Anti-amyloid ß autoantibodies in cerebral amyloid angiopathy-related inflammation: implications for amyloid-modifying therapies.

OBJECTIVE: Cerebral amyloid angiopathy-related inflammation (CAA-ri) is characterized by vasogenic edema and multiple cortical/subcortical microbleeds, sharing several aspects with the recently defined amyloid-related imaging abnormalities (ARIA) reported in Alzheimer's disease (AD) passive immunization therapies. Herein, we investigated the role of anti-amyloid ß (Aß) autoantibodies in the acute and remission phases of CAA-ri. METHODS: We used a novel ultrasensitive technique on patients from a retrospective multicenter case-control study, and evaluated the anti-Aß autoantibody concentration in the cerebrospinal fluid (CSF) of 10 CAA-ri, 8 CAA, 14 multiple sclerosis, and 25 control subjects. Levels of soluble Aß40, Aß42, tau, P-181 tau, and APOE genotype were also investigated. RESULTS: During the acute phase of CAA-ri, anti-Aß autoantibodies were specifically increased and directly correlated with Aß mobilization, together with augmented tau and P-181 tau. Following clinical and radiological remission, autoantibodies progressively returned to control levels, and both soluble Aß and axonal degeneration markers decreased in parallel. INTERPRETATION: Our data support the hypothesis that the pathogenesis of CAA-ri may be mediated by a selective autoimmune reaction against cerebrovascular Aß, directly related to autoantibody concentration and soluble Aß. The CSF dosage of anti-Aß autoantibodies with the technique here described can thus be proposed as a valid alternative tool for the diagnosis of CAA-ri. Moreover, given the similarities between ARIA developing spontaneously and those observed during immunization trials, anti-Aß autoantibodies can be considered as novel potential biomarkers in future amyloid-modifying therapies for the treatment of AD and CAA.

An autoinflammatory neurological disease due to interleukin 6 hypersecretion.

Autoinflammatory diseases are rare illnesses characterized by apparently unprovoked inflammation without high-titer auto-antibodies or antigen-specific T cells. They may cause neurological manifestations, such as meningitis and hearing loss, but they are also characterized by non-neurological manifestations. In this work we studied a 30-year-old man who had a chronic disease characterized by meningitis, progressive hearing loss, persistently raised inflammatory markers and diffuse leukoencephalopathy on brain MRI. He also suffered from chronic recurrent osteomyelitis of the mandible. The hypothesis of an autoinflammatory disease prompted us to test for the presence of mutations in interleukin-1-pathway genes and to investigate the function of this pathway in the mononuclear cells obtained from the patient. Search for mutations in genes associated with interleukin-1-pathway demonstrated a novel NLRP3 (CIAS1) mutation (p.I288M) and a previously described MEFV mutation (p.R761H), but their combination was found to be non-pathogenic. On the other hand, we uncovered a selective interleukin-6 hypersecretion within the central nervous system as the likely pathogenic mechanism. This is also supported by the response to the anti-interleukin-6-receptor monoclonal antibody tocilizumab, but not to the recombinant interleukin-1-receptor antagonist anakinra. Exome sequencing failed to identify mutations in other genes known to be involved in autoinflammatory diseases. We propose that the disease described in this patient might be a prototype of a novel category of autoinflammatory diseases characterized by prominent neurological involvement.

Iron-related MRI images in patients with pantothenate kinase-associated neurodegeneration (PKAN) treated with deferiprone: results of a phase II pilot trial.

BACKGROUND: The safety and efficacy of the oral iron-chelating agent deferiprone on magnetic resonance pallida iron concentration and on clinical status were investigated in 10 patients affected by pantothenate kinase-associated neurodegeneration. METHODS: Nine patients (age range, 7-39 years) completed the study. RESULTS: A significant median reduction in globus pallidus iron content as assessed by T2* relaxometry (and calculated R2* maps; P=.008) was observed at the end of the study. None of the patients demonstrated a change in clinical status as assessed by the Burke-Fahn and Marsden Dystonia Rating scales and by a health-related quality-of-life scale. Deferiprone was well tolerated, and no serious adverse events occurred. CONCLUSIONS: Future trials assessing the clinical efficacy of chelating therapy should consider early symptomatic patients and a longer treatment period.

A novel polymorphic AP-1 binding element of the GFAP promoter is associated with different allelic transcriptional activities.

