Severe hyposmia distinguishes neuropathologically confirmed dementia with Lewy bodies from Alzheimer’s disease dementia

Abstract

Many subjects with neuropathologically-confirmed dementia with Lewy bodies (DLB) are never diagnosed during life, instead being categorized as Alzheimer’s disease dementia (ADD) or unspecified dementia. Unrecognized DLB therefore is a critical impediment to clinical studies and treatment trials of both ADD and DLB. There are studies that suggest that olfactory function tests may be able to distinguish DLB from ADD, but few of these had neuropathological confirmation of diagnosis. We compared University of Pennsylvania Smell Identification Test (UPSIT) results in 257 subjects that went on to autopsy and neuropathological examination. Consensus clinicopathological diagnostic criteria were used to define ADD and DLB, as well as Parkinson’s disease with dementia (PDD), with (PDD+AD) or without (PDD-AD) concurrent AD; a group with ADD and Lewy body disease (LBD) not meeting criteria for DLB (ADLB) and a clinically normal control group were also included. The subjects with DLB, PDD+AD and PDD-AD all had lower (one-way ANOVA p < 0.0001, pairwise Bonferroni p < 0.05) first and mean UPSIT scores than the ADD, ADLB or control groups. For DLB subjects with first and mean UPSIT scores less than 20 and 17, respectively, Firth logistic regression analysis, adjusted for age, gender and mean MMSE score, conferred statistically significant odds ratios of 17.5 and 18.0 for the diagnosis, vs ADD. For other group comparisons (PDD+AD and PDD-AD vs ADD) and UPSIT cutoffs of 17, the same analyses resulted in odds ratios ranging from 16.3 to 31.6 (p < 0.0001). To our knowledge, this is the largest study to date comparing olfactory function in subjects with neuropathologically-confirmed LBD and ADD. Olfactory function testing may be a convenient and inexpensive strategy for enriching dementia studies or clinical trials with DLB subjects, or conversely, reducing the inclusion of DLB subjects in ADD studies or trials.

About the Authors:

Thomas G. Beach

Contributed equally to this work with: Thomas G. Beach, Charles H. Adler

Roles Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Supervision, Writing – original draft, Writing – review & editing

* E-mail: [email protected]

Affiliation: Banner Sun Health Research Institute, Sun City, Arizona, United States of America

ORCID logo http://orcid.org/0000-0003-3296-6128

Charles H. Adler

Contributed equally to this work with: Thomas G. Beach, Charles H. Adler

Roles Conceptualization

Affiliation: Department of Neurology, Mayo Clinic, Scottsdale, Arizona, United States of America

Nan Zhang

Roles Conceptualization

Affiliation: Department of Biostatistics, Mayo Clinic, Scottsdale, Arizona, United States of America

Geidy E. Serrano

Roles Conceptualization

Affiliation: Banner Sun Health Research Institute, Sun City, Arizona, United States of America

ORCID logo http://orcid.org/0000-0002-9527-2011

Lucia I. Sue

Roles Conceptualization

Affiliation: Banner Sun Health Research Institute, Sun City, Arizona, United States of America

Erika Driver-Dunckley

Roles Conceptualization

Affiliation: Department of Neurology, Mayo Clinic, Scottsdale, Arizona, United States of America

Shayamal H. Mehta

Roles Conceptualization

Affiliation: Department of Neurology, Mayo Clinic, Scottsdale, Arizona, United States of America

Edouard E. Zamrini

Roles Conceptualization

Affiliation: Banner Sun Health Research Institute, Sun City, Arizona, United States of America

Marwan N. Sabbagh

Roles Conceptualization

Affiliation: Cleveland Clinic Lou Ruvo Center for Brain Health, Las Vegas, Nevada, United States of America

Holly A. Shill

Roles Conceptualization

Affiliation: Barrow Neurological Institute, Phoenix, Arizona, United States of America

Christine M. Belden

Roles Conceptualization

Affiliation: Banner Sun Health Research Institute, Sun City, Arizona, United States of America

David R. Shprecher

Roles Conceptualization

Affiliation: Banner Sun Health Research Institute, Sun City, Arizona, United States of America

Richard J. Caselli

Roles Conceptualization

Affiliation: Department of Neurology, Mayo Clinic, Scottsdale, Arizona, United States of America

Eric M. Reiman

Roles Conceptualization

Affiliation: Banner Alzheimer’s Institute, Phoenix, Arizona, United States of America

Kathryn J. Davis

Roles Conceptualization

Affiliation: Banner Sun Health Research Institute, Sun City, Arizona, United States of America

Kathy E. Long

Roles Conceptualization

Affiliation: Banner Sun Health Research Institute, Sun City, Arizona, United States of America

Lisa R. Nicholson

Roles Conceptualization

Affiliation: Banner Sun Health Research Institute, Sun City, Arizona, United States of America

Anthony J. Intorcia

Roles Conceptualization

Affiliation: Banner Sun Health Research Institute, Sun City, Arizona, United States of America

Michael J. Glass

Roles Conceptualization

Affiliation: Banner Sun Health Research Institute, Sun City, Arizona, United States of America

Jessica E. Walker

Roles Conceptualization

Affiliation: Banner Sun Health Research Institute, Sun City, Arizona, United States of America

Michael M. Callan

Roles Conceptualization

Affiliation: Banner Sun Health Research Institute, Sun City, Arizona, United States of America

Javon C. Oliver

Roles Conceptualization

Affiliation: Banner Sun Health Research Institute, Sun City, Arizona, United States of America

Richard Arce

Roles Conceptualization

Affiliation: Banner Sun Health Research Institute, Sun City, Arizona, United States of America

Richard C. Gerkin

Roles Conceptualization

Affiliation: School of Life Sciences, Arizona State University, Tempe, Arizona, United States of America

Introduction

Dementia due to AD (ADD) is often associated with comorbid brain disease that may affect clinical presentation, rate of cognitive decline, and response to therapeutic agents [1–22]. Additional concurrent pathology could be unresponsive to therapies directed at the “primary” pathology. It is apparent then, that clinical trials for ADD could suffer from decreased effect size if this were true.

The most common comorbidity in ADD is Lewy body disease. Slightly more than one-half or more of all those meeting clinicopathological ADD diagnostic criteria also have α-synuclein pathology [9,23–25] with morphological features similar to Parkinson’s disease (PD). This is broadly termed “Lewy body disease” (LBD). Similarly, about one-half of those with dementia and PD (PDD) [26–38] and three-quarters or more of those with dementia with Lewy bodies (DLB), have clinically significant AD histopathology [39–42]. In the majority of subjects with ADD and DLB (ADD/DLB), the typical clinical signs and symptoms of DLB [43,44] are absent and thus this co-existence is recognized only at autopsy [22,45–47]. This clinical inability to separate ADD from DLB hampers clinical trials for both conditions. Several autopsy-validated studies have indicated that cognitive decline is faster in elderly subjects dying with ADD who also have LBD [3,22,48–51], and disease duration has been reported to be shorter in those with coexistent ADD and DLB [40,52]. There is therefore a critical need for better clinical differentiation of these two conditions.

There are numerous published clinical studies that suggest that olfactory function tests may be useful in differentiating amongst cerebrovascular and neurodegenerative disorders [53–64] and, in particular, in distinguishing DLB from ADD [65–70], but the studies with later neuropathological establishment of the specific molecular pathology are the most informative. Possibly the first such study, done by Oxford University [71], investigated the neuropathological correlates of anosmia in subjects with dementia. Anosmia was defined on the basis of being able or unable to detect the scent of lavender oil. Seventeen subjects had neuropathological DLB, defined as the concurrent presence of Lewy bodies in both the substantia nigra and cingulate gyrus. Sixteen of these had concurrent ADD while another 43 subjects had ADD alone, defined as probable or definite CERAD AD [72], without LBD. Anosmia was significantly (p = 0.029) more common in DLB (41%) than in ADD (16%).

