On Thinking and Feeling

Sarah Getz and Bonnie Levin have published a broad and wideranging review of cognitive and neuropsychiatric symptoms in early PD.

The bottom line of this article underscores the tennet that PD is not just a movement disorder!

Although a noticeable proportion of people with PD may develop dementia, a significant body of work has shown that even at the earliest stages (including the prodromal or pre-motor stages), there are detectable memory deficits. One particular aspect of difficulty is in ‘executive function’ – the thinking process that allows for planning, initiating and concentrating on a task as well as ‘thinking outside the box’. I think this has interesting significance when considering the daily function of people with Parkinson’s, such as driving (see an earlier blog post from the PREDICT-PD blog).

Depression, fatigue and apathy are all very common symptoms that have a major impact on the quality of life of people with PD, not to mention their family and caregivers. Fatigue has been reported to occur in up to 2 in every 3 people with PD and has been described as the most debilitating symptom. Apathy is a real danger – muscles, be they physical, cognitive or emotional, need use. Apathy robs the person of the drive to exercise those muscles and thereby jeopardises their future ability to move, think and feel as they once did. It goes hand in hand with depression and also with increasing disability do to PD.

As we learn more about these less visible aspects of PD, we now need to search for ways to treat them. This is particularly important as the bedrock of PD treatment may make some aspects of thinking and feeling worse.

RNR

 https://doi.org/10.1093/arclin/acx091

Cognitive and Neuropsychiatric Features of Early Parkinson's Disease.

Getz SJ, Levin B.

Arch Clin Neuropsychol. 2017 Nov 1;32(7):769–85. 

The clinical definition of Parkinson's disease (PD) is based on cardinal motor features including bradykinesia as well as an additional symptom of tremor, postural instability, or rigidity. Evidence from neuropathological, imaging, and clinical research suggests a premotor, early phase of PD pathology. Further understanding of the earliest biomarkers of PD is crucial for the development of neuroprotective, disease modifying, cognitive, and psychiatric interventions. Recent research has explored early non-motor markers of PD pathology. This issue is especially timely as the International Parkinson and Movement Disorder Society has recently provided a research definition for prodromal PD which includes combinations of prodromal markers and risk factors aimed at identifying target populations for disease-prevention trials. In this review of early PD, we will outline early non-motor symptoms, early cognitive and neuropsychiatric features, neuropsychological assessment strategies, emerging evidence for early biomarkers, and treatment recommendations.

Let's not forget about cognition..

There have been a few recent studies looking at cognition before development of Parkinson's Disease and this nice review paper from Germany brings a lot of the important findings together. There is a building consensus that a sub-clinical decline in cognition (i.e. problems with memory and thinking that are not severe enough to impair daily living) is present in a number of patients before development of Parkinsons Disease. However, it is also clear that not all patients have these problems - I think, as with Parkinsons subtypes, teasing out the differences between these patients may well shed further light on the underlying disease process.

Conceptually, there are different ways of looking at the time before Parkinson's diagnosis - probably the most robust being large prospective population studies which have been able to look at participants over many years until a proportion develop Parkinsons. Only 4 of these were identified and it is difficult to compare them directly due to differing methodologies; 2 of these studies showed poorer cognitive performance in those who eventually developed Parkinsons, 1 didn't show a difference and the final study didn't directly compare this outcome. 

Another methodology, the one used in PREDICT-PD, is identifying participants at higher risk of Parkinsons disease to see whether there are differences in cognition between higher and lower risk groups. The PARS study looked at participants with two risk markers - poor smell and reduced dopamine binding on PET scan and found significant differences in 2 aspects of cognition. In PREDICT-PD, we have also found poorer overall cognitive scores in the higher risk group. 

The authors are circumspect about the limitations of the studies so far and certainly there are a number of studies, particularly in popluations with genetic risk for Parkinsons disease, which don't show positive findings. However, by combining findings in specific domains, there are definite signs that poorer executive function is commonly found before diagnosis of Parkinsons. 

Presence of Cognitive Impairment in prodromal Parkinsons Disease by study type, from Fengler et al, Cognitive Changes in prodromal Parkinson's disease: A review. 

We continue to work on cognition in our cohort - for the moment it's a case of watch this space. 

-Anna


https://www.ncbi.nlm.nih.gov/pubmed/28980730

Mov Disord. 2017 Oct 5. doi: 10.1002/mds.27135. 

Cognitive changes in prodromal Parkinson's disease: A review. 

