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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 sexmatched 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.

The hippocampal formation (HF) is known from pathological and MRI studies to be severely atrophied in established Alzheimer's disease. However, it is unclear when the earliest changes in the HF occur. We performed a longitudinal study of asymptomatic individuals at risk of autosomal dominant familial Alzheimer's disease in order to assess presymptomatic changes in the HF. Seven at risk members of a familial Alzheimer's disease pedigree associated with the amyloid precursor protein 717 valine to glycine mutation underwent serial MR scanning and neuropsychological assessments over 3 years. These assessments were compared with results from 38 normal controls. During the study three at risk subjects became clinically affected. Volumetric measurement of the HF showed that asymmetrical atrophy developed in these subjects before the appearance of symptoms. Verbal and visual memory measures declined in parallel with hippocampal loss. A loss of up to 8% per annum of the volume of the HF occurred in the 2 years over which symptoms first appeared. These findings may have implications for early diagnosis of Alzheimer's disease.

Volumetric magnetic resonance imaging analyses of 30 subjects were undertaken to quantify the global and temporal lobe atrophy in semantic dementia and Alzheimer's disease. Three groups of 10 subjects were studied: semantic dementia patients, Alzheimer's disease patients, and control subjects. The temporal lobe structures measured were the amygdala, hippocampus, entorhinal cortex, parahippocampal gyrus, fusiform gyrus, and superior, middle, and inferior temporal gyri. Semantic dementia and Alzheimer's disease groups did not differ significantly on global atrophy measures. In semantic dementia, there was asymmetrical temporal lobe atrophy, with greater left-sided damage. There was an anteroposterior gradient in the distribution of temporal lobe atrophy, with more marked atrophy anteriorly. All left anterior temporal lobe structures were affected in semantic dementia, with the entorhinal cortex, amygdala, middle and inferior temporal gyri, and fusiform gyrus the most severely damaged. Asymmetrical, predominantly anterior hippocampal atrophy was also present. In Alzheimer's disease, there was symmetrical atrophy of the entorhinal cortex, hippocampus, and amygdala, with no evidence of an anteroposterior gradient in the distribution of temporal lobe or hippocampal atrophy. These data demonstrate that there is a marked difference in the distribution of temporal lobe atrophy in semantic dementia and Alzheimer's disease. In addition, the pattern of atrophy in semantic dementia suggests that semantic memory is subserved by anterior temporal lobe structures, within which the middle and inferior temporal gyri may play a key role.

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.

The effectiveness of blastocyst culture and transfer in human in-vitro fertilization (IVF) was evaluated in a prospective randomized trial in patients having a moderate to good response to gonadotrophin stimulation. Embryos were transferred either on day 3 after culture to around the 8-cell stage in Ham's F-10 medium supplemented with fetal cord serum, or on day 5 after culture to the blastocyst stage in the sequential serum-free media G 1.2 and G 2.2. The pregnancy rates after transfer on day 3 or day 5 were equivalent, 66 and 71% respectively; however, significantly more embryos were transferred on day 3 (3.7) than on day 5 (2.2). The number of blastocysts transferred did not affect the implantation rate, and pregnancy rates when either two or three blastocysts were transferred were 68 and 87% respectively. The implantation rate of the blastocysts (50.5% fetal heart beat) was significantly higher compared to the cleavage stage embryos transferred on day 3 (30.1%). The percentage of blastocyst development was not affected by the number of 2-pronuclear embryos, or by maternal age. Irrespective of the number of blastocysts formed, pregnancy rates were similar. Furthermore, the pregnancy rate following blastocyst transfer in patients with 10 or more follicles at the time of human chorionic gonadotrophin administration was not affected by patient age. More than 60% of patients having blastocyst culture and transfer had supernumerary embryos for cryopreservation. The establishment of a pregnancy following thaw and transfer confirmed the viability of cryopreserved blastocysts cultured in the absence of serum or co-culture. The ability to transfer just two blastocysts while maintaining high pregnancy rates will therefore help to eliminate high order multiple gestations and improve the overall efficiency of human IVF.

Cerebral cortical dysgenesis (CD) is a heterogeneous disorder of cortical development and organization commonly associated with epilepsy, with a variety of subtypes. We reviewed the clinical, EEG and neuroimaging features in 100 adult patients with CD. There were 39 men and 61 women with a median age of 27 years (range 15-63 years). All patients were referred because of medically refractory epilepsy. Median age at seizure onset was 10 years (range 3 weeks to 39 years); in 30 patients, onset was in adulthood. The epilepsy was classified as generalized in 16 patients and localization-related in 84. Of the latter, the epileptic syndromes in decreasing frequency were frontal (32%), temporal (31%), parietal (14%) and occipital (7%). Only 15% of patients had a history of status epilepticus. Prenatal/perinatal problems were reported in 32 patients but these were severe in only four: exposure to drugs (three) and infection (one) during the first trimester. Delayed developmental milestones were seen in 10%, mental retardation in 9%, additional congenital abnormalities in 4% and neurological deficits in 14% of patients. Diagnosis of CD was based on neuroimaging in 70, pathology in four and both methods in the remaining 26. The following subcategories were identified: agyria/diffuse macrogyria (four patients), focal macrogyria (16), focal polymicrogyria (one), focal macrogyria/polymicrogyria associated with a cleft (11), minor gyral abnormalities (seven), subependymal grey matter heterotopia (20), bilateral subcortical laminar grey matter heterotopia (eight), tuberous sclerosis (five), focal cortical dysplasia/microdysgenesis (seven) and dysembryoplastic neuroepithelial tumours (DNT) (21). Sixty-eight percent of patients had normal CT and 19 out of 36 patients had normal previous conventional MRI. MRI-based hippocampal volume measurements in 47 patients revealed ratios (smaller: larger hippocampus) of < 0.90 in 16, 0.90-0.94 in 14 and > or = 0.95 in 17 patients. EEGs were normal in only five patients. Alpha rhythm was preserved in 78 patients, including one patient with bilateral posterior macrogyria. Localized polymorphic slow activity was present in 43 patients. Five of 68 patients with focal/unilateral CD had only bilateral independent/synchronous spiking and 14 out of 32 with diffuse/bilateral CD only focal/unilateral spiking. In 60 patients with nondiffuse CD or with abnormal gyration or DNT, the epileptiform abnormalities were less extensive than coextensive with the lesion in 28, more extensive than and overlapped the lesion in 18 and remote from the lesion in five; nine patients did not have epileptiform abnormalities. There was poor correlation between the epileptic syndromes and EEG abnormalities and the location/extent of CD as defined by MRI and pathology.(ABSTRACT TRUNCATED AT 400 WORDS)

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