A similar study [73] from the University of Southern California defined anosmia as the inability to detect the odor of N-butyl alcohol, finding anosmia in 47% of those with the Lewy body variant (LBV, n = 17) of AD versus 22% of those with AD alone (n = 89). This proportional difference was highly significant (p = 0.0004). The diagnosis of LBV was defined as the presence of Lewy bodies in both brainstem and cerebral cortex while ADD was defined as CERAD probable or definite AD. The independent odds ratio for anosmia as a predictor of LBV was 5.4, vs 7.3 for visual hallucinations.

In a study of a mixed group of non-demented and demented subjects with and without parkinsonism from the Rush Memory and Aging Project [74], lower scores on the Brief Smell Identification Test were significant predictors of limbic and neocortical LBD stages (9 and 13 subjects, respectively). The presence of any Lewy bodies accounted for 15.4% of test variance, as compared to 4.1% due to a composite measure of AD histopathology.

Incidental Lewy body disease (ILBD) refers to the presence of LBD in asymptomatic elderly people and is likely to be a prodromal stage of PD or DLB as striatal dopaminergic markers are halfway between asymptomatic elderly people without LBD and clinically-manifest PD [75–78]. One neuropathologically-informed study has reported that olfactory function in subjects with ILBD is also halfway between PD and asymptomatic elderly people without LBD, suggesting that hyposmia may be useful as a prodromal marker [79]. Another prior study found an OR of 11.0 for the prediction of ILBD in those amongst the lowest tertile of olfactory function [80]. Supporting the possible usefulness of hyposmia as a prodromal biomarker are the findings that it is present in some clinically normal GBA and LRRK2 mutation carriers [81,82], is common in idiopathic REM sleep behavior disorder (iRBD) [83–85], is a significant and independent predictor of phenoconversion from iRBD to parkinsonism or dementia [86] and is associated with decreased striatal dopamine transporter imaging [87,88]. A likely causative factor underlying the impairment of olfaction in LBD is the near-universal occurrence of early-stage α-synuclein pathology within the olfactory bulb [89–92].

In this study we sought to determine the diagnostic utility of hyposmia as a diagnostic predictor of neuropathologically-identified DLB with comorbid ADD, as compared with ADD alone, using the largest set to date of neuropathologically-examined subjects. Furthermore, we did similar analyses on the diagnostic utility of hyposmia for distinguishing Parkinson’s disease with dementia from ADD alone.

Materials and methods

Subject selection

Subjects were selected by database searches of the Arizona Study of Aging and Neurodegenerative Disorders (AZSAND)/ Banner Sun Health Research Institute Brain and Body Donation Program (www.brainandbodydonationprogram.org) [93], a subset of whom were also enrolled in the National Institute on Aging Arizona Alzheimer’s Disease Core Center. Search criteria specified that subjects died with dementia, one or more completed University of Pennsylvania Smell Identification Tests (UPSIT) accompanied by Mini Mental State Examinations (MMSE), assessments of the presence or absence of parkinsonism and visual hallucinations, and a full neuropathological examination after death. Selected subjects met “intermediate” or “high” National Institute on Aging-Reagan Institute (NIA-RI) clinicopathological criteria [94] for ADD, with or without also meeting “intermediate” or “high” clinicopathological criteria for DLB [43,44], or alternatively, for groups with Parkinson’s disease dementia or Alzheimer’s disease with Lewy body pathology (ADLB) [91], the latter defined as having pathologically-confirmed CNS LBD but not meeting DLB pathology distribution and density thresholds. Briefly, intermediate and high NIA-RI criteria stipulate Braak neurofibrillary stages III or IV versus V and VI, respectively. DLB intermediate and high criteria are based on comparison of Lewy body pathology stage with AD pathology stage; when AD pathology stage is high, only the neocortical Lewy body stage qualifies for DLB, while when AD pathology stage is intermediate, either a limbic or neocortical Lewy body stage qualifies for DLB. Parkinson’s disease with dementia (PDD) is defined as meeting clinicopathological diagnostic criteria for PD as well as clinical criteria for dementia, and is further subdivided by the presence (PDD+AD) or absence (PDD-AD) of intermediate or high NIA-RI criteria AD pathology. ADLB is defined as intermediate or high NIA-RI AD criteria together with any Lewy body stage not qualifying for DLB, which can be either limbic or brainstem stages. A control subject group, without clinical parkinsonism or dementia, and without α-synuclein pathology at autopsy, was also included. For all subjects, most other major neuropathological disorders were excluded; this included subjects with progressive supranuclear palsy, multiple system atrophy and corticobasal degeneration. As mean UPSIT did not differ between ADD and the neuropathologically-defined ADLB (n = 30) and AD-VaD (n = 25) groups, these were grouped for the primary analyses. Cases with DLB in the absence of intermediate or high NIA-RI status were not included in statistical analyses in this study as there were only 4 cases with UPSIT data available.

Subject characterization

Most subjects had serial standardized research cognitive evaluations, done by teams of nurses, medical assistants, behavioral neurologists, movement disorders neurologists, neuropsychologists and psychometrists using standardized research-quality assessment batteries [93], including the Mini Mental State Examination (MMSE), National Alzheimer’s Coordinating Center (NACC) Uniform Data Set (UDS) and the Unified Parkinson’s Disease Rating Scale (UPDRS). Subjects had olfactory testing with the University of Pennsylvania Smell Identification Test (UPSIT) [95–97] every third year on average. The presence or absence of DLB core clinical features [43,44], including the presence or absence of parkinsonism, visual hallucinations, fluctuations in attention or cognition and clinical history consistent with REM sleep behavior disorder (RBD), were recorded for each subject at each visit; to assist with the latter, the Mayo Sleep Questionnaire [98–101] was administered. The presence or absence of parkinsonism and visual hallucinations were noted for 103 and 88 (respectively) of the 125 total ADD, ADLB and ADD/DLB subjects, by formal examination as part of the Unified Parkinson’s Disease Rating Scale (UPDRS) and/or as part of the Uniform Data Set (UDS) of the National Alzheimer’s Coordinating Center (NACC). For those that did not have either UPDRS or UDS data available, the presence of parkinsonism and visual hallucinations was additionally noted by review of private medical records. These determinations were made within the same year (matched year) as the first UPSIT administration, for comparison with first UPSIT as a diagnostic predictor, while for comparison with mean UPSIT score, the cumulative recorded presence of visual hallucinations and parkinsonism, at any timepoint within the clinical observation period was used.

All subjects received identical neuropathological examinations, including summary regional brain density measures for total amyloid plaques, neurofibrillary tangles, Lewy body pathology regional and summary density scoring, and staging using the Unified Staging System for Lewy Body Disorders [91], as well as assignment of CERAD neuritic plaque density and Braak neurofibrillary stage, as described previously [93].

The corresponding author had access to personally-identifying information for subjects in this study.

Statistical analysis

Demographic and post-mortem characteristics were analyzed using one-way analysis of variance (ANOVA), Chi-square tests and unpaired t-tests as appropriate. Receiver-operator characteristics analysis was implemented for first and mean UPSIT scores to separately predict the diagnosis of DLB, ADLB, PDD+AD and PDD-AD vs ADD. Youden index was used as the criteria to choose the optimum cut-off point for UPSIT scores. In the analyses comparing ADD/DLB and ADLB with ADD, sensitivity, specificity, and accuracy for predicting the presence of Lewy body disease, based on UPSIT cutoff scores vs the presence or absence of visual hallucinations and parkinsonism, were further calculated. Firth logistic regression models adjusted for age, gender and corresponding MMSE scores were used to estimate odds ratios for different predictors and areas under the curve (AUC) for each model. The AUCs for the models were compared using Delong’s method [102].

