Cerebellar vermis: a vulnerable location of remote brain haemorrhages after thrombolysis for ischaemic stroke.

Extra-ischaemic (remote) brain heamorrhages after thrombolysis for ischaemic stroke occur in less than 3 % of treated patients, but it worsens prognosis. Little attention has been paid to the location of the haematomas. Among 12 patients with remote brain haemorrhage after thrombolysis, we report three patients with haemorrhage in the cerebellar vermis (25 %), with poor outcome. Previous hypertensive vasculopathy is deemed to be the most plausible cause.

Ataxia of Charlevoix-Saguenay: MR and Clinical Results in Lower-Limb Musculature.

OBJECTIVE: Peripheral neuropathy is a cardinal manifestation of the autosomal recessive spastic ataxia of Charlevoix- Saguenay (ARSACS), although its type of neuromuscular involvement has not been definitely established, and magnetic resonance imaging (MRI) plays an important role in the assessment of muscle and nerve diseases. The objective of this work has been to define the patterns of muscle weakness and of abnormal muscular MRI in ARSACS. PATIENTS AND METHODS: Five patients with a molecular diagnosis of ARSACS, aged 39 to 59 years, whose electrophysiological findings were consistent with an axonal neuropathy of distal distribution superimposed on a developmental defect of myelinization, underwent neurological and MRI lower-limb examinations. Conventional FSE T1-weighted and STIR sequences were performed, looking for fatty infiltration and oedema in the musculature of the thighs, legs and feet, together with their distribution along the longitudinal axis of the muscle bellies. RESULTS: On clinical examination, paralysis was apparent in foot muscles; moderate weakness, in leg musculature; and normal strength, in thigh muscles. MRI demonstrated massive fat deposition in the foot muscles and medial gastrocnemii in every case, distal fat infiltration and oedema in every leg muscle group, and preservation of thigh muscles, albeit with diffuse minimal non-specific fat infiltration. An inverse correlation between strength and degree of fat infiltration in lower-limb muscles became apparent. CONCLUSION: The preponderance of weakness and MRI abnormalities in distal muscle groups was concordant with the presence of a length-dependent axonopathy, as described in ARSACS.Ataxie de Charlevoix-Saguenay : IRM et observations cliniques au niveau de la musculature des membres inférieurs.

The Interface between Depression and Alzheimer's Disease. A Comprehensive Approach.

Depression and Alzheimer's disease (AD) are frequent interacting diseases in the elderly with a negative impact on the quality of life of patients and caregivers. Late-life depression may be regarded either as an early symptom of AD or a risk factor for AD, depending on the context. This review was focused on the latest developments in the fields of the neurobiological basis and treatment of depression in AD. We found that some plausible hypotheses are emerging to correlate with depression in AD, such as neuroinflammation and dysimmune regulation. It seems that depression is not related to amyloid deposition, but this issue is not completely resolved. The response to antidepressants is controversial according to the evidence from 10 small double-blind randomized placebo-controlled clinical trials with antidepressants in AD patients with depression: four with sertraline, one with three arms (sertraline, mirtazapine, placebo), one with fluoxetine, one with imipramine, one with clomipramine, one with escitalopram, and one with vortioxetine. The total number of treated patients completing the trials was 638. The main criterion of a positive response was a reduction in the scores of clinical scales for depression of at least 50%. The weighted OR (odds ratio) was calculated with the method of Mantel-Haenszel: 1.29; 95% CI: 0.77-2.16. No significant differences were found compared with placebo. Antidepressants did not have a meaningful negative influence on cognition, which was measured with the mini-mental state examination (MMSE) in 18 clinical trials. Alternatives other than drugs are also discussed. Although there have been important advances in this field, pathophysiology and treatment deserve further research.

Apathy and neurocognitive correlates: review from the perspective of 'precision psychiatry'.

