The clinical profile of right temporal lobe atrophy.

Frontotemporal lobar degeneration is currently associated with three syndromic variants. Disorders of speech and language figure prominently in two of the three variants, and are associated with left-sided frontotemporal atrophy. The detailed characterization of these syndromes contrasts with the relative paucity of information relating to frontotemporal lobar degeneration primarily affecting the right cerebral hemisphere. The objective of this study was to identify the clinical profile associated with asymmetrical, predominantly right-sided, temporal lobe atrophy. Twenty patients with predominant right temporal lobe atrophy were identified on the basis of blinded visual assessment of the MRI scans. The severity of right temporal lobe atrophy was quantified using volumetric analysis of the whole temporal lobes, the amygdala and the hippocampus. Profiles of cognitive function, behavioural and personality changes were obtained on each patient. The pattern of atrophy and the clinical features were compared with those observed in a group of patients with semantic dementia and predominant left-sided temporal lobe atrophy. The mean right temporal lobe volume in the right temporal lobe atrophy group was reduced by 37%, with the mean left temporal lobe volume reduced by 19%. There was marked atrophy of the right hippocampus and right amygdala, with mean volumes reduced by 41 and 51%, respectively (left hippocampus and amygdala volumes were reduced by 18 and 33%, respectively). The most prominent cognitive deficits were impairment of episodic memory and getting lost. Prosopagnosia was a symptom in right temporal lobe atrophy patients. These patients also exhibited a variety of behavioural symptoms including social disinhibition, depression and aggressive behaviour. Nearly all behavioural disorders were more prevalent in the right temporal lobe atrophy patient group than the semantic dementia group. Symptoms particular to the right temporal lobe atrophy patient group included hyper-religiosity, visual hallucinations and cross-modal sensory experiences. The combination of clinical features associated with predominant right temporal lobe atrophy differs significantly from those associated with the other syndromes associated with focal degeneration of the frontal and temporal lobes and it is, therefore, proposed that this right temporal variant should be considered a separate syndromic variant of frontotemporal lobar degeneration.

Partial epilepsy syndrome in a Gypsy family linked to 5q31.3-q32.

PURPOSE: The restricted genetic diversity and homogeneous molecular basis of Mendelian disorders in isolated founder populations have rarely been explored in epilepsy research. Our long-term goal is to explore the genetic basis of epilepsies in one such population, the Gypsies. The aim of this report is the clinical and genetic characterization of a Gypsy family with a partial epilepsy syndrome. METHODS: Clinical information was collected using semistructured interviews with affected subjects and informants. At least one interictal electroencephalography (EEG) recording was performed for each patient and previous data obtained from records. Neuroimaging included structural magnetic resonance imaging (MRI). Linkage and haplotype analysis was performed using the Illumina IVb Linkage Panel, supplemented with highly informative microsatellites in linked regions and Affymetrix SNP 5.0 array data. RESULTS: We observed an early-onset partial epilepsy syndrome with seizure semiology strongly suggestive of temporal lobe epilepsy (TLE), with mild intellectual deficit co-occurring in a large proportion of the patients. Psychiatric morbidity was common in the extended pedigree but did not cosegregate with epilepsy. Linkage analysis definitively excluded previously reported loci, and identified a novel locus on 5q31.3-q32 with an logarithm of the odds (LOD) score of 3 corresponding to the expected maximum in this family. DISCUSSION: The syndrome can be classified as familial temporal lobe epilepsy (FTLE) or possibly a new syndrome with mild intellectual deficit. The linked 5q region does not contain any ion channel-encoding genes and is thus likely to contribute new knowledge about epilepsy pathogenesis. Identification of the mutation in this family and in additional patients will define the full phenotypic spectrum.

Extratemporal ictal clinical features in hippocampal sclerosis: their relationship to the degree of hippocampal volume loss and to the outcome of temporal lobectomy.

