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PubMed2004

The application of serial MRI analysis techniques to the study of cerebral atrophy in late-onset dementia.

We have used a serial MR image analysis technique previously developed for studies of cerebral atrophy in early-onset dementia and applied it to a study of late-onset dementia patients with images acquired using a different scanner and scan sequence. Validation and optimisation tests showed that with only small changes to key analysis parameters the technique can successfully be applied to previously untested data with dissimilar image characteristics. The overall accuracy in estimation of cerebral atrophy using the technique was determined to be between 2 and 4 ml (1sigma) depending on the conditions during image acquisition. By comparing the results of alternative registration techniques we demonstrate the potential of using of fully automated 9 DOF image registration as an effective and efficient means of correcting for scanner pixel size variations, even in the presence of significant cerebral atrophy. Applied to the late-onset dementia study, patients were found to have significantly increased mean atrophy rates (p<0.001) compared to controls. In general the analysis technique is shown to be a robust, accurate and transferable tool of potential value for future studies of dementia and related neuro-degenerative disorders.

Adult↗

PubMed2005

Age effects on atrophy rates of entorhinal cortex and hippocampus.

The effects of age, subcortical vascular disease, apolipoprotein E (APOE) epsilon4 allele and hypertension on entorhinal cortex (ERC) and hippocampal atrophy rates were explored in a longitudinal MRI study with 42 cognitively normal (CN) elderly subjects from 58 to 87 years old. The volumes of the ERC, hippocampus, and white matter hyperintensities (WMH) and the presence of lacunes were assessed on MR images. Age was significantly associated with increased atrophy rates of 0.04+/-0.02% per year for ERC and 0.05+/-0.02% per year for hippocampus. Atrophy rates of hippocampus, but not that of ERC increased with presence of lacunes, in addition to age. WMH, APOE epsilon4 and hypertension had no significant effect on atrophy rates. In conclusion, age and presence of lacunes should be taken into consideration in imaging studies of CN subjects and AD patients to predict AD progression and assess the response to treatment trials.

Aged↗

PubMed2006

Clinical significance of corpus callosum atrophy in a mixed elderly population.

Corpus callosum (CC) is the main tract connecting the hemispheres, but the clinical significance of CC atrophy is poorly understood. The aim of this work was to investigate clinical and functional correlates of CC atrophy in subjects with age-related white matter changes (ARWMC). In 569 elderly subjects with ARWMC from the Leukoaraiosis And DISability (LADIS) study, the CC was segmented on the normalised mid-sagittal magnetic resonance imaging (MRI) slice and subdivided into five regions. Correlations between the CC areas and subjective memory complaints, mini mental state examination (MMSE) score, history of depression, geriatric depression scale (GDS) score, subjective gait difficulty, history of falls, walking speed, and total score on the short physical performance battery (SPPB) were analyzed. Significant correlations between CC atrophy and MMSE, SPPB, and walking speed were identified, and the CC areas were smaller in subjects with subjective gait difficulty. The correlations remained significant after correction for ARWMC grade. In conclusion, CC atrophy was independently associated with impaired global cognitive and motor function in subjects with ARWMC.

Age Factors↗

PubMed2004

An automated algorithm for the computation of brain volume change from sequential MRIs using an iterative principal component analysis and its evaluation for the assessment of whole-brain atrophy rates in patients with probable Alzheimer's disease.

This article introduces an automated method for the computation of changes in brain volume from sequential magnetic resonance images (MRIs) using an iterative principal component analysis (IPCA) and demonstrates its ability to characterize whole-brain atrophy rates in patients with Alzheimer's disease (AD). The IPCA considers the voxel intensity pairs from coregistered MRIs and identifies those pairs a sufficiently large distance away from the iteratively determined PCA major axis. Analyses of simulated and real MRI data support the underlying assumption of a linear relationship in paired voxel intensities, identify an outlier distance threshold that optimizes the trade-off between sensitivity and specificity in the detection of small volume changes while accounting for global intensity changes, and demonstrate an ability to detect changes as small as 0.04% of brain volume without confounding effects of between-scan shifts in voxel intensity. In eight patients with probable AD and eight age-matched normal control subjects, the IPCA was comparable to the established but partly manual digital subtraction (DS) method in characterizing annual rates of whole-brain atrophy: resulting rates were correlated (Spearman rank correlation = 0.94, P < 0.0005) and comparable in distinguishing probable AD from normal aging (IPCA-detected atrophy rates: 2.17 +/- 0.52% per year in the patients vs. 0.41 +/- 0.22% per year in the controls [Wilcoxon-Mann-Whitney test P = 7.8 x 10(-4)]; DS-detected atrophy rates: 3.51 +/- 1.31% per year in the patients vs. 0.48 +/- 0.29% per year in the controls [P = 7.8 x 10(-4)]). The IPCA could be used in tracking the progression of AD, evaluating the disease-modifying effects of putative treatments, and investigating the course of other normal and pathological changes in brain morphology.