Results and discussion

Clinical, demographic and neuropathological characteristics of the compared groups (total n = 287) are shown in Table 1. Of the disease groups, the PDD+AD and PDD-AD groups were the youngest, had the highest final UPDRS scores, the highest final MMSE scores, the lowest plaque and tangle scores and the highest Lewy pathology scores. The ADD/DLB, ADLB, PDD+AD and PDD groups all had higher proportions of men. The ADLB group had the lowest final MMSE score. As expected, the control group was significantly different from the dementia groups in all clinical and neuropathological measures. Neuropathologically, the ADD and ADD/DLB groups were not different in their density scores or stages for amyloid plaques (total plaques), neuritic plaques and neurofibrillary tangles.

[Figure omitted. See PDF.]

Table 1. Clinical and neuropathological characteristics of study subjects.

https://doi.org/10.1371/journal.pone.0231720.t001

Comparison of UPSIT scores, including the first UPSIT score and the mean of all UPSIT scores, showed that all groups with Lewy body pathology, except the ADLB group, had significantly lower UPSIT scores than the non-Lewy body pathology groups (Fig 1). The mean UPSIT score for the 4 DLB subjects without ADD was 12.8 (not shown on graph).

[Figure omitted. See PDF.]

Fig 1. First and mean UPSIT scores in the diagnostic groups.

Both first UPSIT and mean UPSIT scores are significantly different between groups (ANOVA, p < 0.001). For both first and mean UPSIT scores, the control group scores are significantly higher than all other groups, and both the ADD and ADLB groups have mean scores that are significantly higher than the ADD/DLB, PDD+AD (PDAD on the graph) and PDD-AD (PDD on the graph) groups (Bonferroni p < 0.05). First and mean UPSIT scores were not significantly different within diagnostic groups. Error bars = standard deviation.

https://doi.org/10.1371/journal.pone.0231720.g001

Control subjects had significantly more UPSITs (mean 1.9, range 1–4) than ADD (mean 1.6, range 1–4), ADD/DLB (mean 1.35, range 1–3) ADLB (mean 1.52; range 1–3), PDD+AD (1.33; 1–3) or PDD-AD (1.37, range 1–2) groups but this did not differ between the diseased groups. Logistic regression analysis of the combined disease groups (n = 163 after exclusion of cases with incomplete neuropathology scores) found a unitary increase in the brain regional sum of α-synuclein pathology score (maximum score of 40) was significantly associated with a mean UPSIT score less than the median of all cases (OR 1.12, 95% CI 1.08–1.17, p < 0.000001). Higher regional brain scores for amyloid plaque density score as well as higher age at death were not significant predictors, while higher neurofibrillary tangle density scores as well as lower last MMSE test scores independently approached the significance level (p = 0.08 and p = 0.07, respectively).

Logistic regression analysis and receiver-operator characteristics (ROC) indicated that the UPSIT cutoff scores giving the greatest accuracy for separating ADD from ADD/DLB were 19 or less for the first UPSIT (median of ADD/DLB and ADD first UPSIT scores was 20) and 17 for the mean UPSIT. Using these cutoffs, a first UPSIT score less than 20 gave an odds ratio (OR) of 17.5 for a diagnosis of ADD/DLB, while for mean UPSIT, a score less than 17 resulted in an OR of 18.0 for the diagnosis (Table 2). These ORs were considerably greater than those derived from the presence or absence of the two most common DLB core clinical features, visual hallucinations and parkinsonism (Table 2, Fig 2a and 2b), and were highly significant (p < 0.0001) whereas only the OR for cumulatively-observed hallucinations was significant (OR 3.3; p = 0.01). Similarly, the area under the curves (AUC) were significantly greater for first and mean UPSIT as compared with those for matched-year or cumulative hallucinations and parkinsonism.

[Figure omitted. See PDF.]

Fig 2. Comparison of ROC curves for the discrimination of ADD/DLB vs ADD using a) using first UPSIT scores and b) using mean UPSIT scores, with those using presence or absence of visual hallucinations and parkinsonism within the same year of observation.

https://doi.org/10.1371/journal.pone.0231720.g002

[Figure omitted. See PDF.]

Table 2. Comparison of first UPSIT score and mean of all UPSIT scores with visual hallucinations and parkinsonism as predictors of ADD/DLB vs ADD.

https://doi.org/10.1371/journal.pone.0231720.t002

To determine whether the inclusion of ADLB subjects with the ADD group affected the primary analysis of ADD/DLB vs ADD, logistic regression analysis and ROC curves were used to compare the ADD and ADD/DLB groups after exclusion of the 30 subjects with ADLB, and to compare the ADD group with a composite ADLB-DLB group. The results after exclusion of the ADLB group were very similar to those obtained with the ADD and ADLB groups together (Fig 3a and 3b). All comparisons that were statistically significant in the primary analysis were also significant after exclusion of the ADLB subjects. A first UPSIT cutoff score of 19 gave an OR of 28.3 for separating ADD from ADD/DLB while a mean UPSIT cutoff of 20 gave an OR of 24.4 for predicting ADD/DLB (both with p < 0.0001). The results with ADLB and ADD/DLB subjects grouped together and compared with the ADD group showed much less predictive power for both first and mean UPSIT scores (Fig 4a and 4b).

[Figure omitted. See PDF.]

Fig 3. Comparison of ROC curves after exclusion of 30 ADLB subjects from the ADD group.

a) using first UPSIT scores and b) using mean UPSIT scores.

https://doi.org/10.1371/journal.pone.0231720.g003

[Figure omitted. See PDF.]

Fig 4. Comparison of ROC curves after combining the ADLB subjects with the ADD/DLB subjects.

a) using first UPSIT scores and b) using mean UPSIT scores.

https://doi.org/10.1371/journal.pone.0231720.g004

With the same analyses applied to the discrimination of PDD+AD and PDD-AD from ADD (Fig 5a and 5b), odds ratios were of similar magnitudes with similar UPSIT cutoffs. For PDD+AD vs ADD (Fig 5a), a first UPSIT cutoff score of 17 gave an OR of 20.3 for separating PD+AD from ADD, while a mean UPSIT cutoff of 17 gave an OR of 31.6 this distinction (both with p < 0.0001). For PDD-AD vs ADD (Fig 5a), a first UPSIT cutoff score of 17 gave an OR of 16.3 for separating PDD-AD from ADD, while a mean UPSIT cutoff of 17 gave an OR of 25.7 for this distinction (both with p < 0.0001).

[Figure omitted. See PDF.]

Fig 5. ROC curves for the discrimination of a) PDD+AD vs ADD subjects and b) PDD-AD, using first and mean UPSIT scores.

https://doi.org/10.1371/journal.pone.0231720.g005

The results of this study show that the presence of diagnostically significant brain loads of α-synuclein pathology have a pronounced effect on olfaction that is much greater than that conferred by ADD pathology, and that this might be exploited to make the clinical differentiation between such subjects, even in the absence of other clinical features. Why ADLB subjects would have relatively preserved olfaction compared to ADD/DLB subjects was initially puzzling to us, as both have severe α-synuclein pathology in the olfactory bulb (median score of 4/4 in both groups in this study). However, the frontal cortex and amygdala also contribute to the subjective sense of smell [103], and for both of these areas, α-synuclein pathology is significantly more severe in ADD/DLB than in ADLB with median amygdala scores of 4/4/ vs 3/4 and median frontal cortex scores of 1/4/ vs 0/4, respectively (p < 0.001, Mann-Whitney U-tests).

