Biomedical subjects

Jennifer L Whitwell

Publications and source records attributed to Jennifer L Whitwell.

18 recordsLinked to original sources

PubMed2006

Argyrophilic grains: a distinct disease or an additive pathology?

BACKGROUND: Argyrophilic grains (AG) are silver-positive spindle-shaped lesions found at postmortem. Their significance is controversial. OBJECTIVE: To determine clinical correlates of AG and MRI patterns of atrophy that could allow premortem recognition of this pathology. METHODS: Cases with AG were identified from a longitudinal study of aging and dementia. Clinical features were compared between subjects with and without dementia. Voxel-based morphometry (VBM) was used to assess patterns of grey matter atrophy in subjects compared to controls. Whole brain volumes (WBV) were compared across groups. RESULTS: Twenty-two cases (14 females; median age at death of 90 years; range: 70-101) with AG were identified. Eight of the 22 were demented. Those with dementia had higher Braak (p=0.02) and lower Mini-Mental State Examination (MMSE) (p=0.002). VBM demonstrated hippocampal atrophy in those with dementia (N=3) but no atrophy in those without (N=9). There was no difference in WBV between groups. CONCLUSION: AG is a feature of old age commonly occurring in non-demented subjects. In this age group, the presence of AG may reduce the threshold for dementia.

Aged↗

PubMed2006

Voxel-based morphometry in autopsy proven PSP and CBD.

The aim of this study was to compare the patterns of grey and white matter atrophy on MRI in autopsy confirmed progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD), and to determine whether the patterns vary depending on the clinical syndrome. Voxel-based morphometry was used to compare patterns of atrophy in 13 PSP and 11 CBD subjects and 24 controls. PSP and CBD subjects were also subdivided into those with a dominant dementia or extrapyramidal syndrome. PSP subjects showed brainstem atrophy with involvement of the cortex and underlying white matter. Frontoparietal grey and subcortical grey matter atrophy occurred in CBD. When subdivided, PSP subjects with an extrapyramidal syndrome had more brainstem atrophy and less cortical atrophy than CBD subjects with an extrapyramidal syndrome. PSP subjects with a dementia syndrome had more subcortical white matter atrophy than CBD subjects with a dementia syndrome. These results show regional differences between PSP and CBD that are useful in predicting the underlying pathology, and help to shed light on the in vivo distribution of regional atrophy in PSP and CBD.

Aged↗

PubMed2006

Imaging correlates of posterior cortical atrophy.

The aim of this study was to compare patterns of cerebral atrophy on MRI, and neurochemistry on magnetic resonance spectroscopy (MRS), in patients with posterior cortical atrophy (PCA) and typical Alzheimer's disease (AD). Voxel-based morphometry was used to assess grey matter atrophy in 38 patients with PCA, 38 patients with typical AD, and 38 controls. Clinical data was assessed in all PCA patients. Single voxel (1)H MRS located in the posterior cingulate was analyzed in a subset of patients with PCA, typical AD, and control subjects. PCA showed a pattern of atrophy affecting occipital, parietal and posterior temporal lobes, compared to controls. The pattern was bilateral, but more severe on the right. Patients with PCA showed greater atrophy in the right visual association cortex than patients with typical AD, whereas those with AD showed greater atrophy in the left hippocampus than those with PCA. (1)H MRS suggested loss of neuronal integrity and glial activation in subjects with PCA and typical AD. The differing patterns of atrophy on MRI suggest that PCA should be considered a distinct entity from typical AD.

Aged↗

PubMed2006

Clinicopathological and imaging correlates of progressive aphasia and apraxia of speech.