Aged↗

PubMed2004

Grey and white matter atrophy in early clinical stages of primary progressive multiple sclerosis.

BACKGROUND: There is little information available on grey and white matter (GM and WM) atrophy in primary progressive multiple sclerosis (PPMS) and on their relationships with clinical and other magnetic resonance imaging (MRI) measures. AIM: To evaluate disease progression in the early phase of PPMS, focusing on axonal loss as assessed by volumetric MRI measures of WM and GM, and to determine their relationships with clinical outcomes and lesion load measures. METHODS: Forty-three patients with PPMS within 5 years of symptom onset and 45 control subjects were studied. Three-dimensional brain scans were acquired and segmented into WM, GM, and cerebrospinal fluid (CSF) using SPM99. Brain parenchymal (BPF), WM (WMF), and GM fractions (GMF) normalized against total intracranial volumes were estimated. T2-weighted (T2) and enhancing lesion loads were also determined. Expanded Disability Status Scale (EDSS) and Multiple Sclerosis Functional Composite (MSFC) scores were recorded in all patients. RESULTS: There were significant differences between patients and controls in BPF, WMF, and GMF values (P < 0.001). BPF (r = -0.469; P = 0.002) and WMF (r = -0.532; P < 0.001) but not GMF (r = -0.195; P = 0.2) correlated with EDSS scores. BPF (r = 0.518; P = 0.001), WMF (r = 0.483; P = 0.001), and GMF (r = 0.337; P = 0.031) correlated with MSFC scores. Correlations with enhancing lesion and T2 loads were only significant for BPF and WMF. CONCLUSIONS: Brain atrophy is seen in the early stages of PPMS and affects both GM and WM. WM atrophy appears more closely related to clinical outcome and WM focal damage than GM atrophy in this patient group.

Adult↗

PubMed2006

3D pattern of brain atrophy in HIV/AIDS visualized using tensor-based morphometry.

UNLABELLED: 35% of HIV-infected patients have cognitive impairment, but the profile of HIV-induced brain damage is still not well understood. Here we used tensor-based morphometry (TBM) to visualize brain deficits and clinical/anatomical correlations in HIV/AIDS. To perform TBM, we developed a new MRI-based analysis technique that uses fluid image warping, and a new alpha-entropy-based information-theoretic measure of image correspondence, called the Jensen-Rényi divergence (JRD). METHODS: 3D T1-weighted brain MRIs of 26 AIDS patients (CDC stage C and/or 3 without HIV-associated dementia; 47.2+/-9.8 years; 25M/1F; CD4+ T-cell count: 299.5+/-175.7/microl; log10 plasma viral load: 2.57+/- 1.28 RNA copies/ml) and 14 HIV-seronegative controls (37.6+/-12.2 years; 8M/6F) were fluidly registered by applying forces throughout each deforming image to maximize the JRD between it and a target image (from a control subject). The 3D fluid registration was regularized using the linearized Cauchy-Navier operator. Fine-scale volumetric differences between diagnostic groups were mapped. Regions were identified where brain atrophy correlated with clinical measures. RESULTS: Severe atrophy ( approximately 15-20% deficit) was detected bilaterally in the primary and association sensorimotor areas. Atrophy of these regions, particularly in the white matter, correlated with cognitive impairment (P = 0.033) and CD4+ T-lymphocyte depletion (P = 0.005). CONCLUSION: TBM facilitates 3D visualization of AIDS neuropathology in living patients scanned with MRI. Severe atrophy in frontoparietal and striatal areas may underlie early cognitive dysfunction in AIDS patients, and may signal the imminent onset of AIDS dementia complex.

Acquired Immunodeficiency Syndrome↗

PubMed2005

Insulin-like growth factor I slows the rate of denervation induced skeletal muscle atrophy.

Loss of the nerve supply to skeletal muscle results in a relentless loss of muscle mass (atrophy) over time. The ability of insulin-like growth factor-1 to reduce atrophy resulting from denervation was examined after transection of the sciatic nerve in transgenic MLC/mIGF-1 mice that over-express mIGF-1 specifically in differentiated myofibres. The cross sectional area (CSA) of all types of myofibres and specifically type IIB myofibres was measured in tibialis anterior muscles from transgenic and wild-type mice at 28 days after denervation. There was a marked myofibre atrophy ( approximately 60%) in the muscles of wild-type mice over this time with increased numbers of myofibres with small CSA. In the muscles of MLC/mIGF-1 mice, over-expression of mIGF-1 reduced the rate of denervation induced myofibre atrophy by approximately 30% and preserved myofibres with larger CSA, compared to wild-type muscles. It is proposed that the protective effect of mIGF-1 on denervated myofibres might be due to reduced protein breakdown.

