and associated with a wide range of adverse health outcomes. There is limited data on the prevalence of MPS and its significance.

Objective: To determine the prevalence of MPS in the community ambulant population and to evaluate the relationship of MPS with prodromal features of Parkinson’s disease (PD) and cognition.

Methods: This cross-sectional community-based study involved participants aged ≥50 years. Parkinsonian signs were assessed using the modified Unified Parkinson’s Disease Rating Scale (mUPDRS) and cognition using the Montreal Cognitive Assessment (MoCA). Premotor symptoms of PD were screened using a self-reported questionnaire. Linear regression was used to assess the association of MPS with premotor symptoms of PD and cognitive impairment.

Results: Of 392 eligible participants, MPS was present in 105 (26.8%). Mean age of participants with MPS was 68.8 +/- 6.9 years and without MPS was 66.1 +/- 5.9 years (p < 0.001). Multivariate analysis revealed that MoCA scores were significantly lower in the MPS group (b= –0.152, 95% CI = –0.009, –0.138, p < 0.05). A significant correlation between the presence of REM sleep behavior disorder (RBD) and total MPS scores (b= 0.107, 95% CI = 0.053, 1.490, p < 0.05) was also found. Neither vascular risk factors nor other premotor symptoms were significantly associated with MPS.

Conclusion: MPS is common and closely related to cognitive impairment and increasing age. Presence of RBD is predictive of higher MPS scores. This study highlights the necessity of other investigations or sensitive risk markers to identify subjects at future risk of PD.

The main purpose was to know how frequent subtle motor symptoms were in an elderly community without Parkinson´s and evaluate if these features were associated with a loss of cognitive abilities or other features known to be part of the early phase of Parkinson’s including reduced sense of smell, constipation, depression and sleep disturbances. 

To do that, participants were evaluated with motor and memory tasks as well as answering a self-reported questionnaire about the other symptoms mentioned. 

The authors found that one quarter of the group had subtle movement symptoms and this proportion increased with age, with 3 out of 10 people older than 75 having some kind of movement abnormalities. It is important to note that none of these symptoms were strong enough to make the diagnosis of Parkinson’s. They also found that cognitive and motor symptoms were highly associated.

We can extract several conclusions from these results. It is undeniable that once we get older our movement becomes slower and clumsier. The point here is when these motor symptoms occur together with mild memory problems it could mean that some neurodegenerative condition apart from simple aging is occurring.  

In order to these findings be more convincing, we would need to know how many of these people ended up having Parkinson’s or other conditions like Alzheimer’s over time. This was not reported in the study and so further studies are needed.

Cristina Simonet

Great Debates

While there are many great debates happening this week in the UK, perhaps the most interesting happened at today’s biannual meeting of the Association of British Neurologists Movement Disorders Special Interest Group, held in the beautiful Oxford Town Hall. The opening session of the meeting was a debate between two giants of the international Parkinson’s world: Professor Donald Grosset from Glasgow, and Professor Ron Postuma from Montreal.

The topic they were debating was “Should research focus on prodromal disease prevention or improving symptomatic therapies?” Professor Grosset set out the reasons for focussing on better treatments in the complex phase of the disease – when the treatments that we have either fail to work or side effects become increasingly troublesome and diffucult to manage. He also pointed out the near-total lack of well-proven treatments for many of the non-motor aspects of Parkinson’s (a point we have laboured in previous blog posts here). He suggested that detection of the prodromal stage was hit-and-miss and that the best case scenario was that trials in this group would costs hundreds of millions of pounds which would be better served investing in treatments for people with definite Parkinson’s.