PURPOSE: Since extratemporal clinical features in patients with unilateral hippocampal sclerosis (HS) are likely to indicate aberrant ictal spread or a more extensive epileptogenic zone, we asked whether such features are associated with more severe HS and a worse outcome following temporal lobectomy. PATIENTS AND METHODS: We reviewed all patients (174) who had undergone temporal lobectomy for histologically proven unilateral HS related temporal lobe epilepsy between 1997-2005 at the National Hospital for Neurology and Neurosurgery. We divided patients into those with severe HS (side-to-side ratio < 0.6) and those with mild HS (side-to-side ratio > 0.75). We examined all seizures recorded on electroencephalography (EEG) video telemetry in these patients for clinical features of temporal lobe epilepsy. The postsurgical outcome was classified using the Engel classification at the time of follow up (median 4.7 years, range 1-9 years). RESULTS: Patients (28 out 39) with severe HS had atypical features compared to 7 out of 27 in the mild HS [Chi square (chi(2)) test, p = 0.0013]. The mean number of atypical clinical features was 2.2 in the severe HS group and 0.62 in the mild HS group (Mann Whitney U Test, p < 0.001). The percentage of postsurgery seizure freedom (class 1 Engel classification) was 87%, and there was no significant effect of the presence of atypical clinical features. CONCLUSIONS: This study shows that atypical (extratemporal) clinical features tend to occur more frequently in patients with severe HS and do not correlate with worse surgical outcome.

Mapping the progression of progranulin-associated frontotemporal lobar degeneration.

BACKGROUND: A 55-year-old woman was followed over a 13-year period as part of a longitudinal study of people at risk for familial dementia. She was a member of a family with an autosomal dominant familial dementia that fulfilled consensus criteria for frontotemporal lobar degeneration. The patient was initially asymptomatic but developed progressive behavioral and cognitive decline characterized by apathy, impaired emotion recognition, mixed aphasia and parietal lobe dysfunction. INVESTIGATIONS: Clinical assessments, neuropsychometry, volumetric brain MRI, and genetic mutation screening. DIAGNOSIS: Progranulin-associated frontotemporal lobar degeneration. MANAGEMENT: Explanation of the patient's condition and genetic counseling for her family.

Visual assessment of atrophy on magnetic resonance imaging in the diagnosis of pathologically confirmed young-onset dementias.

OBJECTIVES: To investigate the diagnostic accuracy of visual inspection of magnetic resonance imaging (MRI) in a range of pathologically confirmed diseases causing young-onset dementia and to assess the sensitivity and specificity of atrophy patterns for Alzheimer disease (AD) and frontotemporal lobar degeneration (FTLD). DESIGN: Sixty-two patients with pathologically confirmed diseases that may present as young-onset dementia were selected from a biopsy and postmortem series. The first diagnostic T1-weighted volumetric MRI was obtained for each patient, together with images from 22 healthy control subjects. All MRIs were assessed for regional atrophy independently by 3 neuroradiologists, blinded to all clinical details except age. Observers were also asked to use their clinical judgment to form a diagnosis. RESULTS: Eighty-seven percent of dementia cases were distinguished from controls after visual inspection of MRI, and a correct pathologically confirmed diagnosis was given in 58% of cases. Hippocampal atrophy was noted in 92% of AD cases but was commonly seen in other dementias and controls. A bilateral symmetrical pattern of hippocampal atrophy discriminated AD from FTLD with 47% specificity, while posterior greater than anterior gradient of atrophy was 92% specific for AD. Atrophy of the anterior, inferior, and lateral temporal lobes was suggestive of FTLD pathology (> or =90% sensitivity), while anterior greater than posterior gradient of atrophy and hemispheric asymmetry of atrophy were each at least 85% specific for FTLD. CONCLUSION: Despite variation and overlap of atrophy patterns, visual inspection of regional atrophy on MRI may aid in discriminating AD and FTLD.

Magnetic resonance imaging signatures of tissue pathology in frontotemporal dementia.

