Emotional processing in RRMS patients: Dissociation between behavioural and neurophysiological response.

BACKGROUNG: Multiple sclerosis (MS) results in a broad range of symptoms, including motor, visual, cognitive, and neuropsychiatric deficits. Some studies, considering affective facial expressions to study emotion processing, demonstrated emotion recognition difficulties in MS patients. OBJECTIVE: We investigated the impact of MS on the emotional-behaviour rating and neurophysiological response (Event Related Potentials-ERP) through a battery of affective visual stimuli selected from the International Affective Picture System (IAPS). METHODS: Twenty patients with diagnosis of Relapsing Remitting MS (RRMS) and 20 Healthy Controls (HC) matched by age, gender and education were enrolled. Each of them, after a neuropsychological assessment, were asked to evaluate arousal and valence of affective visual stimuli. RESULTS: Our results showed higher P300 amplitudes in RRMS patients than HC group for pleasant and unpleasant images. Moreover, RRMS patients showed lower Reaction Time (RT) respect HC in valence rating. No other effect did emerge between groups. CONCLUSION: Our study shows early compensatory cerebral mechanisms in RRMS patients throughout emotional information processing, particularly for unpleasant and pleasant stimuli. We hypothesize that this compensatory cerebral mechanism reduces the behavioural dissimilarity between patients and HC.

Cognitive Impairment in Relapsing-Remitting Multiple Sclerosis Patients with Very Mild Clinical Disability.

Cognitive dysfunction affects 40-65% of multiple sclerosis (MS) patients and can occur in the early stages of the disease. This study aimed to explore cognitive functions by means of the Italian version of the minimal assessment of cognitive function in MS (MACFIMS) in relapsing-remitting MS (RRMS) patients with very mild clinical disability to identify the primarily involved cognitive functions. Ninety-two consecutive RRMS patients with Expanded Disability Status Scale (EDSS) scores ≤ 2.5 and forty-two healthy controls (HC) were investigated. Our results show that 51.1% of MS patients have cognitive dysfunction compared to HC. An impairment of verbal and visual memory, working memory, and executive functions was found in the RRMS group. After subgrouping RRMS by EDSS, group 1 (EDSS ≤ 1.5) showed involvement of verbal memory and executive functions; moreover, group 2 (2 ≤ EDSS ≤ 2.5) patients were also impaired in information processing speed and visual memory. Our results show that utilizing a comprehensive neuropsychological assessment, approximately half of MS patients with very mild physical disability exhibit cognitive impairment with a primary involvement of prefrontal cognitive functions. Detecting impairment of executive functions at an early clinical stage of disease could be useful to promptly enroll MS patients in targeted rehabilitation.

Epidemiology of Huntington disease: first post-HTT gene analysis of prevalence in Italy.

Huntington disease (HD) prevalence shows geographic variability and has been recently updated by taking into account the mutation diagnostic test. In Italy, the last epidemiological estimation was reported well before the HTT gene discovery and the availability of the corresponding genetic test. It reported a prevalence of affected subjects ranging between 2.3 and 4.8/100,000 in some restricted areas of Northern Italy. We have performed a service-based epidemiological analysis in a very restricted geographic area named Molise, where our institutions currently operate and represent the only point of reference for rare neuropsychiatric diseases. The estimated prevalence rate found was 10.85/100,000 (95% confidence interval (CI): 7.20-14.50), remarkably higher than that previously described before the gene test analysis was available, and expected to an increase of an additional 17% by 2030, because of Italian population aging. According to our analysis, we estimate that about 6500 subjects are currently affected by HD in Italy, and that this number will further increase in the next decades because of population aging, variable phenotype penetrance and improved life expectancy.

The Corticospinal Tract in Huntington's Disease.