ADD and DLB often co-exist unknown to clinicians, and as this comorbidity may affect the presentation, rate of cognitive decline, and response to therapeutic agents [1–22], clinical trials for both conditions may be impaired. The most common comorbidity in ADD is LBD, affecting somewhat more than one-half or more of all those meeting clinicopathological ADD diagnostic criteria [9,23–25]. Dementia with Lewy bodies has greater α-synuclein pathology than ADLB and therefore may be more resistant to therapeutic agents targeting AD molecular lesions. In the majority of subjects with ADD and DLB, the typical clinical signs and symptoms of DLB [43,44] are absent and thus this co-existence is recognized only at autopsy [22,45–47]. Disease duration has been reported to be shorter in those with coexistent ADD and DLB [40,52]. There is therefore a critical need for better clinical differentiation of these two conditions.

Definitive laboratory-based biomarkers for DLB are not yet available. Molecular imaging of striatal dopamine receptors, and myocardial scintigraphy with [123] meta-iodobenzylguanidine (MIBG) have both been used as diagnostic adjuncts for DLB [104,105] with promising but not yet definitive results from small autopsy-confirmed studies [106,107]. Dopaminergic imaging may be less helpful in DLB as compared to PD, due to less consistent degeneration of nigrostriatal dopaminergic neuronal and nerve terminals [108–112]. Biofluids and PET imaging approaches have so far been unsuccessful in providing the required accuracy for identifying LBD [113–115]. Simulation studies have suggested that cortical biopsy [116–119] would have high sensitivity and specificity for DLB, and usage of needle cores rather than open biopsy may reduce morbidity to acceptable levels [116]. Biopsy of the peripheral nervous system [120], particularly the submandibular gland [121–124], also shows promise for diagnosing DLB. Autopsy studies have suggested that biopsy of the olfactory bulb would identify more than 90% of all subjects with LBD [90]. Better clinical diagnostic methods for DLB are critically needed, as improved sensitivity in the clinical identification of DLB would greatly assist recruitment for clinical trials and would allow exclusion or stratification of DLB subjects within ADD clinical trials.

Numerous studies have indicated the potential for olfactory function tests to distinguish different cerebrovascular and neurodegenerative disorders [53–64] and, in particular, to distinguish PD and DLB from ADD [65–70], but the great majority of these studies lack certainty due the reliance on a clinical diagnosis as gold standard. Several studies with neuropathological confirmation of LBD have suggested that loss of olfactory function may be more pronounced in DLB but these have been limited by small subject numbers [71–74].

As the first and mean UPSIT scores were not significantly different, it seems probable that hyposmia is a relatively early clinical occurrence in ADD/DLB, and hence smell testing could be helpful in the identification of prodromal DLB. Support for this possibility comes from studies of incidental Lewy body disease (ILBD), defined as the presence of LBD in asymptomatic elderly people. ILBD is a probable prodromal stage of PD or DLB as dopaminergic markers are halfway between asymptomatic elderly people without LBD and clinically-manifest PD [75–78]. Our group has previously reported that olfactory function in subjects with ILBD is also halfway between PD and asymptomatic elderly people without LBD [79]; another clinicopathological study found an OR of 11.0 for hyposmia in the prediction of ILBD, using as a cutoff the lowest tertile of olfactory function [80], and these postmortem studies have been further confirmed by the in vivo association of hyposmia with decreased striatal dopamine transporter imaging [87,88]. Additional support comes from reports of hyposmia in some clinically normal GBA and LRRK2 mutation carriers [81,82] and in idiopathic REM sleep behavior disorder (iRBD) [83–86].

Conclusions

In this study we sought to determine the diagnostic utility of hyposmia as a diagnostic predictor of neuropathologically-identified ADD/DLB, using considerably larger subject numbers than previous studies. Our results confirm those of the prior studies, where subjects with ADD/DLB have been repeatedly found to have worse olfactory function than ADD. The odds ratios for ROC-determined first and mean UPSIT score cutoffs, 17.5 and 18.0, respectively, were surprisingly stronger than the ORs for both visual hallucinations and parkinsonism (1.7–4.4), two of the key core clinical DLB features. These figures suggest that olfactory testing should be considered as a core clinical feature of DLB and could potentially be of great assistance in the clinical separation of ADD and DLB, allowing stratification of clinical trial subjects. Larger neuropathologically-examined subject numbers would help to confirm the results of the present study but if results from the prior three neuropathologically-confirmed studies are added to this, there are 137 LBD cases and 365 controls (ADD or normal controls), all with the same general finding of much lower olfactory test scores in the LBD groups. We cannot be sure, due to insufficient numbers of pure DLB cases in our study, that olfactory testing might be equally useful for the separation of pure DLB from ADD, but the low mean UPSIT score of the 4 cases in the present study is consistent with that observed for the mixed ADD/DLB cases.

Supporting information

[Figure omitted. See PDF.]

S1 Data.

https://doi.org/10.1371/journal.pone.0231720.s001

(XLSX)

Citation: Beach TG, Adler CH, Zhang N, Serrano GE, Sue LI, Driver-Dunckley E, et al. (2020) Severe hyposmia distinguishes neuropathologically confirmed dementia with Lewy bodies from Alzheimer’s disease dementia. PLoS ONE 15(4): e0231720. https://doi.org/10.1371/journal.pone.0231720

References

1. Sonnen JA, Santa CK, Hemmy LS, Woltjer R, Leverenz JB, Montine KS, et al. (2011) Ecology of the aging human brain. Arch Neurol 68, 1049–1056. pmid:21825242

2. Brenowitz WD, Keene CD, Hawes SE, Hubbard RA, Longstreth WT Jr., Woltjer RL, et al. (2017) Alzheimer’s disease neuropathologic change, Lewy body disease, and vascular brain injury in clinic- and community-based samples. Neurobiol Aging 53, 83–92. pmid:28236716

3. Wilson RS, Capuano AW, Bennett DA, Schneider JA, Boyle PA (2016) Temporal course of neurodegenerative effects on cognition in old age. Neuropsychology 30, 591–599. pmid:27111293

4. Caselli RJ, Beach TG, Knopman DS, Graff-Radford NR (2017) Alzheimer Disease: Scientific Breakthroughs and Translational Challenges. Mayo Clin Proc 92, 978–994. pmid:28578785

5. White LR, Edland SD, Hemmy LS, Montine KS, Zarow C, Sonnen JA, et al. (2016) Neuropathologic comorbidity and cognitive impairment in the Nun and Honolulu-Asia Aging Studies. Neurology 86, 1000–1008. pmid:26888993

6. Kawas CH, Kim RC, Sonnen JA, Bullain SS, Trieu T, Corrada MM (2015) Multiple pathologies are common and related to dementia in the oldest-old: The 90+ Study. Neurology 85, 535–542. pmid:26180144

7. Sonnen JA, Crane PK, Haneuse S, Li G, Schellenberg GD, Craft S, et al. (2007) Pathological correlates of dementia in a longitudinal, population-based sample of aging. Ann Neurol 62, 406–413. pmid:17879383

8. Jellinger KA, Attems J (2014) Challenges of multimorbidity of the aging brain: a critical update. J Neural Transm

9. Beach TG, Adler CH, Sue LI, Serrano G, Shill HA, Walker DG, et al. (2015) Arizona Study of Aging and Neurodegenerative Disorders and Brain and Body Donation Program. Neuropathology