Apraxia of speech (AOS) is a motor speech disorder characterized by slow speaking rate, abnormal prosody and distorted sound substitutions, additions, repetitions and prolongations, sometimes accompanied by groping, and trial and error articulatory movements. Although AOS is frequently subsumed under the heading of aphasia, and indeed most often co-occurs with aphasia, it can be the predominant or even the sole manifestation of a degenerative neurological disease. In this study we determine whether the clinical classifications of aphasia and AOS correlated with pathological diagnoses and specific biochemical and anatomical structural abnormalities. Seventeen cases with initial diagnoses of a degenerative aphasia or AOS were re-classified independently by two speech-language pathologists--blinded to pathological and biochemical findings--into one of five operationally defined categories of aphasia and AOS. Pathological diagnoses in the 17 cases were progressive supranuclear palsy in 6, corticobasal degeneration in 5, frontotemporal lobar degeneration with ubiquitin-only-immunoreactive changes in 5 and Pick's disease in 1. Magnetic resonance imaging analysis using voxel-based morphometry (VBM), and single photon emission tomography were completed, blinded to the clinical diagnoses, and clinicoimaging and clinicopathological associations were then sought. Interjudge clinical classification reliability was 87% (kappa = 0.8) for all evaluations. Eleven cases had evidence of AOS, of which all (100%) had a pathological diagnosis characterized by underlying tau biochemistry, while five of the other six cases without AOS did not have tau biochemistry (P = 0.001). A majority of the 17 cases had more than one yearly evaluation, demonstrating the evolution of the speech and language syndromes, as well as motor signs. VBM revealed the premotor and supplemental motor cortices to be the main cortical regions associated with AOS, while the anterior peri-sylvian region was associated with non-fluent aphasia. Refining the classification of the degenerative aphasias and AOS may be necessary to improve our understanding of the relationships among behavioural, pathological and imaging correlations.

Aged↗

PubMed2006

Longitudinal stability of MRI for mapping brain change using tensor-based morphometry.

Measures of brain change can be computed from sequential MRI scans, providing valuable information on disease progression, e.g., for patient monitoring and drug trials. Tensor-based morphometry (TBM) creates maps of these brain changes, visualizing the 3D profile and rates of tissue growth or atrophy, but its sensitivity depends on the contrast and geometric stability of the images. As part of the Alzheimer's Disease Neuroimaging Initiative (ADNI), 17 normal elderly subjects were scanned twice (at a 2-week interval) with several 3D 1.5 T MRI pulse sequences: high and low flip angle SPGR/FLASH (from which Synthetic T1 images were generated), MP-RAGE, IR-SPGR (N = 10) and MEDIC (N = 7) scans. For each subject and scan type, a 3D deformation map aligned baseline and follow-up scans, computed with a nonlinear, inverse-consistent elastic registration algorithm. Voxelwise statistics, in ICBM stereotaxic space, visualized the profile of mean absolute change and its cross-subject variance; these maps were then compared using permutation testing. Image stability depended on: (1) the pulse sequence; (2) the transmit/receive coil type (birdcage versus phased array); (3) spatial distortion corrections (using MEDIC sequence information); (4) B1-field intensity inhomogeneity correction (using N3). SPGR/FLASH images acquired using a birdcage coil had least overall deviation. N3 correction reduced coil type and pulse sequence differences and improved scan reproducibility, except for Synthetic T1 images (which were intrinsically corrected for B1-inhomogeneity). No strong evidence favored B0 correction. Although SPGR/FLASH images showed least deviation here, pulse sequence selection for the ADNI project was based on multiple additional image analyses, to be reported elsewhere.

Aged↗

PubMed2006

Patterns of atrophy in pathologically confirmed FTLD with and without motor neuron degeneration.

The authors used voxel-based morphometry to compare the patterns of brain atrophy in two variants of pathologically confirmed frontotemporal lobar degeneration (FTLD): FTLD with motor neuron disease (FTLD-MND) and FTLD with ubiquitin-only-immunoreactive neuronal changes (FTLD-U). Patterns of atrophy were distinct and different from each other. A localized pattern of frontal lobe atrophy was found in FTLD-MND with a more widespread pattern of atrophy affecting the frontal and temporal lobes in FTLD-U.

Age Factors↗

PubMed2006

Visual hallucinations in posterior cortical atrophy.

