Two recent studies revive the notion that it might be possible, quite literally, to catch a whiff of neurodegenerative disease before the body and mind slip away for good. New York scientists report in the January 13 issue of the Journal of Neuroscience that an Alzheimer disease mouse model steadily loses its sense of smell as amyloid-β accumulates in the brain’s olfactory areas. And in a small study of Parkinson disease patients published in the December 9, 2009, issue, European researchers found that performance on a standard sniff test dropped in parallel with gray matter atrophy in brain regions important for olfaction. By reinforcing the idea that olfactory function dwindles early in disease, the studies suggest that smell-based tests could prove useful as part of future screens for early detection of Alzheimer or Parkinson disease.

Scientists have long recognized that people with early AD (Mesholam et al., 1998; Murphy, 1999) or PD (Ansari and Johnson, 1975) have trouble detecting and naming odors. Meanwhile, postmortem analyses have mapped pathological changes in these diseases to various brain regions, including olfactory centers. In the first study, senior investigator Donald Wilson, Nathan Kline Institute for Psychiatric Research, Orangeburg, New York, and colleagues sought to examine the relationship between those two variables—olfactory dysfunction and Aβ pathology—in Tg2576 AD transgenic mice. A key benefit of working with rodent models is the ability to get behavioral data and immediately afterward analyze the brain tissue, first author Daniel Wesson told ARF. “Our goal was to see if there was a correlation between Aβ and olfactory problems, with the hopes that we'd then have an understanding of whether olfactory problems could indicate AD progression in humans,” he said. The research combined the Wilson lab’s focus on sensory perception with the AD expertise of Nathan Kline investigators Efrat Levy and Ralph Nixon, who are coauthors on the paper.

Analyzing three- to 29-month-old Tg2576 mice and non-transgenic controls, Wesson and colleagues found that smell faculties waned with age in the amyloidosis mice. To assess olfaction, the researchers measured how long the animals sniffed at scented Q-tips after repeated presentations of the same odor. Normally, mice become less interested in things they have already smelled; thus, shorter sniffs of familiar scents reflect learning. Compared to the wild-type mice in the current study, older Tg2576 mice spent more time investigating smells upon initial exposure, and took longer at all ages to learn smells over repeated presentations. This suggests that AD mice not only have a harder time detecting new odors, but also cannot learn and remember the smells as well as wild-type mice, Wesson said.

These sensory deficits correlated with Aβ burden in brain structures needed for odor processing. As early as three to four months of age, well before Aβ deposition is typically detectable elsewhere in the brains of Tg2576 mice, the scientists found traces of non-fibrillar amyloid in the olfactory bulb. “This not only supports the use of olfactory screens in early diagnosis of AD, but also supports the hypothesis that early amyloid deposition may impair normal olfactory processing in a manner that disrupts perception,” Wesson said.

The finding that Aβ seemed to collect first in the olfactory bulb was “the main news” of the study, wrote Robert Wilson, Rush University Medical Center, Chicago, in an e-mail to ARF. While pathological studies have shown olfactory areas to be among the earliest sites of AD pathogenesis, most have focused on olfactory cortical areas such as the entorhinal cortex, Wilson noted (see full comment below). In a recent study of 471 cognitively normal seniors, he and colleagues found that impaired olfaction correlated both with the level of their AD pathology and their risk of succumbing to mild cognitive impairment (Wilson et al., 2009).

A similar theme could be emerging in Parkinson disease. In the December 19, 2009, Journal of Neuroscience, a research team led by Birgit Westermann of the University of Basel, Switzerland, reports that lower scores on a standardized smell test correlate with gray matter atrophy in olfactory-related brain areas of PD patients. First author Elise Wattendorf and colleagues used voxel-based morphometry to analyze magnetic resonance imaging (MRI) scans of 15 people with early PD, 12 with moderately advanced PD, and 17 age-matched healthy controls. In recent functional MRI studies of PD patients, Westermann and colleagues found reduced neuronal activity in the amygdala and hippocampus during olfactory stimulation (Westermann et al., 2008; Welge-Lüssen et al., 2009). Those observations suggested that there could be a structural readout for olfactory dysfunction in PD, and the present study confirmed this.

The MRI findings differed between the two PD groups, though. In people with more severe disease, performance on the olfactory test battery correlated with atrophy in the right amygdala. However, milder PD patients showed the correlation in a different brain area—the right piriform cortex. Work by Donald Wilson and others has shown that this brain region is critical for learning and remembering odors over repeated exposures (Wilson, 2008), and it was one of the areas in which the Nathan Kline scientists found Aβ deposition in AD mice.

