Associations Between Free and Cued Selective Reminding Test and Cerebrospinal Fluid Biomarkers in Amnestic Mild Cognitive Impairment.

Background: The Free and Cued Selective Reminding Test (FCSRT), assessing verbal episodic memory with controlled learning and semantic cueing, has been recommended for detecting the genuine encoding and storage deficits characterizing AD-related memory disorders. Objective: The present study aims at investigating the ability of FCSRT in predicting cerebrospinal fluid (CSF) evidence of amyloid-ß positivity in subjects with amnestic mild cognitive impairment (aMCI) and exploring its associations with amyloidopathy, tauopathy and neurodegeneration biomarkers. Methods: 120 aMCI subjects underwent comprehensive neurological and neuropsychological examinations, including the FCSRT assessment, and CSF collection; CSF Aß42/40 ratio, p-tau181, and total-tau quantification were conducted by an automated CLEIA method on Lumipulse G1200. Based on the Aß42/40 ratio value, subjects were classified as either A+ or A-. Results: All FCSRT subitem scores were significantly lower in A+ group and significantly predicted the amyloid-ß status, with Immediate Total Recall (ITR) being the best predictor. No significant correlations were found between FCSRT and CSF biomarkers in the A- aMCI group, while in the A+ aMCI group, all FCSRT subitem scores were negatively correlated with CSF p-tau181 and total-tau, but not with the Aß42/40 ratio. Conclusions: FCSRT confirms its validity as a tool for the diagnosis of AD, being able to predict the presence of amyloid-ß deposition with high specificity. The associations between FCSRT subitem scores and CSF p-tau-181 and total-tau levels in aMCI due to AD could further encourage the clinical use of this simple and cost-effective test in the evaluation of individuals with aMCI.

Cerebrospinal fluid neurofilament light chain and total-tau as biomarkers of neurodegeneration in Alzheimer's disease and frontotemporal dementia.

INTRODUCTION: CSF Neurofilament light chain(NfL) is a promising biomarker of neurodegeneration, but its utility in discriminating between Alzheimer's disease(AD) and frontotemporal dementia(FTD) is limited. METHODS: 105 patients with clinical-biological diagnosis of mild cognitive impairment(MCI) due to AD (N = 72) or clinical diagnosis of FTD (N = 33) underwent neuropsychological assessment and CSF Aß42/40, p-tau181, total-tau and NfL quantification. Group comparisons, correlations between continuous variables and ROC curve analysis were carried out to assess NfL role in discriminating between MCI due to AD and FTD, exploring the associations between NfL, ATN biomarkers and neuropsychological measures. RESULTS: NfL levels were significantly lower in the AD group, while levels of total-tau were higher. In the FTD group, significant correlations were found between NfL, p-tau181 and total-tau, and between NfL and cognitive performances. In the AD group, NfL levels were directly correlated with total-tau and p-tau181; Aß42/40 ratio was inversely correlated with total-tau and p-tau181, but not with NfL. Moreover, p-tau181 and t-tau levels were found to be associated with episodic memory and lexical-semantic impairment. Total-tau/NfL ratio differentiated prodromal-AD from FTD with an AUC of 0.951, higher than the individual measures. DISCUSSION & CONCLUSIONS: The results support that NfL and total-tau levels reflect distinct pathophysiological neurodegeneration mechanisms, independent and dependent of Aß pathology, respectively, Combining them may enhance both markers reliability, their ratio showing high accuracy in distinguishing MCI due to AD from FTD. Moreover, our results revealed associations between NfL and disease severity in FTD and between tauopathy and episodic memory and lexical-semantic impairment in prodromal-AD.

Elevated serum Neurofilament Light chain (NfL) as a potential biomarker of neurological involvement in Myotonic Dystrophy type 1 (DM1).