The Glial Fibrillary Acidic Protein (GFAP) gene encodes a cytoskeletal protein belonging to the intermediate filament family whose expression is considered as a marker of astrocytes differentiation. GFAP expression, shown to be upregulated as a consequence of brain gliosis, depends on hormones, growth factors, cytokine, and transcription factors and, among these latters, activator protein 1 (AP-1) has been demonstrated to play a crucial role. In this study, we have focused on a 2.2 kb sequence of the regulatory region located upstream of the GFAP gene, searching in a panel of control individuals for single-nucleotide polymorphisms (SNPs) that could modulate GFAP transcription. Among four SNPs of the GFAP promoter whose alleles have been predicted by in silico analysis to induce differences in the pattern of binding transcription factors, we have identified a new AP-1 binding site lying at -250 bp upstream from the GFAP transcriptional start site. The two alleles of this polymorphic locus have shown to bind the AP-1 complex to different extents, thus promoting variable transcriptional activities of the GFAP promoter. Therefore, these SNP alleles may, among others, mediate the effects of GFAP mutations, thus explaining the phenotypic heterogeneity of Alexander disease.

Angiographically proven cervical venous engorgement: a possible concurrent cause in the pathophysiology of Hirayama's myelopathy.

The objective of this study is to discuss the possible role of cervical posterior epidural plexus engorgement during cervical flexion in the pathogenesis of Hirayama myelopathy. In Hirayama disease, MRI during neck flexion often shows that the posterior dura detaches from the posterior arches compressing the spinal cord. Autopsies demonstrated asymmetric changes in the anterior horns consistent with chronic ischemic damage, attributed to arterial insufficiency during flexion or to microcirculatory changes due to compression by the tight dura. In a 15-year-old patient with 5-year history of distal upper limbs weakness, MRI demonstrated marked venous engorgement of the posterior epidural plexus in cervical flexion, confirmed by angiography. Laminectomy from C3 to C6 with duraplasty was performed. At one-year follow-up, the clinical condition of the patient remained stable. In Hirayama myelopathy, compression of the spinal cord by the tight dura is probably the most important pathogenetic factor. However, venous congestion in flexion might play an additional role in determining spinal cord ischemic changes.

Age-related iron deposition in the basal ganglia: quantitative analysis in healthy subjects.

PURPOSE: To determine the values of iron accumulation in the basal ganglia of healthy volunteers of different ages with R2* and raw signal intensity measurements from T1-weighted magnetic resonance (MR) images, supported by voxel-based relaxometry (VBR), and to compare them with previously reported iron concentrations found in autopsy material. MATERIALS AND METHODS: The ethics committee approved the study, and the participants or their parents gave written informed consent. Eighty subjects (41 female and 39 male subjects; age range, 1-80 years) were examined at 1.5 T. For each subject, R2* values were calculated. Curves for R2* versus age were obtained for globus pallidus (GP), putamen, caudate nucleus, substantia nigra (SN), and frontal white matter (FWM). To highlight possible differences in iron concentration among the age decades, VBR was applied. Signal intensity values were estimated on T1-weighted fast low-angle shot images, and regions of interest were drawn in each nucleus. R2* values were also compared with iron concentrations reported in a postmortem study. Statistical analysis was performed (t test), and a difference with P < .05 (FDR corrected) was significant. RESULTS: The curves for R2* versus age showed an exponential increase with increasing age in all the basal ganglia. VBR demonstrated significant differences (P < .05, corrected) in the comparison between the 2nd and the following decades for lenticular nuclei. Good correlation coefficients were found for GP (R(2) = 0.64), putamen (R(2) = 0.51), and SN (R(2) = 0.53) when compared with findings in the postmortem study. Signal intensity curves were similar to the R2* curves. CONCLUSION: R2* measurements can be used to quantify brain iron accumulation and thus may allow better evaluation of neurodegenerative diseases associated with iron deposition.

Adult-onset Alexander disease: a series of eleven unrelated cases with review of the literature.