Ron Postuma countered his argument and opened with the metaphor central to preventive medicine: people are falling over a waterfall and nearly drowning in the pool below. A man is pulling them out one by one and calls to a bystander to help. The bystander walks away, but returns at the top of the waterfall to stop people from falling down in the first place. Although  this metaphor may seem simplistic, it highlights the importance of focussing on the earliest stages. He went on to simplify the drug treatment of established Parkinson’s as “playing with neurotransmitters” – and no matter how successful one might be at doing that, there is an underlying progression of brain death. To deal with that means to effect a change before disease causing cascade of events has become unstoppable – i.e. in the earliest (prodromal) stages. Finally, he highlighted the seismic changes that have occurred in medicine in the last two generations. Penicillin used to be so expensive that patients given penicillin had their urine collected, the excreted penicillin extracted and given back to the patients to make each vial go further. Wards for women with infected wombs after miscarriages who would almost inevitably succumb to their infections closed within weeks. The AIDS wards that were in most hospitals in the 70s and 80s were empty just a few years after HIV medication started being used. New treatments for advanced cancer have changed the landscape for some of these diseases (including nilotonib which is currently being trialed in Parkinson’s), and the last two years has brought these game-changing experiences to neurological diseases with drugs such as Nucinercin – effectively curing an incurable genetic condition that killed children in their first few years. The message, he said, was clear – things we now take for granted were once hard and very expensive, and for Parkinson’s there is change on the horizon.

The rest of the meeting continued with many other fascinating and useful talks from some of the leaders of British neurology, and has offered many insights and ideas that we at Predict-PD can use to help bring us closer to a robust identificaiton of prodromal Prkinson’s and therefore, another step closer to a cure.

RNR

Is the horizon getting closer ?

Week after week we talk about the need for a disease modifying drug in Parkinson’s, and week after week we hope to reassure you, dear reader, (as well as ourselves) that this Holy Grail is getting ever closer. 

This week marks the publication of a study that may mark a turning point in this journey. Prothena Pharmeceuticals have run a study looking at the safety and tolerability of a new compound (excitingly called PRX002/RG7935). This is a compound that sticks to the toxic protein that is understood to cause the brain cell loss in Parkinson’s – α-synuclein. Once it sticks to this substance, it ‘flags’ the body’s immune system to come and clear up the mess. This, we think, reduces the amount of the α-synuclein that is floating around and causing damage. 

In this study 80 participants with mild-moderate Parkinson’s were given one of six different doses of this medicine or salt-water (placebo) through a ‘drip’. They attended once a month and the infusion lasted 1-2 hours. Neither the participants nor the investigators knew how much (if any) of the drug they were getting. They received three infusions in total.

I must stress that this study wasn’t designed to see if this did anything at all for their Parkinson’s. The study was too small, and too short for any changes to be detected. The primary purpose of this study was to evalute whether the medicine was safe and tolderable, with secondary objectives of studying what happens to the drug when it is in the body.

Overall, of the 55 participants that had any strength of the medicine, 50 completed the study, and 5 did not manage all 24 weeks of the study. 1 stopped because their Parkinson’s worsened, 1 decided to withdraw (reason not stated), 2 (both in the highest dose group) stopped because of side effects, and 1 also in the highest group withdrew. I also note that 3 out of 25 getting placebo also withdrew.

This study is a vital step. After extensive laboratory testing, a compound like this will be given to a very small number of totally healthy volunteers to ensure it is safe in humans. Then it will be given to a small number of volunteers with the condition to make sure it is safe in the ‘target’ population and to determine a range of safe doses, which is this study. Then it will be given to a moderately large sample to see if there are any suggestions of positive effects and to refine the ideal dose, and finally it will undergo a large study of affected individuals where the investigators (and cruicially the funders) hope to find that it has a true benefit.

All the participants in this study had had Parkinson’s for around 3 years (although this was as much as 15 years) and was moderately advanced. We hope that in future studies, the investigators take people with the earliest possible disease duration and learn lessions from the Alzheimer’s journey. 

This compound has been being studied in the earliest stages of the research process for around 10 years. The next stage of the path for this compound, the PASADENA trial, started almost exactly 1 year ago, and will be running until February 2021. I would expect results to come out towards the end of 2021, and then (hopefully) a phase 3 study will start which will take several more years to run and analyse. If all these steps are successful, we may be in a position to prescribe this medication in around 7-10 years from now.

