One of the scary things I learned about PD when I was interning with a neurologist was that it seems doctors generally don't know why some people get it and others don't; it seemed kind of random. It might be the case that Michael's PD wasn't caused directly by some unavoidable toxic effect of the amphetamines, but by the fact that he was pushing his brain to work too hard without sleep, and that that was causing him to lose brain cells. It'd be like driving your car around the world without stopping to change the oil; eventually you're going to start causing permanent damage to the car.

Right now we live in a society where a ton of people don't get as much sleep as they should, and it would be pretty big news (I think) if it became known that long-term sleep deprivation was what was causing PD. It'll take a bunch of experimentation to be sure, but even the mere suspicion would be big news.

Here's my thinking:

1. Some big problems in society have been caused by an unnatural environment and had simple solutions

- Scurvy was caused by vitamin C deficiency
- Acne in most people appears to be caused by an unnatural diet

2. It is unnatural to be getting less than 8-9 hours of sleep a night

It seems like there's a good amount of evidence that people used to get more sleep when there weren't any candles or electric lights. See below.

http://en.wikipedia.org/wiki/Segmented_sleep

Segmented sleep, also known as divided sleep, bimodal sleep pattern, or interrupted sleep, is a polyphasic or biphasic sleep pattern where two or more periods of sleep are punctuated by a period of wakefulness. Along with a nap (siesta) in the day, it has been argued that this is the natural pattern of human sleep. A case has been made that maintaining such a sleep pattern may be important in regulating stress.

Historian A. Roger Ekirch (2001,2005) argues that before the Industrial Revolution, segmented sleep was the dominant form of human slumber in Western civilization. He draws evidence from documents from the ancient, medieval, and modern world, which he discovered over the course of fifteen years of research. Other historians, such as Craig Koslofsky,[4] have endorsed Ekirch's discovery and analysis.

BBC - The myth of the eight hour sleep
http://www.bbc.co.uk/news/magazine-16964783

In the early 1990s, psychiatrist Thomas Wehr conducted an experiment in which a group of people were plunged into darkness for 14 hours every day for a month.

It took some time for their sleep to regulate but by the fourth week the subjects had settled into a very distinct sleeping pattern. They slept first for four hours, then woke for one or two hours before falling into a second four-hour sleep.

Though sleep scientists were impressed by the study, among the general public the idea that we must sleep for eight consecutive hours persists.

In 2001, historian Roger Ekirch of Virginia Tech published a seminal paper, drawn from 16 years of research, revealing a wealth of historical evidence that humans used to sleep in two distinct chunks.

His book At Day's Close: Night in Times Past, published four years later, unearths more than 500 references to a segmented sleeping pattern - in diaries, court records, medical books and literature, from Homer's Odyssey to an anthropological account of modern tribes in Nigeria.

Much like the experience of Wehr's subjects, these references describe a first sleep which began about two hours after dusk, followed by waking period of one or two hours and then a second sleep.

A population-based study indicated that, over the past 50 years, sleep duration in adult and adolescent Americans has decreased by 1.5–2 h per night in adults and adolescents, with 30% reporting sleep of 6 h per night or less.

Source: National Health Interview Survey. Morbidity and Mortality Weekly Report, 54 (2005), p. 933
Quote in: 2012 - The impact of sleep deprivation on neuronal and glial signaling pathways important for memory and synaptic plasticity

Check out:
1966 - THE PREVALENCE, NATURAL HISTORY AND DEMENTIA OF PARKINSON'S DISEASE

3. The long-term effects of getting less than 8-9 hours of sleep a night have not been studied, so it's an open question what it's doing to people

4. Amphetamines are drugs associated with pushing your brain to operate without sleep, and they're also associated with causing Parkinson's Disease

If this was the only piece of evidence I was relying on, I'd consider the whole PD-sleep connection to be really flimsy; after all, couldn't the amphetamines be having some kind of toxic effect completely unrelated to its keeping you awake? After all, lots of people take caffeine and 5-Hour Energy, and we haven't heard anything about these people being struck with Parkinson's Disease. But if you consider this connection along with the occupation connection, and consider both of those along with the fact that we're pushing ourselves to go with less sleep than in the past and nobody knows what problems it may be causing, all of those things combined seem to make the sleep-PD hypothesis pretty promising IMO.

