A kinetics-based approach to amyloid PET semi-quantification.

PURPOSE: To develop and validate a semi-quantification method (time-delayed ratio, TDr) applied to amyloid PET scans, based on tracer kinetics information. METHODS: The TDr method requires two static scans per subject: one early (~ 0-10 min after the injection) and one late (typically 50-70 min or 90-100 min after the injection, depending on the tracer). High perfusion regions are delineated on the early scan and applied onto the late scan. A SUVr-like ratio is calculated between the average intensities in the high perfusion regions and the late scan hotspot. TDr was applied to a naturalistic multicenter dataset of 143 subjects acquired with [18F]florbetapir. TDr values are compared to visual evaluation, cortical-cerebellar SUVr, and to the geometrical semi-quantification method ELBA. All three methods are gauged versus the heterogeneity of the dataset. RESULTS: TDr shows excellent agreement with respect to the binary visual assessment (AUC = 0.99) and significantly correlates with both validated semi-quantification methods, reaching a Pearson correlation coefficient of 0.86 with respect to ELBA. CONCLUSIONS: TDr is an alternative approach to previously validated ones (SUVr and ELBA). It requires minimal image processing; it is independent on predefined regions of interest and does not require MR registration. Besides, it takes advantage on the availability of early scans which are becoming common practice while imposing a negligible added patient discomfort.

Clinical and MRI Predictors of Conversion From Mild Behavioural Impairment to Dementia.

OBJECTIVE: As an analogy with mild cognitive impairment (MCI), the mild behavioral impairment (MBI) construct has been proposed as a diagnostic label for those presenting late-onset behavioral symptoms. To date, however, the clinical, cognitive, and structural imaging features associated with an increased risk of conversion from MBI to dementia are poorly understood. METHODS: We retrospectively analyzed the cognitive performance and structural brain MRI of 113 subjects, with a clinical follow-up of at least 4 years available. Subjects were randomly assigned to a Group A (56 subjects; age: 65.4 ± 7.9 years, 15 females, MMSE score: 28.4 ± 2.3)) or to a Group B (57 subjects, age: 66.6 ± 6.4, 17 females, MMSE score: 28.0 ± 1.4). In the Group A, cognitive and structural variables were compared between converters (at 4 years) and nonconverters and then verified in the Group B group. RESULTS: In the Group A, 14 patients converted to behavioral-variant of frontotemporal dementia (bv-FTD) and 4 to Alzheimer's Disease (AD). Converters presented at baseline lower executive function scores and total Theory of Mind (ToM scores), as well as more severe focal frontal atrophy. In the Group B, 13 subjects converted to bv-FTD and none to AD. The combination of the variables identified in the Group A significantly (p <0.001) discriminated between converters and nonconverters in the Group B with a sensitivity of 0.615 and a specificity of 1 (total accuracy 91.22%). CONCLUSION: The combined presence of executive deficit, impaired ToM, and presence of isolated frontal atrophy was associated with risk of progression from MBI to a clinically evident neurodegenerative condition, mainly bv-FTD, over a 4-year period.

Assessing upper limb function in multiple sclerosis using an engineered glove.

BACKGROUND AND PURPOSE: The importance of upper limb function in multiple sclerosis (MS) is increasingly recognized, especially for the evaluation of patients with progressive MS with reduced mobility. Two sensor-engineered gloves, able to measure quantitatively the timing of finger opposition movements, were previously used to assess upper limb disability in MS. The aims of the present study were: (1) to confirm the association between glove-derived variables and standard measures of MS disability in a larger cohort; (2) to assess the correlation with quantitative magnetic resonance imaging (MRI) and quality of life (QoL) measures; and (3) to determine if the glove-derived variables offer advantages over the standard measure for assessing upper limb function in MS, namely, the Nine-Hole Peg Test (9HPT). METHODS: Sixty-five patients with MS, stable on disease-modifying treatment, were evaluated at baseline using the glove, and through clinical examination (Expanded Disability Status Scale, Symbol Digit Modalities Test, Timed 25-Foot Walk Test and 9HPT), MRI evaluation and QoL questionnaires. Correlations between the glove-derived variables and clinical, MRI and QoL variables were assessed using Spearman's rank correlation coefficient analysis. RESULTS: Glove-derived variables significantly differed between patients with relapsing-remitting and those with progressive MS, with similar or slightly higher correlations of the 9HPT with clinical variables. We found greater correlations of the QoL physical component with glove-derived variables than with the 9HPT, and a significant correlation of its mental component with the glove-derived variables but not with the 9HPT. CONCLUSION: The study results, confirming previous findings and showing advantages over the 9HPT, encourage the investigation of sensitivity to change in glove-derived variables in a longitudinal setting.