RNR

Safety and Tolerability of Multiple Ascending Doses of PRX002/RG7935, an Anti-α-Synuclein Monoclonal Antibody, in Patients With Parkinson Disease: A Randomized Clinical Trial.

JAMA Neurol. Published online June 18, 2018. doi:10.1001/jamaneurol.2018.1487

Joseph Jankovic, MD; Ira Goodman, MD; Beth Safirstein, MD; Tonya K. Marmon, DrPH; Dale B. Schenk, PhD; Martin Koller, MD, MPH; Wagner Zago, PhD; Daniel K. Ness, DVM, PhD; Sue G. Griffith, MD, PhD, MRCP; Michael Grundman, MD, MPH; Jay Soto, BS; Susanne Ostrowitzki, MD, PhD;Frank G. Boess, PhD; Meret Martin-Facklam, PhD; Joseph F. Quinn, MD; Stuart H. Isaacson, MD; Omid Omidvar, MD; Aaron Ellenbogen, DO;Gene G. Kinney, PhD

Importance:Aggregated α-synuclein is believed to be central to the pathogenesis of Parkinson disease (PD). PRX002/RG7935 (PRX002) is a humanized monoclonal antibody designed to target aggregated forms of α-synuclein, thereby inhibiting neuron-to-neuron transfer of presumed pathogenic forms of α-synuclein, potentially resulting in neuronal protection and slowing disease progression.

Objective:To evaluate the safety and tolerability of multiple intravenous infusions of PRX002 in patients with idiopathic PD.

Design, Setting, and Participants:Multicenter, randomized, double-blind, placebo-controlled, multiple ascending-dose trial at 8 US study centers from July 2014 to September 2016. Eligible participants were aged 40 to 80 years with mild to moderate idiopathic PD (Hoehn and Yahr stages 1-3).

Interventions:Participants were enrolled into 6 ascending-dose cohorts and randomly assigned to receive PRX002 (0.3 mg/kg, 1.0 mg/kg, 3.0 mg/kg, 10 mg/kg, 30 mg/kg, or 60 mg/kg) or placebo. Participants received 3 intravenous infusions every 4 weeks of PRX002 or placebo and were monitored during a 24-week observational period.

Main Outcomes and Measures:Safety and tolerability assessments included physical and neurological examinations, laboratory tests, vital signs, and adverse events. Pharmacokinetic parameters included maximum PRX002 concentration, area under the curve, and half-life.

Results:Of the 80 participants, most were white (97.5%; n = 78) and male (80%; n = 64); median (SD) age was 58 (8.4) years. PRX002 was generally safe and well tolerated; no serious or severe PRX002-related treatment-emergent adverse events (TEAEs) were reported. The TEAEs experienced by at least 5% of patients receiving PRX002, irrespective of relatedness to study drug, were constipation (9.1%; n = 5), infusion reaction (7.3%; n = 4), diarrhea (5.5%; n = 3), headache (5.5%; n = 3), peripheral edema (5.5%; n = 3), post-lumbar puncture syndrome (5.5%; n = 3), and upper respiratory tract infection (5.5%; n = 3). No antidrug antibodies were detected. Serum PRX002 levels increased in an approximately dose-proportional manner; mean terminal elimination half-life was similar across all doses (10.2 days). Rapid dose- and time-dependent mean reductions from baseline vs placebo in free serum α-synuclein levels of up to 97% were seen after a single infusion at the highest dose (F78,284 = 1.66; P = .002), with similar reductions after 2 additional infusions. Mean cerebrospinal fluid PRX002 concentration increased with PRX002 dose and was approximately 0.3% relative to serum across all dose cohorts.

Conclusions and Relevance:Single and multiple doses of PRX002 were generally safe and well tolerated and resulted in robust binding of peripheral α-synuclein and dose-dependent increases of PRX002 in cerebrospinal fluid, reaching cerebrospinal fluid concentrations that may be expected to engage extracellular aggregated α-synuclein in the brain. Findings support the design of an ongoing phase 2 clinical study (NCT03100149).