PURPOSE OF REVIEW: From the perspective of motivated behaviour and the so-called 'precision psychiatry', we try to identify recent advances in the neurocognitive and biological correlates of apathy. RECENT FINDINGS: New evidence supports the notion that apathy is a common transdiagnostic and heterogeneous clinical syndrome, now conceptualized as a reduction in 'goal-directed' activity. Similarly, abundant evidence has been found related to neurocognitive correlates of apathy and the associations between clinical apathy and the processes primarily responsible for mediating motivational drive and effort-based decision making.Notwithstanding that the neurobiological basis is still poorly understood, there is some agreement in recent articles about a common system-level mechanism underlying apathy, pointing at specific medial frontal cortex and subcortical structures, including anterior cingulate cortex, medial orbitofrontal cortex and ventral striatum and related circuitry. SUMMARY: Although difficulties in interpreting the results of these studies are apparent, because of different concepts of apathy used and methodological shortcomings identified, we have found consistent advances in the neurocognitive and biological correlates of apathy, relevant for the deep phenotyping proposed by the 'precision psychiatry' approach. This framework may eventually facilitate the identification of predictive-risk models and new specific therapeutic targets in psychiatry.

The effects of pregnancy on relapse rates, disability and peripartum outcomes in women with multiple sclerosis: a systematic review and meta-analysis.

Background: Although previous cohort studies of women with multiple sclerosis (MS) yielded a reduction in relapse rate during pregnancy, the effect size has not been quantified in a comprehensive manner. In addition, the effects on disability progression and peripartum outcomes have been controversial. The purpose of this work is to assess the effect of pregnancy on disease activity, and to assess the effects of MS on pregnancy as well. Materials & methods: We searched in PubMed, Cochrane Library and EMBASE for cohort studies dealing with the effects of pregnancy on relapse rates, disability progression and peripartum outcomes in women with MS. The evaluated outcomes were: changes in the annualized relapse rate (ARR) in pregnancy and puerperium, disability worsening compared with the year before pregnancy, and peripartum outcomes, which were compared with the ones of non-MS women. In the majority of cohorts included here, the women were not under disease modifying therapies during pregnancy. Results: We found 23 cohort studies measuring changes in the ARR during pregnancy and puerperium; 12 were prospective and 11 retrospective. In 17 cohorts there was significant reduction in the ARR during pregnancy compared with prepregnancy period. The pooled mean reduction in the ARR was -0.5 (95% CI: 0.67-0.38), p < 0.001, from 15 cohorts included in meta-analysis. In 18 cohorts the ARR increased in the 3-month puerperium relative to prepregnancy year period; the pooled mean increase in the ARR was 0.22 (95% CI: 0.11-0.33), p < 0.001, from 14 cohorts included in meta-analysis. Disability worsening was addressed in 18 cohorts, and in 14 of them there were no significant changes. Peripartum complications and obstetrical outcomes were assessed in 16 cohorts, of whom 13 were retrospective, without finding significant differences. Conclusion: Pregnancy is associated with lower disease activity, and puerperium with higher disease activity. Disability does not change significantly after pregnancy. The obstetrical outcomes are not very different from those of non-MS women in most cohorts.

Frontal Dysexecutive Syndrome in Brain Tumors: A Pragmatic Insight to an Old Problem.

Brain tumors have long been considered one of the most prevalent causes of potentially reversible cognitive impairment. An accurate underlying cause of cognitive impairment due to brain tumor needs to be evaluated pragmatically. Patterns of cognitive impairment associated with brain tumors depend mainly on their location, lateralization, pathological classification and secondary effects of the treatment, as well as the structural plasticity and diaschisis. Hence, it is not rare that lesions with different locations and histologies may manifest with a similar pattern of cognitive impairment due to the complex interplay of determinants. We herein report 3 patients with brain tumors affecting different locations and with differing histologies, who shared a similar presentation as "frontal dysexecutive syndrome" masqueraded as psychiatric conditions. Detailed examination of saccades and pursuit along with eye movements and conventional motor examinations were essential not only to diagnose brain tumor as the potential cause of cognitive impairment, but also to rule out other coexisting etiologies with completely different underlying pathological mechanisms (i.e., Huntington's disease in 1 of the cases). A detailed neurological examination, including eye movement assessment, in patients with psychiatric symptoms provides not only important clues to delineate the underlying anatomical substrate involved, but also helps clinicians to make an accurate diagnosis and to select appropriate therapeutic options.

Carotid intima-media thickness as a predictor of response to cholinesterase inhibitors in Alzheimer's disease: an open-label trial.

