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Atale of two etiologies Loss and recovery of olfactory function.

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cant contribution to what we know about migraine in
the general population, while at the same time underscoring the large gaps in our understanding of this complex neurophysiological disorder.
A Tale of Two Etiologies:
Loss and Recovery of
Olfactory Function
Andrew Charles, MD and K.C. Brennan, MD
Headache Research and Treatment Program,
Department of Neurology
David Geffen School of Medicine at University of
California Los Angeles
Los Angeles, CA
References
1. Selby G, Lance J. Observations on 500 cases of migraine and allied
vascular headache. J Neurol Neurosurg Psychiatry 1960;23:23–32.
2. Lipton R, Bigal M, Ashina S, et al. Cutaneous allodynia in the
migraine population. Ann Neurol (in press).
3. Ashkenazi A, Sholtzow M, Shaw JW, et al. Identifying cutaneous allodynia in chronic migraine using a practical clinical
method. Cephalalgia 2007;27:111–117.
4. Landy SH, McGinnis JE, McDonald SA. Clarification of developing and established clinical allodynia and pain-free outcomes. Headache 2007;47:247–252.
5. LoPinto C, Young WB, Ashkenazi A. Comparison of dynamic
(brush) and static (pressure) mechanical allodynia in migraine.
Cephalalgia 2006;26:852– 856.
6. Lovati C, D’Amico D, Rosa S, et al. Allodynia in different
forms of migraine. Neurol Sci 2007;28(suppl 2):S220 –S221.
7. Mathew NT, Kailasam J, Seifert T. Clinical recognition of allodynia in migraine. Neurology 2004;63:848 – 852.
8. Jakubowski M, Silberstein S, Ashkenazi A, Burstein R. Can allodynic migraine patients be identified interictally using a questionnaire? Neurology 2005;65:1419 –1422.
9. Campbell JN, Meyer RA. Mechanisms of neuropathic pain.
Neuron 2006;52:77–92.
10. Burstein R, Cutrer MF, Yarnitsky D. The development of cutaneous allodynia during a migraine attack: clinical evidence for
the sequential recruitment of spinal and supraspinal nociceptive
neurons in migraine. Brain 2000;123:1703–1709.
11. Cutrer FM, Black DF. Imaging findings of migraine. Headache
2006;46:1095–1107.
12. Young WB, Richardson ES, Shukla P. Brush allodynia in hospitalized headache patients. Headache 2005;45:999 –1003.
13. Lovati C, D’Amico D, Rosa S, et al. Allodynia in different
forms of migraine. Neurol Sci 2007;28:S220 –S221.
14. Rozen TD, Haynes GV, Saper JR, Sheftell FD. Abrupt onset
and termination of cutaneous allodynia (central sensitization)
during attacks of SUNCT. Headache 2005;45:153–155.
15. Burstein R, Collins B, Jakubowski M. Defeating migraine pain
with triptans: a race against the development of cutaneous allodynia. Ann Neurol 2004;55:19 –26.
16. Jakubowski M, Levy D, Goor-Aryeh I, et al. Terminating migraine with allodynia and ongoing central sensitization using
parenteral administration of COX1/COX2 inhibitors. Headache 2005;45:850 – 861.
17. Silberstein SD, Young WB, Hopkins MM, et al. Dihydroergotamine for early and late treatment of migraine with cutaneous
allodynia: an open-label pilot trial. Headache 2007;47:878 – 885.
18. Linde M, Elam M, Lundblad L, et al. Sumatriptan (5-HT1B/
1D-agonist) causes a transient allodynia. Cephalalgia 2004;24:
1057–1066.
132
Annals of Neurology
Vol 63
No 2
February 2008
A growing body of evidence suggests that decline in
olfactory function may herald the onset of the clinical
signs of Parkinson’s disease (PD) and Alzheimer’s disease.1 Moreover, pathological studies of brains from
asymptomatic older individuals have identified pathological hallmarks of these diseases in regions involved
in processing olfactory input, suggesting that these
brain regions may be targeted early in the disease process. Two longitudinal studies2,3 reported in this issue
of Annals illustrate the range of responses of the olfactory neural circuit to various pathological insults, from
functional recovery to an early indicator of PD.
In the first population-based study to examine olfactory dysfunction as a clinical risk marker for incident
PD,3 the 12-item Brief Smell Identification Test (BSIT) was administered to 2,906 Japanese-American
men participating in the Honolulu-Asia Aging Study.
Men with prevalent dementia, PD, or nasal congestion
at the time of olfactory testing were excluded, leaving
2,267 men. The incidence of PD was inversely related
to baseline performance on the B-SIT. The relative
odds of developing PD over the first 4 years of
follow-up were 5.2 (95% confidence interval,
1.5–25.6) for subjects in the lowest quartile (B-SIT
0 –5) compared with subjects in the two highest quartiles (B-SIT 8 –12) after adjustment for cognitive impairment, midlife coffee and pack-years of cigarette intake, bowel movement frequency, and daytime
sleepiness. For subjects in the second quartile (B-SIT
6 –7), their relative odds were 3.1 (95% confidence interval, 0.6 –16.1, not significant). No relation was seen
between baseline odor naming performance and incident PD cases during years 4 to 8 of follow-up.
