Letter to editors
The olfactory bulb is highly susceptible to Lewy-related pathology (i.e. Lewy bodies and Lewy neurites).1 We herein report the frequency of Lewy-related pathology in a range of non-Alzheimer disorders and the factors that might contribute to risk for Lewy-related pathology using multiple logistic regression methods.
Excluding Alzheimer disease and overt Lewy body disease, olfactory bulbs from 375 consecutive elderly brains were studied with α-synuclein immunohistochemistry. We scored 1) the density and distribution of olfactory Lewy-related pathology 2) Lewy-related pathology in additional brain regions vulnerable for Lewy-related pathology and 3) phospho-tau immunoreactivity. Genotyping for APOE and MAPT was performed in progressive supranuclear palsy (PSP) and corticobasal degeneration cases.
Olfactory Lewy-related pathology was detected in 43 cases (11%) (Table 1). The distribution and the morphology of Lewy-related pathology were similar to previous reports (Supplemental Figure). Twenty-one out of 43 cases (49%) were discovered to have Lewy-related pathology in the olfactory bulb, and in six cases (14%) it was restricted to the olfactory bulb (Supplemental Table), further supporting the value of olfactory bulb for screening for Lewy-related pathology.2 Subjects with Lewy-related pathology were older and had greater Braak neurofibrillary tangle (NFT) stage for both the overall cohort and for the PSP subgroup. Logistic regression modeling revealed Braak NFT stage (odds ratio: 4.4, p = 0.003) as an independent variable for Lewy-related pathology in PSP, and both Braak NFT stage (odds ratio: 1.8, p = 0.01) and age (odds ratio: 1.1, p = 0.04) were significant for the overall cohort. Within the olfactory bulb, no correlation was found between tau burden and Lewy-related pathology (r = 0.08, p = 0.60). Neither APOE nor MAPT genotypes were associated olfactory bulb Lewy-related pathology.
Table 1. Demographic, pathologic and olfactory screening characteristics across various neurological conditions.
Demographic and pathologic characteristics of various disorders.
| Age | Female | Braak NFT | Thal amyloid | Brain Weight | ||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
|
| ||||||||||||
| N | LRP (%) | LRP | No LRP | LRP | No LRP | LRP | No LRP | LRP | No LRP | LRP | No LRP | |
| Overall | 375 | 43 (11%) | 80 (71, 85)* | 75 (70, 83) | 51% | 47% | II (II, III) ** | II (I, II) | 1 (0, 3) | 1 (0, 2) | 1160 (1020, 1260) | 1140 (1040, 1260) |
| PSP | 161 | 18 (11%) | 79 (73, 82)* | 74 (70, 78) | 44% | 43% | II (II, III) ** | II (I, II) | 0 (0. 3) | 0 (0, 2) | 1210 (1020, 1300) | 1160 (1080, 1260) |
| CBD | 35 | 6 (17%) | 75 (71, 81) | 72 (67, 76) | 33% | 59% | II (0, III) | II (I, III) | 0 (0, 2) | 0 (0, 2) | 1165 (1080, 1220) | 1080 (960, 1220) |
| FTLD | 29 | 2 (7%) | 81 (73, 88) | 77 (72, 84) | 0% | 41% | 0 (0, 0) | I (0, II) | 1 (1, 1) | 0 (0, 1) | 1150 (940, 1360) | 1000 (890, 1090) |
| ALS | 18 | 2 (11%) | 71 (70, 71) | 70 (68, 78) | 100% | 63% | II (II, III) | II (I, II) | 2 (2, 2) | 0 (0, 2) | 1160 (1120, 1200) | 1140 (1010, 1280) |
| AGD | 7 | 2 (29%) | 94 (89, 98) | 87 (74, 91) | 100% | 80% | III (III, IV) | III (II, III) | 1 (1, 1) | 0 (0, 1) | 1040 (1010, 1070) | 1055 (983, 1090) |
| HpScl | 8 | 0 (0%) | NA | 91 (90, 95) | NA | 68% | NA | II (I, II) | NA | 1 (0, 3) | NA | 1220 (1190, 1235) |