Trial Registration:ClinicalTrials.gov Identifier: NCT02157714.

Changing Tack

In a very wide ranging and well written review, two leaders of the Parkinson’s field lay down set the terms of engagement and (to mix my combative metaphors), lay down the gauntlet in the quest to find disease modifying treatments.

After defining three kinds of ‘disease modification’ (neuroprotection: preventing the progression of PD; neurorescue: repairing damaged brain cells; neurorestoration: replacing what has been lost), they provide a brief but comprehensive overview of why every attempt so far has failed, from both a mechanistic perspective as well as a methodological perspective.

The key messages to take from this article are thus:

1.     We really need to stop thinking of Parkinson’s as a single condition. As well as many different ways that people experience their Parkinson’s (the different phenotypes), there are also many different molecular and cellular processes. Each person will likely have a different milieu of process that results in their particular phenotype.

2.     Once we can do this, we can start approaching disease modification in a more personalised way. This means recruiting the people with the right kind of Parkinson’s, at the right time, to the right study. We need to become much more sophisticated in the way we study new treatments, probably recruiting very specific groups of participants, for example people with particular genetic changes related to their Parkinson’s, and testing cocktails of treatments, rather than our current blunderbuss approach.

3.     Given that Parkinson’s is a complex, and slowly progressive condition, we must have better progression markers on which to design our studies.

This is going to require a lot of work, with the Parkinson’s population, scientists, clinicians, and industry. In order to get the highly effective treatments that our oncologists have avaiable to them, we need to change the terms of warfare.

What can we all do in the mean time? Pay attention to these three battles. Not necessarily throw the baby out with the bathwater if a particular study doesn’t prove miraculous (which it almost certainly won’t). And if you have Parkinson’s: exercise more!

At PREDICT-PD towers, we strongly believe that identifying the disease earlier, in the prodromal phase, will bring us closer to many of these objectives. Earlier disease is more likely to be simpler disease; it may be possible to identify early phenotypes that map onto particular pathological pathways; we have an opportunity to identify biomarkers that predict the development of established Parkinson’s, thus giving an ideal method of proving efficacy of new treatments.

RNR

Disease modification in Parkinson's Disease: Current approaches, challenges, and future considerations.

Anthony E Lang and Alberto J Espay.

Mov Disord, 2018 vol. 386 p. 896.

http://doi.wiley.com/10.1002/mds.27360

The greatest unmet therapeutic need in Parkinson's disease is the development of treatment that slows the relentless progression of the neurodegenerative process. The concept of "disease modification" encompasses intervention types ranging from those designed to slow the underlying degeneration to treatments directed at regenerating or replacing lost neurons. To date all attempts to develop effective disease-modifying therapy have failed. Many reasons have been proposed for these failures including our rudimentary understanding of disease pathogenesis and the assumption that each targeted mechanisms of disease apply to most patients with the same clinical diagnosis. Here we review all aspects of this broad field including general concepts and past challenges followed by a discussion of treatment approaches under the following 4 categories: (1) α-synuclein, (2) pathogenic mechanisms distinct from α-synuclein (most also potentially triggered by α-synuclein toxicity), (3) non-SNCA genetic subtypes of "PD," and (4) possible disease-modifying interventions not directly influencing the underlying PD pathobiology. We emphasize treatments that are currently under active clinical development and highlight a wide range of important outstanding questions and concerns that will need to be considered to advance the field of disease modification in PD. Critically, it is unknown whether the dysfunctional molecular pathways/organelles amenable to modification occur in a sequential fashion across most clinically affected individuals or manifest differentially in independent molecular subtypes of PD. It is possible that there is no "order of disruption" applicable to most patients but, rather, "type of disruption" applicable to subtypes dependent on unknown factors, including genetic variability and other causes for heterogeneity in PD. Knowing when (early vs late), which (eg, synaptic transmission, endosomal sorting and maturation, lysosomal degradation, mitochondrial biogenesis), and in whom (PD subtype) specific disrupted cell pathways are truly pathogenic versus compensatory or even protective, will be important in considering the use of single or combined ("cocktails") putative disease-modifying therapies to selectively target these processes. Beyond the current phase 2 or 3 studies underway evaluating treatments directed at oxidative stress (inosine), cytosolic Ca2+ (isradipine), iron (deferiprone), and extracellular α-synuclein (passive immunization), and upcoming trials of interventions affecting c-Abl, glucagon-like peptide-1, and glucocerebrosidase, it might be argued that further trials in populations not enriched for the targeted pathogenic process are doomed to repeat the failures of the past. © 2018 International Parkinson and Movement Disorder Society.

