On dopamine and depression

                                                 How true is this in Parkinson's???

We are learning ever more about the manifestations of non-motor symptoms in Parkinson's Disease and their presence from even before diagnosis. It's fair to say that for many patients, it's actually the non-motor symptoms rather than the motor symptoms that cause much of the burden of the disease. To effectively target these symptoms it's vital that we understand the underlying cause. 

Neuropsychiatric symptoms (e.g. depression, anxiety, hallucinations) have been assumed to be directly linked with dopamine dysregulation - the same process leading to movement problems.  It makes sense - dopamine regulating drugs can be an effective treatment for people with schizophrenia so dopamine is already implicated in neuropsychiatric symptoms. 

However, there are other potentially blame-worthy processes going on in the course of Parkinson's Disease and teasing out their contributions is the aim of this paper, from a team based in South Korea. The authors looked at a group of newly diagnosed Parkinson's patients who were assessed clinically for neuropsychiatric symptoms then had PET scans specific for the dopamine activity and MRI to look more globally at brain atrophy. 

The first important finding was that a high proportion, almost 60% of patients, had at least one neuropsychiatric symptom. The imaging results paint an intriguing picture, with thinning (neuronal loss) in specific areas being linked to specific symptoms - for example temporal lobe atrophy was associated with aggression/agitation. Dopamine activity, on the other hand, was not linked with any of the symptoms.

There are some issues with the kind of exploratory analysis in this study - when a lot of comparisons are made it is likely that, by chance, there will be some positive results. It is also important to consider that there are likely links between the different neuropsychiatric symptoms that mean they can't be considered independently of each other. But I think it's an important reminder that, just as Parkinson's is more than just a movement problem, it's underlying cause is more than a dopamine problem.  

-Anna

https://www.ncbi.nlm.nih.gov/pubmed/28951497

J Neurol Neurosurg Psychiatry. 2017 Sep 26. pii: jnnp-2017-316075. doi: 10.1136/jnnp-2017-316075. [Epub ahead of print]

Effects of dopaminergic depletion and brain atrophy on neuropsychiatric symptoms in de novo Parkinson's disease.

Ye BS, Jeon S, Yoon S, Kang SW, Baik K, Lee Y, Chung SJ, Oh JS, Moon H, Kim JS, Lee PH, Sohn YH.

Abstract

BACKGROUND:

Neuropsychiatric symptoms impact the patients' quality of life and caregivers' burdens in Parkinson's disease (PD). We aimed to investigate the effects of striatal dopaminergic depletion and brain atrophy on the neuropsychiatric symptoms of patients with PD.

METHODS:

Two hundred and seven patients with de novo drug-naïve PD underwent dopamine transporter (DAT) positron emission tomography and brain MRI scanning. In addition, the patients were assessed with caregiver-administered neuropsychiatric inventory (NPI) questionnaires. To evaluate the effects of DAT uptake, subcortical volume and cortical thinning on the patients' neuropsychiatric symptoms, we performed logistic regression and negative binomial regression analyses on the NPI data after controlling for possible confounders.

RESULTS:

Frontal cortical thinning was associated with the presence of nighttime behaviour and irritability, and the thinning correlated with the severity of the nighttime behaviour. Temporal cortical thinning was associated with the presence of aggression/agitation, and it correlated with the severity of the aggression/agitation. Subcortical atrophy in the accumbens was associated with the presence of disinhibition and correlated with the severity of the disinhibition. Putamen atrophy and insular thinning were independently associated with the presence of apathy, but only insular thinning correlated with the severity of the apathy. Of the predictors, only frontal cortical thinning correlated with the total NPI score.

CONCLUSIONS:

The results of this study suggested that accumbens atrophy and frontotemporal cortical thinning, especially frontal cortical thinning, independently contributed to neuropsychiatric symptoms in patients with PD, while DAT uptake did not affect the neuropsychiatric symptoms.

Brain Training

If the first maxim of a doctor is “First do no harm”, a close runner up should be “Use only treatments that work”. The bookshops and app-stores are full of brain training methods. For the most part, these are not evidence based and while entertaining, are unlikely to be the reason why someone is awarded a Nobel prize.

Targeted cognitive training however is perhaps a different kettle of fish. This study assessed the effects of a multi-domain cognitive training regime over three months, and then the residual effects after 18 months. Participants underwent a series of cognitive and behavioural tasks at each assessment. Some of the participants then went on to have MRI imaging at the later time point to see the effects.