| PA | 21 | 3 (14%) | 90 (86, 92)* | 81 (77, 84) | 33% | 33% | III (III, III) | II (II, III) | 3 (2, 3) | 3 (3, 3) | 1120 | 1110 (1048, 1210) |
| PART | 19 | 4 (21%) | 88 (79, 94) | 86 (81, 92) | 75% | 40% | III (II, III) | III (II, III) | 2 (0, 4) | 0 (0, 2) | 930 (880, 1150) | 1175 (1020, 1330) |
| MSA | 8 | 0 (0%) | NA | 66 (65, 71) | NA | 25% | NA | II (II, III) | NA | 0 (0, 3) | NA | 1120 (980, 1400) |
| CVD | 34 | 3 (10%) | 81 (73, 83) | 82 (76, 87) | 33% | 45% | II (0, III) | II (I, III) | 1 (1, 1) | 0 (0, 1) | 1120 (95, 1150) | 1240 (967, 1260) |
| Normal | 35 | 3 (9%) | 69 (58, 83) | 75 (67, 84) | 100% | 59% | II (0, III) | II (I, III) | 1 (0, 1) | 0 (0, 1) | 1135 (1090, 1180) | 1080 (1020, 1275) |
indicates p < 0.05 and
indicates p < 0.01.
Abbreviations: N = number of cases; LRP = Lewy-related pathology; No LRP = no Lewy-related pathology; Age = age at death; Female = frequency of women; Braak NFT = neurofibrillary tangle stage; Thal amyloid = amyloid phase. ALS = amyotrophic lateral sclerosis; AGD = argyrophilic grain disease; HpScl = hippocampal sclerosis; CBD = corticobasal degeneration; FTLD = frontotemporal lobar degeneration; MSA = multiple system atrophy; PA = pathological aging; PART = primary age-related tauopathy; PSP = progressive supranuclear palsy ; CVD = cerebrovascular dementia; Normal = neurologically normal; NA = not available.
Regarding Lewy-related pathology among other neurodegenerative disorders, we confirm that Lewy-related pathology appears to be associated with aging, which is in line with previous report in multicenter elderly cohort;3, 4 however, the underlying mechanism of Lewy-related pathology in aging remains to be determined. In contrast, it has been reported that subjects with Lewy bodies in the setting of advanced AD had both younger age at death and age of dementia onset, compared with those without Lewy-related pathology.5 In a hospital-based cohort, Jellinger reported an association between concurrent Lewy-related pathology and Alzheimer pathology regardless of age at death in the 7th to 10th decade.6 These findings suggest that disease-specific factors accelerate Lewy-related pathology in the olfactory bulb in AD. The current study is the largest series of pathologically confirmed PSP to undergo screening for olfactory bulb Lewy-related pathology. It is noteworthy that Alzheimer-type tau pathology quadruples the risk for Lewy-related pathology in PSP even though cases with advanced Alzheimer pathology were specifically excluded.
In this study, we confirm that olfactory bulb screening identifies Lewy-related pathology in a range of non-AD neurological conditions in which this pathology was not previously suspected; moreover, in some cases this is the only brain region affected. The pathogenesis of olfactory bulb Lewy-related pathology might be different from that found in AD.
Supplementary Material
Supplemental Figure. Distribution and morphology of Lewy-related pathology in olfactory bulb (a–c). Three distribution patterns were detected; (a) only in anterior olfactory nucleus, (b) only in peripheral regions of olfactory bulb, including inner plexiform and mitral cell layers, (c) in both regions. Representative morphological features in Lewy-related pathology in olfactory bulb (d–f). Hyaline type Lewy bodies (d) were infrequent compared to cortical type Lewy bodies (e). Lewy neurites, dots, and threads were frequent, and some spheroids were also detected (arrow). Scale bar = 20 µm (a–f).