BACKGROUND: Cholinesterase inhibitors are modestly effective in treating patients with Alzheimer's disease. However, there may be important inter-individual variations ranging from no improvement at all to significant improvement and long periods of stabilization. Carotid atherosclerosis is associated with cognitive decline in elderly people. OBJECTIVE: The objective of this study was to investigate whether carotid intima-media thickness (IMT) predicts response to cholinesterase inhibitors in Alzheimer's disease. PATIENTS AND METHODS: A series of 54 patients with mild to moderate Alzheimer's disease were enrolled consecutively in an open-label trial. At baseline, all patients were assessed on the following clinical scales: Mini-Mental State Examination, Clinical Dementia Rating, the Hachinski Ischemic Scale, Blessed Dementia Rating Scale, Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog), Neuropsychiatric Inventory (NPI) and a daily-living activities scale (Disability Assessment for Dementia [DAD]). Investigations included magnetic resonance imaging of the brain and a colour echo-Doppler scan of the carotid arteries to measure the maximum IMT. Patients were then commenced on galantamine treatment for 6 months, after which scores on the ADAS-cog, NPI and DAD scales were reassessed. RESULTS: A total of 50 patients completed the study. Their mean age was 77.78 years (SD 6.51 years); 34 patients were female. Galantamine treatment decreased the mean NPI score from 17.68 to 13.86 points, but this difference was not statistically significant (p=0.07). On the ADAS-cog scale, a modest and nonsignificant mean difference of -0.4 points (p=0.7) was observed. A weak (correlation coefficient r=0.4) but significant correlation between IMT and changes in clinical scale score was found, with low carotid IMT being shown to be a predictor of response on both the ADAS-cog (p=0.003) and NPI (p=0.006) scales; these findings were corroborated in multivariate analysis. For men, the correlation was stronger (r=0.7 and 0.8 for the ADAS-cog and NPI scales, respectively). CONCLUSION: Although the magnitude of effect was moderate, carotid IMT could be a significant predictor of clinical response to cholinesterase inhibitors in patients with Alzheimer's disease.

Comparative test-retest reliability of metabolite values assessed with magnetic resonance spectroscopy of the brain. The LCModel versus the manufacturer software.

OBJECTIVE: Reproducibility is an essential strength of any diagnostic technique for cross-sectional and longitudinal works. To determine in vivo short-term comparatively, the test-retest reliability of magnetic resonance spectroscopy (MRS) of the brain was compared using the manufacturer's software package and the widely used linear combination of model (LCModel) technique. METHODS: Single-voxel H-MRS was performed in a series of patients with different pathologies on a 1.5 T clinical scanner. Four areas of the brain were explored with the point resolved spectroscopy technique acquisition mode; the echo time was 35 milliseconds and the repetition time was 2000 milliseconds. We enrolled 15 patients for every area, and the intra-individual variations of metabolites were studied in two consecutive scans without removing the patient from the scanner. Curve fitting and analysis of metabolites were made with the software of GE and the LCModel. Spectra non-fulfilling the minimum criteria of quality in relation to linewidths and signal/noise ratio were rejected. RESULTS: The intraclass correlation coefficients for the N-acetylaspartate/creatine (NAA/Cr) ratios were 0.93, 0.89, 0.9 and 0.8 for the posterior cingulate gyrus, occipital, prefrontal and temporal regions, respectively, with the GE software. For the LCModel, the coefficients were 0.9, 0.89, 0.87 and 0.84, respectively. For the absolute value of NAA, the GE software was also slightly more reproducible than LCModel. However, for the choline/Cr and myo-inositol/Cr ratios, the LCModel was more reliable than the GE software. The variability we have seen hovers around the percentages observed in previous reports (around 10% for the NAA/Cr ratios). CONCLUSION: We did not find that the LCModel software is superior to the software of the manufacturer. Reproducibility of metabolite values relies more on the observance of the quality parameters than on the software used.

Levetiracetam plasma level monitoring during pregnancy, delivery, and postpartum: clinical and outcome implications.