BACKGROUND: The pathologic substrates of frontotemporal dementia (FTD) are difficult to predict in vivo. OBJECTIVE: To determine whether different pathologic substrates of FTD have distinct patterns of regional atrophy on magnetic resonance imaging (MRI). DESIGN: Retrospective case study. SETTING: The Institute of Neurology, University College London, and the Institute of Psychiatry, King's College London. Patients Twenty-one cases of FTD selected on pathologic grounds (9 with ubiquitin-positive [tau- and alpha-synuclein-negative] inclusions [FTD-U], 7 with Pick disease [PiD], and 5 with familial FTD with tau exon 10+16 mutations [tau exon 10+16]) and 20 healthy controls were studied. MAIN OUTCOME MEASURES: Patterns of gray matter atrophy in each group as assessed by voxel-based morphometry (VBM) and a blinded visual assessment of each MRI study. RESULTS: All pathologic substrates were associated with atrophy that involved the inferior and medial temporal and inferior frontal lobes. Additionally, specific VBM signatures were identified for each subgroup: FTD-U was associated with asymmetric (left > right) temporal lobe atrophy, PiD was associated with severe dorsolateral bifrontal atrophy, and tau exon 10+16 was associated with asymmetric (right > left) medial temporal lobe atrophy. The VBM findings were supported by blinded visual assessment. CONCLUSION: These findings suggest that MRI patterns of regional gray matter atrophy constitute signatures of tissue pathology in FTD.

Rheumatoid arthritis of the cervical spine: current techniques for management.

The incidence of rheumatoid arthritis in the European and North American population is significant. Rheumatoid arthritis can result in serious damage to the cervical spine and the central neuraxis, ranging from mild instability to myelopathy and death. Aggressive conservative care should be established early. The treating physician should not be lulled into a false sense of security by reports suggesting that cervical subluxations are typically asymptomatic [76-78]. Gradual spinal cord compression can result in severe neurologic deficits that may be irreversible despite appropriate surgical intervention when applied too late. [figure: see text] The treatment of rheumatoid disease in the cervical spine is challenging. Many details must be considered when diagnosing and attempting to institute a treatment plan, particularly surgical treatment. The pathomechanics may result in either instability or ankylosis. The superimposed deformities may be either fixed or mobile. The algorithm suggested by the authors can be used to navigate through the numerous details that must be considered to formulate a reasonable surgical plan. Although these patients are [figure: see text] frail, an "aggressive" surgical solution applied in a timely fashion yields better results than an incomplete or inappropriate surgical solution applied too late. When surgical intervention is anticipated, it should be performed before the development of severe myelopathy. Patients who progress to a Ranawat III-B status have a much higher morbidity and mortality rate associated with surgical intervention than do patients who ambulate. Although considered aggressive by some, "prophylactic" stabilization and fusion of a [figure: see text] relatively flexible, moderately deformed spine before the onset of severe neurologic symptoms may be reasonable. This approach ultimately may serve the patient better than "observation" if the patient is slowly drifting into a severe spinal deformity or shows signs of early myelopathy or paraparesis.

The dysmorphic cervical spine in Klippel-Feil syndrome: interpretations from developmental biology.

The authors conducted a study to identify radiological patterns of Klippel-Feil syndrome (KFS), and they present a new interpretation of the origin of these patterns based on recent advances in understanding of embryonic development of the spine and its molecular genetic control. The authors studied radiographs and computerized tomography (CT) scans as well as magnetic resonance images or CT myelograms obtained in 30 patients with KFS who were referred for treatment between 1982 and 1996; the patients had complained of various neuroorthopedic complications. Homeotic transformation due to mutations or disturbed expression of Hox genes is a possible mechanism responsible for C-1 assimilation, which was found to have occurred in 19 cases (63%). Notochordal defects and/or signaling problems, which result in reduced or impaired Pax-1 gene expression, may underlie vertebral fusions. This, together with asymmetrical distribution of paraxial mesoderm cells and a possible lack of communication across the embryonic midline, could cause asymmetrical fusion patterns, which were present in 17 cases (57%). The wide and flattened shape of the fused vertebral bodies and their resemblance to the embryonic cartilaginous vertebrae as well as the process of progressive bone fusion with age suggest that the fusions occur before or, at the latest, during chondrification of vertebrae. The authors suggest that the aforementioned mechanisms are likely to be, at least in part, responsible for the observed patterns in KFS that affect the craniovertebral junction and the cervical spine.