Animals↗

PubMed2006

A modified Hammersmith functional motor scale for use in multi-center research on spinal muscular atrophy.

The Hammersmith functional motor scale for children with spinal muscular atrophy was modified to establish a standard measure of functional ability in children with non-ambulant spinal muscular atrophy types 2 and 3 in a longitudinal multi-center clinical trial. This study assessed the intra- and interrater reliability and the test-retest stability of a modified version of the scale. Both intra- and interrater reliability were established. Results indicate that the scale is reliable and stable over a 6 month period. Reliability was maintained when patient sample criteria were expanded to include children younger than 30 months and children with popliteal angles greater than 20 degrees . These data establish the modified Hammersmith functional motor scale for children with spinal muscular atrophy as a reliable instrument for use in multi-center treatment trials in non-ambulant spinal muscular atrophy children. Our data provides additional support for the use of original scale items in terms of ease of administration, usefulness and reliability, while incorporating modifications to optimize its use in a multi-center clinical research setting.

Child, Preschool↗

PubMed2006

Atypical presentations of spinal muscular atrophy type III (Kugelberg-Welander disease).

Spinal muscular atrophy type III (SMA III, Kugelberg-Welander disease) typically presents with symmetric proximal weakness, areflexia, and hypotonia. We present four children with spinal muscular atrophy type III who had atypical phenotypes. Three patients clearly had asymmetric weakness at presentation and two had upper motor neuron signs in the lower extremities (one patient had both features). Two of the patients had prolonged evaluations before the diagnosis was made. All patients had Gowers signs and two had pes planus. In patients with proximal muscle weakness the presence of asymmetrical weakness, upper motor neuron signs, or both, may be compatible with spinal muscular atrophy type III. The diagnosis of spinal muscular atrophy should be considered when other possibilities have been excluded.

Brain↗

PubMed2006

Therapeutics development for spinal muscular atrophy.

Spinal muscular atrophy is an autosomal recessive motor neuron disease that is the leading inherited cause of infant and early childhood mortality. Spinal muscular atrophy is caused by mutation of the telomeric copy of the survival motor neuron gene (SMN1), but all patients retain a centromeric copy of the gene, SMN2. SMN2 produces reduced amounts of full-length SMN mRNA, and spinal muscular atrophy likely results from insufficient levels of SMN protein in motor neurons. The SMN protein plays a well-established role in assembly of the spliceosome and may also mediate mRNA trafficking in the axon and nerve terminus of neurons. In patients, spinal muscular atrophy disease severity correlates inversely with increased SMN2 gene copy number and, in transgenic mice lacking endogenous SMN, increasing SMN2 gene copy number from two to eight prevents the SMA disease phenotype. These observations suggest that increasing SMN expression levels may be beneficial to SMA patients. Currently pursued therapeutic strategies for SMA include induction of SMN2 gene expression, modulation of splicing of SMN2-derived transcripts, stabilization of SMN protein, neuroprotection of SMN deficit neurons, and SMN1 gene replacement. Early clinical trials of candidate therapeutics are now ongoing in SMA patients. Clinical trials in this disease present a unique set of challenges, including the development of meaningful outcome measures and disease biomarkers.

Animals↗

PubMed2004

Comparison of magnetic resonance imaging in subtypes of multiple system atrophy.

Some abnormal findings in routine MRI have been proposed as helpful discriminators for distinguishing multiple system atrophy (MSA) from Parkinson's disease (PD). However, what the most distinguishing MRI findings for MSA-p (parkinsonism dominant) or MSA-c (cerebellar dominant) are separately has not been systematically analyzed. To determine what the most helpful discriminators for MSA-p or MSA-c are and whether those findings are correlated with the presence of parkinsonism or cerebellar dysfunction, we compared 10 previously reported MRI findings in 36 patients with probable MSA-p, 27 patients with probable MSA-c and 30 patients with PD separately. In our results, hyperintense rim and putaminal atrophy among supratentorial parameters and the parameters of infratentorial atrophy were significantly prominent in MSA-p comparing to PD. Hyperintense rim showed the highest specificity in MSA-p patients (90.0%) with relatively suboptimal sensitivity (72.2%). In MSA-c, all infratentorial parameters had strong discriminating power comparing to PD. Signal increase in the middle cerebellar peduncle showed the highest specificity (100%) and had fair sensitivity (85.2%) in MSA-c. Compared between MSA-p and MSA-c, supratentorial parameters were not valid to differentiate MSA-c from MSA-p except for putaminal atrophy. On the contrary, infratentorial parameters were good for distinguishing MSA-c from MSA-p except dilatation of the fourth ventricle. Parkinsonism was not correlated with a hyperintense rim, but cerebellar symptoms were correlated with signal increase in the middle cerebellar peduncle. Our findings suggest the characteristic MRI can be helpful for differentiating MSA-p and MSA-c from PD, respectively, although they do not reflect the presence or lateralization of parkinsonism.