10. Bennett DA, Schneider JA, Arvanitakis Z, Kelly JF, Aggarwal NT, Shah RC, et al. (2006) Neuropathology of older persons without cognitive impairment from two community-based studies. Neurology 66, 1837–1844. pmid:16801647

11. Negash S, Bennett DA, Wilson RS, Schneider JA, Arnold SE (2011) Cognition and neuropathology in aging: multidimensional perspectives from the Rush Religious Orders Study and Rush Memory And Aging Project. Curr Alzheimer Res 8, 336–340. pmid:21222592

12. Schneider JA, Arvanitakis Z, Bang W, Bennett DA (2007) Mixed brain pathologies account for most dementia cases in community-dwelling older persons. Neurology 69, 2197–2204. pmid:17568013

13. Dugger BN, Clark CM, Serrano G, Mariner M, Bedell BJ, Coleman RE, et al. (2014) Neuropathologic heterogeneity does not impair florbetapir-positron emission tomography postmortem correlates. J Neuropathol Exp Neurol 73, 72–80. pmid:24335535

14. Serrano GE, Sabbagh MN, Sue LI, Hidalgo JA, Schneider JA, Bedell BJ, et al. (2014) Positive florbetapir PET amyloid imaging in a subject with frequent cortical neuritic plaques and frontotemporal lobar degeneration with TDP43-positive inclusions. J Alzheimers Dis 42, 813–821. pmid:24927705

15. Arvanitakis Z, Leurgans SE, Barnes LL, Bennett DA, Schneider JA (2011) Microinfarct pathology, dementia, and cognitive systems. Stroke 42, 722–727. pmid:21212395

16. Boyle PA, Wilson RS, Yu L, Barr AM, Honer WG, Schneider JA, et al. (2013) Much of late life cognitive decline is not due to common neurodegenerative pathologies. Ann Neurol 74, 478–489. pmid:23798485

17. Nag S, Yu L, Boyle PA, Leurgans SE, Bennett DA, Schneider JA (2018) TDP-43 pathology in anterior temporal pole cortex in aging and Alzheimer’s disease. Acta Neuropathol Commun 6, 33- pmid:29716643

18. Nelson PT, Abner EL, Schmitt FA, Kryscio RJ, Jicha GA, Smith CD, et al. (2010) Modeling the association between 43 different clinical and pathological variables and the severity of cognitive impairment in a large autopsy cohort of elderly persons. Brain Pathol 20, 66–79. pmid:19021630

19. Smith VD, Bachstetter AD, Ighodaro E, Roberts K, Abner EL, Fardo DW, et al. (2018) Overlapping but distinct TDP-43 and tau pathologic patterns in aged hippocampi. Brain Pathol 28, 264–273. pmid:28281308

20. Josephs KA, Dickson DW, Tosakulwong N, Weigand SD, Murray ME, Petrucelli L, et al. (2017) Rates of hippocampal atrophy and presence of post-mortem TDP-43 in patients with Alzheimer’s disease: a longitudinal retrospective study. Lancet Neurol 16, 917–924. pmid:28919059

21. Josephs KA, Whitwell JL, Weigand SD, Murray ME, Tosakulwong N, Liesinger AM, et al. (2014) TDP-43 is a key player in the clinical features associated with Alzheimer’s disease. Acta Neuropathol 127, 811–824. pmid:24659241

22. Malek-Ahmadi M, Beach TG, Zamrini E, Adler CH, Sabbagh MN, Shill HA, et al. (2019) Faster cognitive decline in dementia due to Alzheimer’s disease with clinically undiagnosed Lewy body disease. PLoS One 14 (6):e0217566. pmid:31237877

23. Tsuang DW, Riekse RG, Purganan KM, David AC, Montine TJ, Schellenberg GD, et al. (2006) Lewy body pathology in late-onset familial Alzheimer’s disease: a clinicopathological case series. J Alzheimers Dis 9, 235–242. pmid:16914833

24. Uchikado H, Lin WL, DeLucia MW, Dickson DW (2006) Alzheimer disease with amygdala Lewy bodies: a distinct form of alpha-synucleinopathy. J Neuropathol Exp Neurol 65, 685–697. pmid:16825955

25. Hamilton RL (2000) Lewy bodies in Alzheimer’s disease: a neuropathological review of 145 cases using alpha-synuclein immunohistochemistry. Brain Pathol 10, 378–384. pmid:10885656

26. Bertrand E, Lechowicz W, Szpak GM, Lewandowska E, Dymecki J, Wierzba-Bobrowicz T (2004) Limbic neuropathology in idiopathic Parkinson’s disease with concomitant dementia. Folia Neuropathol 42, 141–150. pmid:15535032

27. Kovari E, Gold G, Herrmann FR, Canuto A, Hof PR, Bouras C, et al. (2003) Lewy body densities in the entorhinal and anterior cingulate cortex predict cognitive deficits in Parkinson’s disease. Acta Neuropathol (Berl) 106, 83–88.

28. Mattila PM, Rinne JO, Helenius H, Dickson DW, Roytta M (2000) Alpha-synuclein-immunoreactive cortical Lewy bodies are associated with cognitive impairment in Parkinson’s disease. Acta Neuropathol (Berl) 100, 285–290.

29. Hurtig HI, Trojanowski JQ, Galvin J, Ewbank D, Schmidt ML, Lee VM, et al. (2000) Alpha-synuclein cortical Lewy bodies correlate with dementia in Parkinson’s disease. Neurology 54, 1916–1921. pmid:10822429

30. Mattila PM, Rinne JO, Helenius H, Dickson DW, Roytta M (2000) Alpha-synuclein-immunoreactive cortical Lewy bodies are associated with cognitive impairment in Parkinson’s disease. Acta Neuropathol (Berl) 100, 285–290.

31. Braak H, Rub U, Jansen Steur EN, Del Tredici K, de Vos RA (2005) Cognitive status correlates with neuropathologic stage in Parkinson disease. Neurology 64, 1404–1410. pmid:15851731

32. Jellinger KA (2009) Significance of brain lesions in Parkinson disease dementia and Lewy body dementia. Front Neurol Neurosci 24, 114–125. pmid:19182469

33. Burack MA, Hartlein J, Flores HP, Taylor-Reinwald L, Perlmutter JS, Cairns NJ (2010) In vivo amyloid imaging in autopsy-confirmed Parkinson disease with dementia. Neurology 74, 77–84. pmid:20038776

34. Irwin DJ, White MT, Toledo JB, Xie SX, Robinson JL, Van DV, et al. (2012) Neuropathologic substrates of Parkinson disease dementia. Ann Neurol 72, 587–598. pmid:23037886

35. Sabbagh MN, Adler CH, Lahti TJ, Connor DJ, Vedders L, Peterson LK, et al. (2009) Parkinson disease with dementia: comparing patients with and without Alzheimer pathology. Alzheimer Dis Assoc Disord 23, 295–297. pmid:19812474

36. Compta Y, Parkkinen L, O’Sullivan SS, Vandrovcova J, Holton JL, Collins C, et al. (2011) Lewy- and Alzheimer-type pathologies in Parkinson’s disease dementia: which is more important? Brain 134, 1493–1505. pmid:21596773

37. Hely MA, Reid WG, Adena MA, Halliday GM, Morris JG (2008) The Sydney multicenter study of Parkinson’s disease: the inevitability of dementia at 20 years. Mov Disord 23, 837–844. pmid:18307261

38. Akhtar RS, Xie SX, Brennan L, Pontecorvo MJ, Hurtig HI, Trojanowski JQ, et al. (2016) Amyloid-Beta Positron Emission Tomography Imaging of Alzheimer’s Pathology in Parkinson’s Disease Dementia. Mov Disord Clin Pract 3, 367–375. pmid:27500181