Alexander disease (AD) in its typical form is an infantile lethal leucodystrophy, characterized pathologically by Rosenthal fibre accumulation. Following the identification of glial fibrillary acidic protein (GFAP) gene as the causative gene, cases of adult-onset AD (AOAD) are being described with increasing frequency. AOAD has a different clinical and neuroradiological presentation with respect to early-onset AD, as abnormalities are mainly concentrated in the brainstem-spinal cord junction. We report detailed clinical and genetic data of 11 cases of AOAD, observed over a 4-year period, and a review of the previously reported 25 cases of genetically confirmed AOAD. In our series, onset occurred as late as age 62, and up to 71 in an affected deceased relative. Most cases appeared sporadic, but family history may be misleading. The most frequent symptoms were related to bulbar dysfunction-with dysarthria, dysphagia, dysphonia (seven patients)-, pyramidal involvement (seven patients) and cerebellar ataxia (seven patients). Four patients had palatal myoclonus. Sleep disorders were also observed (four cases). Bulbar symptoms, however, were infrequent at onset and two symptomatic patients had an almost pure pyramidal involvement. Two subjects were asymptomatic. Misdiagnosis at presentation was frequent and MRI was instrumental in suggesting the correct diagnosis by showing, in all cases, mild to severe atrophy of the medulla oblongata extending caudally to the cervical spinal cord. In ten patients, molecular studies revealed six novel missense mutations and three previously reported changes in GFAP. The last typical patient carried no definitely pathogenic mutation, but a missense variant (p.D157N), supposedly a rare polymorphism. Revision of the literature and the present series indicate that the clinical picture is not specific, but AOAD must be considered in patients of any age with lower brainstem signs. When present, palatal myoclonus is strongly suggestive. Pyramidal involvement, cerebellar ataxia and urinary disturbances are common. Less frequent findings include sleep disorders and dysautonomia. Fluctuations may occur. The course is variable, usually slowly progressive and less severe than the AD forms with earlier onset. AOAD is more common than previously thought and might even be the most common form of AD. The diagnosis is strongly suggested by MRI and confirmed by GFAP gene analysis.

Prognostic factors for survival in 676 consecutive patients with newly diagnosed primary glioblastoma.

Reliable data on large cohorts of patients with glioblastoma are needed because such studies differ importantly from trials that have a strong bias toward the recruitment of younger patients with a higher performance status. We analyzed the outcome of 676 patients with histologically confirmed newly diagnosed glioblastoma who were treated consecutively at a single institution over a 7-year period (1997-2003) with follow-up to April 30, 2006. Survival probabilities were 57% at 1 year, 16% at 2 years, and 7% at 3 years. Progression-free survival was 15% at 1 year. Prolongation of survival was significantly associated with surgery in patients with a good performance status, whatever the patient's age, with an adjusted hazard ratio of 0.55 (p < 0.001) or a 45% relative decrease in the risk of death. Radiotherapy and chemotherapy improved survival, with adjusted hazard ratios of 0.61 (p = 0.001) and 0.89 (p = 0.04), respectively, regardless of age, performance status, or residual tumor volume. Recurrence occurred in 99% of patients throughout the follow-up. Reoperation was performed in one-fourth of these patients but was not effective, whether performed within 9 months (hazard ratio, 0.86; p = 0.256) or after 9 months (hazard ratio, 0.98; p = 0.860) of initial surgery, whereas second-line chemotherapy with procarbazine, lomustine, and vincristine (PCV) or with temozolomide improved survival (hazard ratio, 0.77; p = 0.008). Surgery followed by radiotherapy and chemotherapy should be considered in all patients with glioblastoma, and these treatments should not be withheld because of increasing age alone. The benefit of second surgery at recurrence is uncertain, and new trials are needed to assess its effectiveness. Chemotherapy with PCV or temozolomide seems to be a reasonable option at tumor recurrence.

Spontaneous intracranial hypotension with deep brain swelling.

Spontaneous intracranial hypotension (SIH) is caused by leakage of CSF, and characterized on MRI by brain sagging, dilatation of veins and dural sinuses, subdural fluid collections and post-contrast enhancement of the thickened dura. A few cases may present a very severe brain sagging through the tentorial notch and swelling of the diencephalic-mesencephalic structures, with absent or scarce subdural collections and post-contrast enhancement. These patients may have surprisingly few neurological signs or may become drowsy and even lapse into coma due to central herniation. We retrospectively examined the diffusion studies obtained in five patients with these MRI findings, in seven patients with SIH without brain swellings and in ten controls. Mean diffusivity was increased in SIH patients with brain swelling in areas draining into the deep venous system, collected by the vein of Galen (vG) and straight sinus (SS). In the hypothesis that central herniation might be responsible for venous stagnation because of impaired flow of the vG into the SS, the vG/SS angle was measured. The angle formed by the vG entering the SS was not altered in patients without brain swelling (group E, 67.8 degrees +/- 10.3 degrees, mean +/- SD, range 49-80 degrees) when compared to controls (group C, 73.3 degrees +/- 12.3 degrees, mean +/- SD, range 56-95 degrees). It was, however, grossly decreased in patients with brain swelling (group D, 40.7 degrees +/- 12.8 degrees, mean +/- SD, range 22-61 degrees), P < 0.001 for comparison with groups E and C. As suggested by previous studies, downward stretching of the vG and narrowing of the vG/SS angle may cause a functional stenosis at the vG-SS junction. We suggest that in the application of the Monro-Kellie doctrine to SIH, the brain volume should not be considered as always invariable.