BACKGROUND: Cognitive and behavioural symptoms due to involvement of the central nervous system (CNS) are among the main clinical manifestations of Myotonic Dystrophy type 1 (DM1). Such symptoms affect patients' quality of life and disease awareness, impacting on disease prognosis by reducing compliance to medical treatments. Therefore, CNS is a key therapeutic target in DM1. Deeper knowledge of DM1 pathogenesis is prompting development of potential disease-modifying therapies: as DM1 is a rare, multisystem and slowly progressive disease, there is need of sensitive, tissue-specific prognostic and monitoring biomarkers in view of forthcoming clinical trials. Circulating Neurofilament light chain (NfL) levels have been recognized as a sensitive prognostic and monitoring biomarker of neuroaxonal damage in various CNS disorders. METHODS: We performed a cross-sectional study in a cohort of 40 adult DM1 patients, testing if serum NfL might be a potential biomarker of CNS involvement also in DM1. Moreover, we collected cognitive data, brain MRI, and other DM1-related diagnostic findings for correlation studies. RESULTS: Mean serum NfL levels resulted significantly higher in DM1 (25.32 ± 28.12 pg/ml) vs 22 age-matched healthy controls (6.235 ± 0.4809 pg/ml). Their levels positively correlated with age, and with one cognitive test (Rey's Auditory Verbal learning task). No correlations were found either with other cognitive data, or diagnostic parameters in the DM1 cohort. CONCLUSIONS: Our findings support serum NfL as a potential biomarker of CNS damage in DM1, which deserves further evaluation on larger cross-sectional and longitudinal studies to test its ability in assessing brain disease severity and/or progression.

Neurological Erdheim-Chester Disease Manifesting with Subacute or Progressive Cerebellar Ataxia: Novel Case Series and Review of the Literature.

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 Syndromes in an Italian Cohort: Clinical Spectrum, High Genetic Variability and Muscle Involvement.

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.

Subclinical epileptiform activity during sleep in Alzheimer's disease and mild cognitive impairment.

OBJECTIVE: Recent findings suggested that subclinical epileptiform activity is prevalent during sleep in a significant proportion of Alzheimer's Disease (AD) patients. THE AIMS OF OUR STUDY WERE: (A) comparing the frequency of subclinical epileptiform activity during the sleep in a sample diagnosed with 'probable' AD and Mild Cognitive Impairment (MCI) due to AD, and in healthy subjects; (B) evaluating epileptiform EEG activity as a function of different sleep stages within a well-controlled polysomnographic setting. METHODS: We prospectively enrolled 50 'probable' AD patients (73 ± 7.0 years) and 50 subjects with MCI due to AD (72 ± 6.7 years) without history of seizures, comparing them with 50 controls (69 ± 6.7 years). Patients underwent to a full-night video-PSG. RESULTS: Subclinical epileptiform activity was detected in 6.38% of 'probable' AD patients, 11.63% of MCI due to AD subjects and 4.54% of controls (p = 0.43). The comparisons between the three groups for the frequency of epileptiform activity did not reach statistically significant differences neither for total sleep nor for any sleep period considered. CONCLUSIONS: Our study shows that, when controlling for sleep stages and the influence of psychoactive drugs, AD patients and MCI due to AD subjects do not exhibit a higher frequency of epileptiform discharges during sleep compared to healthy subjects. SIGNIFICANCE: Subclinical epileptiform activity during sleep does not discriminate 'probable' AD from MCI due to AD and healthy controls.

Predicting progression of amnesic MCI: The integration of episodic memory impairment with perfusion SPECT.

The present study aimed at assessing if the ability to predict progression from amnesic Mild Cognitive Impairment (aMCI) to dementia is improved by considering the presence at the baseline of Single Photon Emission Computed Tomography (SPECT) perfusion abnormalities in addition to a defect of long term memory. The Episodic Memory Score (EMS), a global index which integrates results obtained in subtests of the Rey's Verbal Learning Test and the Rey-Osterrieth Figure recall, were taken into account to evaluate defects of long term memory. The study sample consisted of 42 subjects affected by aMCI, who were followed-up during a two-year period. At the final follow-up 15 subjects progressed to AD. The EMS predicted progression from aMCI to dementia with a high level of sensitivity and a lower level of specificity, but the association of neuropsychological (EMS) and SPECT data (hypoperfusion in the Posterior Cingulate Cortex) increased the accuracy in predicting conversion from aMCI to AD. The association of results obtained by aMCI patients on memory tests and perfusion SPECT may improve the accuracy in detecting subjects who will progress to dementia. The use of currently available and low-cost investigations could be advantageous in terms of public health policies.

