Food for thought

The race is on, and waiting for the start gun is a loser’s strategy!

At least this is true in the race to beat neurodegenerative diseases such as Alzheimer’s disease or Parkinson’s. Many studies to stop or slow these conditions have failed when they recruit people with established disease. By this point the disease-causing proteins (β-amyloid and tau in the case of Alzheimer’s and α-synuclein in the case of Parkinson’s) are too widespread for benefit to be noticeable. The best metaphor I’ve heard is that it is easier to blow out a match than put out a forest fire.

This week sees the open access publication of a nutritional supplement for prodromal Alzheimer’s disease. Participants were recruited if they fulfilled one of the internationally agreed definitions of Prodromal Alzheimers. To do this they needed some memory impairment that wasn’t severe enough to impact on their daily life, and some other evidence of underlying Alzheimer’s. This could be MRI, amyloid-specific PET scans or spinal fluid findings supportive of Alzheimer’s. Participants either drank a nutritional supplement, that has been designed to give large doses of micronutrients that theoretically counteract some of the damage caused by Alzheimers, or a similar tasting placebo drink. They had neuropsychological assessments at 6 months, 1 year and 2 years from the start.

Unfortunately, this study didn’t reach its primary endpoint of improved composite scores of the neuropsychological testing. However, it also had several secondary outcomes, and they did find that the people taking the supplement had a relative preservation of the hippocampal volume on MRI scans after 2 years compared to those taking placebo. The hippocampus is a brain structure that is central to memory, and is usually found to be shrunken in brain scans of people with Alzheimer’s.

So is this study the death knell for the supplement, especially after studies of its effects in people with established disease also failed to meet their primary target? Well, not necessarily. This study used ‘surrogate outcome measures’. The real question in disease preventing trials is: did the intervention prevent the disease? When dealing with a ‘prodromal’ or ‘prediagnostic’ condition, this might take many years. Clinical trials are incredibily expensive and labour intensive to run and so often use surrogate measures to shorten the duration of the study. This is akin to saying “I can run a mile in 5 minutes, therefore I can run a marathon in 2 hours 10 minutes.” This is misleading, as the two are not necessarily compatible enough to know that performance in one test is indicative of the other. Secondly, the fact that there was less shrinking of a key, and relevant, brain structure suggests that there might be some benefit. There are extension studies that are ongoing and data will be published when those are complete. We eagerly await their results.

As a final thought, this study lends strong support to our endeavours at PREDICT-PD, and those of others around the world. There is a strong desire to get a robust method of diagnosing Parkinson’s. This is not just an abstract academic exercise, but is of key concern to the public and pre-diagnostic states are being carefully examined by industry too. It is essential to bring together all three groups of stakeholders if we are to succeed in our fight against these neurodegenerative diseases.

RNR

http://www.thelancet.com/journals/laneur/article/PIIS1474-4422(17)30332-0/fulltext

Soininen H, Solomon A, Visser PJ, Hendrix SB, Blennow K, Kivipelto M, et al. 24-month intervention with a specific multinutrient in people with prodromal Alzheimer's disease (LipiDiDiet): a randomised, double-blind, controlled trial. The Lancet Neurology. 2017 Dec;16(12):965–75. 

BACKGROUND:Nutrition is an important modifiable risk factor in Alzheimer's disease. Previous trials of the multinutrient Fortasyn Connect showed benefits in mild Alzheimer's disease dementia. LipiDiDiet investigated the effects of Fortasyn Connect on cognition and related measures in prodromal Alzheimer's disease. Here, we report the 24-month results of the trial.

METHODS:LipiDiDiet was a 24-month randomised, controlled, double-blind, parallel-group, multicentre trial (11 sites in Finland, Germany, the Netherlands, and Sweden), with optional 12-month double-blind extensions. The trial enrolled individuals with prodromal Alzheimer's disease, defined according to the International Working Group (IWG)-1 criteria. Participants were randomly assigned (1:1) to active product (125 mL once-a-day drink containing Fortasyn Connect) or control product. Randomisation was computer-generated centrally in blocks of four, stratified by site. All study personnel and participants were masked to treatment assignment. The primary endpoint was change in a neuropsychological test battery (NTB) score. Analysis was by modified intention to treat. Safety analyses included all participants who consumed at least one study product dose. This trial is registered with the Dutch Trial Register, number NTR1705.