Variations in the plasma concentration of levetiracetam during pregnancy and postpartum were prospectively monitored in five women to investigate their potential implications in epilepsy management and child outcome. Under unchanged levetiracetam dosages, the mean concentrations of levetiracetam during the third trimester were 62% of the baseline late (12 month) postpartum levels, but only 47% of the baseline early postpartum (2 month) levetiracetam levels. In dual therapy with lamotrigine, baseline late postpartum levetiracetam clearance was 63.2%, whereas in early postpartum it was 45% of the maximal second-trimester clearance. However, the number of seizures remained unchanged once lamotrigine dose was increased. No woman had adverse effects during the puerperium. The mean umbilical cord/maternal plasma concentration ratio was 1.21. None of the newborns had malformations, with the anthropometric data being normal for their gestational age. The decline in gestational levetiracetam plasma concentration does not seem to be hazardous, but differs according to whether early or late postpartum levels are chosen as baseline levels.

The Risk of Symptomatic Intracranial Hemorrhage after Thrombolysis for Acute Stroke: Current Concepts and Perspectives.

BACKGROUND: Thrombolysis is the standard of treatment for acute ischemic stroke, with a time window of up to 4½ h from stroke onset. Despite the long experience with the use of recombinant tissue plasminogen activator and the adherence to protocols symptomatic intracranial hemorrhage (SICH) may occur in around 6% of cases, with high-mortality rate and poor-functional outcomes. Many patients are excluded from thrombolysis on the basis of an evaluation of known risk factors, but there are other less known factors involved. OBJECTIVE: The purpose of this work is to analyze the less known risk factors for SICH after thrombolysis. A search of articles related with this field has been undertaken in PubMed with the keywords (brain hemorrhage, thrombolysis, and acute ischemic stroke). Some risk factors for SICH have emerged such as previous microbleeds on brain magnetic resonance imaging, leukoaraiosis, and previous antiplatelet drug use or statin use. Serum matrix metalloproteinases have emerged as a promising biomarker for better selection of patients, but further research is needed. CONCLUSIONS: In addition to the already known risk factors considered in the standard protocols, an individualized evaluation of risks is needed to minimize the risk of brain hemorrhage after thrombolysis for ischemic stroke.

Plasmatic B-type natriuretic peptide and C-reactive protein in hyperacute stroke as markers of CT-evidence of brain edema.

OBJECTIVE: Plasmatic B-type-natriuretic peptide (NT-PBNP) and C-reactive protein (CRP) have been reportedly elevated in stroke patients; however their clinical significance remains uncertain. The purpose of this work is to investigate whether elevation of these proteins at baseline predicts CT-evidence of brain edema. METHODS: We recruited 41 consecutive patients with stroke and determined NT-PBNP and CRP at baseline (within 5 hours after onset), after 48-72 hours, and at discharge. Stroke severity was measured by means of the NIHS scale at baseline and at discharge. We also carried out brain CT at admittance and after 48 hours. RESULTS: There were 29 ischemic strokes and 12 hemorrhagic strokes. Evidence of brain edema on delayed scan was seen in 14 patients. Baseline levels of NT-PBNP did not predict CT-evidence of edema but CRP levels did so significantly (0.7 mg/dl in patients without edema versus 4.7 mg in patients with edema; p=0.001). Both NT-PBNP and PC levels correlated poorly to NIHSS score and increased markedly from baseline to the second determination in patients with edema. For these patients the NT-PBNP increase was 133.6 pmol/l in comparison to 1.58 pmol/l in patients without edema (p=0.002). Neither CRP nor NT-PBNP baseline levels were predictive of dependency or death. CONCLUSIONS: We conclude that CRP at baseline but not NT-PBNP predicts CT evidence of brain edema in stroke patients. We hypothesize that NT-PBNP levels elevated in response to edema after 48 hours of admission.

The clinical significance of plasmatic amyloid A{beta}-40 peptide levels in Alzheimer's disease patients treated with galantamine.

