Standard curve calculation per assay
6. CHAPTER VI: DISCUSSION
This thesis has focused on the clinical and physiopathological heterogeneity of DLB, studying the disease from different perspectives. First, I describe three different clinical subtypes according to the predominant features dur-ing the first years of the disease that show different disease evolutions: a cognitive-, a neuropsychiatric- and a parkinsonism-predominant subtype.
These results underscore the importance of the prodromal phase of the dis-ease, a stage for which we do not have yet consensus diagnostic criteria. The different clinical subtypes in this stage of DLB have important implications from the diagnostic and prognostic points of view. Also of note, the thesis describes a novel clustering method to objectively determine these clinical subtypes based on estimation of the phenotypical contribution of hallucina-tions and parkinsonism in the prodromal stage. This thesis also builds on the heterogeneity of the frequent sleep disturbances in DLB and confirms the need for V-PSG to correctly diagnose the sleep problems associated with DLB (chapter IV). That chapter describes in detail the clinical and polysomno-graphic characteristics of sleep in a cohort of mild DLB and emphasizes the importance of V- PSG to correctly diagnose RBD, a core diagnostic feature in DLB. A variety of conditions may mimic RBD, consequently it often goes unnoticed when using a clinical approach. Misdiagnosis of sleep disturbanc-es may obscure the diagnosis of DLB and lead to unsuitable treatments. This thesis also describes for the first time the correlation between the awake occipital EEG frequency and the rate of EMG activity in REM sleep and pro-poses a new and more descriptive method to study sleep in neurodegenera-tive diseases, as the frequent sleep structure abnormalitites present in these disorders may hinder the application of the standard method.
In addition, this thesis studies the physiopathological heterogeneity of the
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show that CSF levels of glial markers were equivalent to controls in DLB and in prodromal DLB. Furthermore, YKL-40 was elevated only in DLB pa-tients with AD copathology (classified according to core AD CSF biomarker levels). CSF YKL-40 also correlated with t-tau and p-tau in DLB and prodro-mal DLB further supporting its relationship to AD copathology. In contrast, neither sTREM2 nor PGRN correlated with any of the AD core biomarkers in either DLB or prodromal DLB. Based on these findings, I describe a dif-ferential pattern of glial activation between DLB and AD and their prodro-mal stages.
Across the following sections, I discuss each main issue addressed in chap-ters III, IV and V
6.1. The clinical heterogeneity in DLB and its significance 6.1.1. Clinical Subtypes in DLB
The existence of clinical subtypes within the DLB syndrome has been previ-ously suggested (94). Nevertheless, rather than systematic studies specifi-cally aimed at disentangling the heterogeneity of the disease, these studies were largely based on a review of the previously reported phenomenology.
Most of the previously suggested subtypes have focused on the presence or absence of psychiatric manifestations and their features, and thus they are used to differentiate between cognitive subtypes and psychotic and/
or delirium subtypes. Chapter III also describes a cognitive-predominant and a neuropsychiatric-predominant subtype, but we did not find a sub-type specifically based on delirium present at onset, as those patients were extremely rare in our cohort. This difference with previous publications might be due to a publication bias, with a higher likelihood of reporting the most severe or striking cases that required hospitalization or
institution-alisation. The focus on the presence of hallucinations or psychiatric man-ifestations for the diagnosis of DLB may result in misdiagnosis such that patients with dementia and hallucinations are most often misdiagnosed as DLB but found to have a diagnosis of AD upon neuropathological exami-nation (264). A motor predominant subtype has not been proposed before within DLB heterogeneity, despite the frequent occurrence of motor symp-toms at DLB onset (18).
In contrast to DLB, clinical heterogeneity in PD has been more profoundly studied. In a similar way to the clinical subtypes of DLB described in this thesis, clinical subtypes that differ in their age-at-onset and progression rate have been also proposed in PD (192–194,265). Although a partial overlap exists, there are important differences between the subtypes de-scribed in PD and the DLB subtypes presented in chapter III. In particular, late onset PD typically shows a faster clinical decline and more frequent co-occurrence of cognitive symptoms (192–194,265), whereas in DLB, the neuropsychiatric-predominant subtype described here is characterized by an older age of onset, but not by a more rapid evolution. In addition, the cognitive-predominant DLB subtype characterized by the predominance of cognitive symptoms from onset, shows the most benign evolution. Of note, our parkinsonism-predominant subtype is characterized by a faster evolu-tion compared with the other two subtypes on top of the predominance of motor symptoms during the prodromal phase of the disease. Considering the age of onset and the evolution, there is an overlap between the late onset PD subgroup and the parkinsonism-predominant DLB subtype de-scribed in this thesis. On the other hand, the cognitive- and neuropsychiat-ric-predominant subtypes described in chapter III differ substantially from the clinical subtypes previously reported in PD.
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