Aged↗

PubMed2005

Rapidly progressive spinal muscular atrophy in an ambulatory 2-year-old male.

A 2-year 9-month-old male was referred for gait disturbances. Main complaints were abnormal gait with frequent falls observed as soon as he began to walk unaided, at 18 months of age. The first neurologic examination revealed symmetric and proximal weakness in the lower limbs with difficulty running and walking upstairs. Deep tendon reflexes were decreased, and generalized hypotonia was observed. Three months later, at 3 years of age, he had lost independent gait, and 1 month later he could not stand unaided. DNA analysis revealed homozygous deletion in exons 7 and 8 of SMN1 gene, confirming the diagnosis of spinal muscular atrophy. According to the current classification, this patient would be classified as spinal muscular atrophy type III. The distinctive feature of this case was the short time elapsed (18 months) between onset of spinal muscular atrophy and the age at which he lost ambulation. This patient reinforces the notion that late onset of symptoms in spinal muscular atrophy and acquisition of independent gait do not exclude a rapidly progressive motor deterioration, which is important when talking with families about outcome. In those rapidly progressive cases, when promptly available, testing for SMN1 gene will prevent unnecessary, invasive, or uncomfortable procedures such as lumbar puncture, electromyography, or spinal cord magnetic resonance imaging.

Child, Preschool↗

PubMed2005

Optic atrophies in metabolic disorders.

Optic nerve involvement in metabolic disorders often results from apoptosis of cells that form or support the optic nerve, the retinal ganglion cell (RGC) axons, the myelin-forming oligodendrocytes, or the supporting vascular system. Given their high energy demands and the long course of their axons, RGCs are particularly sensitive to intracellular metabolic defects. Defects in energy metabolism, formation of reactive oxygen species, and storage of metabolites can all cause apoptosis of RGCs, decreased myelin formation of oligodendrocytes and increased pressure on the optic nerve. Clinically, the loss of RGC axons manifests as pale optic nerves. In general, the ophthalmologist can identify the underlying cause of an optic atrophy by careful examination, neuro-imaging, and family history. In some cases, however, the diagnosis proves elusive. In these instances, and especially when optic atrophy is accompanied by other systemic involvement, a metabolic disorder should be considered. Here, we review the underlying mechanisms of optic atrophy and its significance in metabolic disorders. Early identification of optic atrophy aids the diagnosis and subsequent management of the underlying condition, including anticipation of symptoms, genetic counseling, and possible therapeutic interventions. For many metabolic disorders, molecular testing is available.

Humans↗

PubMed2001

Basic fibroblast growth factor inhibits choriocapillaris atrophy in rabbit.

PURPOSE: To examine the effect of basic fibroblast growth factor on induced choriocapillaris atrophy in vivo. METHODS: Choriocapillaris atrophy was surgically induced in rabbits by a hydraulic retinal detachment followed by debridement of the retinal pigment epithelium under the detached retina. Three concentrations of basic fibroblast growth factor (0.1 microg/0.1 ml, 1 microg/0.1 ml, or 5 microg/0.1 ml) were injected into the subretinal space and into the vitreous cavity 1, 3, and 5 days after the surgery. For control, only Tris buffer was injected in the same manner. The rabbits were euthanized 7 days after the surgery. Choroidal vascular casts were made and examined by scanning electron microscopy. The choriocapillaris atrophy was quantified by computer-assisted image analysis of photographs of the choriocapillaries. The area of the choriocapillaris and number of intercapillary spaces in the choriocapillaris that corresponded to the density of the capillary network were measured. RESULTS: The average area of the choriocapillaris in the eyes treated with 1 microg/0.1 ml of basic fibroblast growth factor was significantly larger at 75.1 +/- 3.0% than that in the control eyes at 67.2 +/- 5.6% (P =.021). The average area of the choriocapillaris in the 0.1 microg/0.1 ml of basic fibroblast growth factor group was not statistically different from the control. The number of intercapillary spaces of the choriocapillaris was 132 +/- 12 in the 0.1 microg/0.1 ml of basic fibroblast growth factor group, 124 +/- 46 in the 1 microg/0.1 ml of basic fibroblast growth factor group, and 75 +/- 14 in the control group. The higher number of spaces in the treated group was statistically significant (P =.026). CONCLUSIONS: Basic fibroblast growth factor decreased the atrophy of the choriocapillaris after removal of the retinal pigment epithelium in rabbit eyes. These results suggest that basic fibroblast growth factor may play a role in the survival of the choriocapillaris in vivo.