The authors report increased cognitive function in several (alhtough not all) domains that was preserved even after a delay despite there overall Parkinson’s condition getting worse.

The imaging findings they report are very hard to interpret. In an earlier report of this study, 44 participants were randomised to either the REHACOP cognitive training programme that formed the intervention, and 19 were randomised to occupational therapy as a control. There was a high drop out rate (7/22 in the intervention group, 4/19 in the control group) which creates a high risk of bias. In this paper, only the participants in the brain training group had repeat imaging at 18 months. Therefore, the findings do not compare the intervention and controls, but just the intervention group to themselves 15 months later. Furthermore, the two of the authors hold copyright for the training programme, and this could create a financial conflict of interest.

While I hope that there can be evidence based treatments that can improve the thinking and behaviour of people with Parkinson’s disease, I think this paper has some significant issues such that it doesn’t provide the evidence that would make me change my practice.  

The search continues

http://rdcu.be/wdRA/

DOI: 10.1111/ene.13472

Long-term effects of cognitive rehabilitation on brain, functional outcome and cognition in Parkinson's disease

Abstract

Background

Cognitive rehabilitation has demonstrated efficacy in producing short-term cognitive and brain changes in Parkinson's disease (PD) patients. To date, no study has assessed the long-term effects of cognitive rehabilitation using neuroimaging techniques in PD. The aim was to assess the longitudinal effects of a 3-month cognitive rehabilitation program evaluating the cognitive, behavioural and neuroimaging changes after 18 months.

Methods

Fifteen PD patients underwent a cognitive, behavioural and neuroimaging assessment at pre-treatment (T₀), post-treatment (T₁) and after 18-months (T₂). This study examined the long-term effects (from T₀ to T₂) and the maintenance of the changes (from T₁ to T₂). T1-weighted, diffusion-weighted, functional magnetic resonance imaging (fMRI) during both a resting-state and a memory paradigm were acquired. Voxel-based-morphometry and tract-based-spatial-statistics were used for grey and white matter analyses. A ROI-to-ROI approach was used for resting-state functional connectivity (FC), and model-based for brain activation during the memory paradigm.

Results

PD patients showed increased cognitive performance, decreased functional disability, increased brain FC and activation at T₂ compared with T₀ (p<.05-FDR). Moreover, patients showed the maintenance of the improvements in cognition and functionality and the maintenance of the increased brain FC and activation at T₂ compared with T₁. However, significant grey matter reduction and alterations of white matter integrity were found at T₂ (p<.05-FWE).

Conclusions

Findings suggest that the improved cognitive performance and the increased brain FC and activation after cognitive rehabilitation were significantly maintained after 18 months in PD patients, despite the structural brain changes, consistent with a progression of neurodegenerative processes.

Global, regional, and national burden of neurological disorders during 1990-2015: a systematic analysis for the Global Burden of Disease Study 2015

Very timely systematic analysis of neurological diseases from the Global Burden of Disease (GBD) study... important take home messages are the clear increased burden of neurological diseases despite decreases in death from communicable disease (or infectious diseases) and stroke... I have shown slides for a number of years from a previous paper from the GBD study which suggested Parkinson's was on the increase even after the effects of an ageing global population were taken into account. This report supports this notion. Alzheimer's and other dementias increased in prevalence over 25 years (1990 to 2015), but after the effect of ageing was taken into account the increased burden was less dramatic. Parkinson's is clearly on the up however and we need to be doing much more to prevent its further rise....

Lancet Neurol. 2017 Sep 15. pii: S1474-4422(17)30299-5. doi: 10.1016/S1474-4422(17)30299-5. [Epub ahead of print]
GBD 2015 Neurological Disorders Collaborator Group

http://www.sciencedirect.com/science/article/pii/S1474442217302995?via%3Dihub

BACKGROUND: Comparable data on the global and country-specific burden of neurological disorders and their trends are crucial for health-care planning and resource allocation. The Global Burden of Diseases, Injuries, and Risk Factors (GBD) Study provides such information but does not routinely aggregate results that are of interest to clinicians specialising in neurological conditions. In this systematic analysis, we quantified the global disease burden due to neurological disorders in 2015 and its relationship with country development level.