Neuroradiology of human prion diseases, diagnosis and differential diagnosis.

Human transmissible spongiform encephalopathies (TSEs), or prion diseases, are invariably fatal conditions associated with a range of clinical presentations. TSEs are classified as sporadic [e.g. sporadic Creutzfeldt-Jakob disease (sCJD), which is the most frequent form], genetic (e.g. Gerstmann-Straussler-Scheinker disease, fatal familial insomnia, and inherited CJD), and acquired or infectious (e.g. Kuru, iatrogenic CJD, and variant CJD). In the past, brain imaging played a supporting role in the diagnosis of TSEs, whereas nowadays magnetic resonance imaging (MRI) plays such a prominent role that MRI findings have been included in the diagnostic criteria for sCJD. Currently, MRI is required for all patients with a clinical suspicion of TSEs. Thus, MRI semeiotics of TSEs should become part of the cultural baggage of any radiologist. The purposes of this update on the neuroradiology of CJD are to (i) review the pathophysiology and clinical presentation of TSEs, (ii) describe both typical and atypical MRI findings of CJD, and (iii) illustrate diseases mimicking CJD, underlining the MRI key findings useful in the differential diagnosis.

Patient with rapidly evolving neurological disease with neuropathological lesions of Creutzfeldt-Jakob disease, Lewy body dementia, chronic subcortical vascular encephalopathy and meningothelial meningioma.

We report a case of rapidly evolving neurological disease in a patient with neuropathological lesions of Creutzfeldt-Jakob disease (CJD), Lewy body dementia (LBD), chronic subcortical vascular encephalopathy and meningothelial meningioma. The coexistence of severe multiple pathologies in a single patient strengthens the need to perform accurate clinical differential diagnoses in rapidly progressive dementias.

Are Raw Scores on Memory Tests Better than Age- and Education- Adjusted Scores for Predicting Progression from Amnesic Mild Cognitive Impairment to Alzheimer Disease ?

In this prospective longitudinal study, conducted in a large sample of amnestic MCI patients over a three-year period, we investigated the recently advanced proposal that unadjusted test scores obtained at baseline on long-term memory tests are more reliable than age- and education-corrected scores in predicting progression from aMCI to AD. Our experimental sample consisted of 270 aMCI patients who underwent extensive neurological and neuropsychological examinations both at baseline and at the follow-up, conducted at least 3 years later. At the follow-up 80 patients had converted to overt dementia. The predictive capacity of raw, age-corrected, education-corrected and fully corrected scores on RAVLT immediate and delayed recall was compared by examining the area under the ROC curves (AUCs) of all of these scores to assess which (raw or corrected) scores achieves the better reliability in predicting conversion to dementia. The condition (aMCI stable vs converted) was analyzed to assess the odds ratios resulting from a logistic regression on the corrected and uncorrected scores of RAVLT immediate and delayed recall. Even if both in immediate and in delayed recall the ROCs of 'raw scores' were generally higher than the other ROCs on corrected scores, these differences did not reach the level of statistical significance, failing to support the claim that unadjusted test scores are superior to age- and education-corrected scores in predicting progression from aMCI to AD.

Clinical reversible myelopathy in T-cell lymphoblastic lymphoma treated with nelarabine and radiotherapy: report of a case and review of literature of an increasing complication.

Eleven cases of neurological defects in T-ALL patients treated with nelarabine have been described in the last 4 years, seven of these after stem cell transplantation (SCT) for T Lymphoblastic Lymphoma (T-LBL). Most of these patients had an unfavorable outcome or irreversible neurological damage. We now report the case of a 41-year-old woman suffering from T-LBL who presented with severe, but reversible myelopathy after receiving nelarabine-based treatment and mediastinal radiotherapy, and we provide a review of the literature on the topic.

Cognitive and behavioral determinants of psychotic symptoms in Alzheimer's disease.