To date there are no conclusive reports on the usefulness of determining amyloid peptides in the serum of patients with Alzheimer's disease (AD). Only anecdotal works deal with the changes in the peptides produced by cholinesterase inhibitors. In this study, the authors investigated and studied the clinical significance of plasmatic Abeta-40 and Abeta-42 peptide levels in a series of 34 consecutive patients with AD. The baseline levels of the Abeta-40 peptide correlated negatively with the Mini Examen Cognoscitivo (Spanish version of the Mini-Mental test) score. Complete follow-up was possible in 22 patients. After 6 months of treatment with galantamine, the mean Abeta-40 peptide levels decreased from 31.86 to 24.22 pg/mL. The baseline levels of Abeta-40 were predictive of response to treatment in the Alzheimer's Disease Assessment Scale-Cognitive Subscale. The authors conclude that determining plasmatic Abeta-40 peptide levels could be useful in predicting and monitoring response to treatment in AD.

The cerebrovascular pathology in Alzheimer's disease and its influence on clinical variables.

Vascular pathology is frequently found in the brains of patients with Alzheimer's disease (AD). The aim of this study is to assess the frequency of vascular pathology in the brain in AD patients in a systematic manner and its clinical significance at presentation. A series of 51 patients with mild to moderate AD were consecutively enrolled. At baseline, every patient underwent the following clinical scales: Mini-Mental, Clinical Dementia Rating Scale, Ischemic Scale, Blessed Dementia Rating Scale, Alzheimer's Disease Assessment Scale Cognitive Subscale, Neuropsychiatric Inventory, and an Activities of Daily Living Scale (Disability Assessment for Dementia). We also carried out magnetic resonance imaging of the brain and color echo Doppler of carotids to measure the intima-media thickness. White matter hyperintensities were quantitatively evaluated with the Wahlund scale. We did not find correlation between intima-media thicknesses of carotids and clinical scales and between the Wahlund scale and clinical scales. The presence or absence of both microinfarctions and hypertension had no influence in the scores of the clinical scales. We conclude that the vascular component is common in AD but only as coincident pathology.

Evidence of brain dysfunction in attention deficit-hyperactivity disorder: a controlled study with proton magnetic resonance spectroscopy.

RATIONALE AND OBJECTIVES: Attention deficit-hyperactivity disorder (ADHD) is a socially disabling condition whose pathophysiology is mostly unknown. Previous magnetic resonance imaging (MRI)-based reports have shown structural abnormalities in the prefrontal region and the striatum, but with inconsistencies across the studies with regard to right/left specificity of changes. Our study is aimed at finding evidence of dysfunction with more refined MRI techniques such as diffusion-weighted MRI and spectroscopy. MATERIALS AND METHODS: We enrolled 22 ADHD children (mean age 9; SD 2.91) and 8 healthy children (mean age 7.5; SD 3). All of them underwent diffusion-weighted MRI in several areas of the brain bilaterally: prefrontal, lentiform nucleus, posterior cingulate, and centrum semiovale; and single-voxel proton magnetic resonance spectroscopy in the left centrum semiovale and right prefrontal region. RESULTS: We did not see either apparent structural abnormalities of the brain in conventional MRI or differences in the apparent-diffusion coefficients in any of the areas studied. However, we observed significant differences in the N-acetyl-aspartate/creatine ratios in relation to controls in the right prefrontal corticosubcortical region: 1.58 (SD 0.09) versus 1.47 (0.08), P = .01); and in the left centrum semiovale: 2.02 (0.13) versus 1.79 (0.13), P = .0003. This finding is consistent with a published report on eight ADHD children in whom N-acetyl-aspartate/creatine ratios were also elevated. CONCLUSIONS: Given these results, we hypothesize that a biochemical dysfunction might underlie in the brain of ADHD children. The N-acetyl-aspartate/creatine ratio may be regarded as a potential marker of the disease.

Magnetic resonance spectroscopy and brain volumetry in mild cognitive impairment. A prospective study.