[Molecular genetic background of developmental bony malformations at the craniocervical junction and cervical spine]. / A nyaki gerinc és a craniocervicalis átmenet csontos-fúziós fejlódési rendellenességeinek molekuláris genetikai háttere.

In this review a new interpretation of the origin of bony developmental malformations affecting the craniocervical junction and the cervical spine is presented based on recent advances in the understanding of embryonic development of the spine and its molecular genetic control. Radiographs, CT and MRI scans or CT myelograms of patients with Klippel-Feil syndrome were used for demonstration. Detailed clinical and radiological analysis of these patients was published earlier [David KM, Stevens JM, Thorogood P, Crockard HA. The dysmorphic cervical spine in Klippel-Feil syndrome: interpretations from developmental biology. Neurosurg Focus 1999;6(6):1.]. Homeotic transformation due to mutations or disturbed expression of Hox genes is a possible mechanism responsible for Cl assimilation. Notochordal defects and/or signalling problems, that result in reduced or impaired Pax-1 gene expression, may underlie vertebral fusions. This, together with asymmetrical distribution of paraxial mesoderm cells and a possible lack of communication across the embryonic mid-line, could cause the asymmetrical fusion patterns. The wide and flattened shape of the fused vertebral bodies, their resemblance to the embryonic cartilaginous vertebrae and the process of progressive bony fusion with age suggest that the fusions occur before or, at the latest, during chondrification of vertebrae. The authors suggest that the aforementioned mechanisms are likely to be, at least in part, responsible for the origin of the bony developmental malformations affecting the craniocervical junction and the cervical spine.

How do providers prioritize prevention? A qualitative study.

BACKGROUND: Preventive care is an essential element of comprehensive primary care medicine, yet many providers do not address the full range of recommended preventive care services. There is little understanding of how, during time-constrained clinical encounters, providers prioritize preventive care services. OBJECTIVES: To identify and compare how Department of Veterans Affairs (VA) primary care providers (PCPs) prioritized general preventive care services, including HIV testing. STUDY DESIGN: A semistructured, qualitative interview design. METHODS: We conducted semistructured phone interviews with 31 PCPs across 2 urban VA facilities. Interviews entailed questions about the most common preventive care services in primary care, how decisions are made to address some preventive care services but not others, and the role of clinical reminders (CRs) in prioritizing care. Interviews were audio-recorded and transcribed verbatim. We conducted an iterative thematic analysis of interview transcripts, utilizing NVivo 8, a qualitative data management and coding software. RESULTS: Most PCPs indicated they did not utilize CRs as a primary means of prioritizing general preventive care. Instead, PCPs prioritized general preventive care by attending to patients' individual needs and/or keeping in mind influential clinical training experiences. Prioritizing HIV testing included 1 or a combination of the following strategies: being attuned to HIV risk factors prior to the appearance of the CR, being prompted by the CR, and having a positive attitude toward CR design. CONCLUSIONS: Prioritizing preventive care can be accomplished using various strategies, including CRs. Healthcare systems might benefit from encouraging PCPs to use a range of strategies.

Association of abnormal ovarian reserve parameters with a higher incidence of aneuploid blastocysts.