Two small prospective studies4,5 and estimates from
functional imaging6,7 support the possibility that olfactory impairment begins 2 to 7 years before meeting the
diagnostic criteria for PD. Ross and colleagues3 have
previously shown that asymptomatic men in the
Honolulu-Asia Aging Study scoring between 0 and 5
on the B-SIT 3 to 4 years before autopsy were significantly more likely to have incidental Lewy bodies in
the substantia nigra and the locus ceruleus (odds ratio,
11.0; 95% confidence interval, 1.3–526) compared to
the highest tercile, suggesting that olfactory impairment might identify a preclinical state of PD.8 Ross
and colleagues’ study3 does not specifically address the
Braak hypothesis,9 which posits that PD pathogenesis
begins in the anterior olfactory nucleus and the dorsal
motor nucleus of the vagus nerve. Because of its limited sample size, it also does not answer the question
that London and colleagues2 posed about whether olfactory impairment is simply a static risk marker for
PD or whether olfaction declines as disease onset approaches. In symptomatic PD, no relation between disease duration or severity and olfactory impairment has
been noted.10
In Ross and colleagues’ study3 (see Table 2 of that
article), subjects in the lowest B-SIT quartile reported
the greatest use of caffeine and smoking. Is it possible
that the caffeine and smoking are contributing to a
“motor reserve,” akin to the effects of education in Alzheimer’s disease, such that the motor impairment is delayed or masked whereas the olfactory impairment is
resistant to the protective effects? The fact that those in
the lowest B-SIT quartile have the shortest time to incident PD, defined by motor criteria, may support this.
In contrast, lifetime caffeine use was associated with
better performance on the 40-item University of Pennsylvania Smell Identification Test in a cross-sectional
study of 173 asymptomatic relatives of PD cases.11
However, the asymptomatic family members in this
study11 were younger (58.1 years; standard deviation,
11.5) than the Honolulu-Asia Aging Study participants, and although these family members were within
10 years of onset of the affected proband, the development and timing of incident PD cannot be estimated.
Strengths of this study included the rigorous screening of participants to exclude those with cognitive impairment or parkinsonism, the extensive data collection
including potential confounders, the 8-year follow-up
period, and the standardized consensus diagnosis of incident PD. Relative weaknesses included the homogeneity of the cohort (only men of Japanese ancestry) and
late age at onset of PD (82.9 ⫾ 3.8 years), which limits the generalizability but not the validity of this study.
No information was provided on subtle motor signs or
phenotype (tremor dominant vs akinetic rigid) that
might have been present at baseline in those who were
destined to experience development of PD. Additional
tests, such as functional imaging, might have improved
the sensitivity of clinical diagnosis in concert with olfactory testing. Examination of longitudinal changes of
the B-SIT will be important to determine the natural
history of olfactory performance as a risk for PD in this
cohort.
In London and colleagues’ article,2 longitudinal odor
identification data were analyzed from 542 patients
who presented to a specialized center for olfactory disorders and who responded to a request for a second
olfactory assessment to be completed in their homes.
After the initial clinical evaluation, presumptive causative factors were assigned to each patient; the most
common factors were upper respiratory tract infection,
head trauma, nasosinus disease, and idiopathic causes.
No mention was made of comorbid neurological illness
in this sample. The first olfactory assessment at the initial visit was the 40-item University of Pennsylvania
Smell Identification Test. For the second assessment,
297 patients completed the University of Pennsylvania
Smell Identification Test and 245 patients completed
the 12-item B-SIT. The results from the latter were
converted to a score on a 40-point scale. The time between the 2 evaluations ranged from 3 months to 24
years with a mean of 3.5 years. Overall, the odor identification function improved in this group of symptomatic patients. Multivariant linear regression analysis
demonstrated three statistically significant predictors of
the amount of change (improvement) in the score of
the second olfactory test: (1) diminished time from initial symptom onset and first testing (median olfactory
impairment was 1 year [0.08 – 66 years]), (2) age
younger than 75 years, and (3) severity of the olfactory
deficit at the first assessment.