BACKGROUND: Visual hallucinations have been reported to occur in up to 25% of patients who meet the criteria for posterior cortical atrophy (PCA). It is not known, however, whether patients who meet the criteria for PCA and have hallucinations are different from those who meet the criteria and do not have hallucinations. OBJECTIVE: To compare the clinical and imaging features of patients with PCA with and without well-formed visual hallucinations. DESIGN: Case-control study. SETTING: Tertiary care medical center. PATIENTS: Fifty-nine patients fulfilling the criteria for PCA were retrospectively identified and divided into 2 groups based on the presence (n = 13) or absence (n = 46) of visual hallucinations. MAIN OUTCOME MEASURES: Statistically significant clinical differences and imaging differences using voxel-based morphometry between the 2 groups. RESULTS: In patients with PCA and hallucinations, parkinsonism and rapid eye movement sleep behavior disorder occurred more frequently, as did myoclonic jerks (P<.001 for both). Voxel-based morphometry showed greater atrophy in a network of structures, including the primary visual cortex, lentiform nuclei, thalamus, basal forebrain, and midbrain, in patients with hallucinations. CONCLUSIONS: Hallucinations in patients with PCA are associated with parkinsonism, rapid eye movement sleep behavior disorder, and myoclonic jerks. The voxel-based morphometry results suggest that hallucinations in PCA cannot be exclusively attributed to atrophy of the posterior association cortices and may involve a circuit of thalamocortical connections.

Age of Onset↗

PubMed2006

Measurements of the amygdala and hippocampus in pathologically confirmed Alzheimer disease and frontotemporal lobar degeneration.

BACKGROUND: Differentiating between Alzheimer disease (AD) and frontotemporal lobar degeneration (FTLD) can be difficult, particularly in the earliest stages of the diseases. Patterns of atrophy on magnetic resonance imaging may help distinguish these diseases and aid diagnosis. OBJECTIVE: To assess the diagnostic utility of magnetic resonance imaging-derived amygdala and hippocampal volumes from patients with pathologically proved AD and FTLD. DESIGN: Cross-sectional volumetric magnetic resonance imaging study of the hippocampus and amygdala. SETTING: Specialist cognitive disorders clinic. Subjects Thirty-seven subjects, including 10 patients with pathologically proved AD, 17 patients with pathologically proved FTLD, and 10 age-matched control subjects. MAIN OUTCOME MEASURES: Hippocampal and amygdala volumes. RESULTS: Geometric mean amygdala and hippocampal volumes were, respectively, 15.0% (95% confidence interval [CI], 4.2%-24.5%) and 16.4% (95% CI, 5.9%-25.6%) lower in the AD than in the control group. In FTLD, the equivalent differences were 43.1% (95% CI, 31.9%-52.6%) in the amygdala and 36.1% (95% CI, 27.5%-43.7%) in the hippocampus. Volumes were significantly lower in the FTLD than in the AD group (P<.01 in both regions). Within the FTLD clinical subgroups, there was evidence of a difference in pattern of atrophy with greater asymmetry (left smaller than right) in semantic dementia compared with frontal variant FTLD (P<.001). On average, the left hippocampus was 14% smaller in semantic dementia than in frontal variant FTLD, whereas the right hippocampus was 37% larger. On average, the left amygdala was 39% smaller in semantic dementia than in frontal variant FTLD, whereas the right amygdala was only 1% smaller. CONCLUSIONS: Hippocampal atrophy is not specific to AD or FTLD. However, severe or asymmetrical amygdala atrophy should suggest FTLD. Atrophy patterns follow clinical syndromes rather than pathology.

Adult↗

PubMed2006

Frontotemporal lobar degeneration without lobar atrophy.