Supplemental Table. Distribution of Lewy-related pathology and olfactory tau pathology of cases with olfactory bulb involvement. These tabulated 21 cases had not been recognized as having Lewy-related pathology before olfactory bulb screening. Numbers represent scores (based upon a 5-point scale) for the density and distribution of Lewy-related pathology: 0 = no Lewy-related pathology; 1 = rare Lewy bodies or Lewy neurites; 2 = more than one Lewy body per field and sparse Lewy neurites; 3 = four or more Lewy bodies and scattered Lewy neurites per field; 4 = numerous Lewy bodies and Lewy neurites. Note that Lewy-related pathology was restricted to olfactory bulb in six cases. The severity of olfactory tau pathology (i.e. NFT and neuropil thread) was scored on a 4-point semiquantitative scale (0 = none, 1 = sparse, 2 = moderate, 3 = frequent). Abbreviations: AON = Lewy-related pathology restricted to anterior olfactory nucleus; Peri = Lewy-related pathology restricted to olfactory bulb periphery; AON+Peri = Lewy-related pathology found in both anterior olfactory nucleus and olfactory bulb periphery; Amy = amygdala; DMN = dorsal motor nucleus of vagus; nbM = nucleus of Meynert basalis; LC = locus ceruleus; SN = substantia nigra; Beach, unified LBD staging system;29 AD = Alzheimer’s disease ; CBD = corticobasal degeneration ; FTLD-TDP = frontotemporal lobar degeneration with TDP-43 inclusions; MSA = multiple system atrophy; Normal = neurologically normal; PA = pathological aging; PART = primary age-related tauopathy ; PSP = progressive supranuclear palsy ; CVD = cerebrovascular disease.
Acknowledgments
We are grateful to family members and caregivers, for without their generous donations, these studies would have been impossible. We would also appreciate the expert technical assistance of Linda Rousseau and Virginia Phillips for histology and Monica Castanedes-Casey for immunohistochemistry. This study was supported by NIH (P50-NS072187, P50 AG016574), the Michael J. Fox Foundation, Mayo Clinic AD and related dementias genetics program and the Mangurian Foundation Lewy Body Dementia Program at Mayo Clinic.
Dr. Ross receives research support from the NIH (P50-NS072187; R01-NS078086; U54-NS100693)
Dr. Murray is supported by 6AZ01.
Dr. Rademakers receives research support from the NIH (R35 NS097261 and P50-AG016574) and the Mildred A. and Henry Uihlein II Professorship.
Dr. Dickson receives research support from the NIH (P50-AG016574; P50-NS072187; P01-AG003949) and the Robert E. Jacoby Professorship.
Footnotes
Financial disclosure of all authors
Dr. Kasanuki reports no disclosures.
Dr. Ross reports no disclosures.
Dr. DeTure reports no disclosures.
Dr. Walton reports no disclosures.
Dr. Sanchez-Contreras reports no disclosures.
Dr. Koga reports no disclosures.
Dr. Rademakers reports no disclosures.
Dr. Dickson reports no disclosures.
Dr. Rademakers is an editorial board member of Acta Neuropathologica and the American Journal of Neurodegenerative Disease.
Dr. Dickson is an editorial board member of Acta Neuropathologica, Annals of Neurology, Brain, Brain Pathology, and Neuropathology, and he is editor in chief of American Journal of Neurodegenerative Disease, and International Journal of Clinical and Experimental Pathology.