Huntington's disease (HD) is characterized by progressive motor impairment. Therefore, the connectivity of the corticospinal tract (CST), which is the main white matter (WM) pathway that conducts motor impulses from the primary motor cortex to the spinal cord, merits particular attention. WM abnormalities have already been shown in presymptomatic (Pre-HD) and symptomatic HD subjects using magnetic resonance imaging (MRI). In the present study, we examined CST microstructure using diffusion tensor imaging (DTI)-based tractography in 30-direction DTI data collected from 100 subjects: Pre-HD subjects (n = 25), HD patients (n = 25) and control subjects (n = 50), and T2*-weighted (iron sensitive) imaging. Results show decreased fractional anisotropy (FA) and increased axial (AD), and radial diffusivity (RD) in the bilateral CST of HD patients. Pre-HD subjects had elevated iron in the left CST, regionally localized between the brainstem and thalamus. CAG repeat length in conjunction with age, as well as motor (UHDRS) assessment were correlated with CST FA, AD, and RD both in Pre-HD and HD. In the presymptomatic phase, increased iron in the inferior portion supports the "dying back" hypothesis that axonal damage advances in a retrograde fashion. Furthermore, early iron alteration may cause a high level of toxicity, which may contribute to further damage.

MRI measures of corpus callosum iron and myelin in early Huntington's disease.

Increased iron in subcortical gray matter (GM) structures of patients with Huntington's disease (HD) has been suggested as a causal factor in neuronal degeneration. But how iron content is related to white matter (WM) changes in HD is still unknown. For example, it is not clear whether WM changes share the same physiopathology (i.e. iron accumulation) with GM or whether there is a different mechanism. The present study used MRI to examine iron content in premanifest gene carriers (PreHD, n = 25) and in early HD patients (n = 25) compared with healthy controls (n = 50). 3T MRI acquisitions included high resolution 3D T1, EPI sequences for diffusion tensor imaging (DTI) as an indirect measure of tissue integrity, and T2*-weighted gradient echo-planar imaging for MR-based relaxometry (R2*), which provides an indirect measure of ferritin/iron deposition in the brain. Myelin breakdown starts in the PreHD stage, but there is no difference in iron content values. Iron content reduction manifests later, in the early HD stage, in which we found a lower R2* parameter value in the isthmus. The WM iron reduction in HD is temporally well-defined (no iron differences in PreHD subjects and iron differences only in early HD patients). Iron level in callosal WM may be regarded as a marker of disease state, as iron does not differentiate PreHD subjects from controls but distinguishes between PreHD and HD.

CAG repeat expansion in Huntington disease determines age at onset in a fully dominant fashion.

OBJECTIVE: Age at onset of diagnostic motor manifestations in Huntington disease (HD) is strongly correlated with an expanded CAG trinucleotide repeat. The length of the normal CAG repeat allele has been reported also to influence age at onset, in interaction with the expanded allele. Due to profound implications for disease mechanism and modification, we tested whether the normal allele, interaction between the expanded and normal alleles, or presence of a second expanded allele affects age at onset of HD motor signs. METHODS: We modeled natural log-transformed age at onset as a function of CAG repeat lengths of expanded and normal alleles and their interaction by linear regression. RESULTS: An apparently significant effect of interaction on age at motor onset among 4,068 subjects was dependent on a single outlier data point. A rigorous statistical analysis with a well-behaved dataset that conformed to the fundamental assumptions of linear regression (e.g., constant variance and normally distributed error) revealed significance only for the expanded CAG repeat, with no effect of the normal CAG repeat. Ten subjects with 2 expanded alleles showed an age at motor onset consistent with the length of the larger expanded allele. CONCLUSIONS: Normal allele CAG length, interaction between expanded and normal alleles, and presence of a second expanded allele do not influence age at onset of motor manifestations, indicating that the rate of HD pathogenesis leading to motor diagnosis is determined by a completely dominant action of the longest expanded allele and as yet unidentified genetic or environmental factors.

Multimodal MRI analysis of the corpus callosum reveals white matter differences in presymptomatic and early Huntington's disease.