Interesting examples:

Adolf Hitler was allegedly a heavy user of amphetamine and/or methamphetamine, and he also suffered from early-onset Parkinson's disease that became severe by the end of the war. In many photos of him you see him with big bags under his eyes, which I interpret as a sign of sleep deprivation.

5. Occupations that seem to correlate with PD seem to also correlate with sleep deprivation.

The literature review below is the most recent review I've seen. It says there are a bunch of problems w/ the existing studies, and not all of the studies' results seem to agree w/ each other and w/ my idea, but some things I noticed multiple studies seemed to find:
- Construction workers have a decreased risk of PD
- Lawyers/medical workers/social workers/teachers are associated with an increased risk of PD

2011.04 - Epidemiology and etiology of Parkinson’s disease: a review of the evidence

Occupational history

Several studies investigated possible associations between a broad range of occupations and PD. A Swedish population-based study [295] reported excess risk among carpenters (OR 6.7, 95% CI 1.76–30) and cleaners (OR 2.8, 95% CI 0.89–8.7, women only). A Canadian hospitalbased case-control study reported that being a teacher, medical worker, forestry, logging, mining or oil field worker, as well as social science or law worker was associated with a increased risk of PD, with the highest risk observed for the category that included forestry, logging, mining or oil field worker (OR 3.79, 95% CI 1.72–8.37) [348]. Further, being a construction worker, management or administration worker, or clerical worker was associated with decreased risk of PD. That teachers and medical workers have an increased risk of PD was not confirmed in a Danish study based on census job codes and hospital discharge PD diagnosis [354]. However, being a paint and wallpaper dealer, psychologist or welfare worker, lawyer, railway and transport worker, or bus driver was associated with increased risk of PD in men. In women, working with laundry and dry-cleaning or cleaning was associated with increased risk. In men, being a construction worker was associated with a decreased risk [354]. In contrast, a US multi-centre study reported increased risk of PD associated with being a construction worker [304]. This study also reported increased risk of PD for legal occupations [304].

Similar to the Canadian [348] and the Danish [354] studies, a US population-based case-control study [345] observed a decreased risk of PD for male construction workers (OR 0.3, 95% CI 0.1–0.7). As in the Canadian study [348], an increased risk was also observed for being a physician(OR 3.7, 95% CI 1.0–13.1) [345]. A case-series study that included more than 2,200 patients with PD or parkinsonism from three movement disorders clinics in New York, Atlanta, and Sunnyvale compared occupational frequencies between patients and the general population [352]. Among patients, more physicians and teachers than expected were observed, but for medical occupations other than physician, fewer cases than expected were observed [352].

A nationwide Swedish study [397] based on census data and hospital discharge PD diagnoses reported that being a teacher, religious, social, or law worker, administrator, sales agent, painter, wall paper hanger, or wood worker was associated with slightly increased risk of PD in men. In women, being an assistant nurse was associated with increased risk [397].

Although there were mutually compatible findings in some of the studies mentioned above, the results overall are not consistent. Methodological limitations include for example use of hospital-based rather than population-based samples that may leave room for selection bias and lack of adjustment for possible confounders, such as smoking and education. Among the occupations with a possible link to PD a few may be associated with environmental exposures, such as organic solvents for painters and wood dust for wood workers. On the other hand, occupations such as teacher, medical worker or administrative worker are not clearly associated with any specific exposure. It has been proposed that the increased risk observed among teachers and medical workers may be due to higher exposure to viral infections in these occupations [348]. The decreased risk observed among construction workers has been hypothesized to be due to higher level of physical activity [345].

Remember: Construction workers are associated with a decreased risk of PD, Lawyers/medical workers/social workers/teachers are associated with an increased risk of PD. With that in mind, look at the recent findings of the top 10 professions w/ the least and most sleep (on average).