METHODS: We estimated global and country-specific prevalence, mortality, disability-adjusted life-years (DALYs), years of life lost (YLLs), and years lived with disability (YLDs) for various neurological disorders that in the GBD classification have been previously spread across multiple disease groupings. The more inclusive grouping of neurological disorders included stroke, meningitis, encephalitis, tetanus, Alzheimer's disease and other dementias, Parkinson's disease, epilepsy, multiple sclerosis, motor neuron disease, migraine, tension-type headache, medication overuse headache, brain and nervous system cancers, and a residual category of other neurological disorders. We also analysed results based on the Socio-demographic Index (SDI), a compound measure of income per capita, education, and fertility, to identify patterns associated with development and how countries fare against expected outcomes relative to their level of development.

FINDINGS: Neurological disorders ranked as the leading cause group of DALYs in 2015 (250·7 [95% uncertainty interval (UI) 229·1 to 274·7] million, comprising 10·2% of global DALYs) and the second-leading cause group of deaths (9·4 [9·1 to 9·7] million], comprising 16·8% of global deaths). The most prevalent neurological disorders were tension-type headache (1505·9 [UI 1337·3 to 1681·6 million cases]), migraine (958·8 [872·1 to 1055·6] million), medication overuse headache (58·5 [50·8 to 67·4 million]), and Alzheimer's disease and other dementias (46·0 [40·2 to 52·7 million]). Between 1990 and 2015, the number of deaths from neurological disorders increased by 36·7%, and the number of DALYs by 7·4%. These increases occurred despite decreases in age-standardised rates of death and DALYs of 26·1% and 29·7%, respectively; stroke and communicable neurological disorders were responsible for most of these decreases. Communicable neurological disorders were the largest cause of DALYs in countries with low SDI. Stroke rates were highest at middle levels of SDI and lowest at the highest SDI. Most of the changes in DALY rates of neurological disorders with development were driven by changes in YLLs.

INTERPRETATION: Neurological disorders are an important cause of disability and death worldwide. Globally, the burden of neurological disorders has increased substantially over the past 25 years because of expanding population numbers and ageing, despite substantial decreases in mortality rates from stroke and communicable neurological disorders. The number of patients who will need care by clinicians with expertise in neurological conditions will continue to grow in coming decades. Policy makers and health-care providers should be aware of these trends to provide adequate services.

FUNDING: Bill & Melinda Gates Foundation.

Such stuff as dreams are made?

Sleep seems to play an interesting role in neurodegenerative disease.  Sleep is important in many metabolic functions and there is some evidence to suggest that disruptions in sleep affect brain protein metabolism. As an example, amyloid beta is released at higher levels during wakefulness - so those who sleep less will be exposed to higher levels of the protein. Another aspect of interest is whether sleep disruption acts as a marker for early neurodegenerative disease, giving an early indication of the build up of abnormal proteins that characterise neurodegenerative disease.


So, disrupted sleep may be a cause or effect of neurodegenerative disease (and it's almost certainly a bidirectional relationship). But wouldn't it be nice if, rather than an expensive immunological treatment, we could prescribe sleep for our patients?


To tease out this relationship, investigators in the US have utilised the large community-based Framingham Heart Study. A sub-group of these participants had extensive sleep investigations and were followed up for dementia for up to 19 years afterwards. They were able to look at different stages of sleep and they found that less REM sleep, which tends to occur in the later stages of the night and is associated with dreaming, was associated with development of all types of dementia.  


As ever, there are difficulties with implying causality with this kind of observational study - whilst the authors controlled for multiple factors known to be associated with dementia risk there are likely to be other confounders - for example anxiety levels were not controlled for in this analysis. It will also be important to understand the role played by sleep disorders such as obstructive sleep apnoea and REM sleep behaviour disorder, which we are exploring in PREDICT.


Having said that, I for one will be using this as an excuse to get my full 8 hours..


https://www.ncbi.nlm.nih.gov/pubmed/28835407

Sleep architecture and the risk of incident dementia in the community.

Neurology. 2017 Sep 19;89(12):1244-1250. doi: 10.1212/WNL.0000000000004373. Epub 2017 Aug 23.

Pase MP, Himali JJ, Grima NA, Beiser AS, Satizabal CL, Aparicio HJ, Thomas RJ, Gottlieb DJ, Auerbach SH, Seshadri S

OBJECTIVE:

Sleep disturbance is common in dementia, although it is unclear whether differences in sleep architecture precede dementia onset. We examined the associations between sleep architecture and the prospective risk of incident dementia in the community-based Framingham Heart Study (FHS).

METHODS:

Our sample comprised a subset of 321 FHS Offspring participants who participated in the Sleep Heart Health Study between 1995 and 1998 and who were aged over 60 years at the time of sleep assessment (mean age 67 ± 5 years, 50% male). Stages of sleep were quantified using home-based polysomnography. Participants were followed for a maximum of 19 years for incident dementia (mean follow-up 12 ± 5 years).

