F. Federico

Localised 1H-MR spectroscopy for metabolic characterisation of diffuse and focal brain lesions in patients infected with HIV

OBJECTIVES To evaluate the role of proton MR spectroscopy (1H-MRS) in detecting metabolic changes in diffuse or focal lesions in the brain of patients infected with HIV. METHODS Sixty HIV seropositive patients (25 with HIV related encephalopathies, 20 with toxoplasmosis, eight with progressive multifocal leukoencephalopathies (PMLs), and seven with lymphomas) and 22 HIV seronegative neurological controls were examined with a combined MRI and1H-MRS technique using a Siemens 1.5 Tesla Magnetom. Spectra (Spin Echo sequence, TE 135 ms) were acquired by single voxel, localised on focal lesions in toxoplasmosis, PML, lymphomas, and HIV encephalopathies and on the centrum semiovale of neurological controls. Choline (Cho), creatine (Cr), N-acetyl aspartate (NAA), lactate, and lipids were evaluated in each spectrum and NAA/Cr, NAA/Cho, and Cho/Cr ratios were calculated. RESULTS A significant decrease in NAA/Cr and NAA/Cho ratios were found in all HIV diagnostic groups in comparison with neurological controls (p<0.003), suggesting neuronal or axonal damage independent of brain lesion aetiology. However, the NAA/Cr ratio was significantly lower in PML and lymphomas than in HIV encephalopathies (p<0.02) and toxoplasmosis (p<0.05). HIV encephalopathies, lymphomas, and toxoplasmosis showed a significant increase in the Cho/Cr ratio in comparison with neurological controls (p<0.03) without between group differences. The presence of a lipid signal was more frequent in lymphomas (71%) than in other HIV groups (Fisher’s test, p=0.00003). The presence of mobile lipid resonance together with a high Cho/Cr ratio in lymphomas may be related to an increased membrane synthesis and turnover in tumour cells. A lactate signal (marker of inflammatory reaction), was found in all but one patient with PML lesions (75%), but had a lower incidence in the other HIV diagnostic groups (Fisher’s test, p=0.00024). CONCLUSION 1H-MRS shows a high sensitivity in detecting brain involvement in HIV related diseases, but a poor specificity in differential diagnosis of HIV brain lesions. Nevertheless, the homogeneous metabolic pattern that characterises PML suggests the usefulness of 1H-MRS as an adjunct to MRI in differentiating CNS white matter lesions, such as HIV encephalopathies, from PML.

Proton magnetic resonance spectroscopy in Parkinson's disease and progressive supranuclear palsy.

OBJECTIVES: Proton magnetic resonance spectroscopy (1H-MRS) localised to the lentiform nucleus, was carried out in eight patients with idiopathic Parkinsons disease and five patients with progressive supranuclear palsy. The aim of the study was to assess the concentration of N-acetyl-aspartate (NAA), creatine and phosphocreatine (Cr), and choline containing compounds (Cho) in the putamen and globus pallidus of these patients. METHODS: Peak ratios obtained from patients were compared with those from nine healthy age matched controls. RESULTS: NAA/Cho and NAA/Cr ratios were reduced significantly in patients with progressive supranuclear palsy. CONCLUSION: These results suggest an NAA deficit, due to neuronal loss, in the lentiform nucleus of these patients. 1H-MRS is a non-invasive technique that can provide useful information concerning striatal neuronal loss in the basal ganglia of patients with parkinsonian syndromes.

High resolution proton MR spectroscopy of cerebrospinal fluid in MS patients. Comparison with biochemical changes in demyelinating plaques

Proton magnetic spectroscopy (1H-MRS) investigation was performed on CSF samples of patients with neurological inflammatory diseases including 52 cases of multiple sclerosis (MS). 12 acute idiopathic polyneuropathies, 20 acute meningitides (10 viral and 10 bacterial). Spectra were compared with those acquired in 18 neurological controls. High CSF lactate levels were found in MS patients during clinical exacerbation of relapsing-remitting course (p = 0.036 vs neurological controls). In MS patients with MRI evidence of Gd-enhanced plaques CSF lactate was higher than in patients with MRI inactive plaques (p = 0.017). CSF lactate positivity correlated with number of CSF mononuclear cells in MS patients with clinical activity (p = 0.05) as well as in MS patients with MRI enhancement (p = 0.003). A comparative 1H-MRS investigation in vivo on localized demyelinating areas confirmed an elevated lactate signal in Gd-enhanced (61%) more frequently than in unenhanced (22%) plaques (p = 0.03). MS patients with high lactate signal in active plaques showed high lactate levels in CSF. Increased CSF lactate was found also in patients with acute meningitis and idiopathic polyneuropathy. These data suggest that changes in lactate levels may depend on anaerobic glycolytic metabolism in activated leukocytes during inflammatory diseases. A decrease of CSF formulate levels was found in MS patients during active and inactive clinical phase (p = 0.037, p=0.05 vs neurological controls respectively). Formate changes might be related to a disorder of choline-glycine cycle in MS. 1H-MRS in vivo showed significant increase of choline in acute plaques, whereas a decrease of N-acetyl aspartate was found in chronic plaques; these metabolites are undetectable in CSF. CSF glucose levels were lower in bacterial than in viral meningitis (p = 0.014) and in neurological controls (p = 0.05). These observations suggest that 1H-MRS may be able to detect CSF metabolic impairment in neurological inflammatory diseases. In MS some CSF findings reflect metabolic changes occurring in brain demyelinating areas, and they could be useful foe evaluation of disease activity in different stages of disease evolution.