OBJECTIVE: To assess the accuracy of magnetic resonance spectroscopy (1H-MRS) and brain volumetry in mild cognitive impairment (MCI) to predict conversion to probable Alzheimer's disease (AD). METHODS: Forty-eight patients fulfilling the criteria of amnestic MCI who underwent a conventional magnetic resonance imaging (MRI) followed by MRS, and T1-3D on 1.5 Tesla MR unit. At baseline the patients underwent neuropsychological examination. 1H-MRS of the brain was carried out by exploring the left medial occipital lobe and ventral posterior cingulated cortex (vPCC) using the LCModel software. A high resolution T1-3D sequence was acquired to carry out the volumetric measurement. A cortical and subcortical parcellation strategy was used to obtain the volumes of each area within the brain. The patients were followed up to detect conversion to probable AD. RESULTS: After a 3-year follow-up, 15 (31.2%) patients converted to AD. The myo-inositol in the occipital cortex and glutamate+glutamine (Glx) in the posterior cingulate cortex predicted conversion to probable AD at 46.1% sensitivity and 90.6% specificity. The positive predictive value was 66.7%, and the negative predictive value was 80.6%, with an overall cross-validated classification accuracy of 77.8%. The volume of the third ventricle, the total white matter and entorhinal cortex predict conversion to probable AD at 46.7% sensitivity and 90.9% specificity. The positive predictive value was 70%, and the negative predictive value was 78.9%, with an overall cross-validated classification accuracy of 77.1%. Combining volumetric measures in addition to the MRS measures the prediction to probable AD has a 38.5% sensitivity and 87.5% specificity, with a positive predictive value of 55.6%, a negative predictive value of 77.8% and an overall accuracy of 73.3%. CONCLUSION: Either MRS or brain volumetric measures are markers separately of cognitive decline and may serve as a noninvasive tool to monitor cognitive changes and progression to dementia in patients with amnestic MCI, but the results do not support the routine use in the clinical settings.

The effect of drugs for Alzheimer disease assessed by means of neuroradiological techniques.

UNLABELLED: Cholinesterase inhibitors constitute the standard of care for Alzheimer's disease in western countries. Donepezil, rivastigmine and galantamine had showed similar efficacy according to meta-analysis from randomised clinical trials. A mean modest 2 point-improvement has been observed in the Alzheimer's disease Assessment Scale (ADAS). Memantine has emerged as an alternative for advanced stages of the disease. Apart from clinical scales, neuroradiologic techniques have proven useful to assess the effect of these drugs on the brain of AD patients. METHODS: An extensive search for papers dealing with neuroradiological techniques in the assessment of AD drugs has been conducted, especially based on MEDLINE and EMBASE systems. RESULTS: Several techniques have demonstrated to be useful to assess the effects of drugs and disease progression. Magnetic Resonance Imaging (MRI)-based volumetry of the hippocampus showed more consistency to monitor progression than clinical variables, and thus, the sample size for clinical trials may be reduced. Donepezil is able to slow progression of atrophy in two controlled studies suggesting a neuroprotective effect. Proton Magnetic Resonance Spectroscopy (MRS) measures metabolite concentration of living tissues. In AD the most characteristic findings are decreased N-acetyl aspartate (neuronal marker) and choline-compounds elevation (marker of cell membrane turnover and degradation). A placebo controlled trial showed that treatment with donepezil increased transiently the NAA/Cr ratio in both hippocampi in AD. Changes in aspartate levels correlated to clinical response to rivastigmine in a non-randomised trial. Some studies evaluated cholinesterase inhibition in vivo with PET (Positron Emission Tomography) with higher reductions for rivastigmine than for donepezil in several cortical areas. Metabolism of glucose was also studied in patients taking galantamine or rivastigmine. Rivastigmine may stabilise glucose metabolism in a small series of AD patients. Correlation between glucose metabolism and changes in clinical scales has been observed in patients treated with galantamine. Most studies point to the frontal cortex as the best area to detect changes after treatment with cholinesterase inhibitors. CONCLUSIONS: Neuroradiologic techniques are of help to evaluate the effect of drugs in AD, and to monitor disease progression.

Changes in metabolite ratios after treatment with rivastigmine in Alzheimer's disease: a nonrandomised controlled trial with magnetic resonance spectroscopy.

