A 68-year-old man presented with a 4-month history of progressive memory loss and mood disorders. Neurologic examination revealed severe impairment of attention and verbal skills, without motor and sensory deficits. His medical history included mild arterial hypertension, idiopathic partial epilepsy, and obsessive compulsive disorder.Brain MRI showed the presence of bilateral, asymmetric, swollen white matter lesions in the cerebral hemispheres, hyperintense in T2-weighted images, that partially involved the left frontal cortex (figure). On diffusion-weighted sequences, the white matter abnormalities were consistent with vasogenic edema. No pathologic contrast enhancement was present.Routine blood tests, inflammatory markers, autoantibodies, neoplastic markers, and paraneoplastic antibodies were within normal limits. CSF examination revealed increased level of proteins (152 mg/dL) and cell count (14 leukocyte/L), without intrathecal synthesis of oligoclonal bands. Bacterioscopic and virologic tests (including HIV and JCV) were negative, both on CSF and serum. Search for tumor or infection by total body CT scan was negative.Stereotactic biopsy of the left frontal white matter lesion showed gliosis without signs of infections or neoplasm.After the biopsy, the patient was treated with dexamethasone 24 mg/day IV for 20 days with marked clinical improvement. A control CSF analysis performed 3 months later was within normal limits (Ͻ1 leukocyte/ L, protein 27 mg/dL). Brain MRI demonstrated a reduction in number and extension of the white matter T2-hyperintense lesions (figure). T2*-weighted gradient echo images showed the presence of multiple microhemorrhages scattered over the entire cerebral cortex. No microbleeds were present in basal ganglia, thalami, and posterior fossa (figure).Diagnosis of probable cerebral amyloid angiopathy-related inflammation (CAA-ri) was made upon clinical and MRI findings, supported by the demonstration of APOE ⑀4 homozygosity.A search for A␤ deposits in brain tissue and vessel walls on the biopsy sample was negative; a possible explanation is the deep white matter target, with absence of cortex and leptomeninges in the specimen. The A␤ 1-42 protein in the CSF was reduced both in the first (129 pg/mL) and second (125 pg/mL) lumbar puncture compared to normal values (682-1,063 pg/mL). The A␤ 1-40 protein was also investigated (457 pg/mL in the first CSF; 238 pg/mL in the second); however, due to the large variability of this assay as reported in literature, the meaning of these values is unclear.We hypothesized a spontaneous autoimmune process against CNS A␤ proteins, and assessed the levels of anti-A␤ 1-40 and 1-42 autoantibodies in our patient's CSF, both before and after steroid treatment, compared to 6 age-matched controls (mean age: 63 Ϯ 19 years) and 4 patients with MS (mean age: 45 Ϯ 17 years). We used our ELISA, as described, 1 and detected a marked increase of anti-A␤ 1-40 and 1-42 autoantibodies in the CSF of our CAA-ri patient obtained prior to treatment compared to controls and ...

Generation of reactive oxygen species during dopamine (DA) oxidation could be one of the factors leading to the selective loss of nigral dopaminergic neurons in Parkinson’s disease (PD). Vesicular monoamine transporter type 2 (VMAT2) proteins in nerve terminals uptake dopamine into synaptic vesicles, preventing its cytoplasmic accumulation and toxic damage to nigral neurons. Polymorphisms in VMAT2 gene and in its regulatory regions might therefore serve as genetic risk factors for PD. In the present study, we have analyzed 8 single-nucleotide polymorphisms (SNPs) located within/around the VMAT2 gene for association with PD in an Italian cohort composed of 704 PD patients and 678 healthy controls. Among the 8 SNPs studied, only the 2 located within the promoter region (rs363371 and rs363324) were significantly associated with PD. In the dominant model, odds ratios were 0.72 (95% confidence interval [CI]: 0.6–0.9, p < 0.005) for rs363371 and 0.76 (95% CI: 0.6–0.9, p = 0.01) for rs363324; in the additive model, odds ratios were 0.78 (95% CI: 0.65–0.94, p = 0.008) for rs363371 and 0.85 (95% CI: 0.7–20.92, p = 0.04) for rs363324. There were no significant relationships between the remaining SNPs (rs363333, rs363399, rs363387, rs363343, rs4752045, and rs363236) and the risk of sporadic PD in any genetic model. This study adds to the previous evidence suggesting that variability in VMAT2 promoter region may confer a reduced risk of developing PD, presumably via mechanisms of gene overexpression.

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Retinal vasculopathy with cerebral leukodystrophy (RVCL) is an adult-onset disorder caused by C-terminal heterozygous frameshift (fs) mutations in the human 3'-5' DNA exonuclease TREX1. Hereditary systemic angiopathy (HSA) is considered a variant of RVCL with systemic involvement of unknown genetic cause, described in a unique family so far. Here we describe the second case of RVCL with systemic involvement, characterized by cerebral calcifications and pseudotumoral lesions, retinopathy, osteonecrosis, renal and hepatic failure. The genetic screening of TREX1 in this patient revealed the novel heterozygous T270fs mutation on the C-terminal region. On the same gene, we found the V235fs mutation, formerly shown in RVCL, in one patient previously reported with HSA. These mutations lead to important alterations of the C-terminal of the protein, with the loss of the transmembrane helix (T270fs) and the insertion of a premature stop codon, resulting in a truncated protein (V235fs). Functional analysis of T270fs-mutated fibroblasts showed a prevalent localization of the protein in the cytosol, rather than in the perinuclear region. RVCL with systemic involvement is an extremely rare condition, whose diagnosis is complex due to multiorgan manifestations, unusual radiological and histopathological findings, not easily attributable to a single disease. It should be suspected in young adults with systemic microangiopathy involving retina, liver, kidney, bones and brain. Here we confirm the causative role played by TREX1 autosomal dominant fs mutations disrupting the C-terminal of the protein, providing a model for the study of stroke in young adults.