The association between retinal nerve fibre layer thickness and N-acetyl aspartate levels in multiple sclerosis brain normal-appearing white matter: a longitudinal study using magnetic resonance spectroscopy and optical coherence tomography.

BACKGROUND AND PURPOSE: N-acetyl aspartate (NAA) assessed using proton magnetic resonance spectroscopy (1 H MRS) has a high pathological specificity for axonal density. Retinal nerve fibre layer thickness (RNFLT) measured by using optical coherence tomography is increasingly used as a surrogate marker of neurodegeneration in multiple sclerosis (MS). Our aim was to investigate the relation between RNFLT and NAA/creatine in brain normal-appearing white matter (NAWM), their dynamics over time and the association with clinical outcome measures in relapsing MS. T2 WM lesions served as control tissue. METHODS: Forty-three MS patients underwent standardized neurological examination including the Expanded Disability Status Scale (EDSS), Multiple Sclerosis Functional Composite (MSFC) score, optical coherence tomography and magnetic resonance imaging including 1 H MRS at baseline and after 1 year. RESULTS: At baseline, NAA/creatine level was lower in T2 WM lesions than in NAWM (1.64 ± 0.16 vs. 1.88 ± 0.24, P < 0.001). Lowest levels were found in secondary progressive MS (SPMS). Mean RNFLT was higher in clinically isolated syndrome than in the combined group of relapsing-remitting MS and SPMS (99.8 ± 12.3 µm vs. 92.4 ± 12.8 µm, P = 0.038). In all patients, mean RNFLT decreased by 1.4% during follow-up. At baseline, MSFC z-scores correlated with NAA/creatine levels both in NAWM (r = 0.42; P = 0.008) and T2 WM lesions (r = 0.52, P = 0.004). NAWM NAA/creatine variation correlated with the RNFLT change over 1 year (ρ = 0.43, P = 0.046). CONCLUSIONS: N-acetyl aspartate/creatine level reduction correlated with RNFLT thinning over 1 year in an EDSS stable MS cohort suggesting that these techniques might be sensitive to detect subclinical disease progression.

The association between olfactory bulb volume, cognitive dysfunction, physical disability and depression in multiple sclerosis.

BACKGROUND AND PURPOSE: Olfactory bulb atrophy is associated with cognitive dysfunction in Parkinson's and Alzheimer's disease, and with major depression. It has been suggested that olfactory bulb atrophy or dysfunction is therefore a marker of neurodegeneration. Multiple sclerosis (MS) is now also recognized as having a significant neurodegenerative component. Thus, the aim of this study was to investigate associations between physical and cognitive disability, depression and olfactory bulb volume in MS. METHODS: In total, 146 patients with MS (mean age 49.0 ± 10.9 years, disease duration 21.2 ± 9.3 years, median Expanded Disability Status Scale (EDSS) score 3.0 (range 0-7.5), 103 relapsing-remitting, 35 secondary progressive and eight primary progressive MS) underwent a standardized neurological examination, comprehensive neuropsychological testing and magnetic resonance imaging (MRI); data of 27 healthy people served as age- and gender-matched control subjects. The olfactory bulb was semi-automatically segmented on high-resolution three-dimensional T1-weighted MRI. RESULTS: Mean olfactory bulb volume was lower in MS patients than healthy controls (183.9 ± 40.1 vs. 209.2 ± 59.3 µl; P = 0.018 adjusted to intracranial volume). Olfactory bulb volume was similar across clinical disease subtypes and did not correlate with cognitive performance, EDSS scores or total proton density/T2 white matter lesion volume. However, in progressive MS, the mean olfactory bulb volume correlated with depression scores (Spearman's rho = -0.38, P < 0.05) confirmed using a multivariate linear regression analysis including cognitive fatigue scores. This association was not observed in relapsing-remitting MS. CONCLUSION: Olfactory bulb volume was lower in MS than in healthy controls. Olfactory bulb volume does not seem to mirror cognitive impairment in MS; however, it is associated with higher depression scores in progressive MS.

An updated Italian normative dataset for the Stroop color word test (SCWT).