Recent magnetic resonance imaging (MRI) studies suggest that abnormalities in Huntington's disease (HD) extend to white matter (WM) tracts in early HD and even in presymptomatic stages. Thus, changes of the corpus callosum (CC) may reflect various aspects of HD pathogenesis. We recruited 17 HD patients, 17 pre-HD subjects, and 34 healthy age-matched controls. Three-dimensional anatomical MRI and diffusion tensor images of the brain were acquired on a 3T scanner. Combining region-of-interest analyses, voxel-based morphometry, and tract-based spatial statistics, we investigated callosal thickness, WM density, fractional anisotropy, and radial and axial diffusivities. Compared with controls, pre-HD subjects showed reductions of the isthmus, likely due to myelin damage. Compared with pre-HD subjects, HD patients showed reductions of isthmus and body, with axonal damage confined to the body. Compared with controls, HD patients had significantly decreased callosal measures in extended regions across almost the entire CC. At this disease stage, both myelin and axonal damage are detectable. Supplementary multiple regression analyses revealed that WM reduction density in the isthmus as well as Disease Burden scores allowed to predict the "HD development" index. While callosal changes seem to proceed in a posterior-to-anterior direction as the diseases progresses, this observation requires validation in future longitudinal investigations.

Whole body cholesterol metabolism is impaired in Huntington's disease.

We previously reported impaired cholesterol biosynthesis in rodent Huntington Disease (HD) models and HD patients' fibroblasts and post mortem brains. We also found that plasma levels of 24S-hydroxycholesterol (24OHC), the brain specific elimination product of cholesterol considered a marker of brain cholesterol turnover, were significantly reduced in HD patients at any disease stage. In the present study we analysed by mass spectrometry the fasting plasma levels of cholesterol, its biosynthetic precursors lanosterol and lathosterol, of the whole-body elimination products 27-hydroxycholesterol and of brain 24OHC in a cohort of premanifest and HD patients at different disease stages. We found that the cholesterol precursors lanosterol and lathosterol (both index of whole body cholesterol synthesis), the levels of the bile acid precursor 27-hydroxycholesterol, and of the brain specific 24OHC, were all significantly reduced in manifest HD patients, suggesting that whole-body and brain cholesterol homeostasis are both impaired in HD.

Four novel SPG3A/atlastin mutations identified in autosomal dominant hereditary spastic paraplegia kindreds with intra-familial variability in age of onset and complex phenotype.

Mutation of the atlastin gene (SPG3A) is responsible for approximately 10% of autosomal dominant hereditary spastic paraplegia (AD-HSP) cases. The goal of this study was to identify novel disease causing atlastin mutations. Atlastin nucleotide variations were detected by direct sequencing of all 14 exons in 70 autosomal dominant (AD), 16 single sibship and 14 sporadic spastic paraplegia patients. Six mis-sense mutations (four of which were novel) were identified in six unrelated AD-HSP kindreds in exons 4, 7 and 8 of the atlastin gene. One kindred with a novel mutation showed variability in clinical phenotype and age of onset. Mutations are predicted to decrease GTPase activity, cause morphological abnormalities of the endoplasmic reticulum and prevent maturation of the Golgi complex resulting in impaired vesicle trafficking. Our study significantly adds to the spectrum of mutations and clinical phenotype of SPG3A. We advocate that all spastin mutation negative AD-HSP kindreds should be screened for pathogenic atlastin mutations regardless of age of onset or phenotypic complexity.

ZPLD1 gene is disrupted in a patient with balanced translocation that exhibits cerebral cavernous malformations.

The past few years have seen rapid advances in our understanding of the genetics and molecular biology of cerebral cavernous malformations (CCM) with the identification of the CCM1, CCM2, and CCM3 genes. Recently, we have recruited a patient with an X/3 balanced translocation that exhibits CCM. By fluorescent in situ hybridization analysis, sequence analysis tools and database mining procedures, we refined the critical region to an interval of 200-kb and identified the interrupted ZPLD1 gene. We detected that the mRNA expression level of ZPLD1 gene is consistently decreased 2.5-fold versus control (P=0.0006) with allelic loss of gene expression suggesting that this protein may be part of the complex signaling pathway implicated in CCM formation.

ATP13A2 missense mutations in juvenile parkinsonism and young onset Parkinson disease.