FINDINGS:Between April 20, 2009, and July 3, 2013, 311 of 382 participants screened were randomly assigned to the active group (n=153) or control group (n=158). Mean change in NTB primary endpoint was -0·028 (SD 0·453) in the active group and -0·108 (0·528) in the control group; estimated mean treatment difference was 0·098 (95% CI -0·041 to 0·237; p=0·166). The decline in the control group was less than the prestudy estimate of -0·4 during 24 months. 66 (21%) participants dropped out of the study. Serious adverse events occurred in 34 (22%) participants in the active group and 30 (19%) in control group (p=0·487), none of which were regarded as related to the study intervention.

INTERPRETATION:The intervention had no significant effect on the NTB primary endpoint over 2 years in prodromal Alzheimer's disease. However, cognitive decline in this population was much lower than expected, rendering the primary endpoint inadequately powered. Group differences on secondary endpoints of disease progression measuring cognition and function and hippocampal atrophy were observed. Further study of nutritional approaches with larger sample sizes, longer duration, or a primary endpoint more sensitive in this pre-dementia population, is needed.

FUNDING:European Commission 7th Framework Programme.

Alzheimers and Parkinsons: More in common than that which divides?

Both have eponymous names and are linked by neurodegeneration with the build up of abnormal protein deposition. However, Parkinsons and Alzheimers are often studied as separate entities due to clinical symptoms and the different types of proteins which build up - amyloid and tau in Alzheimer's and alpha-synuclein in Parkinson's.

With more recognition of cognitive problems in Parkinsons, however, the question of whether these could be partly caused by Alzheimer's-type pathology has intrigued scientists. We know in Lewy Body Disease, there is evidence of amyloid as well as alpha-synuclein pathology. However, many studies and risk scores looking to predict Parkinson's patients who are more prone to dementia have not included these features - for example this risk score looked at clinical features such as age and cognitive score at baseline http://predictpd.blogspot.co.uk/2017/09/predicting-cognition-in-parkinsons.html.

This study, from investigators in Pennsylvania, specifically looked at whether biomarkers associated with Alzheimer's had any bearing on subsequent development of dementia. 100 Parkinson's patients had genetic blood tests and biochemical spinal fluid tests as well as clinical examination. Of 16 biomarkers assessed, 6 were associated with cognitive decline: total daily dose of dopamine, presence of hallucinations, APOE E4 genotype, COMT genotype, lower CSF Aβ levels, and MRI measure of atrophy. APOE genotype (the commonest sporadic Alzheimers risk gene) had the strongest impact.

This is important in the clinic - assessing for hallucinations and monitoring for cognitive decline in these patients. But also highlights the importance of building connections between the Alzheimers and Parkinsons research communities. Most excitingly, it suggests that treatments currently being developed for Alzheimers may have some role in Parkinsons in the future too.

 

-Anna

http://onlinelibrary.wiley.com/doi/10.1002/mds.27204/full

Mov Disord. 2017 Nov 23. doi: 10.1002/mds.27204. [Epub ahead of print]

APOE, thought disorder, and SPARE-AD predict cognitive decline in established Parkinson's disease.

Tropea TF, Xie SX, Rick J, Chahine LM, Dahodwala N, Doshi J, Davatzikos C, Shaw LM, Van Deerlin V, Trojanowski JQ, Weintraub D, Chen-Plotkin AS.

BACKGROUND:

People with PD are at high risk of developing cognitive impairment and dementia. Cross-sectional studies have identified candidate biomarkers associated with cognitive decline. However, longitudinal studies on this topic are rarer, and few have investigated the use of biomarker panels encompassing multiple modalities. The objective of this study was to find baseline predictors of cognitive decline in longitudinally followed, nondemented Parkinson's disease patients.