Different roles of matrix metalloproteinases-2 and -9 after human ischaemic stroke

Accumulating data suggest that matrix metalloproteinases (MMPs), in particular MMP-2 and MMP-9, are deleterious after acute ischaemic stroke. A beneficial effect of MMPs in the repairing phases of cerebral ischaemia has also been proposed. This study investigated the relationship between MMP-2 and MMP-9 and stroke subtypes, clinical recovery and haemorrhagic transformation (HT). We measured MMP-9 and MMP-2 plasma levels in 29 patients with ischaemic stroke at days one and seven. MMP-2 levels increased only in lacunar strokes, whilst MMP-9 increased only in patients with more severe stroke. Basal MMP-2 levels were higher in patients with stable or recovering symptoms whilst MMP-9 values at day seven were correlated with worse clinical outcome. No differences related to the presence of HT were found. This study sustains a different behaviour of MMPs after ischaemic stroke. MMP-2 seems to be expressed early and related to better outcome, whilst MMP-9 seems to be late and related to more severe stroke.

Primary hemifacial spasm and arterial hypertension : A multicenter case-control study

Article abstract In a case–control study, the authors found that arterial hypertension occurred more frequently among 115 patients with primary hemifacial spasm than among 115 neurologic controls matched for age (±5 years), sex, and referral center. The association was not confounded by education level, smoking history, diabetes, or other diseases (adjusted OR 2.64; 95% CI 1.3 to 5.33, p = 0.007). Hypertension was significantly associated with the outcome in the left-sided group (OR 4.0; 95% CI 1.4 to 11.5), but data concerning patients with right-sided spasm were inconclusive (OR 1.05; 95% CI 0.36 to 3.1). In our sample, hypertension either preceded or followed the onset of hemifacial spasm.

The THRombolysis and STatins (THRaST) study

Objective: To assess the impact on stroke outcome of statin use in the acute phase after IV thrombolysis. Methods: Multicenter study on prospectively collected data of 2,072 stroke patients treated with IV thrombolysis. Outcome measures of efficacy were neurologic improvement (NIH Stroke Scale [NIHSS] ≤ 4 points from baseline or NIHSS = 0) and major neurologic improvement (NIHSS ≤ 8 points from baseline or NIHSS = 0) at 7 days and favorable (modified Rankin Scale [mRS] ≤ 2) and excellent functional outcome (mRS ≤ 1) at 3 months. Outcome measures of safety were 7-day neurologic deterioration (NIHSS ≥ 4 points from baseline or death), symptomatic intracerebral hemorrhage type 2 with NIHSS ≥ 4 points from baseline or death within 36 hours, and 3-month death. Results: Adjusted multivariate analysis showed that statin use in the acute phase was associated with neurologic improvement (odds ratio [OR] 1.68, 95% confidence interval [CI] 1.26–2.25; p < 0.001), major neurologic improvement (OR 1.43, 95% CI 1.11–1.85; p = 0.006), favorable functional outcome (OR 1.63, 95% CI 1.18–2.26; p = 0.003), and a reduced risk of neurologic deterioration (OR: 0.31, 95% CI 0.19–0.53; p < 0.001) and death (OR 0.48, 95% CI 0.28–0.82; p = 0.007). Conclusion: Statin use in the acute phase of stroke after IV thrombolysis may positively influence short- and long-term outcome.

Anticonvulsant properties of some calcium antagonists on sound-induced seizures in genetically epilepsy prone rats.