Fengler S, Liepelt-Scarfone I, Brockmann K, Schäffer E, Berg D, Kalbe E 

Although other nonmotor phenomena representing possible prodromal symptoms of Parkinson's disease have been described in some detail, the occurrence and characteristics of cognitive decline in this early phase of the disease are less well understood. The aim of this review is to summarize the current state of research on cognitive changes in prodromal PD. Only a small number of longitudinal studies have been conducted that examined cognitive function in individuals with a subsequent PD diagnosis. However, when we consider data from at-risk groups, the evidence suggests that cognitive decline may occur in a substantial number of individuals who have the potential for developing PD. In terms of specific cognitive domains, executive function in particular and, less frequently, memory scores are reduced. Prospective longitudinal studies are thus needed to clarify whether cognitive, and specifically executive, decline might be added to the prodromal nonmotor symptom complex that may precede motor manifestations of PD by years and may help to update the risk scores used for early identification of PD. © 2017 International Parkinson and Movement Disorder Society.

Hepatitis C virus infection and risk of Parkinson's disease: a systematic review and meta-analysis

Results from our study using HES data earlier this year have been meta-analysed with data from other published studies. The results are not surprising (Hep C is associated with increased risk of PD) but the mechanism is intriguing and requires further study... whether it is a percularlity of the virus, the treatment or a shared susceptibility remains to be seen...

Eur J Gastroenterol Hepatol. 2017 Oct 18. doi: 10.1097/MEG.0000000000000991. [Epub ahead of print]
Wijarnpreecha K, Chesdachai S, Jaruvongvanich V, Ungprasert P.

https://insights.ovid.com/pubmed?pmid=29049127

BACKGROUND/OBJECTIVE: Hepatitis C virus (HCV) infection is one of the most common infections worldwide. Recent epidemiologic studies have suggested that patients with HCV infection might be at an increased risk of Parkinson's disease. However, the data on this relationship remain inconclusive. This meta-analysis was conducted with the aim to summarize all available evidence.

PATIENTS AND METHODS: A literature search was performed using MEDLINE and EMBASE database from inception to May 2017. Studies that reported relative risks, odd ratios (ORs), or hazard ratios comparing the risk of Parkinson's disease among HCV-infected patients versus participants without HCV infection were included. Pooled OR and 95% confidence interval were calculated using a random-effect, generic inverse variance method.

RESULTS: Of 468 studies, five studies with 323 974 participants met our eligibility criteria and were included in the analysis. We found a higher risk of Parkinson's disease among patients with chronic HCV infection compared with participants without HCV infection with the pooled OR of 1.35 (95% confidence interval: 1.19-1.52). The statistical heterogeneity of this study was insignificant (I=3%). The main limitation of this meta-analysis was the limited accuracy of diagnosis in the primary studies as they were coding-based studies.

CONCLUSION: This study demonstrated a higher risk of Parkinson's disease among HCV-infected patients. Further studies are required to clarify how this risk should be addressed in the clinical picture.

What's in a name? Parkinson's Disease (Lewy bodies subtype) vs Lewy Body Dementia

This is a timely paper given ongoing questions about nomenclature in Parkinsons. Previously, people who developed dementia and then problems with movement were classified as having dementia with lewy bodies, whereas those who developed dementia after their initial movement problems were given a diagnosis of Parkinson's Disease dementia. For those who develop both problems around the same time, the diagnostic label can feel quite arbitrary. The MDS guidelines in 2015 challenged this paradigm by allowing for a diagnosis of Parkinson's disease in the context of dementia - suggesting the term PD (dementia with Lewy bodies subtype). 

But more recently the DLB consortium brought out specific guidelines for diagnosis of DLB - suggesting we still use this diagnostic term where dementia occurs before or concurrently with parkinsonism. They do acknowledge that "in practice the term that is most appropriate to the clinical situation should be used and generic terms such as lewy body disease may be helpful". 

Classifying both diseases along the same continuum is largely in keeping with their underlying pathophysiology. Both are characterised by lewy body inclusions of alpha-synuclein protein in the brain - and are likely to be different outward manifestations of the same underlying process. A further line of evidence for this is that rapid eye movement sleep behaviour disorder, which confers increased risk of both diseases, is also now recognised to be characterised by lewy body pathology. 

In this paper in JNNP, authors from Bologna aimed to look at the validity of guidelines for diagnosis of DLB, performing a systematic review and meta-analysis of papers in which the authors had corroborated the clinical diagnosis with pathological assessment of brain tissue. They included studies with over 1500 patients and looked at diagnostic criteria over time, finding overall that with revised criteria over time, the sensitivity (likelihood of correct diagnosis) increased but specificity (likelihood of not having the disease after being given the diagnosis) declined. We seem to be picking up more of the people who truly have the disease but also diagnosing more people with the disease who don't have it. 

