Prodromal DLB

Previous and current consensus diagnostic criteria of DLB require the pres-ence of dementia. As such, the criteria neglect the existpres-ence of a prodromal phase of the disease. There are currently no established diagnostic criteria for the prodromal phase of DLB, which hinders the study of this stage as it makes selection of patients difficult, which in turn compromises the agree-ment and harmonization between researchers and centers (50). This lack of diagnostic criteria may be one of the reasons why literature on prodro-mal DLB is scarce, and restricted to retrospective studies or focused only on patients with RBD (94,106). Both instances may derive from biases as the features of DLB patients with or without RBD may vary (107).

Nevertheless, the study of the prodromal phase of DLB is crucial for several reasons. On the one hand, for a better understanding of the physiopathology of the disease and its progression. On the other, for the correct diagnosis of the patients from the beginning of their symptoms, which will help in determining whether to initiate treatment with appropriate disease-modifying drugs (when

available) and, from a social point of view, this will improve understanding and awareness of the patient, relatives and society to DLB (94).

Mild cognitive impairment (MCI) is the transitional stage between normal cognition and dementia in which cognitive decline does not affect the nor-mal functioning in the patient’s daily life (15,108). It has been profoundly studied in AD in contrast to DLB, where a great heterogeneity exists. Thus, the problem of the underdiagnosis of DLB becomes greater in the phase of MCI. The existence of diagnostic criteria and biomarkers in CSF for prodro-mal AD but not DLB means that clinicians have tended to misdiagnose DLB more frequently as AD. This etiologic label is more difficult to change later when other clinical features linked to DLB or the absence of AD suggestive biomarkers arise as the clinician must make this change understandable for patients and caregivers (94).

1.5.3.1. Clinical features of the prodromal phase of DLB

With the limitations commented above, most authors agree on the presence of a non-amnestic MCI as the main prodromal form in patients who are evolving to DLB (50,109–112). MCI-DLB is characterized by a predominantly dysexecutive cognitive profile, due to a dopaminergic dysfunction in fronto-striatal networks and relative preservation of hippocampus (109,112), with impairment in visual cognitive domains as well as social cognition deficits being common (50,110,111). The presence of multidomain amnestic MCI or even pure amnestic MCI, manifested by the impairment on free recall and visual recognition, is also present in the prodromal phase of DLB excluding the diagnosis of DLB in cases with amnestic MCI (110,111). DLB patients also present more often than AD patients with non-cognitive symptoms such as depression, visual hallucinations and RBD (50). In around one quarter

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idal signs being the best clinical predictor of evolution to DLB (50,113). In DLB, motor symptoms evolve slowly at the beginning, and faster near phe-noconversion in contrast to PD, where progression of motor symptoms and signs followed a more linear progression. Regarding parkinsonian features, speech, voice, hypomimia, bradykinesia and reduced slim swim were the first manifestations, with rest tremor not as frequent at diagnosis and ap-pearing only 2-1 years before phenoconversion, and with very low scores in the UPDRS-III (18). Delirium and transient alterations of consciousness are frequently reported in the early stage. On the other hand, fluctuations is the core feature more infrequently present at the prodromal stage of DLB, being more evident in later stages (50). When present, dream enactment is first referred 8.2 to 9 years before the diagnosis of DLB (18).

Some evaluations can facilitate DLB diagnosis in its prodromal stage. Within the neuropsychological evaluation, mistakes in the angles in the pentagon copy are highly suggestive of evolution to DLB in MCI patients (113). Re-garding cognition, screening tests Montreal cognitive assessment (MoCA) scores starts to deviate from controls around 9 years before the diagnosis of DLB and Minimental state examination (MMSE), less sensitive in this pa-thology, deviates from the normal performance in a mean of 5 years prior to phenoconversion (18). At parkinsonism onset, semantic verbal fluency also predicted the development of DLB compared with PD (114). Verbal fluency is a useful test to monitor the cognitive evolution in DLB (115). When a more complete neuropsychological evaluation is available, tests assessing color vision can manifest an impairment more than 12 years prior the di-agnosis of DLB (18), while trail making test -B (TMT-B) is impaired about six years before diagnosis (115). This points to a long prodromal phase in the disease that can be detected with the appropriate neuropsychological evaluation, especially when using tests directed towards assessing the ex-ecutive and visuoperceptive domains.

1.5.3.2. Biomarkers in prodromal DLB

Structural neuroimaging studies have shown preservation of hippocampal volumes compared with prodromal AD that is of great help in the differ-ential diagnosis between these two entities at the MCI stage (110,112). A bilateral grey matter atrophy in insulae and anterior cingulate cortex have been also described in prodromal phases of DLB (116,117). Functional neuroimaging studies consistently show specific hypoperfusion in temporal lobes in prodromal DLB (114,118) and hypoperfusion in the right frontal and parietal cortex together with the anterior insula as well as a hyper-perfusion in left superior frontal gyrus are also described compared with healthy volunteers. When compared to prodromal AD, lower relative per-fusion in prodromal DLB in the fusiform gyrus has been found (118). The presence of the cingulate sign may be useful for distinguishing prodromal DLB, although it is more evident in patients in the middle of the disease and decreases with the progression. When a posterior hypoperfusion is evident in prodromal DLB but the cingulate sign is absent it is indicative of a faster worsening and may point to a higher AD pathology (119). Dopaminergic imaging in prodromal DLB, has a lower sensitivity than in DLB, around a 50%, but it can be useful in the differential diagnosis in MCI as a positive dopamine transporter SPECT (DaTscan) points to an evolution to DLB with around 90% specificity (25,106). A reduced putamen to caudate ratio has been also described in prodromal DLB (114).

Most of the few existing studies on CSF biomarkers in prodromal DLB have focused on AD core biomarkers. Aβ40, Aβ42, t-tau and p-tau are less al-tered in the prodromal stage of DLB in comparison with the prodromal stage of AD, and are poor at differentiating prodromal DLB from controls (120). Nevertheless, the utility of AD core biomarkers in the clinical

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been noted due to its link to a worse evolution and the possibility of de-tection those patients with an increased risk for higher cortical Lewy body related pathology (54).