BACKGROUND: Frontotemporal lobar degeneration with ubiquitin-only-immunoreactive neuronal inclusions (FTLD-U) is the most common form of frontotemporal dementia. Neuronal loss and gliosis in cornu ammonis 1 and the subiculum of the hippocampus are features of hippocampal sclerosis (HpScl), which occurs in many cases of FTLD-U. OBJECTIVE: To determine if there were any clinical or magnetic resonance imaging correlates of HpScl in FTLD-U. DESIGN: We reviewed demographics and clinical features of 24 cases of FTLD-U and subjectively assessed the severity of neuronal loss and frequency of ubiquitin-positive neuronal lesions in the frontal and temporal cortices and the dentate gyrus of the hippocampus. SETTING: Mayo Clinic, Rochester, Minn. Patients Twenty-six cases were identified from the medical records linkage system query that met clinical criteria and had autopsy material available for additional studies. Two cases were excluded from further analysis after pathologic studies revealed coexisting Alzheimer disease, leaving 24 cases included in the study. Cases were subdivided based on the presence or absence of HpScl. MAIN OUTCOME MEASURES: Patterns of gray matter atrophy were assessed in cases of FTLD-U with and without HpScl using voxel-based morphometry. RESULTS: Six of the 24 cases of FTLD-U did not have HpScl. No differences were found in demographic or clinical features, including disease duration, between cases with and without HpScl; however, voxel-based morphometry analysis revealed minimal cortical atrophy in cases without HpScl, which was significantly different from the pattern of moderate to severe frontal and temporal lobe atrophy in FTLD-U with HpScl. This finding was in keeping with histopathologic observations. CONCLUSIONS: Despite similar clinical features, cases of FTLD-U with HpScl differ from those without HpScl with respect to pathologic findings and structural imaging. Specifically, FTLD-U without HpScl showed on average minimal or no cortical atrophy, even at end-stage disease. Consequently, FTLD-U without HpScl does not conform to the proposed FTLD staging scheme, is underrecognized, and may have different genetic and environmental underpinnings.

Aged↗

PubMed2006

Rates of cerebral atrophy in autopsy-confirmed progressive supranuclear palsy.

OBJECTIVE: To determine the rates of cerebral atrophy and ventricular expansion in six patients with autopsy confirmed progressive supranuclear palsy (PSP) and multiple antemortem volumetric head MRI scans. METHODS: This study uses the boundary shift integral to determine rates of cerebral atrophy and ventricular expansion in six patients with pathologically confirmed PSP compared with six age- and sex-matched control subjects. RESULTS: Patients with PSP had a rate of cerebral atrophy and ventricular expansion of 1.3 and 7.0% per year compared with 0.4 and 1.8% in control subjects. INTERPRETATION: These rates provide a benchmark that can be used to monitor future treatment response in PSP.

Aged↗

PubMed2005

A volumetric magnetic resonance imaging study of the amygdala in frontotemporal lobar degeneration and Alzheimer's disease.

The amygdala is severely atrophied at post-mortem in frontotemporal lobar degeneration (FTLD), and may contribute to the prominent behavioural changes that are early features of FTLD. The aim of this study was to assess amygdala atrophy using MRI in the main syndromic variants of FTLD and Alzheimer's disease (AD). Brain and amygdala volumes, adjusted for intracranial volume, were measured on 46 clinically diagnosed FTLD patients [22 frontal variant FTD (FTD), 14 semantic dementia (SD), 10 progressive non-fluent aphasia (PNFA)], 20 AD patients, and 17 controls. While severe amygdala atrophy was present in both FTLD (41% smaller than controls on the left; 33% on the right) and in AD (22% on the left; 19% on the right), the FTLD group had significantly greater amygdala atrophy (z = 3.21, p = 0.001 left, z = 2.50, p = 0.01 right) and left/right asymmetry (z = 2.03, p = 0.04) than AD. Amygdala atrophy was greater in SD than FTD, PNFA and AD (p < 0.02 for all). Highly asymmetrical atrophy was present in SD, greater on the left (z = 3.23, p = 0.001), and to a lesser extent in PNFA. Despite an overlap between clinical and radiological features of FTLD and AD, marked amygdala atrophy points towards a diagnosis of FTLD, with left greater than right atrophy suggestive of one of the language variants.

Aged↗

PubMed2005

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.