Part of the problem is overlap of clinical symptoms - some patients with Alzheimer's disease present similarly to those with dementia with lewy bodies. But the study also underlines the issues with our classification, some of those 'misdiagnosed' had Parkinson's Disease. If we start to consider both as part of a spectrum of lewy body diseases Parkinson's wouldn't be a misdiagnosis - which challenges both our conceptions of disease (clinical vs pathological entity) and diagnosis. What do you think?

-Anna

Accuracy of clinical diagnosis of dementia with Lewy bodies: a systematic review and meta-analysis

Giovanni Rizzo, Simona Arcuti, Massimiliano Copetti, Maria Alessandria, Rodolfo Savica, Andrea Fontana, Rocco Liguori, Giancarlo Logroscino

Background 

The diagnosis of dementia with Lewy bodies (DLB) is based on diagnostic clinical criteria, which were updated over the years.

Objective 

To evaluate, through a systematic review, accuracy of the diagnostic criteria, testing a possible improvement over time.

Methods 

We searched on MEDLINE and SCOPUS databases for studies reporting diagnostic parameters regarding the clinical diagnosis of DLB until October 2016. We performed meta-analysis, using a Bayesian approach, on those using pathological examination as gold standard, subclassified based on the different diagnostic criteria used.

Results 

We selected 22 studies on 1585 patients. Pooled sensitivity, specificity and accuracy were 60.2%, 93.8%, 79.7%, respectively, for criteria antecedents to McKeith 1996. For McKeith 1996-possible, pooled sensitivity, specificity and accuracy were 65.6%, 80.6%, 77.9% in early stages and 72.3%, 64.3%, 66% in late stages, respectively. For McKeith 1996-probable, pooled sensitivity, specificity and accuracy were 19.4%, 95.1%, 77.7% in early stages and 48.6%, 88%, 79.2% in late stages, respectively. McKeith criteria 2005 were evaluated only in late stages: pooled sensitivity, specificity and accuracy were 91.3%, 66.7% and 81.6%, respectively, for possible diagnosis (only one study) and 88.3%, 80.8%, 90.7% for probable diagnosis, decreasing to 85.6%, 77.1% and 81.7% if only considering clinical settings focused on dementia diagnosis and care.

Conclusions and relevance 

Diagnostic criteria have become more sensitive and less specific over time, without substantial change in the accuracy. Based on current data, about 20% of DLB diagnosis are incorrect. Future studies are needed to evaluate if the recently released revised consensus criteria will improve the diagnostic accuracy of DLB.

http://dx.doi.org/10.1136/jnnp-2017-316844

Safe Driving

One of the obligations of doctors diagnosing someone with Parkinson’s disease is to advise them to tell the DVLA (Driving and Vehicle Licensing Authority – the UK’s driving license agency) of their diagnosis. When this happens, the DVLA then sends a form to the physician to ask for a professional judgement on their risk to themselves or others on the road.

The guidance for doctors is relatively scant:

! - Must notify the DVLA. 

May drive as long as safe vehicle control is maintained at all times. 

If the individual's condition is disabling and/or there is clinically significant variability in motor function, the licence will be refused or revoked. 

If driving is not impaired, licensing will be considered subject to satisfactory medical reports. 

A licence may be issued subject to regular review.

(from https://www.gov.uk/guidance/neurological-disorders-assessing-fitness-to-drive#parkinsons-disease)

This article aims to help clinicians with some real-world evidence. They did assessments of vision, thinking and movement in healthy older adults as well as people with Parkinson’s. They then assessed their driving in a ‘kitted out’ car with lots of sensors and cameras to allow later scoring of errors etc. The participants then drove an 18 mile route in Iowa, on a mixture of road types. They then invited the participants to return two years later.

The first thing to say is that no one was told to stop the driving assessment early. The people with Parkinson’s were moderately affected (Hoehn & Yahr stage 2, where 1 is minimal symptoms affecting 1 side only – 5 being bed-bound), so the findings are not necessarily applicable to people who’ve just been diagnosed (nor those with more advanced disease).

The headlines from the paper are that people with PD made more mistakes at the beginning of the study (40 PD vs 32 controls), and two years later made significantly more mistakes (50 PD vs 35 control). Serious errors were, however, rare overall (but slightly more common in people with PD). Interestingly, when you only looked at those who did return, the baseline error rate was the same.