AIMS: To investigate the relationship between psychotic symptoms and cognitive impairment in Alzheimer's disease (AD). METHODS: A total of 108 subjects affected by AD were subdivided into subjects without delusions (ND), subjects with paranoid delusions (PD), subjects with delusional misidentifications (DM), subjects with both DM and PD (DM+PD), subjects with visual hallucinations (v-HALL), and subjects without visual hallucinations (N-HALL). RESULTS: PD and ND subjects performed similarly on neuropsychological tests, while DM patients performed significantly worse than PD and ND patients. v-HALL patients performed worse than N-HALL patients on memory, visuospatial, and executive functions. As for behavioral features, DM and v-HALL subjects reported higher scores on the abnormal motor behavior subscale of the neuropsychiatric inventory (NPI); PD subjects reported higher scores on the disinhibition subscale of the NPI. The severity of PD was predicted by the severity of disinhibition (B = 0.514; p = 0.016) but not by neuropsychological performances. The severity of DM was predicted by age (B = 0.099; p = 0.048) and MMSE (B = -0.233; p = 0.001). The severity of v-HALL was predicted by age (B = 0.052; p = 0.037) and scores on an immediate visual memory task (B = -0.135; p = 0.007). CONCLUSIONS: The occurrence of PD may require the relative sparing of cognitive functions and be favored by frontal lobe dysfunction, while DM is associated with the overall level of cognitive impairment. Finally, v-HALL are associated with the impairment of visuospatial abilities.

Typicality of words produced on a semantic fluency task in amnesic mild cognitive impairment: linguistic analysis and risk of conversion to dementia.

Semantic and, to a lesser extent, phonological verbal fluency tasks are impaired in Alzheimer's disease (AD) and in amnesic mild cognitive impairment (aMCI). Furthermore, both fluency tasks have been considered as possible markers of conversion from aMCI to AD. Up to recent years, the use of fluency tasks has been limited to word count, but, more recently, linguistic variables, such as word frequency, age of acquisition, familiarity, and typicality, have also been considered. In particular, attention has been focused on typicality of words produced on semantic verbal fluency tasks, because the tendency to produce only the more typical members of various categories points to an impoverishment of semantic memory. The aim of our study was to compare in aMCI, AD, and control subjects a lexical (word frequency) and a lexical-semantic variable (item typicality) in a semantic verbal fluency task, and to evaluate the possible value of these variables in predicting conversion from aMCI to AD during a 2 years follow-up period. We found no difference in mean typicality of words produced by aMCI and AD subjects whereas both groups produced words of higher mean typicality than control subjects. Furthermore, to assess the relationship between typicality values and risk of conversion to AD, the aMCI group was split in two subgroups, including subjects who obtained a mean typicality value lower or higher than the median value of the whole aMCI group. Consistent with our hypothesis, conversion to AD was significantly more frequent in high typicality than in low typicality subjects.

Human brain networks in cognitive decline: a graph theoretical analysis of cortical connectivity from EEG data.

The aim of this study was to investigate the neuronal network characteristics in physiological and pathological brain aging. A database of 378 participants divided in three groups was analyzed: Alzheimer's disease (AD), mild cognitive impairment (MCI), and normal elderly (Nold) subjects. Through EEG recordings, cortical sources were evaluated by sLORETA software, while graph theory parameters (Characteristic Path Length λ, Clustering coefficient γ, and small-world network σ) were computed to the undirected and weighted networks, obtained by the lagged linear coherence evaluated by eLORETA software. EEG cortical sources from spectral analysis showed significant differences in delta, theta, and alpha 1 bands. Furthermore, the analysis of eLORETA cortical connectivity suggested that for the normalized Characteristic Path Length (λ) the pattern differences between normal cognition and dementia were observed in the theta band (MCI subjects are find similar to healthy subjects), while for the normalized Clustering coefficient (γ) a significant increment was found for AD group in delta, theta, and alpha 1 bands; finally, the small world (σ) parameter presented a significant interaction between AD and MCI groups showing a theta increase in MCI. The fact that AD patients respect the MCI subjects were significantly impaired in theta but not in alpha bands connectivity are in line with the hypothesis of an intermediate status of MCI between normal condition and overt dementia.