Animals↗

PubMed2003

Foveal congenital hypertrophy of the retinal pigment epithelium in the setting of geographic atrophy from age-related macular degeneration.

PURPOSE: To report a case of presumed congenital hypertrophy of the retinal pigment epithelium in the fovea of an 88-year-old woman in the setting of geographic atrophy from age-related macular degeneration. DESIGN: Observational case report. METHODS: An 88-year-old woman was examined. RESULTS: Best-corrected visual acuity was 20/63 in the right eye and 20/50 in the left eye. Multifocal areas of geographic atrophy and large-sized drusen were seen in the maculae of both eyes. Biomicroscopic examination of the right eye showed hyperpigmentation consistent with congenital hypertrophy of the retinal pigment epithelium through the center of the macula. No prior photographic documentation of the retina was available. CONCLUSION: This case suggests that foveal congenital hypertrophy of the retinal pigment epithelium may be seen in the setting of macular geographic atrophy. Although it is theoretically possible that the hyperpigmentation is reactive rather than congenital, the pigmentation is typical for congenital hypertrophy and is unlike any reactive pigmentation in our experience or described in a MEDLINE search of features of age-related macular degeneration. The case suggests that a hypertrophic process of the retinal pigment epithelium may coexist within or immediately adjacent to the anatomic boundaries of an atrophic process such as geographic atrophy from age-related macular degeneration.

Aged↗

PubMed2003

A novel RDH5 gene mutation in a patient with fundus albipunctatus presenting with macular atrophy and fading white dots.

PURPOSE: To report a novel homozygous RDH5 gene mutation in a 76-year-old fundus albipunctatus who developed macular atrophy with the disappearance of white dots. DESIGN: Observational case report. METHODS: Direct genomic sequencing for RDH5 mutations was done after complete ophthalmic examination. RESULTS: Fundoscopy revealed only macular atrophy with notable absence of white dots. A homozygous G490T (Val164Phe) missense RDH5 gene mutation was detected. CONCLUSIONS: This is the first reported long-term case of fundus albipunctatus demonstrating macular atrophy with fading of the typical white dots. Gene studies may be the only method for distinguishing fundus albipunctatus from other types of macular atrophy in the elderly.

Aged↗

PubMed2003

The association of autosomal dominant optic atrophy and moderate deafness may be due to the R445H mutation in the OPA1 gene.

PURPOSE: To examine the involvement of the optic atrophy 1 (OPA1) gene in optic atrophy associated with moderate deafness. DESIGN: Observational case report. The entire coding sequence of the OPA1 gene was directly sequenced in the case of a patient suffering from optic atrophy associated with moderate deafness. RESULTS: A de novo heterozygous mutation R445H in the OPA1 gene was found. No similar mutation was detected in either of the patient's parents or in the 100 chromosome controls. CONCLUSION: The R445H mutation in OPA1 might be the cause of the association between dominant optic atrophy and moderate deafness, a phenotype that may be currently underdiagnosed.

Adult↗

PubMed1993

Parapapillary chorioretinal atrophy in normal-pressure glaucoma.

Parapapillary chorioretinal atrophy has been shown to be associated with glaucomatous optic nerve damage. We sought to determine whether eyes with normal-pressure glaucoma have an unusually large parapapillary atrophy as compared to eyes with primary open-angle glaucoma. Color stereoscopic optic disk photographs of 34 patients with normal-pressure glaucoma and 283 patients with primary open-angle glaucoma were morphometrically analyzed. Both groups were matched for neuroretinal rim area and visual field loss. Severely myopic eyes were excluded. The parapapillary atrophy was differentiated into a peripheral Zone Alpha with irregular pigmentation and a central Zone Beta with visible sclera. Zones Alpha and Beta did not differ significantly between the two groups in either frequency or size. Eyes with normal-pressure glaucoma do not have an abnormally large parapapillary atrophy as compared to eyes with primary open-angle glaucoma, which is diagnostically and pathogenetically important.

Adult↗