What biological mechanisms might underpin this regenerative capacity of the olfactory neural circuit? Stem
cells in the olfactory epithelium in the nose regenerate
primary olfactory neurons, and there is evidence that
neurogenesis contributes interneurons to the human olfactory bulb throughout adulthood.12 Mechanisms of
plasticity in the brain including reorganization of cortical maps, neurogenesis, and axon sprouting, also seen
in recovery from vascular insults,13 may contribute to
functional improvement in this odor naming test. Indeed, the temporal window of effectiveness for these
cellular and network-based regenerative mechanisms
may be limited by the time from the initial insult and
may wane with increasing age of the individual.14
The third predictor (severity of olfactory deficit) is
not clearly delineated and depends on the definition of
improvement. In Table 2 of this study,2 the authors
demonstrate that a lower B-SIT score at the first evaluation is associated with a larger absolute change (improvement) in the score of the second test. In Table 4
of this study,4 the authors demonstrate that a higher
B-SIT score at the first evaluation is associated with a
greater likelihood that the score of the second test will
fall in the range of “normal” olfactory functioning. Finally, the authors did not find statistically significant
differences between the scores of the two tests among
the four major presumptive causative factors. Without
pathological validation of their initial clinical impressions, it is difficult to interpret this finding. It is
tempting to speculate that some of the patients in the
“idiopathic” group might have had subclinical neurodegenerative disease, which may account for the less
robust recovery in this group.
This study2 was composed of individuals who voluntarily performed a second test at home and returned
it to the investigators. The initial sample sizes for each
Albers and Marder: Olfactory Loss and Recovery
133
causative class that were mailed smell tests were not
provided, and these data would have addressed the issue of how representative the sample populations were.
In addition, an odor threshold test and a subjective olfactory acuity scale would have provided more insight
into the olfactory recovery and the perceived improvement, respectively.
From these two studies2,3 one can hypothesize that a
longitudinal characterization of odor naming function
might increase the specificity of detection of neurodegenerative disease on a preclinical basis relative to one
evaluation. That is, an odor-naming deficit in an
asymptomatic individual that declines over time (as opposed to improving or remaining stable) may be a
more specific risk marker for neurodegenerative disease.
We look forward to future prospective studies that may
directly examine this hypothesis. Although olfaction
may not routinely be tested as part of the neurological
examination, an increasing body of work, including
these two articles,2,3 points to its increasing relevance,
particularly as the population ages. Furthermore, a
deeper understanding of the mechanisms used by the
olfactory neural circuit to recover function and the development of technology to harness this regenerative
potential may lead to novel methods to restore function in other nervous system circuits.
Mark W. Albers, MD, PhD,1
Karen S. Marder, MD, MPH2
1
Department of Neurology
MassGeneral Institute for Neurodegenerative Disease,
Massachusetts General Hospital, Harvard Medical
School
Boston, MA
2
Department of Neurology
Gertrude H. Sergievsky Center, Taub Institute for
Research in Alzheimer’s Disease and the Aging Brain,
Columbia University College of Physicians and
Surgeons
New York, NY
134
Annals of Neurology
Vol 63
No 2
February 2008
References
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as a predictor of neurodegenerative disease. Curr Neurol Neurosci Rep 2006;6:379 –386.
2. London B, Nabet B, Fisher AR, et al. Predictors of prognosis in
patients with olfactory disturbance. Ann Neurol 2008.
3. Ross GW, Petrovich H, Abbott RD, et al. Association of olfactory dysfunction with risk of future Parkinson’s disease. Ann
Neurol 2008;167–173.
4. Ponsen MM, Stoffers D, Booij J, et al. Idiopathic hyposmia as
a preclinical sign of Parkinson’s disease. Ann Neurol 2004;56:
173–181.
5. Marras C, Goldman S, Smith A, et al. Smell identification ability in twin pairs discordant for Parkinson’s disease. Mov Disord
2005;20:687– 693.
6. Morrish PK, Rakshi JS, Bailey DL, et al. Measuring the rate of
progression and estimating the preclinical period of Parkinson’s
disease with [18F]dopa PET. J Neurol Neurosurg Psychiatry
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SPECT imaging correlates with odor identification in early Parkinson disease. Neurology 2005;64:1716 –1720.
8. Ross GW, Abbott RD, Petrovitch H, et al. Association of olfactory dysfunction with incidental Lewy bodies. Mov Disord
2006;21:2062–2067.
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2003;24:197–211.
10. Doty RL, Deems DA, Stellar S. Olfactory dysfunction in
parkinsonism: a general deficit unrelated to neurologic signs, disease stage, or disease duration. Neurology 1988;38:1237–1244.
11. Siderowf A, Jennings D, Connolly J, et al. Risk factors for
Parkinson’s disease and impaired olfaction in relatives of patients with Parkinson’s disease. Mov Disord 2007;22:
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12. Curtis MA, Kam M, Nannmark U, et al. Human neuroblasts
migrate to the olfactory bulb via a lateral ventricular extension.
Science 2007;315:1243–1249.
13. Carmichael ST. Cellular and molecular mechanisms of neural
repair after stroke: making waves. Ann Neurol 2006;59:
735–742.
14. Rawson NE, LaMantia A-S. A speculative essay on retinoic acid
regulation of neural stem cells in the developing and aging olfactory system. Exp Gerontol 2007;42:46 –53.
DOI: 10.1002/ana.21330
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