1. The anticonvulsant activity of calcium channel antagonists, was studied after intraperitoneal or oral administration in genetically epilepsy prone rats (GEPR). 2. Flunarizine, dihydropyridines and HA 1004, administered intraperitoneally, were the most potent compounds. Diltiazem, prenylamine, perhexiline, verapamil and methoxyverapamil, given intraperitoneally, were able to reduce the incidence of the tonic phase but were completely ineffective in preventing clonic and running phases of sound-induced seizures in GEPR. Similar anticonvulsant activity was observed when these compounds were administered orally. 3. After intracerebroventricular administration of some of the hydrosoluble calcium antagonists studied, the anticonvulsant effects were similar to those observed after systemic administration. 4. The systemic administration of Bay K 8644, a dihydropyridine analogue, having the ability to stimulate calcium entry into cells produced a dose-dependent increase in clonic and tonic convulsions and other epileptic phenomena, which were prevented by pretreatment with nimodipine or nitrendipine. 5. The possible role of purinergic, excitatory amino acid, GABA-benzodiapine mechanisms as well as the role of Ca2(+)-calmodulin and calcium channel binding sites on the anticonvulsant effects of some calcium antagonists are discussed.

Metabolic Changes in Neuronal Migration Disorders: Evaluation by Combined MRI and Proton MR Spectroscopy

Summary: Purpose: To assess the role of 1H‐magnetic resonance spectroscopy (MRS) in detecting biochemical abnormalities in neuronal migration disorders (NMDs).

Axonal damage in multiple sclerosis plaques: a combined magnetic resonance imaging and 1H-magnetic resonance spectroscopy study

The purpose of this study was to compare magnetic resonance imaging (MRI) features and proton MR spectroscopy (1H-MRS) patterns of multiple sclerosis (MS) plaques in order to define the metabolic substrate in different lesion subtypes. Combined MRI and single-voxel 1H-MRS investigation was performed in 54 MS patients (47 relapsing remitting (RR) and seven secondary progressive (SP)). Sixty-seven MS lesions were selected. Thirty-seven lesions were Gadolinium (Gd) enhancing (nine isointense and 28 hypointense on pre-contrast T(1)-weighted scans) and 30 Gd unenhancing (six isointense and 24 hypointense on pre- and post-contrast T(1)-weighted scans). Choline (Cho), creatine (Cr), N-acetyl aspartate (NAA) and lactate were evaluated in 1H spectra acquired from MS plaques and from normal white matter (NWM) of 22 neurological controls. MS lesions of RR patients were characterized by a significant increase of Cho/Cr and decrease of NAA/Cr and NAA/Cho ratios. No significant metabolite changes were found in lesions of SP patients. Gd enhancing plaques showed lactate signal with higher frequency (37.8%) than Gd unenhancing plaques (16.7%) (p=0.04). A significant increase of Cho/Cr was found in Gd enhancing lesions when compared to controls (p<0.01), and to Gd unenhancing lesions (p<0.05). In particular, there was evidence of a significant increase of Cho/Cr in pre-contrast T(1) hypointense Gd enhancing lesions (p<0.01 vs. controls). The Gd unenhancing lesions (p<0.01), in particular the T(1) hypointense group (p<0.05), showed a significant decrease of NAA/Cr only when compared to controls. These data confirm that in vivo MRS indicates key pathological features of MS plaques. The increased Cho/Cr ratio found in Gd-enhancing plaques, in particular in the T(1) hypointense lesions, may reflect increased membrane cell turnover. The T(1) hypointense Gd unenhancing plaques better reflect axonal damage, as suggested by the decrease of NAA/Cr. Nevertheless, the lack of statistical differences in NAA/Cr between plaque subgroups suggests that axonal impairment might occur even in the early stages.

Cortical Thinning and Clinical Heterogeneity in Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) has heterogeneous clinical features that could be translated into specific patterns of brain atrophy. In the current study we have evaluated the relationship between different clinical expressions of classical ALS and measurements of brain cortical thickness. Cortical thickness analysis was conducted from 3D-MRI using FreeSurfer software in 29 ALS patients and 20 healthy controls. We explored three clinical traits of the disease, subdividing the patients into two groups for each of them: the bulbar or spinal onset, the higher or lower upper motor neuron burden, the faster or slower disease progression. We used both a whole brain vertex-wise analysis and a ROI analysis on primary motor areas. ALS patients showed cortical thinning in bilateral precentral gyrus, bilateral middle frontal gyrus, right superior temporal gyrus and right occipital cortex. ALS patients with higher upper motor neuron burden showed a significant cortical thinning in the right precentral gyrus and in other frontal extra-motor areas, compared to healthy controls. ALS patients with spinal onset showed a significant cortical thinning in the right precentral gyrus and paracentral lobule, compared to healthy controls. ALS patients with faster progressive disease showed a significant cortical thinning in widespread bilateral frontal and temporal areas, including the bilateral precentral gyrus, compared to healthy controls. Focusing on the primary motor areas, the ROI analysis revealed that the mean cortical thickness values were significantly reduced in ALS patients with higher upper motor neuron burden, spinal onset and faster disease progression related to healthy controls. In conclusion, the thickness of primary motor cortex could be a useful surrogate marker of upper motor neuron involvement in ALS; also our results suggest that cortical thinning in motor and non motor areas seem to reflect the clinical heterogeneity of the disease.