High-Resolution Anatomy from in Situ Human Brain

We have generated a spatially accurate, high-resolution three-dimensional (3D) volume of brain anatomy from cryosectioned whole human head. The head of a female cadaver was cryosectioned on a heavy duty cryomacrotome (PMV, Stockholm Sweden) modified for quantitative digital image capture. Serial images (1024², 24-bit) were captured directly from the cryoplaned specimen blockface in 500-μm intervals and reconstructed to a 3D data volume. Data were placed into the Talairach coordinate system to create a volume of brain anatomy for atlas reference. We resampled the volume at 500 μm along the sagittal, coronal, and horizontal planes and enhanced the images by digitally editing the background. The spatial resolution of the original digitized images provided sufficient anatomic detail to clearly delineate gray and white matter and neural structures, including major fiber pathways, sub-thalamic nuclei, and laminae. We developed a compact disk and controlling software program to enable the viewer to select planes of orientation, display, and copy individual sections at higher resolution. Animation proved useful in the conveyance of system anatomy as structures are shown traversing through the neuroaxis. Postmortem cryosectioning paired with this computerized presentation allowed the complete 3D volume data to be distributed and shared as an educational, clinical, and research resource.     

Immune complex vasculitis associated with mediterranean spotted fever

We report a case of mediterranean spotted fever complicated by leucocytoclastic vasculitis. Rickettsia conorii, IgA, complement and fibrin deposits were found in a skin biopsy. Treatment with tetracycline was successful.     

Automated 3D mapping of hippocampal atrophy and its clinical correlates in 400 subjects with Alzheimer's disease,mild cognitive impairment,and elderly controls

We used a new method we developed for automated hippocampal segmentation, called the auto context model, to analyze brain MRI scans of 400 subjects from the Alzheimer's disease neuroimaging initiative. After training the classifier on 21 hand‐labeled expert segmentations, we created binary maps of the hippocampus for three age‐ and sex‐matched groups: 100 subjects with Alzheimer's disease (AD), 200 with mild cognitive impairment (MCI) and 100 elderly controls (mean age: 75.84; SD: 6.64). Hippocampal traces were converted to parametric surface meshes and a radial atrophy mapping technique was used to compute average surface models and local statistics of atrophy. Surface‐based statistical maps visualized links between regional atrophy and diagnosis (MCI versus controls: P = 0.008; MCI versus AD: P = 0.001), mini‐mental state exam (MMSE) scores, and global and sum‐of‐boxes clinical dementia rating scores (CDR; all P < 0.0001, corrected). Right but not left hippocampal atrophy was associated with geriatric depression scores (P = 0.004, corrected); hippocampal atrophy was not associated with subsequent decline in MMSE and CDR scores, educational level, ApoE genotype, systolic or diastolic blood pressure measures, or homocysteine. We gradually reduced sample sizes and used false discovery rate curves to examine the method's power to detect associations with diagnosis and cognition in smaller samples. Forty subjects were sufficient to discriminate AD from normal and correlate atrophy with CDR scores; 104, 200, and 304 subjects, respectively, were required to correlate MMSE with atrophy, to distinguish MCI from normal, and MCI from AD. Hum Brain Mapp 2009. © 2009 Wiley‐Liss, Inc.     

Relationships between IQ and regional cortical gray matter thickness in healthy adults

Prior studies show positive correlations between full-scale intelligence quotient (FSIQ) and cerebral gray matter measures. Few imaging studies have addressed whether general intelligence is related to regional variations in brain tissue and the associated influences of sex. Cortical thickness may more closely reflect cytoarchitectural characteristics than gray matter density or volume estimates. To identify possible localized relationships, we examined FSIQ associations with cortical thickness at high spatial resolution across the cortex in healthy young adult (age 17-44 years) men (n = 30) and women (n = 35). Positive relationships were found between FSIQ and intracranial gray and white matter but not cerebrospinal fluid volumes. Significant associations with cortical thickness were evident bilaterally in prefrontal (Brodmann's areas [BAs] 10/11, 47) and posterior temporal cortices (BA 36/37) and proximal regions. Sex influenced regional relationships; women showed correlations in prefrontal and temporal association cortices, whereas men exhibited correlations primarily in temporal-occipital association cortices. In healthy adults, greater intelligence is associated with larger intracranial gray matter and to a lesser extent with white matter. Variations in prefrontal and posterior temporal cortical thickness are particularly linked with intellectual ability. Sex moderates regional relationships that may index dimorphisms in cognitive abilities, overall processing strategies, or differences in structural organization.     

Recombinant adeno-associated virus-mediated gene transfer into hematopoietic progenitor cells [published erratum appears in Blood 1995 Feb 1;85(3):862]

Recombinant adeno-associated viruses (rAAV) containing only the inverted terminal repeats (ITR) from the wild-type virus are capable of stable integration into the host cell genome, and expression of inserted genes in cultured cells. We have now defined the ability of rAAV to introduce genes into primary hematopoietic progenitors. A vector was constructed containing the coding sequences for beta- galactosidase (beta-gal), including a nuclear localization signal, under the control of a strong viral promotor. Infectious vector particles were prepared by cotransfection of the vector plasmid with a second plasmid that contained the coding sequences for AAV proteins into adenovirus-infected human embryonic kidney cells. These vector preparations transferred and expressed the beta-gal gene in human K562 erythroleukemia and Detroit 6 cells. Positive immunoselection yielded a population of enriched CD34+ cells that were transduced with the rAAV beta-gal vector. Nuclear localized enzyme expression was documented in 60% to 70% of infected cells. Progenitor-derived colonies that developed after 2 weeks in clonogenic cultures were shown to have viral- associated DNA at an estimated copy number of 1 to 2 per cell using a semiquantitative polymerase chain reaction (PCR) method. Integration of AAV into hematopoietic progenitors was documented using wild-type virus, as its genome may integrate at a preferred site on chromosome 19. Our data suggest that rAAV will transfer and express genes in primitive hematopoietic progenitors with high frequency, and support the development of this vector system for therapeutic gene transfer.