One large caveat that should be applied to this study is that of the 67 people with PD that started the study, only 28 returned for the 2 year assessment. 12 of these people had stopped driving in between, one had died and 26 declined the invitation to return. Significantly more healthy controls returned at 2 years (and only 1 of those that didn’t had stopped driving between assessments). Also, it should be noted that driving in Iowa is not necessarily the same as driving in the UK (indeed, driving in London is not the same as driving in Norfolk)

So how does this help me in clinic? Well, the factors that were the most significantly associated with predicting poor driving performance were – near visual acuity, change in the useful field of view, trail making tests (which measure planning and ‘executive function’) and the ability  to do everyday tasks (Activities of Daily Living on the UPDRS). Do we in the Parkinson’s field have a duty to do vision testing? It is interesting to see how different areas of research are converging – Have a look at Dr Rimona Weil’s research that has also hit the news recently 
http://www.telegraph.co.uk/science/2017/10/15/cats-dogs-helping-doctors-predict-dementia-people-parkinsons/ or directly to the research website https://vision-in-parkinsons.co.uk

RNR

http://www.neurology.org/lookup/doi/10.1212/WNL.0000000000004629

Longitudinal decline of driving safety in Parkinson disease

ABSTRACT

Objective: To longitudinally assess and predict on-road driving safety in Parkinson disease (PD).

Methods: Drivers with PD (n 5 67) and healthy controls (n 5 110) drove a standardized route in an instrumented vehicle and were invited to return 2 years later. A professional driving expert reviewed drive data and videos to score safety errors.

Results: At baseline, drivers with PD performed worse on visual, cognitive, and motor tests, and committed more road safety errors compared to controls (median PD 38.0 vs controls 30.5; p , 0.001). A smaller proportion of drivers with PD returned for repeat testing (42.8% vs 62.7%; p , 0.01). At baseline, returnees with PD made fewer errors than non-returnees with PD (median 34.5 vs 40.0; p , 0.05) and performed similar to control returnees (median 33). Baseline global cognitive performance of returnees with PD was better than that of non-returnees with PD, but worse than for control returnees (p , 0.05). After 2 years, returnees with PD showed greater cognitive decline and larger increase in error counts than control returnees (median increase PD 13.5 vs controls 3.0; p , 0.001). Driving error count increase in the returnees with PD was predicted by greater error count and worse visual acuity at baseline, and by greater interval worsening of global cognition, Unified Parkinson’s Disease Rating Scale activities of daily living score, executive functions, visual processing speed, and attention.

Conclusions: Despite drop out of the more impaired drivers within the PD cohort, returning drivers with PD, who drove like controls without PD at baseline, showed many more driving safety errors than controls after 2 years. Driving decline in PD was predicted by baseline driving performance and deterioration of cognitive, visual, and functional abnormalities on follow-up. Neurology® 2017;89:1–8

Smoking and age-at-onset of both motor and non-motor symptoms in Parkinson's disease

This is an interesting study that sets out to look at whether smoking history is associated with the age of onset of motor and non-motor symptoms in patients with PD.... lots of observational study data links smoking to a protective effect on PD.... it follows that in those that do get PD, smoking may delay the manifestation of certain signs. It is interesting that perhaps the features most indicative of synucleinopathies (motor signs and RBD) show the strongest associations with smoking status. Depression and constipation (although common in PD) are not PD specific and for constipation the prevalence appears low overall in this group. Ansomia here was ascertained using a questionnaire, which is in adequate because the correlation between objective and subjective anosmia is poor.

Parkinsonism Relat Disord. 2017 Sep 29. pii: S1353-8020(17)30354-1. doi: 10.1016/j.parkreldis.2017.09.022. [Epub ahead of print]
Gigante AF, Martino T, Iliceto G, Defazio G.

http://www.prd-journal.com/article/S1353-8020(17)30354-1/fulltext

INTRODUCTION: Several evidence suggest that smoking may decrease the risk of Parkinson's disease and is associated with an older age-at-onset of motor signs. The relation between smoking and age-at-onset of non-motor symptoms has never been analyzed. Objective of the study is to evaluate whether smoking habit and pack-years of smoking are associated with a delay of age-at-onset of motor signs, and of some non-motor symptoms.

METHODS: The study population consisted of 262 consecutive parkinsonian patients. Information on relevant demographic/clinical data focused on motor signs, REM sleep behavior disorder, constipation, depression, and hyposmia. Patients were stratified according to smoking habit (ever-versus never-smoker) and number of pack-years of smoking was computed. Repeatability of data on age-at-onset was checked 6 months after the initial interview in a randomly recruited subsample.

RESULTS: Smoking habit and number of pack-years smoked were associated with an older in age-at-onset of motor signs, REM sleep behavior disorder and depression. By contrast, smoking did not affect age-at-onset of hyposmia and constipation.

CONCLUSION: information from this study confirms that smoking may be associated with an older age-at-onset of motor signs, and that a similar effect can be observed on some non-motor symptoms like REM sleep behavior and depression.