The Stroop color and word test (SCWT) is widely used to evaluate attention, information processing speed, selective attention, and cognitive flexibility. Normative values for the Italian population are available only for selected age groups, or for the short version of the test. The aim of this study was to provide updated normal values for the full version, balancing groups across gender, age decades, and education. Two kinds of indexes were derived from the performance of 192 normal subjects, divided by decade (from 20 to 90) and level of education (4 levels: 3-5; 6-8; 9-13; >13 years). They were (i) the correct answers achieved for each table in the first 30 s (word items, WI; color items, CI; color word items, CWI) and (ii) the total time required for reading the three tables (word time, WT; color time, CT; color word time, CWT). For each index, the regression model was evaluated using age, education, and gender as independent variables. The normative data were then computed following the equivalent scores method. In the regression model, age and education significantly influenced the performance in each of the 6 indexes, whereas gender had no significant effect. This study confirms the effect of age and education on the main indexes of the Stroop test and provides updated normative data for an Italian healthy population, well balanced across age, education, and gender. It will be useful to Italian researchers studying attentional functions in health and disease.

A normative study of the Italian printed word version of the free and cued selective reminding test.

According to the new research criteria for the diagnosis of Alzheimer's disease, episodic memory impairment, not significantly improved by cueing, is the core neuropsychological marker, even at a pre-dementia stage. The FCSRT assesses verbal learning and memory using semantic cues and is widely used in Europe. Standardization values for the Italian population are available for the colored picture version, but not for the 16-item printed word version. In this study, we present age- and education-adjusted normative data for FCSRT-16 obtained using linear regression techniques and generalized linear model, and critical values for classifying sub-test performance into equivalent scores. Six scores were derived from the performance of 194 normal subjects (MMSE score, range 27-30, mean 29.5 ± 0.5) divided per decade (from 20 to 90), per gender and per level of education (4 levels: 3-5, 6-8, 9-13, >13 years): immediate free recall (IFR), immediate total recall (ITR), recognition phase (RP), delayed free recall (DFR), delayed total recall (DTR), Index of Sensitivity of Cueing (ISC), number of intrusions. This study confirms the effect of age and education, but not of gender on immediate and delayed free and cued recall. The Italian version of the FCSRT-16 can be useful for both clinical and research purposes.

Protective effect of HLA-DRB1 11 and predisposition of HLA-C 04 in the development of severe liver damage in Brazilian patients with chronic hepatitis C virus infection.

The objective of this study was to investigate human leucocyte antigen (HLA) genes in patients chronically infected with hepatitis C virus (HCV) and to analyse the possible role of these genes in the progression of chronic hepatitis C. One hundred and forty-five (145) Brazilian patients infected only with HCV genotype 1 were evaluated. HLA class I (A, B, C) and class II (DRB1, DQA1, DQB1) typing were carried out by PCR-SSO, through Luminex technology. Associations were found with protection against development of liver damage by both DRB1 11 (5.0% versus 18.2%, P=0.0016, OR=0.23, CI 95% = 0.09-0.58; Pc=0.0208) and DRB1 11-DQA1 05-DQB1 03 haplotype (4.2% versus 15.3%, P=0.0032; OR = 0.24, CI 95% = 0.08-0.64). Liver damage was associated with HLA-C 04 in patients with <20 years of infection (38.4% versus 9.1%, P = 0.002, OR = 6.25, CI 95%=1.97-19.7; Pc=0.0238). It is concluded that HLA alleles can influence the development of liver damage in HCV type-1 chronically infected Brazilian patients.

Influence of HLA alleles in response to treatment with pegylated interferon-alpha and ribavirin in patients with chronic hepatitis C.

The objective of this study was to analyse the possible role of HLA polymorphism of chronically infected hepatitis C virus patients in the response outcome to treatment with pegylated interferon-alpha plus ribavirin. To that end, 144 Brazilian patients infected only with genotype 1 of the virus were treated with pegylated interferon-alpha at 1.5 µg kg(-1) in conjunction with ribavirin (1000 mg if patient weight was <75 kg and 1250 mg if >75 kg) for 48 weeks. The patients did not have concomitant HBV or HIV infections or liver disease, did not undergo previous antiviral treatment, and were followed up for 24 weeks after the end of treatment to assure they presented a sustained virological response. Patients were classified according to response to treatment in responsive (SVR), nonresponsive (NRS) and relapsers (REL). HLA class I and class II typing were carried out through PCR-SSO using Luminex technology. A statistically higher frequency of DRB1*11 patients was observed in the SVR group (39.6% vs. 14.3%P = 0.0012; Pc = 0.0156; OR = 3.94; 95% CI = 1.8-8.8). HLA-DQB1*03 patients were also more frequent in the SVR group, but the P value lost significance after Bonferroni correction (62.3% vs. 41.7%P = 0.024; Pc = 0.14, OR = 2.3; 95% CI = 1.14-4.60). HLA class II antigens can positively influence the response to treatment with pegylated interferon-alpha and ribavirin.

