Give us a clue

Bryan unravels some of the mysteries associated with one
of our greatest modern foes – neurological conditions

Imagine for a moment that you are the legendary deerstalker-hatted deductionist, apiarist, violinist and polymath, Sherlock Holmes.

No detail, however small or seemingly irrelevant, escapes your notice or analysis.

You have always prided yourself on the razor-sharpness and astuteness of your perception, so honed as to be a new way of seeing the world, the comprehensiveness of your knowledge, and the singularity of your genius, respected everywhere, which neatly sums up people, motivations and situations immediately in the time it takes to snap two fingers.

No man – or woman – not even so great an adversary as Moriarty, a criminal mastermind par extraordinaire and almost your mental equal, has ever managed to best you. Not really, anyway. Not when you, a master chess player, are always at least 50 steps ahead.

What is prohibitively complicated for others like your 221B Baker Street flat mate and amanuensis, Doctor Watson, strikes you most often as, well, elementary. The machinations of common criminals are to you as transparent as glass, and as easily foiled.

Like the bees that so fascinate you, your manic mind is always buzzing, alighting on one flower of an idea after another, and sipping from the nectar of intuition to make seemingly disparate connections where none was evident before – at least to mere mental mortals.

To energise your cerebral gymnastics and to stave off sleep you turn to psychostimulants such as cocaine and methamphetamine (meth).

In the end, it is these psychostimulants and the resulting circadian rhythm disruption, not the perfidious Moriarty, not the treacherous Reichenbach Falls and not the savage Hound of the Baskervilles, which are your downfall because of the neurotoxicity and neuroinflammation that they induce.

The equivalent of hemlock to a Sherlock is ‘neurodegenerative disorders (NDs)’. These NDs refer to a broad category of illnesses marked by the gradual degradation of neurones with cognitive, motor and behavioural dysfunction as the main symptoms.

Under the umbrella of neurodegenerative diseases are Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD) and amyotrophic lateral sclerosis (ALS)/motor neurone disease (MND).

If NDs have a common denominator it is ‘bad for brain’ neuroinflammation. Inflammatory responses in the brain and spinal cord are generally called ‘neuroinflammatory’.

This article identifies five potentially modifiable risk factors, or clues as Sherlock might refer to them, for neuroinflammation, which may, by extension, if they are properly addressed, reduce the global burden of NDs.

Clue #1: Physical inactivity
Unlike in Sherlock Holmes’ day, a modern lifestyle lends itself to sedentarism at work, at school and at home with technological inventions like computers and smart phones, washing machines, dryers, and cars that reduce or obviate the need for muscular activity and that predispose to the development of chronic diseases like NDs.

Exercise is a virtual panacea for both physical and cognitive function whose myriad benefits have been recognised since Grecian times.

In the central nervous system (CNS), exercise induces the release of neurotransmitters, neurotrophic factors – these are proteins that support the growth and survival of neurones – and stimulates neurogenesis i.e., the growth of new neurones and neuroplasticity or the rewiring and strengthening of the connections between neurones.

Clue #2: Gut dysbiosis
A persistent imbalance of the gut’s microbial community is called dysbiosis, which involves a loss of beneficial microbes, microbial diversity and the appearance of harmful bacteria.

Western diets that are high in red meat, saturated and trans fats, refined sugars and carbohydrates, and low in fiber, antibiotic use, infections and stress contribute to dysbiosis.

In the CNS, gut dysbiosis is linked to neuroinflammation, and the development of neurodegenerative diseases, and bipolar disorder.

Recently, intermittent fasting (IF) and ketogenic diets (KD) have been shown to positively impact the composition and function of the gut microbiota.

Clue #3: 7% solution
In the second Sherlock Holmes novel called The Sign of Four, published in 1890, Holmes rolls up his sleeve and gives himself an injection.

“It is cocaine”, he tells Dr Watson, “a seven-per-cent solution”. Cocaine is a psychostimulant that acts on the CNS through the dopaminergic system.

It blocks the dopamine transporter (DAT), which increases the extracellular concentration of dopamine (DA), and elicits a neuroinflammatory response that may ultimately predispose to and/or accelerate the development of neurodegenerative diseases.

Other drugs of abuse that are associated with the development of neurodegenerative diseases include alcohol and methamphetamines.

Clue # 4: Disrupted sleep
Individuals with neurodegenerative diseases, and psychiatric disorders like depression and anxiety are known to experience sleep disorders.

However, this is perhaps a chicken-and-egg scenario since while these conditions can induce a sleep disorder, a sleep disorder can also contribute to CNS dysfunction. Sleep loss and disrupted sleep are associated with acute and chronic neuroinflammation that may underlie neurodegenerative and psychiatric disorders.

Clue # 5: Heavy metal and pesticide exposure
Exposure to heavy metals such as iron (Fe), copper (Cu), manganese (Mn), chromium (Cr), aluminium (Al), cadmium (Cd) and mercury (Hg) as well as to pesticides like paraquat and rotenone are linked to the development of neurodegenerative and psychiatric diseases, with neuroinflammation as a common underlying mechanism that induces neurotoxicity.

Sir Arthur Conan Doyle, who created the enduring legend of detective Sherlock Holmes in the late 1800s, was a British physician who based the character on a keenly observant surgeon, Doctor Joseph Bell.

With the benefit of hindsight, it is possible to speculate that Sir Arthur Conan Doyle would have eliminated, or at the very least tempered, Holmes’ blithe cocainism given its possible links to neuroinflammation and neurodegeneration.

This is especially notable since Holmes only takes the drug, not for hedonistic reasons, but to optimise his creativity, industry and intelligence.

Surely one so dedicated and monomaniacal as Holmes to the craft of detection would find it anathema to learn that the compulsive use of cocaine was possibly responsible for the murder of a mind – his own.

The slow-paced 2015 movie, Mr Holmes, adapted from a 2005 novel, portrays the eponymous sleuth (Ian McKellen) as a 93-year-old man on the trail of a decades-old cold case whilst in the throes of dementia.

As touched on above, modifiable lifestyle factors to minimize the detrimental effects of neuroinflammation and, by extension, neurodegenerative diseases include diet, exercise, abstention from drug use, minimisation of heavy metal and pesticide exposure, and quality sleep.

Of all these lifestyle factors, exercise is particularly associated with multi-organ benefits including expanded peripheral blood circulation, increased cardiac output, improved vascular elasticity, augmented bone and muscular strength, higher quality of pancreatic beta-cells, decreased intrahepatic storage of fat, improved composition of the gut microbiome, and better brain plasticity and function.

It may sound somewhat far-fetched to claim that one single intervention, exercise, could produce such widely distributed benefits but the fact is that many well-conducted studies support this conclusion and, as Holmes himself famously said: “When you have eliminated all which is impossible, then whatever remains, however improbable, must be the truth”. 

Bryan Oronsky is Chief Medical Officer at EpicentRx. Go to epicentrx.com