2012 - ANALYSIS RANKS MOST SLEEP-DEPRIVED OCCUPATIONS
http://www.sleepys.com/en/info/Analysis ... cupations/
data from National Health Interview Survey (NHIS)

Least sleep:

Home Health Aides
Lawyers
Police Officers
Physicians, Paramedics
Economists
Social Workers
Computer Programmers
Financial Analysts
Plant Operators - similar to miners/oil field workers
Secretaries

Most well rested:

Forest, Logging Workers - this may be a problem for the sleep-PD hypothesis b/c it doesn't agree w/ one of the findings listed above
Hairstylists
Sales Representatives - this may be a problem for the sleep-PD hypothesis b/c it doesn't agree w/ one of the findings listed above
Bartenders
Construction Workers
Athletes
Landscapers
Engineers
Aircraft Pilots
Teachers - this may be a problem for the sleep-PD hypothesis b/c it doesn't agree w/ one of the findings listed above, but other studies say teachers aren't well-rested

One thing to keep in mind is that the sleep data above seem to be based on averages, whereas the risk of PD would not be as determined by the average sleep per profession as the rate of people in the profession who get much less sleep. In other words, if teachers are made up of two extremes, where a bunch of teachers get much less sleep and a bunch of teachers get much more sleep, the average may come out so that it looks like they get more sleep, when in fact there are a larger number of them who are at risk of PD b/c they're not getting much sleep.

a. Teachers have a higher risk of PD and a higher risk of sleep deprivation

Nation's Teachers Battle Sleep Problems
http://health.usnews.com/health-news/fa ... p-problems

The study found that about 43 percent slept an average of six hours or less each night, and 64 percent said they felt drowsy during the school day. Only a third of all school personnel said they got a good night's sleep most of the time.

Source: I got this quote from "2012 - The impact of sleep deprivation on neuronal and glial signaling pathways important for memory and synaptic plasticity"; they were citing National Health Interview Survey, MMWR. Morbidity and Mortality Weekly Report 54 (2005) 933.

6. Misc. Objections and My Responses

from me [I came up w/ this objection]:

If lifetime caffeine intake is associated with a lower risk of PD (or has no association w/ PD), that might disagree w/ the sleep-PD hypothesis.

Response: That's assuming that people who take caffeine are getting less sleep than people who don't take caffeine, though. And it's also assuming that caffeine doesn't have some kind of special protective effect against the negative effects of sleep deprivation.

from me [I came up w/ this objection]:

If smoking is correlated with a reduced risk of PD, and smoking is correlated with short sleep duration, that would seem to be a problem for the sleep-PD hypothesis.

Response: Gotta think about that.

from a psychology professor w/ some knowledge of memory/sleep but no specific expertise in PD:

While sleep deprivation may play a role, I doubt that it could cause PD b/c then you would see a higher rate in populations that are sleep deprived - like shift workers. [later:] I don't know the literature very well, but I know that they have searched for all kinds of triggers. These would be easy to identify in data. Because the cause has been elusive, it is doubtful that there is one cause. You may be right in that sleep is a factor - but is it a cause or a result?

Response:
re: higher rate in sleep-deprived populations - They've done epidemiological studies and it looks like there really is a higher risk in lower-sleep occupations.
re: elusive cause means not likely one cause - I doubt PD is only caused by one thing, but scurvy's cause eluded the world for years even though it had a single simple cause.
re: is sleep a cause or a result of some other underlying factor? - Not sure what this objection means, exactly, yet.

A response from Michael Rae, an associate of Aubrey de Grey

I don't think there's much support for this one ... You've put out that "It is unnatural to be getting less than 8-9 hours of sleep a night" and "The long-term effects of getting less than 8-9 hours of sleep a night have not been studied, so it's an open question what it's doing to people," but (a) if that premise were true, it could be used to support poor sleep being a driver of almost any disease, and more importantly (b) in fact there /are/ quite a few studies on the effects of sleep duration and health: in fact, the relationship between sleep duration many health problems are U-shaped curves, with the lowest risk being associated with somewhat shorter sleeping duration (usually 6-7 hours), with either significantly shorter or longer sleep durations being associated with poorer outcomes. See, for instance, PMID 19645960 for a meta-analyses of prospective studies on diabetes, PMID 21300732 for a single study on cardiovascular outcomes, and PMIDs 19910503 and 20469800 for meta-analyses of total mortality rates, which is a particularly widely-studied relationship.