Dural sinus thrombosis in spontaneous intracranial hypotension: Hypotheses on possible mechanisms.

Dural sinus thrombosis (DST) is rarely associated with spontaneous intracranial hypotension (SIH). Engorgement of the venous system, caused by the CSF loss that occurs in SIH, is considered to favour the thrombosis, although signs of both SIH and DST are usually seen simultaneously at the first diagnostic MRI. We observed two patients with SIH and DST. Changes in pattern of headaches and MRI findings demonstrated that DST followed SIH. In SIH, the velocity of the blood flow in the dural sinuses may be reduced because of dilatation of the venous system which compensates the CSF loss. Other possible mechanisms seem unlikely on the grounds of both clinical presentation and MRI studies.

The diagnostic challenge of Divry van Bogaert and Sneddon Syndrome: Report of three cases and literature review.

Divry van Bogaert Syndrome (DBS) is a familial juvenile-onset disorder characterized by livedo racemosa, white matter disease, dementia, epilepsy and angiographic finding of "cerebral angiomatosis". A similar syndrome including livedo racemosa and cerebrovascular disease, often associated with anticardiolipin antibodies, has been described as Sneddon Syndrome (SS) highlighting the question whether these two conditions have to be considered different entities or indeed different features of a unique syndrome. Herein, we report the clinical, neuroradiological, histopathological findings and follow up of three cases diagnosed as Divry-van Bogaert Syndrome, including an updated review of literature of both DBS and SS cases. Our findings support the assumption that DBS and SS are different disease entities. DBS is characterized by the typical angiographic feature of angiomatosis, a hereditary trait and a juvenile onset of cognitive impairment and leukoaraiosis, whereas SS has less severe manifestations of cerebrovascular disease associated with livedo racemosa but without the characteristic cerebral angiography. The report of our cases and the literature review underline the necessity of a detailed work-up and the collection of larger series to better clarify the DBS and SS phenotype and course.

MR imaging of cerebral cortical involvement in aceruloplasminemia.

Aceruloplasminemia is a rare autosomal recessive disorder. The lack of ceruloplasmin ferroxidase activity leads to parenchymal and reticuloendothelial iron overload, resulting in diabetes and progressive neurodegeneration with extrapyramidal disorders, ataxia, and dementia. We describe the MR imaging findings in a 40-year-old woman with hereditary aceruloplasminemia. The abnormal T2 hypointensities were more marked than those seen in any other condition, including degenerative disorders of the basal ganglia and Wilson disease, and they may be typical of aceruloplasminemia. To our knowledge, involvement of the cortex has not been described and suggests that brain iron accumulation in aceruloplasminemia is more extensive than previously believed, even in asymptomatic patients.

Wallerian degeneration of the pontocerebellar fibers.

Two cases of pontine infarct with Wallerian degeneration (WD) of the pontocerebellar fibers are described. WD of pontocerebellar fibers, seen bilaterally along the transverse pontine fibers, is more visible in the middle cerebellar peduncles and extends into the white matter of the cerebellar hemispheres. Understanding the anatomy of the white matter and the temporal evolution of this degeneration is essential in identifying WD.

Prodromal Alzheimer's disease presenting as cerebral amyloid angiopathy-related inflammation with spontaneous amyloid-related imaging abnormalities and high cerebrospinal fluid anti-Aß autoantibodies.

Cerebral amyloid angiopathy-related inflammation (CAA-ri), a rare form of vasculitis associated with amyloid-ß (Aß) deposition in vessel walls, has been proposed as a spontaneous human model of the amyloid-related imaging abnormalities (ARIA) occurring after anti-Aß immunotherapy for the treatment of Alzheimer's disease (AD). We describe a case of a patient with biopsy-proven CAA-ri and prodromal AD, confirmed by means of neuropsychological examination after 20 months follow-up, presenting with ARIA and high levels of cerebrospinal fluid anti-Aß autoantibodies. This case further supports the analogies between the inflammatory response driven by anti-Aß immunotherapy and that spontaneously occurring in CAA-ri.

MR findings in Leigh syndrome with COX deficiency and SURF-1 mutations.