Treat the person not the scan

When learning clinical medicine, (junior) doctors can often show an over-reliance on blood tests and scans, rather than focussing on the patient and their holistic care. This can lead in turn to more intensive investigation, which is both costly and incurs extra risk, as well as in turn creating more ‘abnormal results’.

An important report has been published in pre-symptomatic Alzheimer’s this week, in the journal Lancet Neurology. The research team at the Salpêtrière Hospital in Paris studied over 300 older adults with subjective, but no objective, memory complaints. The participants completed detailed neuropsychological and cognitive assessment, structural and functional brain scans (MRI and PET), brain-wave tests (EEG), genetic testing and lumbar punctures. These tests were repeated every 6-12 months for over 2 years. They set out to see if they could identify particular markers that would identify who would develop prodromal Alzheimer’s. They separated their cohort into two groups: one with normal amyloid scans and one with evidence of amyloid build up in the brain. (Amyloid is one of two major abnormal proteins that are thought to cause this form of dementia)

With two years of follow up, only four individuals converted to prodromal Alzheimer’s. All four had some evidence of amyloid build up at the beginning of the study, although with such small numbers it is difficult to say this wasn’t due to chance. All four were also older than most (average age 80.2 years compared to 76.8 years), and ¾ had the genetic variant that confers the highest risk of Alzheimers, APOE-ε4, compared to 33/83 who were tested and didn’t progress. Importantly, evidence of amyloid in the brain did not seem to be a good discriminator for likelihood of progression from ‘the worried well’ to prodromal Alzheimers. In fact, the strongest findings from this study were that CSF and imaging markers of increased amyloid were associated with each other!

What does this mean for Parkinson’s? Firstly, we don’t have an equivalent brain scan, i.e. one that shows build up of α-synuclein with which to predict risk. Secondly, with these complex conditions one marker that doesn’t test the function of the individual will be hard pressed to be hugely predictive. Thirdly, one of the biggest limitations of this study is that the follow up was only 2 years. Given all these individuals had normal memory at the beginning, and most were highly educated, it is perhaps not suprising that so few converted to the prodromal stage.

This figure is worth considering as an alternative model of thinking about the earliest stages of Alzheimer’s and perhaps Parkinson’s

Two hypothetical models of the natural history of Alzheimer's disease

(A) Model 1 illustrates the dominant view of progressive deterioration: in Alzheimer's disease, cognition is progressively impaired from the preclinical phase (characterised by amyloid β deposition followed by tau pathology), to the prodromal clinical stage (with subtle cognitive changes), then the clinical stages of MCI and dementia. (B) Model 2 represents an alternative view of preclinical compensation that we have based on our data for brain β-amyloidosis. Cognition remains stable in the preclinical phase of the disease despite underlying brain lesions, until brain compensatory mechanisms are overwhelmed, leading to clinical disease. MCI=mild cognitive impairment. AD=Alzheimer's disease.

RNR

Cognitive and neuroimaging features and brain β-amyloidosis in individuals at risk of Alzheimer's disease (INSIGHT-preAD): a longitudinal observational study.

