Plasma phosphorylated TDP-43 levels are elevated in patients with frontotemporal dementia carrying a C9orf72 repeat expansion or a GRN mutation.

OBJECTIVES: About a half of patients with frontotemporal dementia (FTD) has deposition of phosphorylated TDP-43 protein (pTDP-43) in the brain. We studied pTDP-43 and total TDP-43 levels in plasma and cerebrospinal fluid (CSF) in healthy controls and patients with FTD, including those carrying a repeat expansion in the C9orf72 gene or a mutation in GRN. METHODS: We included 88 plasma samples of 10 C9orf72 expansion carriers, 5 GRN mutation carriers, 51 patients with FTD without a known mutation and 22 healthy controls. We also obtained CSF samples from 25 patients with FTD (2 with C9orf72 expansion and 3 with a GRN mutation) and 22 healthy controls. We measured pTDP-43 and total TDP-43 levels using sandwich ELISA. RESULTS: Patients carrying the C9orf72 repeat expansion or a GRN mutation had significantly higher plasma and CSF levels of pTDP-43 than the remaining patients with FTD (p<0.05). In addition, plasma pTDP-43 levels were higher in patients with FTD carrying a C9orf72 expansion or GRN mutations than in healthy controls (p<0.05). CONCLUSIONS: Our study shows that plasma pTDP-43 levels may be increased in some genetic forms of FTD known to be associated with TDP-43 proteinopathies.

Characterization of the repeat expansion size in C9orf72 in amyotrophic lateral sclerosis and frontotemporal dementia.

Hexanucleotide repeat expansions within the C9orf72 gene are the most important genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The difficulty of developing a precise method to determine the expansion size has hampered the study of possible correlations between the hexanucleotide repeat number and clinical phenotype. Here we characterize, through a new non-radioactive Southern blot protocol, the expansion size range in a series of 38 ALS and 22 FTD heterozygous carriers of >30 copies of the repeat. Maximum, median and modal hexanucleotide repeat number were higher in ALS patients than in FTD patients (P< 0.05 in all comparisons). A higher median number of repeats correlated with a bigger range of repeat sizes (Spearman's ρ = 0.743, P = 1.05 × 10(-11)). We did not find any correlation between age of onset or disease duration with the repeat size in neither ALS nor FTD mutation carriers. Clinical presentation (bulbar or spinal) in ALS patients did not correlate either with the repeat length. We finally analyzed two families with affected and unaffected repeat expansion carriers, compared the size of the repeat expansion between two monozygotic (MZ) twins (one affected of ALS and the other unaffected), and examined the expansion size in two different tissues (cerebellum and peripheral blood) belonging to the same FTD patient. The results suggested that the length of the C9orf72 repeat varies between family members, including MZ twins, and among different tissues from the same individual.

Expansion mutation in C9ORF72 does not influence plasma progranulin levels in frontotemporal dementia.

A hexanucleotide repeat expansion in chromosome 9 open reading frame 72 (C9ORF72) gene has recently been described as a cause of familial and sporadic frontotemporal lobar degeneration. The aim of this study was to assess whether plasma progranulin (GRN) levels could be modulated by the presence of this repeat expansion. Sixty-five patients diagnosed with frontotemporal dementia and 10 family members with familial aggregation of disease were screened for the presence of the hexanucleotide repeat expansion in C9ORF72 gene, using a repeat-primed polymerase chain reaction method. Plasma GRN levels were measured in all subjects through enzyme-linked immunosorbent assay. Seven individuals with the repeat expansion were identified. No differences were found between C9ORF72 repeat expansion carriers and noncarriers (116.4 ± 21 ng/mL and 131.7 ± 36 ng/mL, respectively, p = 0.3). Analysis of family members did not disclose any difference in plasma GRN levels between carriers and noncarriers. In conclusion, plasma GRN levels are not influenced by the hexanucleotide repeat expansion in C9ORF72 gene, and therefore, cannot be used as a reliable biomarker to detect mutation carriers.

Identifying at-risk states beyond positive symptoms: a brief task assessing how neurocognitive impairments impact on misrepresentation of the social world through blunted emotional appraisal / Identificando estados de risco para além dos sintomas positivos: um teste breve que avalia o impacto de disfunções neurocognitivas sobre a interpretação errônea do mundo social resultante de avaliação emocional embotada

OBJECTIVE: Neurocognitive impairments observed in psychotic disorder may impact on emotion recognition and theory of mind, resulting in altered understanding of the social world. Early intervention efforts would be served by further elucidation of this mechanism. METHOD: Patients with a psychotic disorder (n=30) and a reference control group (n=310) were asked to offer emotional appraisals of images of social situations (EASS task). The degree to which case-control differences in appraisals were mediated by neurocognitive alterations was analyzed. RESULTS: The EASS task displayed convergent and discriminant validity. Compared to controls, patients displayed blunted emotional appraisal of social situations (B=0.52, 95 percent CI: 0.30, 0.74, P<0.001; adjusted for age, sex and number of years of education: B=0.44, 95 percent CI: 0.20, 0.68, P<0.001), a difference of 0.88 (adjusted: 0.75) standard deviation. After adjustment for neurocognitive variables, the case-control difference was reduced by nearly 75 percent and was non-significant (B=0.12, 95 percent CI: -0.14, 0.39, P=0.37). CONCLUSIONS: Neurocognitive impairments observed in patients with psychotic disorder may underlie misrepresentation of the social world, mediated by altered emotion recognition. A task assessing the social impact of cognitive alterations in clinical practice may be useful in detecting key alterations very early in the course of psychotic illness.