BACKGROUND: Alzheimer's disease is associated with abnormalities in the levels of some brain metabolites, including decreases in N-acetyl-aspartate (NAA) and increases in myo-inositol and choline levels. Cholinesterase inhibitors have proven modest effects on cognition in patients with mild or moderate Alzheimer's disease; however, there is little information on the effects of these drugs on metabolic parameters in the brain. Magnetic resonance spectroscopy (MRS) provides a method of determining changes in such parameters. OBJECTIVE: To assess the effect of rivastigmine on metabolite levels in different areas of the brain, and whether changes in metabolite levels correlate with clinical outcome, in patients with Alzheimer's disease compared with untreated patients with Alzheimer's disease. METHODS: Twenty-four consecutive patients with mild or moderate Alzheimer's disease were enrolled in the study and were treated with rivastigmine at a target dosage of 12 mg/day for 4 months. A comparison group of ten consecutive untreated patients with Alzheimer's disease with similar cognitive impairment to the treatment group were also enrolled. Each patient underwent assessment using the Mini-Mental State Examination (Spanish version), the Blessed Dementia Rating Scale, the Clinical Dementia Rating scale, the Interview for Deterioration in Daily living activities in Dementia, the Alzheimer's Disease Assessment Scale cognitive and noncognitive subscales, and single-voxel MRS of the frontal, parietal and occipital cortices of the brain to assess levels of brain metabolites (NAA, creatine, choline and myo-inositol) and their ratios to creatine. All assessments were performed at baseline and after 4 months of treatment with rivastigmine, and at baseline and 1 month later in the comparison group. RESULTS: Globally, although there was some mean improvement, no significant changes in the cognitive and noncognitive scale scores between baseline and post-treatment assessments were seen in patients who received rivastigmine. A significant increase in the NAA/creatine ratio in the frontal cortex (1.23 at baseline vs 1.3 after treatment; p = 0.026) and in the myo-inositol/creatine ratio in the occipital cortex (0.61 vs 0.65; p = 0.009) was seen in rivastigmine-treated patients. No other significant changes in the metabolite levels or their ratios to creatine were seen in these patients. After correction for multiple comparisons, the significant effects disappeared. Only in the frontal cortex did the changes in metabolite ratios correlate with changes on the clinical scales. In the comparison group, no significant differences between the metabolite levels or ratios to creatine seen with the two scans were detected. CONCLUSION: Treatment with rivastigmine showed modest neuronal functional recovery in the frontal cortex only (being able to reverse disease-related decreases in NAA/creatine ratio in this area but unable to affect the disease-related increase in myo-inositol/creatine ratio in any cortex). Since the modest clinical changes correlated with the small changes in the metabolite rates, MRS could be useful in monitoring response to current or future treatments for Alzheimer's disease.

Predictors of conversion to dementia of probable Alzheimer type in patients with mild cognitive impairment.

BACKGROUND: Mild Cognitive Impairment is a common condition defined as transitional state between normality and dementia of Alzheimer type. Clinically is characterized by subjective and objective memory loss beyond the expected for age and educational level, although a broad range of cognitive inefficiencies may appear, with preservation of daily living activities. Approximately half the patients convert to dementia within 3 years. Since no all patients convert to dementia it is essential to find reliable predictors so as to start the appropriate treatment as soon as possible. METHOD: Extensive Medline-based search for articles dealing with predictors of conversion to dementia in Mild Cognitive Impairment (MCI). RESULTS: There is a substantial body of literature dealing with predictors of dementia in patients with MCI. These predictors range from a simple delayed recall task on Mini-Mental to sophisticated radiological techniques and CSF biomarkers. Comprehensive neuropsychological tests rarely surpass 70% sensitivity and specificity. The presence of the APOE epsilon 4 allele has been associated with increased risk of conversion but the sensitivity is quite low. CSF biochemical markers are being developed with encouraging results. beta-amyloid 42 protein is usually lower in converters than in people with stable cognitive status and tau protein is higher. The sensitivity is substantial but specificity is so far low. An epitope of tau protein (P231) looks more specific of Alzheimer's disease and therefore a promising biomarker. In the blood, high beta-amyloid protein levels indicate risk of conversion but only a few studies have been published. Hippocampal or entorhinal atrophy on MRI is one of the most used radiological markers of conversion but quantification of atrophy is not simple as it is subject to artifacts and anatomic variations. Proton Magnetic Resonance Spectroscopy (MRS) and Positron Emission Tomography (PET) are emerging as the most promising predictive tools. The highest degree of accuracy (>90%) has been achieved by means of PET plus either memory performance or APOE4 genotype. However, the samples of the published studies are mostly small, and these instruments are not widely available. CONCLUSIONS: There is no enough evidence to recommend specific techniques for predictions. Until an accurate marker is developed, a combined use of cognitive tests, APOE genotype, and a neuroradiological technique is probably the best option for prediction purposes depending on availability and experience.