39. Deramecourt V, Bombois S, Maurage CA, Ghestem A, Drobecq H, Vanmechelen E, et al. (2006) Biochemical staging of synucleinopathy and amyloid deposition in dementia with Lewy bodies. J Neuropathol Exp Neurol 65, 278–288. pmid:16651889

40. Graff-Radford J, Aakre J, Savica R, Boeve B, Kremers WK, Ferman TJ, et al. (2017) Duration and Pathologic Correlates of Lewy Body Disease. JAMA Neurol 74, 310–315. pmid:28114455

41. Barker WW, Luis CA, Kashuba A, Luis M, Harwood DG, Loewenstein D, et al. (2002) Relative frequencies of Alzheimer disease, Lewy body, vascular and frontotemporal dementia, and hippocampal sclerosis in the State of Florida Brain Bank. Alzheimer Dis Assoc Disord 16, 203–212. pmid:12468894

42. Beach TG, Adler CH, Sue LI, Serrano G, Shill HA, Walker DG, et al. (2015) Arizona Study of Aging and Neurodegenerative Disorders and Brain and Body Donation Program. Neuropathology 35, 354–389. pmid:25619230

43. McKeith IG, Dickson DW, Lowe J, Emre M, O’Brien JT, Feldman H, et al. (2005) Diagnosis and management of dementia with Lewy bodies: third report of the DLB Consortium. Neurology 65, 1863–1872. pmid:16237129

44. McKeith IG, Boeve BF, Dickson DW, Halliday G, Taylor JP, Weintraub D, et al. (2017) Diagnosis and management of dementia with Lewy bodies: Fourth consensus report of the DLB Consortium. Neurology 89, 88–100. pmid:28592453

45. McKeith I, Taylor JP, Thomas A, Donaghy P, Kane J (2016) Revisiting DLB Diagnosis: A Consideration of Prodromal DLB and of the Diagnostic Overlap With Alzheimer Disease. J Geriatr Psychiatry Neurol 29, 249–253. pmid:27502299

46. Lebouvier T, Delrieu J, Evain S, Pallardy A, Sauvaget A, Letournel F, et al. (2013) [Dementia: Where are the Lewy bodies?]. Rev Neurol (Paris) 169, 844–857.

47. Nelson PT, Jicha GA, Kryscio RJ, Abner EL, Schmitt FA, Cooper G, et al. (2010) Low sensitivity in clinical diagnoses of dementia with Lewy bodies. J Neurol 257, 359–366. pmid:19795154

48. Olichney JM, Galasko D, Salmon DP, Hofstetter CR, Hansen LA, Katzman R, et al. (1998) Cognitive decline is faster in Lewy body variant than in Alzheimer’s disease. Neurology 51, 351–357. pmid:9710002

49. Kramberger MG, Auestad B, Garcia-Ptacek S, Abdelnour C, Olmo JG, Walker Z, et al. (2017) Long-Term Cognitive Decline in Dementia with Lewy Bodies in a Large Multicenter, International Cohort. J Alzheimers Dis 57, 787–795. pmid:28304294

50. Brenowitz WD, Hubbard RA, Keene CD, Hawes SE, Longstreth WT Jr., Woltjer RL, et al. (2017) Mixed neuropathologies and estimated rates of clinical progression in a large autopsy sample. Alzheimers Dement 13, 654–662. pmid:27870939

51. Kraybill ML, Larson EB, Tsuang DW, Teri L, McCormick WC, Bowen JD, et al. (2005) Cognitive differences in dementia patients with autopsy-verified AD, Lewy body pathology, or both. Neurology 64, 2069–2073. pmid:15985574

52. Ferman TJ, Aoki N, Crook JE, Murray ME, Graff-Radford NR, van Gerpen JA, et al. (2018) The limbic and neocortical contribution of alpha-synuclein, tau, and amyloid beta to disease duration in dementia with Lewy bodies. Alzheimers Dement 14, 330–339. pmid:29100980

53. Doty RL, Perl DP, Steele JC, Chen KM, Pierce JD Jr., Reyes P, et al. (1991) Olfactory dysfunction in three neurodegenerative diseases. Geriatrics 46 Suppl 1, 47–51.

54. Doty RL, Golbe LI, McKeown DA, Stern MB, Lehrach CM, Crawford D (1993) Olfactory testing differentiates between progressive supranuclear palsy and idiopathic Parkinson’s disease. Neurology 43, 962–965. pmid:8492953

55. Wenning GK, Shephard B, Hawkes C, Petruckevitch A, Lees A, Quinn N (1995) Olfactory function in atypical parkinsonian syndromes. Acta Neurol Scand 91, 247–250. pmid:7625148

56. Adler CH, Gwinn KA, Newman S (1998) Olfactory function in restless legs syndrome. Mov Disord 13, 563–565. pmid:9613755

57. McKinnon JH, Demaerschalk BM, Caviness JN, Wellik KE, Adler CH, Wingerchuk DM (2007) Sniffing out Parkinson disease: can olfactory testing differentiate parkinsonian disorders? Neurologist 13, 382–385. pmid:18090718

58. Shah M, Muhammed N, Findley LJ, Hawkes CH (2008) Olfactory tests in the diagnosis of essential tremor. Parkinsonism Relat Disord 14, 563–568. pmid:18321760

59. Rahayel S, Frasnelli J, Joubert S (2012) The effect of Alzheimer’s disease and Parkinson’s disease on olfaction: a meta-analysis. Behav Brain Res 231, 60–74. pmid:22414849

60. Moscovich M, Munhoz RP, Teive HA, Raskin S, Carvalho MJ, Barbosa ER, et al. (2012) Olfactory impairment in familial ataxias. J Neurol Neurosurg Psychiatry 83, 970–974. pmid:22791905

61. Navarro-Otano J, Gaig C, Muxi A, Lomena F, Compta Y, Buongiorno MT, et al. (2014) 123I-MIBG cardiac uptake, smell identification and 123I-FP-CIT SPECT in the differential diagnosis between vascular parkinsonism and Parkinson’s disease. Parkinsonism Relat Disord 20, 192–197. pmid:24252299

62. Georgiopoulos C, Davidsson A, Engstrom M, Larsson EM, Zachrisson H, Dizdar N (2015) The diagnostic value of dopamine transporter imaging and olfactory testing in patients with parkinsonian syndromes. J Neurol 262, 2154–2163. pmid:26122543

63. Krismer F, Pinter B, Mueller C, Mahlknecht P, Nocker M, Reiter E, et al. (2017) Sniffing the diagnosis: Olfactory testing in neurodegenerative parkinsonism. Parkinsonism Relat Disord 35, 36–41. pmid:27890451

64. Katzenschlager R, Lees AJ (2004) Olfaction and Parkinson’s syndromes: its role in differential diagnosis. Curr Opin Neurol 17, 417–423. pmid:15247536

65. Bovi T, Antonini A, Ottaviani S, Antonioli A, Cecchini MP, Di F, et al. (2010) The status of olfactory function and the striatal dopaminergic system in drug-induced parkinsonism. J Neurol 257, 1882–1889. pmid:20635186

66. Westervelt HJ, Bruce JM, Faust MA (2016) Distinguishing Alzheimer’s disease and dementia with Lewy bodies using cognitive and olfactory measures. Neuropsychology 30, 304–311. pmid:26280301

67. Williams SS, Williams J, Combrinck M, Christie S, Smith AD, McShane R (2009) Olfactory impairment is more marked in patients with mild dementia with Lewy bodies than those with mild Alzheimer disease. J Neurol Neurosurg Psychiatry 80, 667–670. pmid:19448090