All told, the data from the New York and European teams raise hope that smell-based tests may eventually be useful, along with other biomarkers, for identifying presymptomatic AD and PD patients. A number of smell tests have already hit the market, though none thus far are FDA approved for identifying people with AD or PD. One example is Sniffin’ Sticks, developed in Germany and used in the Westermann study of PD patients. Sensonics, Inc. of Haddon Heights, New Jersey, sells 10- and 40-item versions of a smell identification test developed by Davangere Devanand and colleagues at Columbia University in New York. The Columbia researchers have used the 10-item scale to classify people with AD or mild cognitive impairment (MCI) (Tabert et al., 2005) and shown that the larger version can be used, along with additional memory tests and MRI measures, to predict conversion to AD in a study of 148 MCI patients (Devanand et al., 2008). In a study of 589 cognitively normal seniors by Robert Wilson and colleagues, a 12-item smell test predicted subsequent development of MCI, suggesting that olfaction impairment may be useful as a preclinical indicator (Wilson et al., 2007).

Meanwhile, on the animal studies front, the Nathan Kline investigators have unpublished data suggesting that lowering amyloid in AD mouse models rescues olfactory perception, Wesson told ARF. They have other preliminary data indicating that their olfactory tests might be more sensitive to AD pathology than are traditional models such as the fear learning test. "Based upon our initial findings, we are working to better establish olfactory dysfunction in AD mouse models as a tool to track changes in AD-related pathologies," Wesson said.—Esther Landhuis.

References:
Wesson DW, Levy E, Nixon RA, Wilson DA. Olfactory Dysfunction Correlates with Amyloid-Beta Burden in an Alzheimer’s Disease Mouse Model. J. Neurosci. 13 Jan 2010;30(2):505-514. Abstract

Wattendorf E, Welge-Luessen A, Fiedler K, Bilecen D, Wolfensberger M, Fuhr P, Hummel T, Westermann B. Olfactory Impairment Predicts Brain Atrophy in Parkinson’s Disease. J. Neurosci. 9 Dec 2009;29(49):15410-15413. Abstract

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Comments on News and Primary Papers

  1. From my standpoint, the main news of the Wilson study (no relation) is the finding that the olfactory bulb was the first site of amyloid deposition in the brain. Pathological studies of aged humans have shown central olfactory regions to be early sites of AD pathologic changes, but most attention has focused on olfactory cortical areas, especially entorhinal cortex. The findings, if applicable to humans, reinforce the idea that olfactory dysfunction is a very early sign of the disease which may prove helpful, in combination with other markers, in detecting affected persons before the disease has caused widespread damage to the brain.

    Impaired olfaction is also a very early sign of PD, but its pathologic basis has been difficult to establish. The Wattendorf study in a very small group of PD patients and controls found impaired olfaction in PD to be associated with atrophy in central olfactory regions (i.e., piriform cortex and amygdala). Better understanding of the pathological basis of this deficit could substantially help with early detection of PD.

    At this point, the implications of these findings are mainly for research, because without disease-altering treatments, the clinical need for early diagnosis is limited. In the meantime, we need more longitudinal and clinical-pathologic research on olfaction in humans.

    View all comments by Robert Wilson
  2. Interesting paper and nice to see some experimental work being done in this area. I would like to refer readers in this field to our recent papers (below), which confirm earlier work by several investigators that olfactory bulb is universally affected in Parkinson disease as well as dementia with Lewy bodies and other Lewy body disorders. In an autopsy series of normal elderly subjects as well as subjects with Alzheimer disease, Lewy bodies and associated synuclein-immunoreactive fibers were found in many cases to be present only in the olfactory bulb, suggesting that olfactory bulb involvement is the first stage of Lewy body disease.

    References:

    . Olfactory bulb alpha-synucleinopathy has high specificity and sensitivity for Lewy body disorders. Acta Neuropathol. 2009 Feb;117(2):169-74. PubMed.

    . Unified staging system for Lewy body disorders: correlation with nigrostriatal degeneration, cognitive impairment and motor dysfunction. Acta Neuropathol. 2009 Jun;117(6):613-34. PubMed.

  3. I know it was a long time ago, but just for the record: One of the first and perhaps one of the most comprehensive studies on olfactory dysfunction in AD was published by an MA student of mine and myself in 1986 (Knupfer and Spiegel: Differences in olfactory test performance between normal aged, Alzheimer and vascular type dementia individuals. Int. J. Geriat. Psychiat. 1: 3-13; 1986). It is rewarding to see that there are now mouse models to simulate the pathophysiology of this relatively early, albeit unspecific sign of AD pathology.

