Functional magnetic resonance imaging with encoding task in patients with mild cognitive impairment and different severity of leukoaraiosis.

Leukoaraiosis is one of the main contributors to mild cognitive impairment due to vascular damage (vascular MCI, VMCI), whose pathophysiology has not been fully elucidated yet. We aimed to shed light on such issue using functional MRI (fMRI). Sixteen patients with VMCI were enrolled and compared with twenty-five patients with MCI but without significant vascular damage (non-vascular MCI, NVMCI) and with fifteen healthy controls (HC). They all underwent fMRI with incidental verbal learning paradigm, using a 3T scanner. Differently from cases with NVMCI (versus HC), VMCI patients presented a higher BOLD activation in the right parieto-occipital cortex and a lower activation in the left superior and middle frontal gyri, anterior cingulum and in left fronto-opercular area when compared to HC. Cortical activation evaluated by fMRI may reflect specific patterns of damage and attempt of compensation in patients with MCI and different severity of leukoaraiosis.

Oxidative Stress Assessment in Alzheimer's Disease: A Clinic Setting Study.

BACKGROUND: Oxidative stress (OS) is a physiological age-related brain process, dramatically overexpressed in neurodegenerative disorders like Alzheimer's disease (AD). Nevertheless, the pathophysiological role of OS in AD pathology has not been clarified yet. OS as a biomarker for AD is a controversial issue. A comparison of previous data is difficult due to a remarkable methodological variability. Most of the previous studies have shown higher levels of OS markers and lower antioxidant power in patients with dementia when compared to mild cognitive impairment (MCI) and healthy controls. METHODS: We followed a strict protocol in order to limit intrasite variability of OS assessment. In addition, we have taken into account possible confounding factors. RESULTS: In agreement with previous reports, we found both lower plasmatic OS and higher plasmatic antioxidant defenses when comparing patients with AD having dementia that is stably treated to patients with MCI-AD. DISCUSSION: A speculative hypothesis based on correlative data is provided.

Olfactory evaluation in Mild Cognitive Impairment: correlation with neurocognitive performance and endothelial function.

Mild Cognitive Impairment (MCI) is an intermediate condition between normal aging and dementia, associated with an increased risk of progression into the latter within months or years. Olfactory impairment, a well-known biomarker for neurodegeneration, might be present in the condition early, possibly representing a signal for future pathological onset. Our study aimed at evaluating olfactory function in MCI and healthy controls in relation to neurocognitive performance and endothelial function. A total of 85 individuals with MCI and 41 healthy controls, matched for age and gender, were recruited. Olfactory function was assessed by Sniffin' Sticks Extended Test (Burghart, Medizintechnik, GmbH, Wedel, Germany). A comprehensive neurocognitive assessment was performed. Endothelial function was assessed by flow-mediated dilation (FMD) of the brachial artery by ultrasound. MCI individuals showed an impaired olfactory function compared to controls. The overall olfactory score is able to predict MCI with a good sensitivity and specificity (70.3 and 77.4% respectively). In MCI, olfactory identification score is correlated with a number of neurocognitive abilities, including overall cognitive status, dementia rating, immediate and delayed memory, visuospatial ability and verbal fluency. FMD was reduced in MCI (2.90 ± 2.15 vs. 3.66 ± 1.96%, P = 0.016) and was positively associated with olfactory identification score (ρs =0.219, P = 0.025). The association remained significant after controlling for age, gender, and smoking. In conclusion, olfactory evaluation is able to discriminate between MCI and healthy individuals. Systemic vascular dysfunction might be involved, at least indirectly, in olfactory dysfunction in MCI.

Disease awareness in myotonic dystrophy type 1: an observational cross-sectional study.