68. Westervelt HJ, Stern RA, Tremont G (2003) Odor identification deficits in diffuse lewy body disease. Cogn Behav Neurol 16, 93–99. pmid:12799595

69. Yoon JH, Kim M, Moon SY, Yong SW, Hong JM (2015) Olfactory function and neuropsychological profile to differentiate dementia with Lewy bodies from Alzheimer’s disease in patients with mild cognitive impairment: A 5-year follow-up study. J Neurol Sci 355, 174–179. pmid:26076880

70. Yoo HS, Jeon S, Chung SJ, Yun M, Lee PH, Sohn YH, et al. (2018) Olfactory dysfunction in Alzheimer’s disease- and Lewy body-related cognitive impairment. Alzheimers Dement 14, 1243–1252. pmid:29936148

71. McShane RH, Nagy Z, Esiri MM, King E, Joachim C, Sullivan N, et al. (2001) Anosmia in dementia is associated with Lewy bodies rather than Alzheimer’s pathology. J Neurol Neurosurg Psychiatry 70, 739–743. pmid:11385006

72. Mirra SS, Heyman A, McKeel D, Sumi SM, Crain BJ, Brownlee LM, et al.(1991) The Consortium to Establish a Registry for Alzheimer’s Disease (CERAD). Part II. Standardization of the neuropathologic assessment of Alzheimer’s disease. Neurology 41, 479–486. pmid:2011243

73. Olichney JM, Murphy C, Hofstetter CR, Foster K, Hansen LA, Thal LJ, et al.(2005) Anosmia is very common in the Lewy body variant of Alzheimer’s disease. J Neurol Neurosurg Psychiatry 76, 1342–1347. pmid:16170073

74. Wilson RS, Yu L, Schneider JA, Arnold SE, Buchman AS, Bennett DA (2011) Lewy bodies and olfactory dysfunction in old age. Chem Senses 36, 367–373. pmid:21257733

75. Beach TG, Adler CH, Sue LI, Peirce JB, Bachalakuri J, Sing-Hernandez JE, et al. (2008) Reduced striatal tyrosine hydroxylase in incidental Lewy body disease. Acta Neuropathol 115, 445–451. pmid:17985144

76. Delledonne A, Klos KJ, Fujishiro H, Ahmed Z, Parisi JE, Josephs KA, et al. (2008) Incidental Lewy body disease and preclinical Parkinson disease. Arch Neurol 65, 1074–1080. pmid:18695057

77. Dickson DW, Fujishiro H, Delledonne A, Menke J, Ahmed Z, Klos KJ, et al. (2008) Evidence that incidental Lewy body disease is pre-symptomatic Parkinson’s disease. Acta Neuropathol 115, 437–444. pmid:18264713

78. Iacono D, Geraci-Erck M, Rabin ML, Adler CH, Serrano G, Beach TG, et al. (2015) Parkinson disease and incidental Lewy body disease: Just a question of time? Neurology 85, 1670–1679. pmid:26468408

79. Driver-Dunckley E, Adler CH, Hentz JG, Dugger BN, Shill HA, Caviness JN, et al. (2014) Olfactory dysfunction in incidental Lewy body disease and Parkinson’s disease. Parkinsonism Relat Disord

80. Ross GW, Abbott RD, Petrovitch H, Tanner CM, Davis DG, Nelson J, et al.(2006) Association of olfactory dysfunction with incidental Lewy bodies. Mov Disord 21, 2062–2067. pmid:16991138

81. Saunders-Pullman R, Stanley K, Wang C, San LM, Shanker V, Hunt A, et al. (2011) Olfactory dysfunction in LRRK2 G2019S mutation carriers. Neurology 77, 319–324. pmid:21753159

82. Beavan M, McNeill A, Proukakis C, Hughes DA, Mehta A, Schapira AH (2015) Evolution of prodromal clinical markers of Parkinson disease in a GBA mutation-positive cohort. JAMA Neurol 72, 201–208. pmid:25506732

83. Iranzo A, Serradell M, Vilaseca I, Valldeoriola F, Salamero M, Molina C, et al. (2013) Longitudinal assessment of olfactory function in idiopathic REM sleep behavior disorder. Parkinsonism Relat Disord 19, 600–604. pmid:23529022

84. Miyamoto T, Miyamoto M, Iwanami M, Hirata K, Kobayashi M, Nakamura M, et al. (2010) Olfactory dysfunction in idiopathic REM sleep behavior disorder. Sleep Med 11, 458–461. pmid:20378403

85. Fantini ML, Postuma RB, Montplaisir J, Ferini-Strambi L (2006) Olfactory deficit in idiopathic rapid eye movements sleep behavior disorder. Brain Res Bull 70, 386–390. pmid:17027774

86. Postuma RB, Iranzo A, Hu M, Hogl B, Boeve BF, Manni R, et al. (2019) Risk and predictors of dementia and parkinsonism in idiopathic REM sleep behaviour disorder: a multicentre study. Brain 142, 744–759. pmid:30789229

87. Wong KK, Muller ML, Kuwabara H, Studenski SA, Bohnen NI (2010) Olfactory loss and nigrostriatal dopaminergic denervation in the elderly. Neurosci Lett 484, 163–167. pmid:20727944

88. Pak K, Kim K, Lee MJ, Lee JM, Kim BS, Kim SJ, et al. (2018) Correlation between the availability of dopamine transporter and olfactory function in healthy subjects. Eur Radiol 28, 1756–1760. pmid:29164380

89. Attems J, Walker L, Jellinger KA (2014) Olfactory bulb involvement in neurodegenerative diseases. Acta Neuropathol 127, 459–475. pmid:24554308

90. Beach TG, White CL III, Hladik CL, Sabbagh MN, Connor DJ, Shill HA, et al. (2009) Olfactory bulb alpha-synucleinopathy has high specificity and sensitivity for Lewy body disorders. Acta Neuropathol 117, 169–174. pmid:18982334

91. Beach TG, Adler CH, Lue L, Sue LI, Bachalakuri J, Henry-Watson J, et al. (2009) Unified staging system for Lewy body disorders: correlation with nigrostriatal degeneration, cognitive impairment and motor dysfunction. Acta Neuropathol 117, 613–634. pmid:19399512

92. Hubbard PS, Esiri MM, Reading M, McShane R, Nagy Z (2007) Alpha-synuclein pathology in the olfactory pathways of dementia patients. J Anat 211, 117–124. pmid:17553102

93. Beach TG, Adler CH, Sue LI, Serrano G, Shill HA, Walker DG, et al. (2015) Arizona Study of Aging and Neurodegenerative Disorders and Brain and Body Donation Program. Neuropathology 35, 354–389. pmid:25619230

94. (1997) Consensus recommendations for the postmortem diagnosis of Alzheimer’s disease. The National Institute on Aging, and Reagan Institute Working Group on Diagnostic Criteria for the Neuropathological Assessment of Alzheimer’s Disease. Neurobiol Aging 18, S1–S2. pmid:9330978

95. Driver-Dunckley E, Adler CH, Hentz JG, Dugger BN, Shill HA, Caviness JN, et al. (2014) Olfactory dysfunction in incidental Lewy body disease and Parkinson’s disease. Parkinsonism Relat Disord 20, 1260–1262. pmid:25172126

96. Stern MB, Doty RL, Dotti M, Corcoran P, Crawford D, McKeown DA, et al. (1994) Olfactory function in Parkinson’s disease subtypes. Neurology 44, 266–268. pmid:8309571

97. Gerkin RC, Adler CH, Hentz JG, Shill HA, Driver-Dunckley E, Mehta SH, et al. (2017) Improved diagnosis of Parkinson’s disease from a detailed olfactory phenotype. Ann Clin Transl Neurol 4, 714–721. pmid:29046880