OBJECTIVE: To estimate the relationship between hormonal parameters of diminished ovarian reserve and the incidence of aneuploid blastocysts. METHODS: This prospective cohort trial was performed in a private in vitro fertilization clinic. Three hundred seventy-two patients underwent in vitro fertilization with blastocyst biopsy and aneuploidy screening of all 23 chromosome pairs. Patients were divided into groups based on baseline hormonal ovarian reserve. Group 1 included normal ovarian reserve (n=279) and group 2 included diminished ovarian reserve with day 2 or 3 follicle-stimulating hormone (FSH) more than 10 milli-international units/mL, antimüllerian hormone 1 ng/mL or less (n=93), or both. Patients with diminished ovarian reserves were further subdivided into three groups. Group A included FSH more than 10 milli-international units and antimüllerian hormone 1 ng/mL or less (n=25); group B included FSH more than 10 milli-international units/mL and antimüllerian hormone more than 1 ng/mL (n=34); and group C included antimüllerian hormone 1 ng/mL or less and day 3 FSH less than 10 milli-international units/L (n=34). RESULTS: Group 2 (diminished ovarian reserve) had a higher percentage of aneuploid blastocysts (66% compared with 51.7%; P<.05) and all aneuploid blastocyst cycles (35.1% compared with 14.3%; P<.001) than group 1 (normal ovarian reserve). However, implantation rates after transfer of euploid blastocysts were similar (69% compared with 61.7%; not significant). The highest percentage of aneuploid blastocysts among diminished ovarian reserve patients was in group A (abnormal FSH and antimüllerian hormone) compared with groups B and C (77.2% compared with 58.5% compared with 58.8%; P<.05). Implantation rates also were no different among the diminished ovarian reserve subgroups (68% compared with 71% compared with 66.7%; not significant). CONCLUSIONS: Infertility patients with hormonal evidence of diminished ovarian reserve have a significantly higher percentage of aneuploid blastocysts. The combination of abnormal serum FSH and antimüllerian hormone correlated with the greatest rate of embryonic aneuploidy. Regardless of ovarian reserve parameters, transfer of euploid blastocysts resulted in equivalent implantation potential. LEVEL OF EVIDENCE: II.

Live birth outcome with trophectoderm biopsy, blastocyst vitrification, and single-nucleotide polymorphism microarray-based comprehensive chromosome screening in infertile patients.

The combination of trophectoderm biopsy, blastocyst vitrification, and single-nucleotide polymorphism microarray-based technology for comprehensive chromosome screening results in high implantation and live birth rates that could contribute to the practical application of single embryo transfer for infertility patients.

Management of poor responders: can outcomes be improved with a novel gonadotropin-releasing hormone antagonist/letrozole protocol?

OBJECTIVE: To compare the efficacy of a microdose GnRH agonist flare (ML) with a GnRH antagonist/letrozole (AL) protocol before IVF-ET in poor responders. DESIGN: Prospective controlled trial. SETTING: Private assisted reproductive technology center. PATIENT(S): Five hundred thirty-four infertile women classified as past or potential poor responders based on clinic-specific criteria. INTERVENTION(S): Poor responders were prospectively assigned to an ML or AL protocol in a 2:1 ratio, respectively. MAIN OUTCOME MEASURE(S): Results of controlled ovarian hyperstimulation and implantation and ongoing pregnancy rates. RESULT(S): Patient characteristics were similar between the two protocol groups. There were no significant differences in mean age, number of oocytes, fertilization rates, number of embryos transferred, or embryo score. Peak E(2) levels were significantly lower in the AL group. Ongoing pregnancy rates were significantly higher in the ML group (52% vs. 37%). Trends toward increased implantation and lower cancellation rates were also noted, but these did not reach statistical significance. CONCLUSION(S): Quantitative results of stimulation between the ML and AL protocols were equivalent with the exception of peak E(2) levels. However, the higher ongoing pregnancy rates and trend toward superior implantation rates would suggest that ML represents a preferred approach for the poor responder. An increased sample size would be necessary to verify these findings.

Parietal lobe deficits in frontotemporal lobar degeneration caused by a mutation in the progranulin gene.