BACKGROUND: Myotonic dystrophy type 1 (Steinert's disease or DM1), the most common form of autosomal dominant muscular dystrophy in adults, is a multisystem disorder, affecting skeletal muscle as well as eyes, heart, gastrointestinal tract, endocrine system, and central nervous system, finally responsible of increasing disabilities and secondary social consequences. To date, DM1-related brain involvement represents a challenging field of research. It is well known that DM1 patients frequently present neuropsychological disturbances and psychiatric comorbidities among which reduced awareness of disease burden and its progression, also defined as anosognosia, is common in clinical practice, this leading to secondary misattribution of symptoms, delay in timely diagnostic procedures and low compliance to treatment. METHODS: Here we present an observational cross sectional study in which disease-related cognitive dysfunctions and quality of life were assessed by a protocol finally designed to estimate the prevalence of disease awareness in a sample of 65 adult-onset DM1 patients. RESULTS: Our analysis showed that in DM1 patients several cognitive functions, including executive and mnesic domains with visuo-spatial involvement, were affected. The assessment of anosognosia revealed that a high percentage (51.6%) of DM1 subjects was disease unaware. The reduced illness awareness occurs across different physical and life domains, and it appears more prominent in Activities and Independence domains investigated by the Individualized Neuromuscular Quality Of Life (INQoL) questionnaire. Moreover, the unawareness resulted significantly related (at p <0.05 and p < 0.01) to the performance failure in cognitive tests, specifically in the domains of visuo-spatial memory, cognitive flexibility and conceptualization. CONCLUSIONS: The obtained data confirm, by a systematic analysis, what's the common clinical perceiving of disease unawareness in Steinert's disease, this related to the already known cognitive-behavioural impairment of frontal type in affected patients. We believe that a deep knowledge of this aspect will be useful for medical practice in the management of patients with DM1, also for guidance in occupational and social interventions, definition of outcome measures and in preparation of trial readiness.

Non-rapid eye movement sleep instability in mild cognitive impairment: a pilot study.

OBJECTIVE: Polysomnographic (PSG) studies in mild cognitive impairment (MCI) are not conclusive and are limited only to conventional sleep parameters. The aim of our study was to evaluate sleep architecture and cyclic alternating pattern (CAP) parameters in subjects with MCI, and to assess their eventual correlation with cognition. METHODS: Eleven subjects with MCI (mean age 68.5 ± 7.0 years), 11 patients with mild probable Alzheimer's disease (AD; mean age 72.7 ± 5.9 years), referred to the Outpatient Cognitive Disorders Clinic, and 11 cognitively intact healthy elderly individuals (mean age 69.2 ± 12.6 years) underwent ambulatory PSG for the evaluation of nocturnal sleep architecture and CAP parameters. RESULTS: Rapid eye movement sleep, CAP rate, and CAP slow components (A1 index) were decreased in MCI subjects and to a greater extent in AD patients, compared to cognitively intact controls. AD showed also decreased slow wave sleep (SWS) relative to healthy elderly individuals. MCI nappers showed decreased nocturnal SWS and A1 subtypes compared to non-nappers. Several correlations between sleep variables and neuropsychological tests were found. CONCLUSIONS: MCI and AD subjects showed a decreased sleep instability correlated with their cognitive decline. Such a decrease may be considered as a potential biomarker of underlying neurodegeneration.

Rippling muscle disease and facioscapulohumeral dystrophy-like phenotype in a patient carrying a heterozygous CAV3 T78M mutation and a D4Z4 partial deletion: Further evidence for "double trouble" overlapping syndromes.

We report the first case of a heterozygous T78M mutation in the caveolin-3 gene (CAV3) associated with rippling muscle disease and proximal myopathy. The patient displayed also bilateral winged scapula with limited abduction of upper arms and marked asymmetric atrophy of leg muscles shown by magnetic resonance imaging. Immunohistochemistry on the patient's muscle biopsy demonstrated a reduction of caveolin-3 staining, compatible with the diagnosis of caveolinopathy. Interestingly, consistent with the possible diagnosis of FSHD, the patient carried a 35 kb D4Z4 allele on chromosome 4q35. We discuss the hypothesis that the two genetic mutations may exert a synergistic effect in determining the phenotype observed in this patient.

Nerve and muscle involvement in mitochondrial disorders: an electrophysiological study.

Involvement of the peripheral nervous system in mitochondrial disorders (MD) has been previously reported. However, the exact prevalence of peripheral neuropathy and/or myopathy in MD is still unclear. In order to evaluate the prevalence of neuropathy and myopathy in MD, we performed sensory and motor nerve conduction studies (NCS) and concentric needle electromyography (EMG) in 44 unselected MD patients. NCS were abnormal in 36.4% of cases, and were consistent with a sensori-motor axonal multineuropathy (multifocal neuropathy), mainly affecting the lower limbs. EMG evidence of myopathy was present in 54.5% of patients, again mainly affecting the lower limbs. Nerve and muscle involvement was frequently subclinical. Peripheral nerve and muscle involvement is common in MD patients. Our study supports the variability of the clinical expression of MD. Further studies are needed to better understand the molecular basis underlying the phenotypic variability among MD patients.

