From: olivercranglejr@gmail.com   
      
   The Scientist » Magazine » Features   
      
   Smell and the Degenerating Brain   
   An impaired sense of smell is one of the earliest symptoms of Alzheimer’s,   
   Parkinson’s, and some other neurodegenerative diseases. Could it be a useful   
   diagnostic tool?   
      
   By Richard L. Doty | October 1, 2013   
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   © SILVIA OTTE/GETTY IMAGES   
      
   James Black, a 62-year-old London taxi cab driver, went to his doctor   
   complaining of memory difficulties and intermittent periods of confusion that   
   he’d been experiencing for 2 years. A minor road accident caused by poor   
   concentration and vision    
   problems had forced him to retire. His wife reported that for more than a   
   decade James had also experienced difficulty smelling—a condition, called   
   hyposmia, that was confirmed by olfactory testing. His neurological   
   examination revealed he was    
   suffering from damage to the brain’s frontal lobe. Ultimately, James was   
   diagnosed with Alzheimer’s disease (AD), the most common dementia-causing   
   disorder.1   
      
      
   OLFACTORY DIAGNOSIS: Patients with Parkinson’s disease (PD; bottom row) have   
   fewer dopamine tranporters (labeled with radioactive ligands in brain scans on   
   right) than healthy controls (top row). Because PD patients have associated   
   olfactory loss,    
   smell testing can help diagnosticians differentiate between PD and other   
   neurodegenerative diseases that also show a decline in brain dopamine   
   receptors.   
   COURTESY OF JACOB DUBROFF   
   James’s situation is far from unique. Olfactory loss is not only an early   
   warning sign of AD, but also of Parkinson’s disease (PD) and some other   
   neurological disorders, presenting long before their classic clinical   
   symptoms. Once such symptoms    
   become evident, evaluation of olfactory ability—which is easily performed   
   using commercially available smell tests—can help ensure the correct   
   diagnosis and treatment strategy. Indeed, a number of diseases often   
   misdiagnosed as AD or PD, such as    
   severe depression or progressive supranuclear palsy, are accompanied by little   
   or no smell loss. Thus, olfactory testing can be useful in differentiating   
   between such oft-confused disorders.   
      
   Importantly, some disorders commonly misdiagnosed as PD do not respond well to   
   L-DOPA and other drugs that increase dopamine, a neurotransmitter involved in   
   the control of motor function. Such agents are the most effective treatments   
   available for PD    
   patients. Thus, olfactory testing can aid physicians in predicting whether   
   patients can derive meaningful benefit from such drugs. In patients with mild   
   to moderate AD, olfactory testing indicates responsiveness to donepezil, a   
   drug that improves    
   cognitive function in some patients.2 In light of these and other findings,   
   the Quality Standards Subcommittee of the American Academy of Neurology and   
   other professional organizations have endorsed smell testing as an aid in the   
   diagnosis of AD and PD.    
   Nevertheless, the importance of olfaction in these diseases is largely   
   overlooked, and such testing is not routinely performed in neurology clinics.   
      
   Predicting decline   
   Numerous studies have used quantitative smell tests in an attempt to identify   
   asymptomatic older persons who are most likely to develop cognitive or motor   
   symptoms indicative of neurodegenerative disease. In a pioneering study   
   published in 1999, Amy    
   Bornstein Graves and her associates at the University of South Florida   
   administered a 12-item version of the University of Pennsylvania Smell   
   Identification Test (UPSIT), termed the B-SIT, to 1,604 community-dwelling   
   senior citizens who showed no signs    
   of dementia.3 Over the course of the two-year study, the olfactory test scores   
   proved to be a better predictor of cognitive decline than scores on a global   
   cognitive test. Overall, individuals who had no sense of smell and who   
   possessed at least one APOE-   
   4 allele—a genetic risk factor for AD—were nearly five times more likely   
   to develop cognitive decline than those of the same age who had no smell   
   dysfunction and who carried no such allele. This risk was increased nearly   
   tenfold in women, whereas in    
   men it went up approximately threefold. Possessing at least one APOE-4 allele   
   in the absence of smell loss did not significantly increase a person’s risk   
   for future cognitive decline.   
      
   Evaluation of olfactory ability can help ensure the correct diagnosis and   
   treatment strategy for neurodegenerative disease. Nev­ertheless, the   
   importance of olfaction is largely overlooked, and such testing is not   
   routinely performed   
   in neurology clinics.   
      
   A more recent study of 1,092 older persons with no signs of dementia (average   
   age 80 years) from a multiethnic community in New York City also observed an   
   association between smell loss and cognitive function. Those individuals with   
   both mild cognitive    
   impairment (MCI) and memory loss had lower scores on the 40-odor UPSIT than   
   those with MCI but no memory loss. The UPSIT scores were also correlated with   
   age, several cognitive measures, and the volume of the hippocampus, a brain   
   structure associated    
   with memory.?4   
      
   Research has also elucidated a link between smell dysfunction and PD. In the   
   1990s, G. Webster Ross and his colleagues at the University of Hawaii   
   administered the B-SIT to 2,276 nonsymptomatic elderly men of Japanese   
   ancestry (average age at the    
   beginning of the study was 80 years). After adjusting for age, smoking   
   behavior, and other confounders, those subjects whose initial olfactory test   
   scores fell within the bottom 25 percent of the group were five times more   
   likely to develop PD than those    
   whose test scores fell within the top 25 percent. Over a four-year period, 35   
   were clinically diagnosed with PD.5   
      
   Further support for olfactory involvement in PD came in 2004, when Mirthe   
   Ponsen and her associates at Vrije Universiteit in Amsterdam published a study   
   of 361 asymptomatic first-degree relatives of PD patients, finding that those   
   whose olfactory test    
   scores were significantly below normal were more likely to develop PD over a   
   two-year period than those with no smell impairment.6   
      
      
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