And contrary to the hypothesis, the sole prospective study I could find on shift work and sleep duration and risk of PD found that "those with 15 years or more of night shift work had a 50% *lower* risk of Parkinson's disease after adjustment for age and smoking (95% confidence interval: 0.26, 0.97; p(trend) = 0.01). Sleep /duration/ was *positively* associated with Parkinson's disease risk: The relative risk was 1.84 (95% confidence interval: 0.99, 3.42) when comparing nurses who reported 9 or more hours of sleep per day with those who slept 6 hours or less (p(trend) = 0.005). These data suggest that working night shifts may be protective against Parkinson's disease or that low tolerance for night shift work is an early marker of Parkinson's disease. Conversely, habitual longer sleep duration may be an earlier marker of Parkinson's disease. " (PMID: 16495472). Closely related is PMID 21402730: "Longer daytime napping was associated with higher odds of Parkinson disease at all 3 clinical stages: the odds ratios comparing long nappers (>1 hour/day) with nonnappers were ... 1.5 (95% confidence interval: 1.2, 1.9) for prediagnostic [ie, semi-prospective] cases. Further control for health status or nighttime sleeping duration [which latter might indicate that the napping was catchup for lack of nighttime sleep] ... made little difference for recent or *prediagnostic* cases [the group of interest]. In the nighttime sleeping analysis, a clear *U-shaped association* with Parkinson disease was observed for established cases; however, this association was attenuated markedly for recent cases and disappeared for prediagnostic cases. This study supports the notion that daytime sleepiness, but not nighttime sleeping duration, is one of the early nonmotor symptoms of Parkinson disease. " In fact, if you look at their Figure 2 <http://aje.oxfordjournals.org/content/173/9/1032/F2.expansion.html> , the semi-prospective relationship (ie, the risk that people without clinical PD will go on to develop it, which is the cohort of interest for the hypothesis) is if anything most suggestive of a *reduced* risk in people getting <5 h of sleep a night and *increased* risk in people sleeping >9 h, consistent with the finding from the Nurses' Health Study op cit.

Moreover, mechanistically, there is some evidence that melatonin antagonism may be protective -- at least it seems to be in animal models (PMID 10405106). As you may know, melatonin is a sleep-promoting hormone that plays a significant role in establishing circadian rhythms.

Also, you note that "Amphetamines are drugs associated with pushing your brain to operate without sleep, and they're also associated with causing Parkinson's Disease," but as noted above there doesn't actually seem to be *much* evidence of this yet in humans -- and if there is, there are clearer mechanistic explanations for it than sleep deprivation (amphetamines primarily work by stimulating dopaminergic neurons, which are lost in PD and which loss is responsible for the classic motor symptoms). Per contra, you argue (contra the objection that "If lifetime caffeine intake is associated with a lower risk of PD (or has no association w/ PD), that might disagree w/ the sleep-PD hypothesis") that "That's assuming that people who take caffeine are getting less sleep than people who don't take caffeine, though. And it's also assuming that caffeine doesn't have some kind of special protective effect against the negative effects of sleep deprivation." I agree with your second counterargument, but the first isn't just an assumption: caffeine use is known to cause insomnia <http://www.mayoclinic.org/healthy-living/nutrition-and-healthy-eating/in-depth/caffeine/art-20045678> and also alters sleep patterns for the worse <http://healthpsych.psy.vanderbilt.edu/2009/CaffeineSleep.htm> ; <http://dx.doi.org/10.5664/jcsm.3170> finds that caffeine disturbs sleep for at least 6 hours prior to habitual bedtime relative to a placebo, and that it does so even when subjects report no sleep disturbance.

My Thoughts on Various Topics

Sleep Deprivation May Be a Factor in Developing Parkinson's Disease