    Kind regards,

    René Spiegel

  4. In Alzheimer disease, a diminished sense of smell and memory impairment are partly the results of oxidative damage done to olfactory and muscarinic receptors, respectively (both are G protein-coupled receptors). Polyphenols help restore the sense of smell and improve short-term memory in three ways: They promote the neurogenesis of the olfactory bulb and nerve cells in the hippocampus, they prevent further oxidative stress, and they partially restore the function of olfactory and muscarinic receptors by adding hydrogen back to G proteins. The smelling of polyphenolic/aromatic compounds may well play an important role in the treatment of Alzheimer disease.

    References:

    . A natural scavenger of peroxynitrites, rosmarinic acid, protects against impairment of memory induced by Abeta(25-35). Behav Brain Res. 2007 Jun 18;180(2):139-45. PubMed.

    . A diet enriched in polyphenols and polyunsaturated fatty acids, LMN diet, induces neurogenesis in the subventricular zone and hippocampus of adult mouse brain. J Alzheimers Dis. 2009;18(4):849-65. PubMed.

References

Paper Citations

  1. . Olfaction in neurodegenerative disease: a meta-analysis of olfactory functioning in Alzheimer's and Parkinson's diseases. Arch Neurol. 1998 Jan;55(1):84-90. PubMed.
  2. . Loss of olfactory function in dementing disease. Physiol Behav. 1999 Apr;66(2):177-82. PubMed.
  3. . Olfactory function in patients with Parkinson's disease. J Chronic Dis. 1975 Oct;28(9):493-7. PubMed.
  4. . Olfactory impairment in presymptomatic Alzheimer's disease. Ann N Y Acad Sci. 2009 Jul;1170:730-5. PubMed.
  5. . Functional imaging of the cerebral olfactory system in patients with Parkinson's disease. J Neurol Neurosurg Psychiatry. 2008 Jan;79(1):19-24. PubMed.
  6. . Olfactory-induced brain activity in Parkinson's disease relates to the expression of event-related potentials: a functional magnetic resonance imaging study. Neuroscience. 2009 Aug 18;162(2):537-43. PubMed.
  7. . Olfaction as a model system for the neurobiology of mammalian short-term habituation. Neurobiol Learn Mem. 2009 Sep;92(2):199-205. PubMed.
  8. . A 10-item smell identification scale related to risk for Alzheimer's disease. Ann Neurol. 2005 Jul;58(1):155-60. PubMed.
  9. . Combining early markers strongly predicts conversion from mild cognitive impairment to Alzheimer's disease. Biol Psychiatry. 2008 Nov 15;64(10):871-9. PubMed.
  10. . Olfactory identification and incidence of mild cognitive impairment in older age. Arch Gen Psychiatry. 2007 Jul;64(7):802-8. PubMed.
  11. . Olfactory dysfunction correlates with amyloid-beta burden in an Alzheimer's disease mouse model. J Neurosci. 2010 Jan 13;30(2):505-14. PubMed.
  12. . Olfactory impairment predicts brain atrophy in Parkinson's disease. J Neurosci. 2009 Dec 9;29(49):15410-3. PubMed.

Other Citations

  1. Tg2576

Further Reading

Papers

  1. . Olfactory impairment in presymptomatic Alzheimer's disease. Ann N Y Acad Sci. 2009 Jul;1170:730-5. PubMed.
  2. . Combining early markers strongly predicts conversion from mild cognitive impairment to Alzheimer's disease. Biol Psychiatry. 2008 Nov 15;64(10):871-9. PubMed.
  3. . Olfactory identification and incidence of mild cognitive impairment in older age. Arch Gen Psychiatry. 2007 Jul;64(7):802-8. PubMed.
  4. . Olfactory dysfunction correlates with amyloid-beta burden in an Alzheimer's disease mouse model. J Neurosci. 2010 Jan 13;30(2):505-14. PubMed.
  5. . Olfactory impairment predicts brain atrophy in Parkinson's disease. J Neurosci. 2009 Dec 9;29(49):15410-3. PubMed.
  6. . Oxidative damage in the olfactory system in Alzheimer's disease. Acta Neuropathol. 2003 Dec;106(6):552-6. PubMed.

Primary Papers

  1. . Olfactory dysfunction correlates with amyloid-beta burden in an Alzheimer's disease mouse model. J Neurosci. 2010 Jan 13;30(2):505-14. PubMed.
  2. . Olfactory impairment predicts brain atrophy in Parkinson's disease. J Neurosci. 2009 Dec 9;29(49):15410-3. PubMed.