METHODS:

We performed a prospective cohort study of 100 PD patients with a median disease duration of 6.4 years. All participants were nondemented at baseline. We examined 16 baseline biomarkers from clinical, genetic, biochemical, and MRI-based imaging modalities for their association with longitudinal cognitive decline for up to 8 years. We investigated biomarkers individually, as well as in a multivariate linear mixed-effects model encompassing multimodal biomarkers, with change in the Mattis Dementia Rating Scale-2 over time as the primary outcome. Annual consensus process-derived cognitive diagnosis was used for Cox proportional hazards modeling of risk for cognitive decline.

RESULTS:

In multivariate analysis, the presence of the APOE E4 allele, thought disorder, and an Alzheimer's disease pattern of brain atrophy (spatial pattern of abnormality for recognition of early Alzheimer's disease index) best predicted cognitive decline, with APOE E4 genotype exerting the greatest effect. The presence of the APOE E4 allele was associated with a 3.5 times higher risk of worsening cognitive diagnosis over time (HR, 3.53; 95% CI, 1.52-8.24; P < 0.05). The APOE genotype effect was not specific to any Mattis Dementia Rating Scale-2 domain.

CONCLUSIONS:

Our results confirm the importance of Alzheimer's disease biomarkers as risk factors for cognitive decline in established Parkinson's disease. © 2017 International Parkinson and Movement Disorder Society.

Please put your cancer in the bagging area

The news this morning carries reports of cancer screening units being located in shopping center car parks. This comes from repeat observations that the in UK, too high a number of people have cancer diagnosed in an emergency admission to hospital, where the condition is potentially too late for curative treatment.

By widening access to tests that can accurately and safely pick up cancer, the theory goes that you can then treat it at an earlier stage, with greater chance of cure, fewer potential side effects, and less cost all round. Everyone is a winner.

This is the premise that we at PREDICT-PD, along with many others around the world are working towards in the ‘war on neurodegenerative diseases’ such as Parkinson’s and Alzheimer’s diseases. Disease modifying trials in Alzheimer’s failed to meet their primary end point and one of the lessons that the research community is learning is that established disease may be too late for disease modifying therapies to be effective. This is most likely due to the irreversible buildup of the disease-causing proteins that ‘clog up’ the brain.  

One word of caution in the cancer tale, is the concept of lead-time bias. If a person dies of cancer age 85 and the cancer is picked up at the age of 83, they are said to have survived for 2 years. Now if their cancer is picked up at the age of 80, but despite treatment, they still die at the age of 85, it looks like they have survived over twice as long, yet they haven’t lived any longer! In simple terms, it is a way to make the headlines look better, wihtout changing the story. This is of great relevance in cancers, especially aggressive ones, but in neurodegenerative disease, identifying the pre-diagnostic or prodromal phase, will be vital for trialing new treatments that do change the course of the disease, and put off the time at which the sypmtoms of Parkinson’s or Alzheimer’s impact on the lives of people with the condition, as well as their families.

RNR

For more information:

http://www.telegraph.co.uk/news/2017/11/21/cancer-tests-supermarket-carparks-bid-boost-detection-rates/

James Parkinson Memorial Day at the Royal London Hospital

16th November was used to mark the 200th Anniversary of James Parkinson's Essay on the Shaking Palsy at the Royal London Hospital. Neurologists, geologists, historians, scientists and students were among those that gathered to hear a series of talks that mainly related to the man himself. There have been numerous other events over the course of the year to mark the 200th anniversary of The Essay, but the focus of many of those was the disease and not the man.

We started the day with a walk around Parkinson's London; taking in the sights of Shoreditch and Hoxton. We then gathered in the Bearsted Lecture Theatre on the Whitechapel Campus of Barts and the London Medical School. We heard talks on the history of Neurology at the London; on Mr Parkinson the surgeon apothecary, the geologist, the political activist and the writer; on the disease that bears his name and on the Jewish East End of London. We rounded off the day with a drinks reception in the Garrod Building and then moved to Apothecaries Hall in central London for dinner.

A further formal report will follow and the recorded lectures will be released in due course...

St Leonard's Church, Shoreditch in which James Parkinson was baptised, married and buried.