OBJECTIVE: To describe the clinical, neuropsychologic, and radiologic features of a family with a C31LfsX35 mutation in the progranulin gene CCDS11483.1). DESIGN: Case series. PATIENTS: A large British kindred (DRC255) with a PGRN mutation was assessed. Affected individuals presented with a mean age of 57.8 years (range, 54-67 years) and a mean disease duration of 6.1 years (range, 2-11 years). RESULTS: All patients exhibited a clinical and radiologic phenotype compatible with frontotemporal lobar degeneration based on current consensus criteria. However, unlike sporadic frontotemporal lobar degeneration, parietal deficits, consisting of dyscalculia, visuoperceptual /visuospatial dysfunction, and/or limb apraxia, were a common feature, and brain imaging showed posterior extension of frontotemporal atrophy to involve the parietal lobes. Other common clinical features included language output impairment with either dynamic aphasia or nonfluent aphasia and a behavioral syndrome dominated by apathy. CONCLUSION: We suggest that parietal deficits may be a prominent feature of PGRN mutations and that these deficits may be caused by disruption of frontoparietal functional pathways.

Role of SOX2 mutations in human hippocampal malformations and epilepsy.

PURPOSE: Seizures are noted in a significant proportion of cases of de novo, heterozygous, loss-of-function mutations in SOX2, ascertained because of severe bilateral eye malformations. We wished to determine the underlying cerebral phenotype in SOX2 mutation and to test the candidacy of SOX2 as a gene contributing to human epilepsies. METHODS: We examined high-resolution MRI scans in four patients with SOX2 mutations, two of whom had seizures. We determined the Sox2 expression pattern in developing murine brain. We searched for SOX2 mutation in 24 patients with typical hippocampal sclerosis and for common variations in SOX2 in 655 patients without eye disease but with epilepsy, including 91 patients with febrile seizures, 93 with hippocampal sclerosis, and 258 with temporal lobe epilepsy. RESULTS: Striking hippocampal and parahippocampal malformations were seen in all cases, with a history of febrile seizures or epilepsy in two of four cases. The Sox2 expression pattern in developing mouse brain supports the pattern of malformations observed. Mutation screening in patients with epilepsy did not reveal any abnormalities in SOX2. No associations were found between any clinical epilepsy phenotype and common variation in SOX2. CONCLUSIONS: SOX2 haploinsufficiency causes mesial temporal malformation in humans, making SOX2 dysfunction a candidate mechanism for mesial temporal abnormalities associated with chronic epilepsy. However, although mutation of SOX2 in humans causes hippocampal malformation, SOX2 mutation or variation is unlikely to contribute commonly to mesial temporal lobe epilepsy or its structural (hippocampal sclerosis) or historic (febrile seizures) associations in humans.

Effect of myomectomy on the outcome of assisted reproductive technologies.

OBJECTIVE: To evaluate the impact of myomectomy on in vitro fertilization-embryo transfer (IVF-ET) and oocyte donation cycle outcome. DESIGN: Retrospective case-controlled study of consecutive fresh IVF-ET and oocyte donation patients during a 2-year interval. SETTING: Private assisted reproductive technology (ART) center. PATIENT(S): Patients with submucosal leiomyomata resected hysteroscopically (group A: 15 oocyte donor recipients; group 1 = 31 IVF-ET patients) and those with intramural components or strictly intramural leiomyomata that distorted or impinged upon the endometrial cavity resected at laparotomy (group B = 26 oocyte donor recipients; group 2 = 29 IVF-ET patients). INTERVENTION(S): Precycle hysteroscopic or abdominal myomectomy and subsequent fresh IVF-ET or oocyte donation. MAIN OUTCOME MEASURE(S): Results of controlled ovarian hyperstimulation as well as ongoing pregnancy and implantation rates were evaluated in comparison with contemporaneous patient groups without such lesions (group C = 552 oocyte donor recipients; group 3: 896 IVF-ET patients). RESULT(S): As would be expected, the mean number and size of leiomyomata were significantly larger in patients who underwent abdominal myomectomy. However, neither ongoing pregnancy nor implantation rates were significantly different in comparison with controls among either oocyte donor recipients (group A: 86.7%, 57.8%; group B: 84.6%, 55.2%; group C 77%, 49.1%). The findings were similar for those undergoing IVF-ET in comparison with controls (group 1: 61%, 24%; group 2: 52%, 26%; group 3: 53%, 23%). CONCLUSION(S): Precycle resection of appropriately selected clinically significant leiomyomata results in IVF-ET or oocyte donation cycle outcomes that are similar to controls.