98. Shprecher DR, Adler CH, Zhang N, Hentz JG, Serrano GE, Dugger BN, et al. (2018) Predicting alpha-synuclein pathology by REM sleep behavior disorder diagnosis. Parkinsonism Relat Disord

99. Adler CH, Hentz JG, Shill HA, Sabbagh MN, Driver-Dunckley E, Evidente VG, et al. (2011) Probable RBD is increased in Parkinson’s disease but not in essential tremor or restless legs syndrome. Parkinsonism Relat Disord 17, 456–458. pmid:21482171

100. Boeve BF, Silber MH, Ferman TJ, Lin SC, Benarroch EE, Schmeichel AM, et al. (2013) Clinicopathologic correlations in 172 cases of rapid eye movement sleep behavior disorder with or without a coexisting neurologic disorder. Sleep Med 14, 754–762. pmid:23474058

101. Boeve BF, Molano JR, Ferman TJ, Lin SC, Bieniek K, Tippmann-Peikert M, et al.(2013) Validation of the Mayo Sleep Questionnaire to screen for REM sleep behavior disorder in a community-based sample. J Clin Sleep Med 9, 475–480. pmid:23674939

102. DeLong ER, DeLong DM, Clarke-Pearson D L (1988) Comparing the areas under two or more correlated receiver operating characteristic curves: A nonparametric approach. Biometrics 44, 837–845. pmid:3203132

103. Patin A, Pause BM (2015) Human amygdala activations during nasal chemoreception. Neuropsychologia 78, 171–194. pmid:26459095

104. Orimo S, Yogo M, Nakamura T, Suzuki M, Watanabe H (2016) (123)I-meta-iodobenzylguanidine (MIBG) cardiac scintigraphy in alpha-synucleinopathies. Ageing Res Rev 30, 122–133. pmid:26835846

105. Albin RL, Fisher-Hubbard A, Shanmugasundaram K, Koeppe RA, Burke JF, Camelo-Piragua S, et al. (2015) Post-Mortem evaluation of amyloid-dopamine terminal positron emission tomography dementia classifications. Ann Neurol 78, 824–830. pmid:26183692

106. Siderowf A, Pontecorvo MJ, Shill HA, Mintun MA, Arora A, Joshi AD, et al. (2014) PET imaging of amyloid with Florbetapir F 18 and PET imaging of dopamine degeneration with 18F-AV-133 (florbenazine) in patients with Alzheimer’s disease and Lewy body disorders. BMC Neurol 14, 79- pmid:24716655

107. McCleery J, Morgan S, Bradley KM, Noel-Storr AH, Ansorge O, Hyde C (2015) Dopamine transporter imaging for the diagnosis of dementia with Lewy bodies. Cochrane Database Syst Rev 1, CD010633- pmid:25632881

108. Walker Z, Jaros E, Walker RW, Lee L, Costa DC, Livingston G, et al. (2007) Dementia with Lewy bodies: a comparison of clinical diagnosis, FP-CIT single photon emission computed tomography imaging and autopsy. J Neurol Neurosurg Psychiatry 78, 1176–1181. pmid:17353255

109. Zaccai J, Brayne C, McKeith I, Matthews F, Ince PG (2008) Patterns and stages of alpha-synucleinopathy: Relevance in a population-based cohort. Neurology 70, 1042–1048. pmid:18362284

110. Colloby SJ, McParland S, O’Brien JT, Attems J (2012) Neuropathological correlates of dopaminergic imaging in Alzheimer’s disease and Lewy body dementias. Brain 135, 2798–2808. pmid:22961551

111. Kraemmer J, Kovacs GG, Perju-Dumbrava L, Pirker S, Traub-Weidinger T, Pirker W (2014) Correlation of striatal dopamine transporter imaging with post mortem substantia nigra cell counts. Mov Disord 29, 1767–1773. pmid:25048738

112. Beach TG, Walker DG, Sue LI, Newell A, Adler CC, Joyce JN (2004) Substantia nigra Marinesco bodies are associated with decreased striatal expression of dopaminergic markers. J Neuropathol Exp Neurol 63, 329–337. pmid:15099023

113. Eusebi P, Giannandrea D, Biscetti L, Abraha I, Chiasserini D, Orso M, et al. (2017) Diagnostic utility of cerebrospinal fluid alpha-synuclein in Parkinson’s disease: A systematic review and meta-analysis. Mov Disord 32, 1389–1400. pmid:28880418

114. Simonsen AH, Kuiperij B, El-Agnaf OM, Engelborghs S, Herukka SK, Parnetti L, et al. (2016) The utility of alpha-synuclein as biofluid marker in neurodegenerative diseases: a systematic review of the literature. Biomark Med 10, 19–34. pmid:26314196

115. Catafau AM, Bullich S (2017) Non-Amyloid PET Imaging Biomarkers for Neurodegeneration: Focus on Tau, Alpha-Synuclein and Neuroinflammation. Curr Alzheimer Res 14, 169–177. pmid:27334945

116. Serrano GE, Intorcia A, Carew J, Chiarolanza G, Hidalgo JA, Sue LI, et al.(2015) Feasibility Study: Comparison of Frontal Cortex Needle Core Versus Open Biopsy for Detection of Characteristic Proteinopathies of Neurodegenerative Diseases. J Neuropathol Exp Neurol 74, 934–942. pmid:26230581

117. Venneti S, Robinson JL, Roy S, White MT, Baccon J, Xie SX, et al. (2011) Simulated brain biopsy for diagnosing neurodegeneration using autopsy-confirmed cases. Acta Neuropathol 122, 737–745. pmid:21959586

118. King A, Maekawa S, Bodi I, Troakes C, Curran O, Ashkan K, et al. (2013) Simulated surgical-type cerebral biopsies from post-mortem brains allows accurate neuropathological diagnoses in the majority of neurodegenerative disease groups. Acta Neuropathol Commun 1, 53- pmid:24252649

119. Elobeid A, Laurell K, Cesarini KG, Alafuzoff I (2015) Correlations between mini-mental state examination score, cerebrospinal fluid biomarkers, and pathology observed in brain biopsies of patients with normal-pressure hydrocephalus. J Neuropathol Exp Neurol 74, 470–479. pmid:25868149

120. Lee JM, Derkinderen P, Kordower JH, Freeman R, Munoz DG, Kremer T, et al. (2017) The Search for a Peripheral Biopsy Indicator of alpha-Synuclein Pathology for Parkinson Disease. J Neuropathol Exp Neurol

121. Adler CH, Dugger BN, Hinni ML, Lott DG, Driver-Dunckley E, Hidalgo J, et al. (2014) Submandibular gland needle biopsy for the diagnosis of Parkinson disease. Neurology 82, 858–864. pmid:24500652

122. Adler CH, Dugger BN, Hentz JG, Hinni ML, Lott DG, Driver-Dunckley E, et al. (2016) Peripheral synucleinopathy in early Parkinson’s eisease: submandibular gland needle biopsy findings. Mov Disord 31, 250–256. pmid:26799362

123. Beach TG, Adler CH, Dugger BN, Serrano G, Hidalgo J, Henry-Watson J, et al. (2013) Submandibular gland biopsy for the diagnosis of Parkinson disease. J Neuropathol Exp Neurol 72, 130–136. pmid:23334596

124. Beach TG, Adler CH, Serrano G, Sue LI, Walker DG, Dugger BN, et al. (2016) Prevalence of submandibular gland synucleinopathy in Parkinson’s disease, dementia with Lewy bodies and other Lewy body disorders. J Parkinsons Dis 6, 153–163. pmid:26756744