 Hoxton Square (southern boundary), the site of James Parkinson's house is directly to the left

Parkinsonia parkinsoni, ammonite 

Dinner at the Apothecaries Hall

To D or not to D, that is the question

At medical school we learned about the role that vitamin D has in bone metabolism, including its transformation from a less active form made by the kidneys to the more active form, which requires adequate sunlight on the skin. Low levels would lead to rickets in children, and osteomalacia in adults. Northern climes were associated with fair skin to allow more of the active vitamin D to be made in the ‘weaker’ sunshine, and that between October and March, even the fairest skinned amongst us would be unable to get enough natural sunshine (I was at medical school in Sheffield).

Since then however, there seems to have been some “mission creep”. Vitamin D now has been associated with countless conditions that seem to have nothing to do with calcium and phosphate turnover. Low levels are associated with worse response to TB treatment; vitamin D supplements are given in the community to people with non-specific aches, pains and low levels of depression; low vitamin D increases your risk of stroke and heart attack.

The brain diseases are involved too. People with MS are exhorted to take on extra vitamin D; low vitamin D levels are associated with a higher incidence of dementia. There is clearly much we have to learn about this intruiging compound, and its functions are clearly much more complex than has previously been thought.

What about Parkinson’s disease? There are several ongoing studies of prodromal Parkinson’s disease – research identifying people who have the underlying process that causes PD, but haven’t yet developed the full motor manifestations that are necessary for the clinical diagnosis. PREDICT-PD is one (and although we are partial, we think it's the best one), but the PRIPS study in Europe and the PARS study in North America are also very well designed studies that are reporting key discoveries in the fight against Parkinson’s.

An article this week reported on the levels of vitamin D in participants of the PARS study. The authors compared those thought to be at high risk of PD based on poor smell and abnormal DaT scans (a kind of brain scan that looks at dopamine transporters) and found no differences between the two groups.

At the moment, therefore, there is no justification for recommending taking vitamin D supplements to reduce your risk of PD. On the other hand, as many of our blog posts have highlighted, getting out and about, and doing some exercise in the sunshine, or even taking a nice holiday to escape the brisk British November greyness, might well do you good!

RNR

https://www.ncbi.nlm.nih.gov/pubmed/28984598

J Alzheimers Dis. 2017;60(3):989-997. doi: 10.3233/JAD-170407.

Vitamin D and the Risk of Dementia: The Rotterdam Study.

Licher S^1,2, de Bruijn RFAG², Wolters FJ^1,2, Zillikens MC³, Ikram MA^1,2,4, Ikram MK^1,2.

Author information

Abstract

BACKGROUND:

Vitamin D has gained interest as a potentially modifiable risk factor for dementia because of its putative neuroprotective effects. However, longitudinal studies examining the association between vitamin D and dementia have provided inconsistent results.

OBJECTIVE:

To determine the relationship of serum vitamin D with prevalent and incident dementia in the general population.

METHODS:

Within the prospective Rotterdam Study, we measured serum 25-hydroxyvitamin D concentrations between 1997 and 2001 using electrochemiluminescence-immunoassay in 6220 participants 55 years or older. We assessed dementia at baseline and continuously during follow-up until 1 January 2015. We used appropriate regression models to determine the relationship of vitamin D with prevalent and incident dementia, including Alzheimer's disease (AD). We adjusted models for age, sex, and season of blood collection. Additionally, we adjusted for ethnicity, education, cardiovascular risk factors, serum calcium, kidney function, depression, outdoor-activity and APOEɛ4 carriership.

RESULTS:

At baseline, 127 of 6,220 participants had dementia, of whom 97 had AD. Lower vitamin D concentrations were associated with a non-significantly higher prevalence of dementia (adjusted OR, per SD decrease 1.20, 95% CI 0.95;1.52), but not with AD (adjusted OR: 0.97, 95% CI 0.74;1.29). Among 6,087 non-demented participants with 68,884 person-years of follow-up, 795 participants developed dementia, of whom 641 had AD. Lower vitamin D concentrations were associated with higher risk of dementia (adjusted HR, per SD decrease 1.11, 95% CI 1.02;1.20) and AD (adjusted HR: 1.13, 95% CI 1.03;1.24).

CONCLUSION:

Lower serum vitamin D concentrations are associated with a higher incidence of dementia.