Severe Hyposmia Distinguishes Neuropathologically Confirmed Dementia with Lewy Bodies from Alzheimer’s Disease Dementia

Abstract

<jats:title>Abstract</jats:title><jats:p>Due to the absence of core clinical features, many subjects with neuropathologically-confirmed dementia with Lewy bodies (DLB) are never diagnosed as such during life. Most of these are diagnosed with 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 numerous published studies that suggest that olfactory function tests may be able to differentiate some neurodegenerative conditions from each other and from normal subjects, but there are very few studies with neuropathological confirmation of diagnosis. We compared University of Pennsylvania Smell Identification Test (UPSIT) results in 209 subjects: 1) 29 concurrently meeting intermediate or high consensus clinicopathological criteria for both DLB and ADD 2) 96 meeting criteria for ADD without DLB 3) 84 control subjects that were non-demented and without parkinsonism at death. The DLB subjects had significantly lower (one-way ANOVA p &lt; 0.0001, pairwise Bonferroni p &lt; 0.05) first and mean UPSIT scores (13.7 and 13.2) than ADD (23.3 and 22.2) or controls (29.6 and 28.9). For 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 predicting a DLB vs ADD diagnosis, as compared to 3.3 for the presence or absence of visual hallucinations throughout the clinical observation period. To our knowledge, this is the largest study to date comparing olfactory function in subjects with neuropathologically confirmed DLB 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.</jats:p>

Olfaction in Neuropathologically Defined Progressive Supranuclear Palsy

“…Hyposmia is likely to begin at prodromal disease stages as it is present in subjects with incidental Lewy body disease and often predates the appearance of motor features. [1][2][3][4][5][6][7][8] On the contrary, patients with clinically determined progressive supranuclear palsy (PSP) have been reported to have normal olfaction. [9][10][11][12][13] However, there is a lack of studies performed regarding pathological confirmation of disease state.…”

“…Previous studies have shown that hyposmia is a feature of idiopathic Parkinson's disease (PD) and dementia with Lewy bodies (DLBs). Hyposmia is likely to begin at prodromal disease stages as it is present in subjects with incidental Lewy body disease and often predates the appearance of motor features 1‐8 . On the contrary, patients with clinically determined progressive supranuclear palsy (PSP) have been reported to have normal olfaction 9‐13 .…”

Alzheimer’s Disease Neuropathological Comorbidities Are Common in the Younger-Old

“…Similarly, up to one-half of subjects with dementia and Parkinson's disease [95][96][97][98][99][100][101][102][103][104][105][106][107] and three-quarters or more of those with DLB, have clinically significant AD pathology [108][109][110][111]. In the great majority of subjects with both ADD and LBD, this co-existence is recognized only at autopsy [41,[112][113][114][115], currently preventing, except for the minority with clinically-typical DLB, the exclusion or stratification of LBD subjects within ADD clinical trials.The presence of LBD in ADD is clearly of clinical significance. Multiple autopsy-validated studies have indicated that cognitive decline is faster in ADD with any degree of associated LBD [26,[42][43][44][45].…”