Does semantic memory impairment in amnestic MCI with hippocampal atrophy conform to a distinctive pattern of progression?

Subjects with Mild Cognitive Impairment (MCI) are normally classified according to the presence of episodic memory deficits associated or not to disturbances of other cognitive domains. The present study had two aims: to identify discrete subtypes of amnestic MCI (a-MCI) with hippocampal atrophy; and to assess if the identified subtypes show different rates of progression to dementia. Sixty-seven a-MCI subjects were enrolled, all showing significant hippocampal atrophy on MRI. The subjects underwent at baseline and at follow-up a comprehensive neuropsychological examination, and were followed-up for five years to detect the conversion to dementia. An exploratory factor analysis on neuropsychological performances at baseline identified three main factors that were subsequently used to perform a k-means cluster analysis. Three cluster of a-MCI subjects were identified: "pure amnestic" (N=29), "multiple domain"(N=16), and "amnestic/semantic"(N=22). The successive discriminant functions were able to correctly classify 88% of the subjects. During the follow-up, 33 subjects converted to dementia (49.2%), 14 "pure amnestic" (48.3%), 11 "multiple domain" (68.5%) and 8 "amnestic/semantic" (36.4%; log-rank: p=0.016); median survival was respectively 36, 22, and 39 months. On Cox proportional hazard model, baseline MMSE (HR=0,709; p=0.006), education (HR=1,115; p=0.011) and belonging to the "multiple domain" subgroup (HR=2,706; p=0.013) were significantly associated to higher rate of conversion to dementia. Our findings confirm the tendency to worst outcome of subjects with multiple domain MCI, and show that the association of episodic and semantic memory deficits, without other cognitive disturbances, could identify a specific cognitive pattern associated to slower cognitive decline, as previously reported in Alzheimer's Disease.

Neuropsychological predictors of conversion from mild cognitive impairment to Alzheimer's disease.

The construct of mild cognitive impairment (MCI) has been proposed to identify patients at risk of developing Alzheimer's disease (AD) in the pre-clinical stage. Although subjects with MCI have an increased risk of progressing to dementia, most remain stable or return to normality. The new criteria for diagnosing prodromal AD assume that, to increase the predictive value of the MCI, in addition to a defect of delayed recall there must also be the presence of abnormal biomarkers, investigating structural and molecular neuroimaging and cerebrospinal fluid (CSF) analysis of amyloid-ß or tau proteins. Although acknowledging that the use of CSF degeneration biomarkers is advisable not only for research, but also for clinical purposes, the present review is centered upon the neuropsychological markers of conversion to AD, which are equally clinically important. In particular, results of this review suggest the following: (a) measures of delayed recall are the best neuropsychological predictors of conversion from MCI to AD; (b) memory tests providing controlled encoding and cued recall are not necessarily better predictors than free recall tests; (c) stringent cut-off points are necessary to increase the specificity of these predictors; (d) multi-domain amnestic MCI patients are the best candidates for clinical trials, but not for treatment with disease-modifying drugs; and (e) not only episodic but also semantic memory is significantly impaired in patients who will convert to AD. These data and the underlying neural mechanisms will be discussed, trying to distinguish results obtained in MCI patients from those obtained in a pre-MCI stage of the AD progression.

Cerebellar degeneration associated with mGluR1 autoantibodies as a paraneoplastic manifestation of prostate adenocarcinoma.

Subacute cerebellar degeneration associated with metabotropic glutamate receptor type 1 (mGluR1) autoantibodies is an uncommon syndrome known to be part of the spectrum of paraneoplastic cerebellar degenerations associated with neuronal autoantibodies. We describe a patient with prostate adenocarcinoma who developed a subacute cerebellar ataxia. Autoantibodies specific to mGluR1 were detected in patient's serum and cerebrospinal fluid (CSF). Immunohistochemistry analyses of patient's prostate adenocarcinoma revealed abundant mGluR1 expression in luminal acinar epithelial cells and binding of patient's IgGs to tumoral mGluR1. These findings suggest that cerebellar degeneration associated with mGluR1 antibodies can be a paraneoplastic accompaniment of prostate adenocarcinoma.