Author Contributions
KK: Acquisition, analysis and interpretation of data; drafting of manuscript; execution of the statistical analysis; writing of the first draft
OAR: Review and critique; interpretation of data
MAD: Acquisition, analysis and interpretation of data; review and critique
RLW: Acquisition, analysis and interpretation of data; review and critique
MSC: Acquisition, analysis and interpretation of data; review and critique
SK: Review and critique
MEM: Acquisition, analysis and interpretation of data; review and critique
RR: Review and critique
DWD: Study concept and design; interpretation of data; review and critique
References
- 1.Braak H, Del Tredici K, Rub U, de Vos RA, Jansen Steur EN, Braak E. Staging of brain pathology related to sporadic Parkinson's disease. Neurobiol Aging. 2003;24(2):197–211. doi: 10.1016/s0197-4580(02)00065-9. [DOI] [PubMed] [Google Scholar]
- 2.Beach TG, Adler CH, Lue L, et al. Unified staging system for Lewy body disorders: correlation with nigrostriatal degeneration, cognitive impairment and motor dysfunction. Acta Neuropathol. 2009;117(6):613–634. doi: 10.1007/s00401-009-0538-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Parkkinen L, Soininen H, Laakso M, Alafuzoff I. Alpha-synuclein pathology is highly dependent on the case selection. Neuropathol Appl Neurobiol. 2001;27(4):314–325. doi: 10.1046/j.0305-1846.2001.00342.x. [DOI] [PubMed] [Google Scholar]
- 4.Zaccai J, Brayne C, McKeith I, Matthews F, Ince PG. Patterns and stages of alpha-synucleinopathy: Relevance in a population-based cohort. Neurology. 2008;70(13):1042–1048. doi: 10.1212/01.wnl.0000306697.48738.b6. [DOI] [PubMed] [Google Scholar]
- 5.Chung EJ, Babulal GM, Monsell SE, Cairns NJ, Roe CM, Morris JC. Clinical Features of Alzheimer Disease With and Without Lewy Bodies. JAMA Neurol. 2015;72(7):789–796. doi: 10.1001/jamaneurol.2015.0606. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Jellinger KA, Attems J. Prevalence of dementia disorders in the oldest-old: an autopsy study. Acta Neuropathol. 2010;119(4):421–433. doi: 10.1007/s00401-010-0654-5. [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Supplemental Figure. Distribution and morphology of Lewy-related pathology in olfactory bulb (a–c). Three distribution patterns were detected; (a) only in anterior olfactory nucleus, (b) only in peripheral regions of olfactory bulb, including inner plexiform and mitral cell layers, (c) in both regions. Representative morphological features in Lewy-related pathology in olfactory bulb (d–f). Hyaline type Lewy bodies (d) were infrequent compared to cortical type Lewy bodies (e). Lewy neurites, dots, and threads were frequent, and some spheroids were also detected (arrow). Scale bar = 20 µm (a–f).
Supplemental Table. Distribution of Lewy-related pathology and olfactory tau pathology of cases with olfactory bulb involvement. These tabulated 21 cases had not been recognized as having Lewy-related pathology before olfactory bulb screening. Numbers represent scores (based upon a 5-point scale) for the density and distribution of Lewy-related pathology: 0 = no Lewy-related pathology; 1 = rare Lewy bodies or Lewy neurites; 2 = more than one Lewy body per field and sparse Lewy neurites; 3 = four or more Lewy bodies and scattered Lewy neurites per field; 4 = numerous Lewy bodies and Lewy neurites. Note that Lewy-related pathology was restricted to olfactory bulb in six cases. The severity of olfactory tau pathology (i.e. NFT and neuropil thread) was scored on a 4-point semiquantitative scale (0 = none, 1 = sparse, 2 = moderate, 3 = frequent). Abbreviations: AON = Lewy-related pathology restricted to anterior olfactory nucleus; Peri = Lewy-related pathology restricted to olfactory bulb periphery; AON+Peri = Lewy-related pathology found in both anterior olfactory nucleus and olfactory bulb periphery; Amy = amygdala; DMN = dorsal motor nucleus of vagus; nbM = nucleus of Meynert basalis; LC = locus ceruleus; SN = substantia nigra; Beach, unified LBD staging system;29 AD = Alzheimer’s disease ; CBD = corticobasal degeneration ; FTLD-TDP = frontotemporal lobar degeneration with TDP-43 inclusions; MSA = multiple system atrophy; Normal = neurologically normal; PA = pathological aging; PART = primary age-related tauopathy ; PSP = progressive supranuclear palsy ; CVD = cerebrovascular disease.