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It is unclear how immune cells traffic between the lymphoid compartment and the central nervous system (CNS), which lacks lymphatic vessels and is shielded by the blood-brain barrier. We studied the expression of CCR7, a chemokine receptor required for migration of T cells and dendritic cells (DCs) to lymphoid organs, in the CNS of patients with multiple sclerosis (MS) to gain insight into pathways for CNS immune cell trafficking. Inflamed MS lesions contained numerous CCR7+ myeloid cells expressing major histocompatibility complex class II, CD68 and CD86, consistent with maturing DCs. CCR7+ DCs also were identified in cerebrospinal fluid (CSF). These observations suggested that the afferent limb of CNS immunity is comprised, in part, of DCs, which are generated within the CNS and migrate to deep cervical lymph nodes through the CSF after antigen capture. Ninety percent of CSF T cells expressed CCR7 and CSF from patients with MS was relatively depleted of CCR7-negative effector-memory T cells. In contrast, all T cells in parenchymal MS lesions lacked CCR7, indicating local retention and differentiation of central-memory T cells upon restimulation by antigen within the CNS. These data suggested that the efferent limb of CNS immunity is executed by central-memory T cells, which enter CSF directly from the circulation.

Mutations in the tau gene cause familial frontotemporal dementia and parkinsonism linked to chromosome 17. Here, we describe two Dutch families with familial frontotemporal dementia associated with the novel missense mutation L315R in exon 11 of tau. The age at onset of disease showed a large variation within each family, ranging from 25 to 64 years. Incomplete penetrance was established in an 82-year-old mutation carrier with no signs of dementia and appeared probable in two additional subjects. The brains of two affected subjects were studied and showed extensive tau pathology in neurons (Pick-like inclusions) and astroglial cells, particularly in the frontotemporal cortex and the hippocampal formation. Sarkosyl-insoluble tau extracted from the cerebral cortex showed the presence of straight and twisted tau filaments and a pattern of pathological tau bands similar to that of Pick's disease. Upon dephosphorylation, only five of the six brain tau isoforms were observed, with the shortest isoform being undetectable. All six tau isoforms were present in soluble brain tau. Recombinant tau proteins with the L315R mutation showed a reduced ability to promote microtubule assembly.

Item does not contain fulltext Mutations in the tau gene cause familial frontotemporal dementia and parkinsonism linked to chromosome 17. In this article, we describe a novel missense mutation, S320F, in the tau gene in a family with presenile dementia. To our knowledge, it is the first mutation to be described in exon 11 of tau. The proband died at age 53 years, after a disease duration of 15 years, and autopsy revealed a neuropathological picture similar to Pick's disease. Recombinant tau protein with the S320F mutation showed a greatly reduced ability to promote microtubule assembly.

Several mutations in the tau gene have been found in families with hereditary frontotemporal dementia and parkinsonism linked to chromosome 17q21-22 (FTDP-17). This study is the first attempt to correlate genotype and phenotype in six families with FTDP-17 with mutations in the tau gene (DK280, G272V, P301L, and R406W). We have investigated tau pathology in 1 P301L and 1 R406W patient. The R406W family showed a significantly higher age at onset (59.2 6 5.5 years) and longer duration of illness (12.7 6 1.5 years) than the families with the other mutations. The six families showed considerable variation in clinical presentation, but none of them had early parkinsonism. Mutism developed significantly later in the R406W family than in the other families. Frontotemporal atrophy on neuroimaging in the R406W family was less severe than in the P301L and DK280 families. The P301L brain contained many pretangles in the frontal and temporal cortex, and the dentate gyrus of hippocampus, showing three tau bands (64, 68, and 72 kd) of extracted tau from the frontal cortex. The presence of many neurofibrillary tangles, many diffuse and classic neuritic plaques in the temporal and parietal cortex, and the hippocampus of the same P301L brain correlated with the presence of four sarkosyl-insoluble (60, 64, 68, and 72 kd) tau bands. The coexistence of characteristic P301L and Alzheimer pathology in the same brain needs further explanation. The R406W brain showed abundant neurofibrillary tangles in several brain regions, and four tau bands (60, 64, 68, and 72 kd) of extracted tau from these regions. The slower progression of the disease in the R406W family might be explained by the microtubule-binding properties of the mutant protein.

Magnetic resonance imaging (MRI) monitoring of disease progression in multiple sclerosis is limited by the lack of correlation of abnormalities seen on T2-weighted imaging, and disability. We studied the histopathology of multiple sclerosis lesions, as depicted by MRI, in a large postmortem sample, focusing on axonal loss. Tissue samples from 17 patients were selected immediately postmortem for histopathological analysis on the basis of T2-weighted imaging, including normal appearing white matter and T1 hypointense lesions. In each region, we measured magnetization transfer ratios (MTR), T1 contrast ratio, myelin, and axonal density. T2 lesions (109 samples) were heterogeneous with regard to MRI appearance on T1 and MTR, whereas axonal density ranged from 0% (no residual axons) to 100% (normal axonal density). Of 64 T2 lesions, 17 were reactive (mild perivascular inflammation only), 21 active, 15 chronically active, and 11 chronically inactive. MTR and T1 contrast ratio correlated strongly with axonal density. Also in normal appearing white matter (24 samples), MTR correlated with axonal density. In conclusion, postmortem tissue sampling by using MRI revealed a range of pathology, illustrating the high sensitivity and low specificity of T2-weighted imaging. T1 hypointensity and MTR were strongly associated with axonal density, emphasizing their role in monitoring progression in multiple sclerosis.

The hypothalamic lateral tuberal nucleus was investigated in 5 young patients, aged 45 to 64 years, with Alzheimer's disease (AD) and in 5 age-matched control subjects. Combining conventional histopathological and immunocytochemical staining with neuronal counts, a peculiar form of neuronal pathology was characterized. Although neurons and neurites in the lateral tuberal nucleus of AD specimens were heavily stained by Alz-50, silver and thioflavine-S stains disclosed few neurofibrillary tangles or neurites. The numbers of neurons in the lateral tuberal nucleus of patients with AD (67,450; SEM = 5,050) were no different from those of control subjects (58,900; SEM = 2,450). In the AD patients, few plaques were present and were almost exclusively of the amorphous variety. We conclude that neurons in the lateral tuberal nucleus show an early stage of AD-related cytoskeletal pathology (Alz-50 positivity), but without plaques or neuronal death.

It is unclear how immune cells traffic between the lymphoid compartment and the central nervous system (CNS), which lacks lymphatic vessels and is shielded by the blood-brain barrier. We studied the expression of CCR7, a chemokine receptor required for migration of T cells and dendritic cells (DCs) to lymphoid organs, in the CNS of patients with multiple sclerosis (MS) to gain insight into pathways for CNS immune cell trafficking. Inflamed MS lesions contained numerous CCR7+ myeloid cells expressing major histocompatibility complex class II, CD68 and CD86, consistent with maturing DCs. CCR7+ DCs also were identified in cerebrospinal fluid (CSF). These observations suggested that the afferent limb of CNS immunity is comprised, in part, of DCs, which are generated within the CNS and migrate to deep cervical lymph nodes through the CSF after antigen capture. Ninety percent of CSF T cells expressed CCR7 and CSF from patients with MS was relatively depleted of CCR7-negative effector-memory T cells. In contrast, all T cells in parenchymal MS lesions lacked CCR7, indicating local retention and differentiation of central-memory T cells upon restimulation by antigen within the CNS. These data suggested that the efferent limb of CNS immunity is executed by central-memory T cells, which enter CSF directly from the circulation.