The Mycobacterium tuberculosis sigma factor sigmaB is required for full response to cell envelope stress and hypoxia in vitro, but it is dispensable for in vivo growth.

The numerous sigma (sigma) factors present in Mycobacterium tuberculosis are indicative of the adaptability of this pathogen to different environmental conditions. In this report, we describe the M. tuberculosis sigma(B) regulon and the phenotypes of an M. tuberculosis sigB mutant strain exposed to cell envelope stress, oxidative stress, and hypoxia. The sigB mutant was especially defective in survival under hypoxic conditions in vitro, but it was not attenuated for growth in THP-1 cells or during mouse and guinea pig infection.

White matter reduced streamline coherence in young men with autism and mental retardation.

BACKGROUND AND PURPOSE: It has been proposed that white matter alterations might play a role in autistic disorders; however, published data are mainly limited to high-functioning autism. The goal of this study was to apply diffusion tensor imaging (DTI) and fiber tractography (FT) to study white matter in low-functioning autism and the relationship between white matter and cognitive impairment. METHODS: Ten low-functioning males with autism (mean age: 19.7 +/- 2.83 years) and 10 age-matched healthy males (mean age: 19.9 +/- 2.64 years) underwent DTI-MRI scanning. fractional anisotropy (FA) maps were analyzed with whole brain voxel-wise and tract-of-interest statistics. Using FT algorithms, white matter tracts connecting the orbitofrontal cortex (OFC) with other brain regions were identified and compared between the two groups. FA mean values of the autistic group were correlated with intelligence quotient (IQ) scores. RESULTS: Low-functioning autistic subjects showed a reduced tract volume and lower mean FA values in the left OFC network compared with controls. In the autistic group, lower FA values were associated with lower IQ scores. CONCLUSIONS: We showed evidence of OFC white matter network abnormalities in low-functioning autistic individuals. Our results point to a relationship between the severity of the intellectual impairment and the extent of white matter alterations.

Autologous haematopoietic stem-cell transplantation in multiple sclerosis: benefits and risks.

Autologous haematopoietic stem-cell transplantation has been evaluated over the last years as a possible new therapeutic strategy in severe forms of multiple sclerosis unresponsive to the approved therapies. Up to now, more than 400 patients have been treated and numerous are the phase I and phase II studies which addressed the feasibility of this treatment, the efficacy, side effects and transplant-related mortality. The clinical response is strongly related to the intensity of the conditioning regimen utilized as well as to the phase of the disease course in which the therapy is carried out. Rapidly evolving multiple sclerosis with a relapsing-remitting clinical course and MRI signs of activity are the cases that can take more advantage. The risk of mortality, which dropped in the last years to 2-3%, is still the main problem of this powerful therapy.

Semi-quantification and grading of amyloid PET: A project of the European Alzheimer's Disease Consortium (EADC).

BACKGROUND: amyloid-PET reading has been classically implemented as a binary assessment, although the clinical experience has shown that the number of borderline cases is non negligible not only in epidemiological studies of asymptomatic subjects but also in naturalistic groups of symptomatic patients attending memory clinics. In this work we develop a model to compare and integrate visual reading with two independent semi-quantification methods in order to obtain a tracer-independent multi-parametric evaluation. METHODS: We retrospectively enrolled three cohorts of cognitively impaired patients submitted to 18F-florbetaben (53 subjects), 18F-flutemetamol (62 subjects), 18F-florbetapir (60 subjects) PET/CT respectively, in 6 European centres belonging to the EADC. The 175 scans were visually classified as positive/negative following approved criteria and further classified with a 5-step grading as negative, mild negative, borderline, mild positive, positive by 5 independent readers, blind to clinical data. Scan quality was also visually assessed and recorded. Semi-quantification was based on two quantifiers: the standardized uptake value (SUVr) and the ELBA method. We used a sigmoid model to relate the grading with the quantifiers. We measured the readers accord and inconsistencies in the visual assessment as well as the relationship between discrepancies on the grading and semi-quantifications. CONCLUSION: It is possible to construct a map between different tracers and different quantification methods without resorting to ad-hoc acquired cases. We used a 5-level visual scale which, together with a mathematical model, delivered cut-offs and transition regions on tracers that are (largely) independent from the population. All fluorinated tracers appeared to have the same contrast and discrimination ability with respect to the negative-to-positive grading. We validated the integration of both visual reading and different quantifiers in a more robust framework thus bridging the gap between a binary and a user-independent continuous scale.