Muscle metabolic alterations assessed by 31-phosphorus magnetic resonance spectroscopy in mild Becker muscular dystrophy.

Although the molecular defect causing Becker muscular dystrophy (BMD) has been identified, the biochemical mechanisms that lead to muscle necrosis remain unclear. Exercise-related muscle metabolism in 9 mildly affected BMD patients was assessed by muscle 31-phosphorus magnetic resonance spectroscopy ((31)P MRS) during an incremental workload. Compared with normal controls, BMD patients showed deregulation of resting pH and intramuscular membrane breakdown. We also observed increased reliance upon anaerobic metabolism during sustained submaximal contraction and maintenance of oxidative function during recovery.

Serum gamma-glutamyltransferase fractions in myotonic dystrophy type I: differences with healthy subjects and patients with liver disease.

OBJECTIVES: Elevation of serum gamma-glutamyltransferase (GGT), in absence of a clinically significant liver damage, is often found in Myotonic Dystrophy type-1 (DM1). In this study we investigated if a specific GGT fraction pattern is present in DM1. DESIGNS AND METHODS: We compared total and fractional GGT values (b-, m-, s-, f-GGT) among patients with DM1 or liver disease (LD) and healthy subjects (HS). RESULTS: The increase of GGT in DM1 and LD, vs HS, was mainly due to s-GGT (median: 32.7; 66.7; and 7.9 U/L, respectively), and b-GGT (8.5; 18.9; and 2.1 U/L). The subset of DM1 patients matched with HS with corresponding serum GGT showed higher b-GGT (6.0 vs 4.2 U/L). CONCLUSIONS: DM1 patients with normal total GGT values showed an alteration of the production and release in the blood of GGT fractions. Since increased s-GGT is also found in LD, a sub-clinical liver damage likely occurs in DM1 subjects apparently free of liver disease.

A standardized clinical evaluation of patients affected by facioscapulohumeral muscular dystrophy: The FSHD clinical score.

To define numerically the clinical severity of facioscapulohumeral muscular dystrophy (FSHD), we developed a protocol that quantifies muscle weakness by combining the functional evaluation of six muscle groups affected in this disease. To validate reproducibility of the protocol, 69 patients were recruited. Each patient was evaluated by at least five neurologists, and an FSHD severity score was given by each examiner. The degree of agreement among clinicians' evaluations was measured by kappa-statistics. Nineteen subjects received a score between 0 and 1, 9 had a score between 2 and 4, 20 received a score between 5 and 10, and 8 had a score between 11 and 15. Of the 13 subjects with D4Z4 alleles within the normal range (ranging from 10 to 150 repeats), 12 obtained a score of 0 and only 1 had a score of 1. Kappa-statistics showed a very high concordance for all muscle groups. We developed a simple, reliable, easily used tool to define the clinical expression of FSHD. Longitudinal studies will assess its sensitivity and utility in measuring changes for widespread use.

Functional diagnostics in mitochondrial diseases.

Mitochondrial diseases (MD) with respiratory chain defects are caused by genetic mutations that determine an impairment of the electron transport chain functioning. Diagnosis often requires a complex approach with measurements of serum lactate, magnetic resonance spectroscopy (MRS), muscle histology and ultrastructure, enzymology, genetic analysis, and exercise testing. The ubiquitous distribution of the mitochondria in the human body explains the multiple organ involvement. Exercise intolerance is a common symptom of MD, due to increased dependence of skeletal muscle on anaerobic metabolism, with an excess lactate generation, phosphocreatine depletion, enhanced free radical production, reduced oxygen extraction and electron flux through the respiratory chain. MD treatment has included antioxidants (vitamin E, alpha lipoic acid), coenzyme Q10, riboflavin, creatine monohydrate, dichloroacetate and exercise training. Exercise is a particularly important tool in diagnosis as well as in the management of these diseases.