OBJECTIVE: To assess the prevalence, nature, and associated phenotypes of ATP13A2 gene mutations among patients with juvenile parkinsonism (onset <21 years) or young onset (between 21 and 40 years) Parkinson disease (YOPD). METHODS: We studied 46 patients, mostly from Italy or Brazil, including 11 with juvenile parkinsonism and 35 with YOPD. Thirty-three cases were sporadic and 13 had positive family history compatible with autosomal recessive inheritance. Forty-two had only parkinsonian signs, while four (all juvenile-onset) had multisystemic involvement. The whole ATP13A2 coding region (29 exons) and exon-intron boundaries were sequenced from genomic DNA. RESULTS: A novel homozygous missense mutation (Gly504Arg) was identified in one sporadic case from Brazil with juvenile parkinsonism. This patient had symptoms onset at age 12, levodopa-responsive severe akinetic-rigid parkinsonism, levodopa-induced motor fluctuations and dyskinesias, severe visual hallucinations, and supranuclear vertical gaze paresis, but no pyramidal deficit nor dementia. Brain CT scan showed moderate diffuse atrophy. Furthermore, two Italian cases with YOPD without atypical features carried a novel missense mutation (Thr12Met, Gly533Arg) in single heterozygous state. CONCLUSIONS: We confirm that ATP13A2 homozygous mutations are associated with human parkinsonism, and expand the associated genotypic and clinical spectrum, by describing a homozygous missense mutation in this gene in a patient with a phenotype milder than that initially associated with ATP13A2 mutations (Kufor-Rakeb syndrome). Our data also suggest that ATP13A2 single heterozygous mutations might be etiologically relevant for patients with YOPD and further studies of this gene in Parkinson disease are warranted.

Low brain-derived neurotrophic factor (BDNF) levels in serum of Huntington's disease patients.

Huntington's disease (HD) is a neurodegenerative disorder characterized by motor, cognitive, and psychiatric symptoms and by a progressive degeneration of neurons in basal ganglia and in brain cortex. Brain-derived neurotrophic factor (BDNF) is a pro-survival factor for striatal neurons. Some evidence implicates a brain BDNF deficiency, related to mutated huntingtin expression, in the selective vulnerability of striatal neurons in HD. We compared BDNF serum levels in 42 patients with HD (range 28-72 years, mean age 51.9 +/- 11.5), and 42 age-matched healthy subjects (range 25-68 years, mean age 48.2 +/- 12.5). We evaluated the potential relationship between BDNF serum levels, CAG repeat number (range 40-54, mean 44.8 +/- 3.4) and duration of illness (range 6-228 months, mean 103.6 +/- 62.1). Serum BDNF levels were significantly lower in patients than in age-matched healthy subjects. Lower BDNF levels were associated with a longer CAG repeat length and a longer duration of illness. Severity of the illness, as assessed by the Unified Huntington's Disease Rating Scale (UHDRS) motor and cognitive scores, was negatively related to serum BDNF levels. These results in vivo confirm that the huntingtin mutation causes BDNF production to decline and show that the BDNF deficiency is detectable in HD patients' sera. Further studies on a larger sample size should confirm whether BDNF concentrations in patients' serum could be a useful clinical marker related to the patients' disease phenotype.

Increased apoptosis, Huntingtin inclusions and altered differentiation in muscle cell cultures from Huntington's disease subjects.

Mutated huntingtin (htt) is ubiquitously expressed in tissues of Huntington's disease (HD) patients. In the brain, the mutated protein leads to neuronal cell dysfunction and death, associated with formation of htt-positive inclusions. Given increasing evidence of abnormalities in HD skeletal muscle, we extensively analyzed primary muscle cell cultures from seven HD subjects (including two unaffected mutation carriers). Myoblasts from presymptomatic and symptomatic HD subjects showed cellular abnormalities in vitro, namely mitochondrial depolarization, cytochrome c release, increased caspase-3, -8, and -9 activities, and defective cell differentiation. Another notable feature was the formation of htt inclusions in differentiated myotubes. This study helps to advance current knowledge about the downstream effects of the htt mutation in human tissues. Further applications may include drug screening using this human cellular model.

The search for cerebral biomarkers of Huntington's disease: a review of genetic models of age at onset prediction.