OBJETIVO: Melhoras neurocognitivas observadas no transtorno psicótico podem ter impacto no reconhecimento de emoções e na teoria da mente, resultando numa alteração na compreensão do mundo social. Esforços para uma intervenção precoce poderiam se beneficiar de uma maior elucidação deste mecanismo. MÉTODO: Pacientes com transtornos psicóticos (n=30) e um grupo controle de referência (n=310) foram convidados a realizar avaliações emocionais de imagens de situações sociais (teste AESS). A relação das diferenças entre casos e controles com as alterações neurocognitivas foi analisada. RESULTADOS: O teste AESS apresentou validade convergente e discriminatória. Quando comparados aos controles, os pacientes apresentaram avaliação emocional embotada das situações sociais (B=0,52, 95 por cento CI: 0,30, 0,74, P<0,001; ajustado para a idade, sexo e número de anos de educação: B=0,44, 95 por cento CI: 0,20, 0,68, P<0001), uma diferença de 0,88 (ajustado: 0,75) desvio-padrão. Após o ajuste para as variáveis neurocognitivas, as diferenças no estudo caso-controle foram reduzidas em quase 75 por cento e deixaram de ser significativas (B=0,12, 95 por cento CI: -0,14, 0.39, P=0,37). CONCLUSÕES: Disfunções neurocognitivas observadas em pacientes com transtornos psicóticos podem ser subjacentes a uma distorção do mundo social, mediada pela alteração no reconhecimento de emoções. Um teste que avalie o impacto social de alterações cognitivas na prática clínica pode ser útil para a detecção das principais alterações nos primeiros estágios de transtornos psicóticos.

Affectively salient meaning in random noise: a task sensitive to psychosis liability.

Stable differences in the tendency to attribute meaning and emotional value to experience may represent an indicator of liability to psychosis. A brief task was developed assessing variation in detecting affectively meaningful speech (speech illusion) in neutral random signals (white noise) and the degree to which this was associated with psychometric and familial vulnerability for psychosis. Thirty patients, 28 of their siblings, and 307 controls participated. The rate of speech illusion was compared between cases and controls. In controls, the association between speech illusion and interview-based positive schizotypy was assessed. The hypothesis of a dose-response increase in rate of speech illusion across increasing levels of familial vulnerability for psychosis (controls, siblings of patients, and patients) was examined. Patients were more likely to display speech illusions than controls (odds ratio [OR] = 4.0, 95% confidence interval [CI] = 1.4-11.7), also after controlling for neurocognitive variables (OR = 3.8, 95% CI = 1.04-14.1). The case-control difference was more accentuated for speech illusion perceived as affectively salient (positively or negatively appraised) than for neutrally appraised speech illusions. Speech illusion in the controls was strongly associated with positive schizotypy but not with negative schizotypy. In addition, the rate of speech illusion increased with increasing level of familial risk for psychotic disorder. The data suggest that the white noise task may be sensitive to psychometric and familial vulnerability for psychosis associated with alterations in top-down processing and/or salience attribution.

Identifying at-risk states beyond positive symptoms: a brief task assessing how neurocognitive impairments impact on misrepresentation of the social world through blunted emotional appraisal.

OBJECTIVE: Neurocognitive impairments observed in psychotic disorder may impact on emotion recognition and theory of mind, resulting in altered understanding of the social world. Early intervention efforts would be served by further elucidation of this mechanism. METHOD: Patients with a psychotic disorder (n=30) and a reference control group (n=310) were asked to offer emotional appraisals of images of social situations (EASS task). The degree to which case-control differences in appraisals were mediated by neurocognitive alterations was analyzed. RESULTS: The EASS task displayed convergent and discriminant validity. Compared to controls, patients displayed blunted emotional appraisal of social situations (B=0.52, 95% CI: 0.30, 0.74, P<0.001; adjusted for age, sex and number of years of education: B=0.44, 95% CI: 0.20, 0.68, P<0.001), a difference of 0.88 (adjusted: 0.75) standard deviation. After adjustment for neurocognitive variables, the case-control difference was reduced by nearly 75% and was non-significant (B=0.12, 95% CI: -0.14, 0.39, P=0.37). CONCLUSIONS: Neurocognitive impairments observed in patients with psychotic disorder may underlie misrepresentation of the social world, mediated by altered emotion recognition. A task assessing the social impact of cognitive alterations in clinical practice may be useful in detecting key alterations very early in the course of psychotic illness.

Stiff man-like syndrome and generalized myokymia in spinocerebellar ataxia type 3.

We describe the novel association of spinocerebellar ataxia type 3/Machado-Joseph disease (SCA3/MJD) phenotype combining classical clinical presentation and semeiology mimicking stiff man syndrome (SMS). The studied pedigree comprises seven affected members in three generations. Their clinical picture consisted of cerebellar ataxia, pyramidal signs, facial myokymia, and ophthalmoplegia. The proband was a 39-year-old man in whom such a clinical picture, 5 years after onset at age 29, evolved to severe SMS and widespread myokymia. Electrophysiological study revealed continuous muscle activity in proximal limb muscles. Molecular study demonstrated the MJD gene mutation in all four examined patients with 73 to 76 CAG repeats in the expanded allele. We conclude that an excess of motor unit activity including stiff man-like syndrome and widespread myokymia may be an integral part of the SCA3 clinical spectrum.