RESULTS:

We observed 32 cases of incident dementia; 24 were consistent with Alzheimer disease dementia. After adjustments for age and sex, lower REM sleep percentage and longer REM sleep latency were both associated with a higher risk of incident dementia. Each percentage reduction in REM sleep was associated with approximately a 9% increase in the risk of incident dementia (hazard ratio 0.91; 95% confidence interval 0.86, 0.97). The magnitude of association between REM sleep percentage and dementia was similar following adjustments for multiple covariates including vascular risk factors, depressive symptoms, and medication use, following exclusions for persons with mild cognitive impairment at baseline and following exclusions for early converters to dementia. Stages of non-REM sleep were not associated with dementia risk.

CONCLUSIONS:

Despite contemporary interest in slow-wave sleep and dementia pathology, our findings implicate REM sleep mechanisms as predictors of clinical dementia.

e-Doc

An article published in the journal Neurology last week confirms that James Parkinson’s legacy has been well and truly digitised.

Researchers in the USA completed a randomised controlled trial of tele-medicine for Parkinson’s disease. Tele-medicine is where the patient and physician are not face to face in a consulting room, but using technology similar to Skype or Facetime to have a consultation at the mutual convenience of both parties. The study showed that it is possible for physicians not only to listen to the patient’s problems, but also to examine them (using internationally recognised Parkinson’s specific examinations), and recommend medication changes that are then prescribed by the local GP.

Although quality of life for the patient and care giver was not better in the tele-medicine group compared to the face-to-face group, it did not get worse either. The telemedicine group felt they had excellent rapport with their ‘eDoc’, and it saved them a huge amount of time (and therefore money) by not having to travel to a regional neuroscience centre.

Although the UK and US are geographically very different, we do have some equivalent problems on this side of the pond. The Neurological Alliance has reported that the lack of neurologists is a major problem for people in the UK with neurological problems. Movement disorder specialists tend to be found only in regional referral hospitals. People with Parkinson’s in both countries have much greater difficulty than most patients in getting to appointments, particularly as the condition progresses.

This paper is also of particular relevance to the PREDICT-PD team. It shows that there is a very large desire and abillity of people with Parkinson’s to engage with online research. We will be recruiting 10,000 people from 60-80 to take part in PREDICT-PD. The researchers in this study were overwealmed by potential participants and even head to turn away almost 1 in 5 participants.

Important things for these researchers, and us too though, is that there is a potential bias due to the “digital divide” – the participants in this study were mainly white, well educated and willing and able to work online. We mustn’t leave behind people that don’t fit this mould.

http://www.neurology.org/content/89/11/1152.full.pdf+html

National randomized controlled trial of virtual house calls for Parkinson disease

Objective: To determine whether providing remote neurologic care into the homes of people with Parkinson disease (PD) is feasible, beneficial, and valuable.

Methods: In a 1-year randomized controlled trial, we compared usual care to usual care supplemented by 4 virtual visits via video conferencing from a remote specialist into patients' homes. Primary outcome measures were feasibility, as measured by the proportion who completed at least one virtual visit and the proportion of virtual visits completed on time; and efficacy, as measured by the change in the Parkinson's Disease Questionnaire–39, a quality of life scale. Secondary outcomes included quality of care, caregiver burden, and time and travel savings.

Results: A total of 927 individuals indicated interest, 210 were enrolled, and 195 were randomized. Participants had recently seen a specialist (73%) and were largely college-educated (73%) and white (96%). Ninety-five (98% of the intervention group) completed at least one virtual visit, and 91% of 388 virtual visits were completed. Quality of life did not improve in those receiving virtual house calls (0.3 points worse on a 100-point scale; 95% confidence interval [CI] −2.0 to 2.7 points; p = 0.78) nor did quality of care or caregiver burden. Each virtual house call saved patients a median of 88 minutes (95% CI 70–120; p < 0.0001) and 38 miles per visit (95% CI 36–56; p < 0.0001).

Conclusions: Providing remote neurologic care directly into the homes of people with PD was feasible and was neither more nor less efficacious than usual in-person care. Virtual house calls generated great interest and provided substantial convenience.

ClinicalTrials.gov identifier: NCT02038959.

Classification of evidence: This study provides Class III evidence that for patients with PD, virtual house calls from a neurologist are feasible and do not significantly change quality of life compared to in-person visits. The study is rated Class III because it was not possible to mask patients to visit type.