Bruno Dubois et al

Lancet Neurology 2018, 17 (4), 335-346

http://www.thelancet.com/journals/laneur/article/PIIS1474-4422(18)30029-2/fulltext?%7B$trackingTag%7D

BACKGROUND:Improved understanding is needed of risk factors and markers of disease progression in preclinical Alzheimer's disease. We assessed associations between brain β-amyloidosis and various cognitive and neuroimaging parameters with progression of cognitive decline in individuals with preclinical Alzheimer's disease.

METHODS:The INSIGHT-preAD is an ongoing single-centre observational study at the Salpêtrière Hospital, Paris, France. Eligible participants were age 70-85 years with subjective memory complaints but unimpaired cognition and memory (Mini-Mental State Examination [MMSE] score ≥27, Clinical Dementia Rating score 0, and Free and Cued Selective Reminding Test [FCSRT] total recall score ≥41). We stratified participants by brain amyloid β deposition on18F-florbetapir PET (positive or negative) at baseline. All patients underwent baseline assessments of demographic, cognitive, and psychobehavioural, characteristics, APOE ε4 allele carrier status, brain structure and function on MRI, brain glucose-metabolism on18F-fluorodeoxyglucose (18F-FDG) PET, and event-related potentials on electroencephalograms (EEGs). Actigraphy and CSF investigations were optional. Participants were followed up with clinical, cognitive, and psychobehavioural assessments every 6 months, neuropsychological assessments, EEG, and actigraphy every 12 months, and MRI, and18F-FDG and18F-florbetapir PET every 24 months. We assessed associations of amyloid β deposition status with test outcomes at baseline and 24 months, and with clinical status at 30 months. Progression to prodromal Alzheimer's disease was defined as an amnestic syndrome of the hippocampal type.

FINDINGS:From May 25, 2013, to Jan 20, 2015, we enrolled 318 participants with a mean age of 76·0 years (SD 3·5). The mean baseline MMSE score was 28·67 (SD 0·96), and the mean level of education was high (score >6 [SD 2] on a scale of 1-8, where 1=infant school and 8=higher education). 88 (28%) of 318 participants showed amyloid β deposition and the remainder did not. The amyloid β subgroups did not differ for any psychobehavioural, cognitive, actigraphy, and structural and functional neuroimaging results after adjustment for age, sex, and level of education More participants positive for amyloid β deposition had the APOE ε4 allele (33 [38%] vs 29 [13%], p<0·0001). Amyloid β1-42concentration in CSF significantly correlated with mean18F-florbetapir uptake at baseline (r=-0·62, p<0·0001) and the ratio of amyloid β1-42to amyloid β1-40(r=-0·61, p<0·0001), and identified amyloid β deposition status with high accuracy (mean area under the curve values 0·89, 95% CI 0·80-0·98 and 0·84, 0·72-0·96, respectively). No difference was seen in MMSE (28·3 [SD 2·0] vs 28·9 [1·2], p=0·16) and Clinical Dementia Rating scores (0·06 [0·2] vs 0·05 [0·3]; p=0·79) at 30 months (n=274) between participants positive or negative for amyloid β. Four participants (all positive for amyloid β deposition at baseline) progressed to prodromal Alzheimer's disease. They were older than other participants positive for amyloid β deposition at baseline (mean 80·2 years [SD 4·1] vs 76·8 years [SD 3·4]) and had greater18F-florbetapir uptake at baseline (mean standard uptake value ratio 1·46 [SD 0·16] vs 1·02 [SD 0·20]), and more were carriers of the APOE ε4 allele (three [75%] of four vs 33 [39%] of 83). They also had mild executive dysfunction at baseline (mean FCSRT free recall score 21·25 [SD 2·75] vs 29·08 [5·44] and Frontal Assessment Battery total score 13·25 [1·50] vs 16·05 [1·68]).

INTERPRETATION:Brain β-amyloidosis alone did not predict progression to prodromal Alzheimer's disease within 30 months. Longer follow-up is needed to establish whether this finding remains consistent.

FUNDING:Institut Hospitalo-Universitaire and Institut du Cerveau et de la Moelle Epinière (IHU-A-ICM), Ministry of Research, Fondation Plan Alzheimer, Pfizer, and Avid.