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Background: In this narrative review, we have surveyed results obtained from a research program dealing with the role of semantic memory disorders as a predictor of progression from mild cognitive impairment (MCI) to Alzheimer's disease (AD). Objectives: In this research program, we have taken into account many different putative markers, provided of a different complexity in the study of the semantic network. These markers ranged from the number of words produced on a semantic fluency task to the following: (a) the discrepancy between scores obtained on semantic vs. phonemic word fluency tests; (b) the presence, at the single-word level, of features (such as a loss of low typical words on a category verbal fluency task) typical of a degraded semantic system; or (c) the presence of more complex phenomena (such as the semantic distance between consecutively produced word pairs) concerning the organization of the semantic network. In the present review, all these studies have been presented, providing separate subsections for (a) methods, (b) results, and (c) a short discussion. Some tentative general conclusions have been drawn at the end of the review. We found that at baseline all these markers are impaired in MCI patients who will later convert to AD, but also that they do not necessarily show a linear worsening during the progression to AD and allow one to make different predictions about the time of development of AD. Our conclusions were that, rather than searching for the best marker of conversion, we should use a range of different markers allowing us to obtain the information most appropriate to the goal of our investigation.

Neurological involvement is relatively common in Erdheim-Chester disease (ECD), a rare clonal disorder of histiocytic myeloid precursors characterized by multisystem involvement. In ECD patients, neurological symptoms can occur either at onset or during the disease course and may lead to various degrees of neurological disability or affect patients' life expectancy. The clinical neurological presentation of ECD often consists of cerebellar symptoms, showing either a subacute or progressive course. In this latter case, patients manifest with a slowly progressive cerebellar ataxia, variably associated with other non-specific neurological signs, infratentorial leukoencephalopathy, and cerebellar atrophy, possibly mimicking either adult-onset degenerative or immune-mediated ataxia. In such cases, diagnosis of ECD may be particularly challenging, yet some peculiar features are helpful to address it. Here, we retrospectively describe four novel ECD patients, all manifesting cerebellar symptoms at onset. In two cases, slow disease progression and associated brain MRI features simulated a degenerative cerebellar ataxia. Three patients received a definite diagnosis of histiocytosis, whereas one case lacked histology confirmation, although clinical diagnostic features were strongly suggestive. Our findings regarding existing literature data focused on neurological ECD will be also discussed to highlight those diagnostic clues helpful to address diagnosis.

Neuroacanthocytosis (NA) syndromes are a group of genetically defined diseases characterized by the association of red blood cell acanthocytosis, progressive degeneration of the basal ganglia and neuromuscular features with characteristic persistent hyperCKemia. The main NA syndromes include autosomal recessive chorea-acanthocytosis (ChAc) and X-linked McLeod syndrome (MLS). A series of Italian patients selected through a multicenter study for these specific neurological phenotypes underwent DNA sequencing of the VPS13A and XK genes to search for causative mutations. Where it has been possible, muscle biopsies were obtained and thoroughly investigated with histochemical assays. A total of nine patients from five different families were diagnosed with ChAC and had mostly biallelic changes in the VPS13A gene (three nonsense, two frameshift, three splicing), while three patients from a single X-linked family were diagnosed with McLeod syndrome and had a deletion in the XK gene. Despite a very low incidence (only one thousand cases of ChAc and a few hundred MLS cases reported worldwide), none of the 8 VPS13A variants identified in our patients is shared by two families, suggesting the high genetic variability of ChAc in the Italian population. In our series, in line with epidemiological data, McLeod syndrome occurs less frequently than ChAc, although it can be easily suspected because of its X-linked mode of inheritance. Finally, histochemical studies strongly suggest that muscle pathology is not simply secondary to the axonal neuropathy, frequently seen in these patients, but primary myopathic alterations can be detected in both NA syndromes.