Histology of the craniocervical junction in chronic rheumatoid arthritis: a clinicopathologic analysis of 33 operative cases.

STUDY DESIGN: A histologic review of surgical specimens with clinical and radiographic correlations. OBJECTIVE: To analyze the histopathology at the craniocervical junction in chronic rheumatoid arthritis (RA). SUMMARY OF BACKGROUND DATA: It has been assumed that the tissue identified on radiography at the craniocervical junction causing anterior spinal cord compression in patients with chronic RA is hypertrophic rheumatoid synovium. To date, no study has positively identified the histology of this tissue. METHODS: Transoral resection of the dens and spinal cord decompression were performed in 33 myelopathic rheumatoid patients with craniocervical instability. The resected specimens were examined histologically. RESULTS: Two unique histologic patterns were identified. Type I synovium has a recognizable synovial structure but without a hyperplastic synovial layer, significant inflammatory cell population, or lymphocytic infiltration typical of early active rheumatoid synovium. Type II synovium is a bland, fibrous, hypercellular tissue that is hypovascular, with little synovium and few inflammatory cells. Clinically and radiologically the two groups are distinct. Patients with Type II synovium are older ( = 0.008) and present with more advanced neurologic involvement caused by spinal cord compression ( = 0.0001). The mean difference in the spinal cord area between the two groups was 20.6 mm (95% confidence interval, 10.0-31.2 mm; = 0.004). CONCLUSIONS: The histologic specimens suggest that ligamentous destruction is followed by replacement of the rheumatoid synovium with fibrous tissue, whereas the osseous structures reveal severe destruction secondary to mechanical instability, rather than to an acute inflammatory process. Early, preemptive surgical intervention may prevent the development of spinal cord injury caused by instability.

Mapping the evolution of regional atrophy in Alzheimer's disease: unbiased analysis of fluid-registered serial MRI.

Alzheimer's disease (AD) is characterized by progressive cerebral atrophy, which may be assessed by using volumetric MRI. We describe a voxel-based analysis of nonlinear-registered serial MRI to demonstrate the most statistically significant (P < 0.001) regions of change at different stages of the disease. We compared presymptomatic (n = 4), mild (n = 10), and moderately affected (n = 12) patients with early- and late-onset AD, with age- and sex-matched controls, and demonstrated increasing global atrophy with advancing disease. Significantly increased rates of hippocampal atrophy were seen in presymptomatic and mildly affected patients. There was a shift in the distribution of temporal lobe atrophy with advancing disease; the inferolateral regions of the temporal lobes showed the most significantly increased rates of atrophy by the time the patients were mildly or moderately affected. Significantly increased rates of medial parietal lobe atrophy were seen at all stages, with frontal lobe involvement occurring later in the disease. Our results suggest that the sites showing the most significant rates of atrophy alter as the disease advances, and that regional atrophy is already occurring before the onset of symptoms. This technique provides insights into the natural history of AD, and may be a valuable tool in assessing the efficacy of disease-modifying treatments, especially if these treatments were to have region-specific effects.

Polymicrogyria and absence of pineal gland due to PAX6 mutation.

Identification of genes involved in human cerebral development is important for our understanding of disorders with potential neurodevelopmental causes such as epilepsy and learning disability. Murine models suggest that PAX6 plays a key role in human brain development. With magnetic resonance imaging in 24 humans heterozygous for defined PAX6 mutations, we demonstrated widespread structural abnormalities including absence of the pineal gland and unilateral polymicrogyria.