White matter proton MR spectroscopy in children with isolated developmental delay: does it mean delayed myelination?

RATIONALE AND OBJECTIVES: Isolated developmental delay (IDD) is a common disorder in preschool and school-age children. Conventional magnetic resonance imaging (MRI) usually does not disclose abnormalities, but a myelination delay is suspected as causative or associated factor. N-acetyl-aspartate is a surrogate marker of neuronal integrity but also of axonal integrity. The goal of our study is to determine whether magnetic resonance spectroscopy (MRS) is able to detect alterations in the white matter supporting the hypothesis of delayed myelination in children with IDD and normal MRI. MATERIALS AND METHODS: In this cross-sectional study, we enrolled 12 consecutive children meeting the criteria if IDD and aged between 3 and 12 years (mean 7.25 years) and 11 healthy children as control group (mean age 7.18, range 3-12 years) on whom we performed conventional MRI and MRS. We did not include children with abnormal MRI. Single voxel (8 cm(3)) was placed in the white matter of the left centrum semiovale. The mode of acquisition was probe-p (PRESS technique) with a TR of 2500 milliseconds and a TE of 30 milliseconds. We measured the metabolite concentration of n-acetyl-aspartate (NAA), choline (Ch), creatine (Cr) y myo-inositol (mI), and ratios of NAA, Ch, and mI to creatine. RESULTS: In children with IDD, we found a significant decrease of the following ratios: NAA/Cr (P < .016), NAA/Ch (P < .026), and NAA/mI (P < .023) in relation to controls. The mean NAA/Cr ratio in IDD children was 1.92 (SD 0.14), and in controls it was 2.09 (SD 0.14); t = 2.62, fd (freedom degrees) = 21, P < .016. No differences were seen in the remaining ratios. CONCLUSIONS: The lower NAA/Cr ratio in children with IDD in relation to controls may be a promising marker of this disorder and supports the hypothesis of delayed myelination. MRS can provide important information in children with neurodevelopmental disorders.

Contrast/Noise ratio on conventional MRI and choline/creatine ratio on proton MRI spectroscopy accurately discriminate low-grade from high-grade cerebral gliomas.

RATIONALE AND OBJECTIVES: Histopathology is the gold standard to establish the grade of brain tumors but biopsy and/or surgery are not always possible. The aim of this study is to determine whether histological grade of tumors may be predicted by means of conventional gadolinium-enhanced MRI and proton magnetic resonance spectroscopy (MRS). MATERIALS AND METHODS: In this study, we included 35 consecutive patients with single brain tumors and final histopathological verification: 12 had low-grade glioma, 16 had high-grade glioma, and 7 had single metastasis. Initially, we carried out T1 and T2 MRI paying attention to the following features: border definition, mass effect, heterogeneity of signal, perilesional edeme, hemorrhage, necrosis, and corpus callosum invasion. Gadolinium-enhancement was evaluated with the contrast-to-noise ratio (CNR). Next, single-voxel proton MRS was carried out to measure the absolute values of metabolites (N-acetyl-aspartate, creatine, choline, and myo-inositol) and their ratios in the area of maximum contrast enhancement. RESULTS: We found that gadolinium-enhancement measured with the CNR (CNR > 35.86) predicted malignancy at 82.6% sensitivity and 91.7% specificity (area under the curve, 0.88; 95% confidence interval [CI], 0.73-0.97). With regard to MRS a choline/creatine ratio higher than 1.56 predicted malignancy at 88.9% sensitivity and 91.7% specificity (area under the curve, 0.94; 95% CI, 0.78-0.99). When we combined the CNR value, the choline/creatine ratio, and the presence of lactates in a model of discriminant analysis the predictive power improved significantly with an area under the curve of 0.99% (95% CI, 0.87-1). However, the used techniques were unable to distinguish metastases from high-grade gliomas accurately. CONCLUSIONS: The intensity of contrast enhancement measured with the CNR, the choline/creatine ratio, and the presence of lactate were the most powerful variables to predict malignancy in brain tumors. The CNR is a simple, objective, and useful tool in the initial assessment of gliomas and metastases.