BACKGROUND AND PURPOSE: In a large number of patients with Leigh syndrome (LS) and cytochrome c oxidase (COX) deficiency, mutations of the SURF-1 gene were recently identified. The aim of the present study was to review the MR findings in patients with LS to verify if the genetically homogeneous patients with LS and SURF-1 mutations (LS SURF-1 patients) had a homogeneous MR pattern that could be used to differentiate them from other patients with LS (LS non-SURF-1 patients). METHODS: T1-, proton density-, and T2-weighted MR images of eight LS SURF-1 patients and 14 LS non-SURF-1 patients were reviewed. Enzymatic activity was determined according to standard methods. Genetic analysis was mostly performed by using stored DNA samples. RESULTS: All LS SURF-1 patients had lesions in the brain stem and subthalamic nuclei. Six had lesions in the cerebellum. Only two had basal ganglial abnormalities. Ten LS non-SURF-1 patients had lesions in the brain stem, but in six they were mild. Ten patients had basal ganglial abnormalities (nine of 10 in the putamina). LS-SURF-1 patients had a more severe clinical course. CONCLUSION: The MR pattern in LS SURF-1 patients is characteristic. Brain stem and subthalamic nuclei lesions may suggest the specific diagnosis. These patients die soon, probably because of lower brain stem involvement. Basal ganglial abnormalities are common only in LS non-SURF-1 patients. The absence of putaminal lesions, therefore, does not exclude the diagnosis of LS.

Constrained spherical deconvolution-based tractography to depict and characterize a case of "hyperplastic fornix dorsalis".

The authors report the relevance of Constrained Spherical Deconvolution (CSD)-based tractography in demonstrating and quantitatively assessing a complex midline structure malformation in a 9-year-old girl with moderate intellectual disability and thickening of corpus callosum (CC) body discovered through conventional MRI (cMRI). Color-encoded fractional anisotropy (FA) maps clearly demonstrated what the cMRI showed as a thicknening of CC: a green, longitudinal bundle running dorsally to the body of CC. A more complex midline maldevelopmental disorder was suspected. CSD-based tractography was performed to virtually dissect the anomalous supracallosal longitudinal bundle (SLB), CC, fornix, anterior commissure (AC) and cingula. In addition, DTI-derived metrics were calculated for each virtually dissected fiber tract. The tractography study evidenced projections of the anomalous SLB in left forceps minor and to parietal regions, and projections of the fornix in right forceps minor. CC virtual dissection showed no gross abnormality, and cingula appeared slightly less extended than normal. The considerable thinning of AC hampered its virtual dissection. DTI-derived metrics suggested alterations in fornix microstructure, attributable to higher fiber density. In investigating white matter, cMRI may not be sufficient in addressing and assessing possible anomalies, while advanced CSD-based tractography and DTI-derived metrics may prove helpful in depicting and characterizing white matter anomalies in developmental disorders.

Brain fluorodeoxyglucose PET in adrenoleukodystrophy.

OBJECTIVE: To investigate the cerebral glucose metabolism in subjects with X-linked adrenoleukodystrophy (X-ALD) by using brain [(18)F]-fluorodeoxyglucose PET (FDG-PET). METHODS: Cross-sectional study in which 12 adults with various forms of X-ALD underwent clinical evaluation and brain MRI, followed by brain FDG-PET, neuropsychological assessment, and personality and psychopathology evaluation using the Symptom Checkist-90-Revised (SCL-90-R) and the Millon Clinical Multiaxial Inventory-III (MCMI-III). RESULTS: When compared to healthy control subjects (n = 27) by using Statistical Parametric Mapping 8 software, the patients with X-ALD-with or without brain MRI changes-showed a pattern of increased glucose metabolism in frontal lobes and reduced glucose metabolism in cerebellum and temporal lobe areas. On single case analysis by Scenium software, we found a similar pattern, with significant (p < 0.02) correlation between the degree of hypermetabolism in the frontal lobes of each patient and the corresponding X-ALD clinical scores. With respect to personality, we found that patients with X-ALD usually present with an obsessive-compulsive personality disorder on the MCMI-III, with significant (p < 0.05) correlation between glucose uptake in ventral striatum and severity of score on the obsessive-compulsive subscale. CONCLUSIONS: We examined cerebral glucose metabolism using FDG-PET in a cohort of patients with X-ALD and provided definite evidence that in X-ALD the analysis of brain glucose metabolism reveals abnormalities independent from morphologic and signal changes detected by MRI and related to clinical severity. Brain FDG-PET may be a useful neuroimaging technique for the characterization of X-ALD and possibly other leukodystrophies.