Cognitive scores in neuropsychological examination at inclusion are sum-marized in table 3. Patients in cluster I had a worse performance in delayed free recall in the FCSRT when compared with patients included in cluster II (p = 0.02) and showed a trend for a worse performance when compared with cluster III (p = 0.06) in post-hoc analyses. There were no other differ-ences between groups.
Table 3. Neuropsychological data of the resultant clusters NEUROPSYCHOLOGICAL
aCluster I vs. Cluster II, p = 0.02; Cluster I vs. Cluster III, p=0.06.
*MMSE: Minimental State Examination, WAIS: Wechsler Adult Intelligence Scale, TMT-A: Trail Making Test A, FCSRT: Free and Cued Selective Reminding Test, VOSP: Visual Object and Space Perception battery, TMT-B: Trail Making Test B.
**Scalar scores according to age and educational level.
Discussion
In this study, we used for the first time a cluster analysis to characterize the different clinical subtypes of DLB based on the main clinical features during the prodromal phase of the disease. We obtained three clusters: a cognitive-predominant (cluster I), a neuropsychiatric-predominant (cluster II) and a parkinsonism-predominant (cluster III). These clusters differed in their clinical presentation, but also in the disease course. The cognitive-pre-dominant cluster was characterized by a long prodromal phase in which cognitive symptoms, mainly memory complaints, predominated. Patients in this cluster had hallucinations and other psychotic symptoms less frequently than patients in other clusters and a later onset. Parkinsonian features also appeared later as compared to the other clusters. The neuropsychiatric-pre-dominant cluster was characterized by an early onset of hallucinations and a higher frequency of psychotic symptoms as the presenting feature. Pa-tients in this cluster had also a late disease onset compared to the other two. The parkinsonism-predominant cluster was featured by predominant motor symptoms during the first years of the disease, a faster progression from symptom onset to dementia compared to the cognitive-predominant cluster, and a low frequency of hallucinations compared to the psychot-ic-predominant cluster.
We have identified only one study using a data-driven approach to investi-gate the features of DLB in a cohort of patients with mild dementia (122).
The authors found that the classical features of DLB aggregated together in their cluster solution supporting the diagnostic clinical criteria of DLB. How-ever, clinical heterogeneity in DLB has not been specifically investigated by a clustering method. In contrast, previous studies have applied different clustering methods in PD avoiding subjective biases (93,191–193). Similar
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their age-at-onset and rate of progression (191–193). In agreement with our data previous studies have described, that patients with earlier onset of parkinsonism are younger than those with earlier dementia or psychosis (194–196). It is remarkable that in some studies (191–193) the late-on-set subgroup in PD was characterised by a faster clinical decline, differing from our late-onset cluster (cluster II, neuropsychiatric-predominant), de-fined by the presence of early hallucinations, but not a faster progression.
Another described predictor for a faster progression in PD and DLB is the presence of concomitant AD pathology measured by CSF or amyloid-PET (48,195,197). It will be important to determine in future studies if those rapid evolution DLB clusters may have more frequency of concomitant AD.
Selection of variables in cluster analysis is critical for the obtained solu-tions. In our study we focused on the clinical features present during the prodromal phase of the disease. These features may capture better the in-itial topography of neuronal dysfunction and loss (117,191,193). As the disease progresses, symptoms and signs tend to converge, reflecting more severe and widespread Lewy-body pathology and neurodegeneration re-sulting in a more homogeneous syndrome. Although criteria for prodromal DLB have been proposed (50,94,109), they are not completely accepted or validated. In fact, one of the challenges in defining criteria in the prodromal phase of DLB is the high heterogeneity observed during this disease stage (109,110). Our findings clearly support the notion that clinical heteroge-neity is larger during the prodromal than the dementia stage. Our results showed that the neuropsychiatric and the parkinsonian-predominant clus-ters presented with clinical features that are characteristic of an underlying synucleinopathy. However, the cognitive-predominant cluster consisted of a syndrome of amnesic mild cognitive impairment (MCI) with a very slow progression. At the clinical level, this cluster partially overlaps with the typical amnesic MCI of AD (198). In fact, previous clinicopathological stud-ies have suggested that Lewy body disorders should be considered in the
differential diagnosis of MCI as a subset of subjects convert to DLB during follow-up (110). The clinical heterogeneity in the prodromal phase of DLB and the potential overlap with a subset of patients with prodromal AD rein-forces the need of developing specific CSF and/or imaging biomarkers for the initial stages of the disease.
It will be important to investigate how clinical heterogeneity in DLB relates to specific neuropathological profiles. Differences in the initial clinical syn-drome could be the result of the different regional burden of α-synuclein pathology (64,93,183). A higher disruption of brainstem integrity could translate into more severe motor features, while a predominant cortical distribution may translate into predominant cognitive or perceptive distur-bances (93,183). In addition, the common presence of coincident pathol-ogies such as AD (93,199), could also influence the clinical manifestation of Lewy body disorders. We applied for the first time a K-means clustering method that yielded three well-defined clusters. The main strength of this study is the detailed characterization of the predominant clinical features during the prodromal phase by a replicable equation. This has been possi-ble due to a structured chart review and questionnaire specifically oriented to detail the main clinical features during the prodromal phase of DLB.
This data-driven approach allowed us to avoid multiple possible biases by defining particular time points.
The main limitations of the study are that part of the data was collected retrospectively, only a small subset of patients had imaging and/or CSF biomarkers, there was no validation in an independent clinical cohort and the absence of neuropathological findings to validate these clusters. In ad-dition, in this study patients were recruited entirely in a memory unit, and this bias could underestimate the proportion of DLB patients with an initial
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In summary, we propose three subtypes of DLB that differ in their clinical manifestations and progression patterns. It will be important to validate these subtypes in independent clinical cohorts with autopsy confirmation to investigate differences in biomarkers and neuropathological traits among the proposed clusters.
Funding
Instituto de Salud Carlos III (FIS PI14/1561 to A.L.) and Fondos FEDER (“Una manera de hacer Europa”) and CIBERNED.