About neuroscience and music (mainly classical). Exploring the relationship of music and the brain based on experience of two careers.

October 11, 2017

Have you Lost Your Sense of Smell?

I still can’t get my mind around the fact that a mysterious agent, whatever it is (or they are), that can cause Parkinson’s Disease (PD) probably enters the body through the nose or the mouth. It, or its evil effect, travel to the brain through the olfactory or the vagus nerves, the former from the nose, the latter from the gut! 

That initially outrageous idea reminds me of a similar drama decades ago when we all knew for sure that stomach ulcers were caused by stress and too much acid. We were shocked when courageous researchers steadfastly asserted that helicobacter pylori, a typical bacterial resident in the stomach usually minding its own business, could occasionally go berserk and dig a hole. Now we add antibiotics to our treatment regimen for ulcers!

A PD agent is probably not a bacterium, virus, or even a tiny newly-discovered prion, but it could behave like H pylori. Or like a zebra mussel, living a quiet peaceful life in lakes in another continent only to become aggressive and devour all its neighbors when introduced into the apparently nurturing environment of the American Great Lakes. (Dr. Siddhartha Mukherjee just used that analogy to try to understand the behavior of some metastatic cancers in last week's New Yorker.) Perhaps certain people are destined for Parkinson's because they unknowingly provide a similar favorable environment for mysterious agents that may be ubiquitous and harmless for most other people.

A recent editorial in NEUROLOGY reminded me that although loss of the sense of smell becomes increasingly likely as we age (isn't aging a relentless wearing-out process?) a substantial (but yet unspecified) proportion of people with hyposmia (reduced) or anosmia (absent) develop Parkinson's, or some form of dementia, possibly including Alzheimer's. My father lost his smell years before symptoms of his dementia appeared in his late '80's. As I pointed out in a previous post, loss of hearing too is not necessarily a 'normal' or inevitable part of aging.

Detecting the earliest evidence of Parkinson's disease among healthy patients could help us test and develop methods to prevent or slow future progression to the typical disabling features of the condition, such as impairment of walking, moving, thinking, and speaking, and tremor, before those symptoms appear when the loss of the critical dopaminergic neurons in the midbrain is complete. According to one hypothesis (Braak), the process usually starts low in the brainstem and very slowly marches upward over years. When it reaches the cerebrum, if you are still alive, the 'late' complication of dementia may ensue 

Degeneration of the olfactory bulb (a tassel-like structure attached to the bottom of the brain just above the nasal cavity) is a common cause of impaired sense of smell and may provide the earliest clue to future PD. The bulb rests upon a thin fragile plate of bone punctured by tiny holes, the lamina cribrosa, through which wire-like nerve fibers (axons) transmit olfactory signals from 6–10 million smell receptors in the nose. 

The olfactory nerves are also called the first cranial nerve (the second transmit vision and the eighth bring sound into the brain); transmit signals gathered by the receptors from the bulb to the brain. (All cranial nerves are paired, one on each side.)

Once an odorant enters the nose, it interacts with the receptors located on the surface of the olfactory cilia and a chemical reaction generates a crescendo of action potentials (signals) in the olfactory nerve. These signals project to higher brain regions involved in conscious thought processes and the limbic system, generating the emotional, motivational, and memory context. 

Approximately 1,000 of human genes participate in recognizing odors. Thus, we can distinguish 4,000–10,000 distinct odor molecules, a scientific discovery that earned a Nobel Prize in 2004. 

Olfactory dysfunction impairs the satisfaction gained from foods and inhibits the detection of environmental hazards (e.g., toxins, fire, spoiled foods, and natural gas leaks). Diminished olfactory inputs also dampen the initial phase of digestion responsible for stimulating exocrine secretions in the mouth, stomach, the secretions that facilitate the absorption and assimilation of micronutrients and fatty acids and contribute to the nature of the microbiome in the host by governing the gut pH.

The prevalence of all-cause hyposmia in the US adult population is discouragingly high: between 13.5% and 24.5%, and increases incrementally with age (17.3% of 60- to 69-year-olds, 29.2% of 70- to 79-year-olds, and 62.5% of 80- to 97-year-olds). Men and African Americans have the highest prevalence of hyposmia. Only 9% of adults actually report a loss in their sense of smell, an observation that suggests a substantial number of cases go undetected (and that a substantial number of people old enough to afford wine judge its quality only by the price of the bottle).

Ninety percent of people with sporadic (not familial) PD, have olfactory dysfunction. In addition, 4 prospective studies have shown that olfactory dysfunction is a risk factor for PD, but the conclusions drawn are almost exclusively from white and Asian populations with less than 5 years of follow-up. It turns out that African Americans have a higher rate of olfactory dysfunction but a lower risk that it will cause PD.

One underlying mechanism behind olfactory dysfunction in PD is the spreading and accumulation of Lewy bodies, enriched with intracytoplasmic inclusions of α-synuclein that arise from peripheral inputs at the olfactory epithelium or the dorsal motor nucleus of the vagus nerve emerging from the stomach.

If you read this and know, or discover, or suspect, that you have impaired sense of smell, don't panic. Among those percentage ranges above, the data does not allow us to separate those with a risk of any neurologic disease, though one can suspect that  the risk is greater if you fall into one of the younger age groups. It is important to be aware of the problem, in case preventive therapy emerges, and to rule out common non-neurologic causes, such as a lifetime of repeated or chronic upper respiratory infections. 

Most doctors, even neurologists, don't test for hyp- or anosmia and that's a shame. The first step in a test would be to ask a simple question: "How is your sense of smell?" If the answer is not "great," then simple office tests, like The Brief Smell Identification Test (BSIT), can quickly and accurately detect and roughly quantitate the degree, just as an audiogram or vision test does.

As of today, we don't have any treatment that will prevent Parkinson's but it is only a matter of time until we do. That might prove to be an active therapy or strict avoidance of a possible multitude of agents -- in the air or food -- that may be a cause. Scott Pruitt and his EPA are now probably going to provide us with more cases for study.

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