The mutation causing Huntington's disease is an expanded CAG trinucleotide repeat number beyond 35 in the 5' translated region of the gene. The mutation penetrance varies widely and depends on the CAG expansion length, the low pathological triplet range (36-41) showing a very low penetrance, possibly associated with late ages at onset. No research has so far yielded biomarkers for accurately predicting either age at onset or disease progression in at risk individuals. Specific markers able to follow-up mutation carrier subjects from the pre-symptomatic stages of life are crucial for testing experimental neuroprotective preventive therapies. Nevertheless, the factor accounting for the largest percentage of age at onset variation is the expanded repeat number within the gene. Over the years, this factor has helped in setting up models for genetically predicting age at onset. Once available for practical application in clinics, such models allowed phenotype-genotype correlations that were hitherto inconceivable. In this review, we discuss how these genetic models have been applied in clinical practice and comment on their potential value in searching for cerebral biomarkers of disease onset and severity and in designing trials of therapeutic drugs.

Adenosine A2A receptor dysfunction correlates with age at onset anticipation in blood platelets of subjects with Huntington's disease.

Huntington's disease (HD) may manifest at an earlier age in affected offspring than in transmitting parents. Earlier onset in successive generations (anticipation) only partially depends on intergenerational parent-child elongation of the CAG expanded mutation. An aberrant amplification of adenosine A(2A) receptor signaling documented in peripheral blood cells of subjects with HD implies that this cellular dysfunction may be related to clinical and genetic features. Prompted by evidence of higher receptor densities in siblings of HD subjects with stronger onset anticipation, in this study we investigated a possible relationship between A(2A) receptor densities and age at onset. We measured adenosine A(2A) receptor densities in blood cell platelets from 32 patients with HD and healthy control siblings, and sought a possible linear correlation between maximum platelet A(2A) receptor binding (B(max)) values for the whole cohort of HD subjects and anticipation in years. The increased B(max) values for the 32 subjects with HD (220 in patients vs. 137 in healthy control subjects, P = 0.0001) correlated significantly with anticipation in years (r2, 0.48, P = 0.0001 by linear correlation analysis). An increased platelet A(2A) receptor B(max) may belong in a cascade of toxic events leading to earlier onset of HD: as such it could be a useful marker of onset anticipation.

Ataxia with isolated vitamin E deficiency: neurological phenotype, clinical follow-up and novel mutations in TTPA gene in Italian families.

Ataxia with vitamin E deficiency (AVED) is a rare autosomal recessive neurodegenerative disorder due to mutations in the alpha-tocopherol transfer protein (TTPA) gene on chromosome 8q13. AVED patients have progressive spinocerebellar symptoms and markedly reduced plasma levels of vitamin E. We studied neurological phenotype at diagnosis, and long-term effect of vitamin E supplementation in 16 patients from 12 Italian families. The most common mutations were the 744delA and 513insTT. Two novel TTPA mutations were identified: a severe truncating mutation (219insAT) in a homozygous patient, and a Gly246Arg missense mutation (G246R) in a compound heterozygous patient. The missense mutation was associated with a mild and slowly progressive form of the disease. Vitamin E supplementation therapy allowed a stabilization of the neurological conditions in most of the patients. However, development of spasticity and retinitis pigmentosa was noted in a few patients during therapy. Prompt genetic characterization of AVED patients may allow an effective early treatment and an adequate genetic counseling.

DJ-1( PARK7), a novel gene for autosomal recessive, early onset parkinsonism.

Four chromosomal loci ( PARK2, PARK6, PARK7, and PARK9) associated with autosomal recessive, early onset parkinsonism are known. We mapped the PARK7 locus to chromosome 1p36 in a large family from a genetically isolated population in the Netherlands, and confirmed this linkage in an Italian family. By positional cloning within the refined PARK7 critical region we recently identified mutations in the DJ-1 gene in the two PARK7-linked families. The function of DJ-1 remains largely unknown, but evidence from genetic studies on the yeast DJ-1 homologue, and biochemical studies in murine and human cell lines, suggests a role for DJ-1 as an antioxidant and/or a molecular chaperone. Elucidating the role of DJ-1 will lead to a better understanding of the pathogenesis of DJ-1-related and common forms of Parkinson's disease.