Functional magnetic resonance evidence of cortical alterations in a case of reversible congenital lymphedema of the lower limb: a pilot study.

We report the first application of brain functional Magnetic Resonance Imaging (fMRI) to congenital peripheral lymphedema patients before and after microsurgical treatment. Our aim was to evaluate the effects of limb shape change on cortical organization of the motor system and how the cortical sensorimotor network restructures after microsurgical therapy. We acquired fMRI during active motor and motor imagery tasks before surgery and six months after surgery in a patient with congenital lymphedema of the left leg. fMRI data revealed activation differences in primary and secondary motor areas between the two scanning sessions for both tasks and also between the patient's and a healthy volunteer's activations. We suggest that these alterations could be related to changes in body schema representation due to the congenital lymphedema.

Involvement of the Mycobacterium tuberculosis secreted antigen SA-5K in intracellular survival of recombinant Mycobacterium smegmatis.

A new protein (SA-5K) secreted in culture filtrates by Mycobacterium bovis, Mycobacterium tuberculosis, and few other mycobacterial species was previously identified and purified in our laboratory. In order to evaluate the putative role of SA-5K during intracellular mycobacterial growth, in the present study the SA-5K gene was cloned and expressed in Mycobacterium smegmatis, a rapid growing non-pathogenic mycobacterium which does not contain the gene for the protein. SA-5K expression in the THP-1 human macrophage cell line infected with the recombinant strain (M. smegmatis-pROL5K) was demonstrated by RT-PCR on RNA extracted from bacterial cells following 24 and 48 h of infection. Intracellular SA5K expression was associated with a higher cfu increase of M. smegmatis-pROL5K in comparison to the negative control strain (M. smegmatis recombinant for the cloning vector) (P=0.01). No significant change in SA-5K synthesis by M. smegmatis-pROL5K was observed when the recombinant strain was grown in vitro in different stress conditions such as iron deprivation, pH 4.5, presence of nitric oxide or hydrogen peroxide. The results presented in this study suggest a possible role for SA-5K in intracellular survival of recombinant M. smegmatis, though the function of the protein remains unknown.

Effectlessness of a new spasmolytic (rociverine) on intraocular pressure, pupil size, and iridocorneal angle in ophthalmically healthy subjects.

Thirty-seven subjects without eye diseases were treated with rociverine, a new direct myolytic and parasympatholytic antispasmodic: 15 by intravenous injection (20 mg) and 22 by oral administration (20 mg three times daily for four days). Intraocular pressure, pupil size, iridocorneal angle, blood pressure, and heart rate were checked before and during treatment. No clinically significant variations were observed in the parameters tested.

A flavonoid sulphate and other compounds from the roots of Centaurea bracteata.

The roots of Centaurea bracteata Scop. (Asteraceae) have been studied for the first time. Twenty-three compounds were isolated and identified, namely a sterol glucoside, two quinic acid derivatives, one sugar, and 19 flavonoids (five sulphates), one of which, centaradixin, resulted in a new natural product. Structural elucidation was performed mainly by means of FABMS, 1D and 2D NMR spectroscopy. NMR data of some sulphate flavonoids are reported for the first time.

Agomelatine but not melatonin improves fatigue perception: a longitudinal proof-of-concept study.

Chronic Fatigue Syndrome (CFS) represents a disabling condition characterized by persistent mental and physical fatigue, bodily discomfort and cognitive difficulties. To date the neural bases of CFS are poorly understood; however, mono-aminergic abnormalities, sleep-wake cycle changes and prefrontal dysfunctions are all thought to play a role in the development and maintenance of this condition. Here we explored in a group of 62 CFS subjects the impact on fatigue levels of agomelatine, an antidepressant with agonist activity at melatonin receptors (MT1 and MT2) and antagonist activity at serotoninergic 2C receptors (5HT2C). To tease out the relative effects of MT-agonism and 5HT2C antagonism on fatigue, we compared agomelatine 50mg u.i.d. with sustained release melatonin 10mg u.i.d. in the first 12-week-long phase of the study, and then switched all melatonin-treated subjects to agomelatine in the second 12-week-long phase of the study. Agomelatine treatment, but not melatonin, was associated with a significant reduction of perceived fatigue and an increase in perceived quality of life. Moreover the switch from melatonin to agomelatine was associated with a reduction of fatigue levels. Agomelatine was well tolerated by all enrolled subjects. Our data, albeit preliminary, suggest that agomelatine treatment could represent a novel useful approach to the clinical care of subjects with CFS.