Atrophy↗

PubMed2005

Comparisons between Alzheimer disease, frontotemporal lobar degeneration, and normal aging with brain mapping.

Alzheimer disease (AD) and frontotemporal lobar degeneration (FTLD) are both common degenerative dementias in the under 65 age group. Although clinical criteria have been defined for both diseases, there is considerable overlap in clinical features, and hence, diagnosis still can be very difficult particularly in the early stages of the disease. As a result, there has been increasing interest in using magnetic resonance imaging to better characterize these diseases and to aid in diagnosis. Voxel-based morphometry (VBM) is an automated technique that assesses patterns of regional gray matter atrophy on magnetic resonance imaging between 2 groups of subjects. It is unbiased in that it looks throughout the whole brain and does not require any a priori assumptions concerning which structures to assess, giving it a significant advantage over traditional region of interest-based methods. Voxel-based morphometry has been widely used to assess patterns of regional atrophy in subjects with AD and FTLD. These studies have demonstrated specific patterns of regional loss in both diseases, compared the 2 diseases to look for differences that could be diagnostically useful, and have correlated regions of gray matter loss to cognitive and behavioral deficits in these subjects. This article will review the findings of these studies and discuss the role of VBM in these neurodegenerative diseases.

Aging↗

PubMed2004

Using nine degrees-of-freedom registration to correct for changes in voxel size in serial MRI studies.

Quantitative longitudinal brain magnetic resonance (MR) studies may be confounded by scanner-related drifts in voxel sizes. Total intracranial volume (TIV) normalisation is commonly used to correct serial cerebral volumetric measurements for these drifts. We hypothesised that automated rigid-body registration of whole brain incorporating automatic scaling correction might also correct for such fluctuations, and might be a more practical alternative. Twenty-three subjects (12 patients with Alzheimer's disease [AD] and 11 controls) had at least two serial T1-weighted volumetric brain MR scans. Ten scans from the control subjects were artificially scaled (stretched) by 1.5, 3.0, 4.6 and 6.1%. A 9-degrees-of-freedom (9dof) registration was used to register the scaled scans back onto the original scans and corresponding scaling factors compared to TIV measurements. A further nine 1-year repeat scans from the AD subjects were artificially scaled and registered (9dof) to baseline. The two correction methods were further assessed using multiple serial scans for each of the 23 subjects (resulting in 49 scan pairs). All serial scans were registered (9dof) to baseline. TIV was measured on all scans. It was found that the 9dof registration successfully recovered the artificially generated scaling changes. Scaling correction using 9dof registration did not alter the amount of brain atrophy measured over the 1-year period in the AD subjects. The 9dof volume scaling factors were very similar to the TIV ratios (repeat TIV over baseline TIV), but less variable (p < 0.001), in both artificial and 'real' scenarios. In the latter, the volume scaling factors allowed identification of two time-points in which a 3% change in voxel size had occurred. Both the 9dof brain registration and TIV correction were successfully able to correct for these fluctuations. Significant shifts in voxel size are a problem in longitudinal brain imaging studies. It is important that such changes are adjusted for: 9dof registration, which is automated and computationally inexpensive, may be superior to the more labour-intensive TIV correction for this purpose.

Alzheimer Disease↗

PubMed2004

Longitudinal patterns of regional change on volumetric MRI in frontotemporal lobar degeneration.

The aim of this study was to assess the longitudinal patterns of regional change in the different syndromic variants of frontotemporal lobar degeneration (FTLD). Ten patients with semantic dementia, 7 with progressive non-fluent aphasia and 29 with frontotemporal dementia had two serial volumetric MR scans. Fluid registration was used to match serial scans from each individual. Voxel-level analysis of change across subject groups was performed using statistical parametric mapping. The analysis showed patterns of increased rates of volume loss (atrophy) in frontal, temporal and parietal regions in the whole FTLD group compared with controls. The different FTLD syndromes displayed different patterns of change. This technique gives an insight into disease evolution over time in these disorders and may be useful as a method of tracking change in clinical trials.

Aged↗

PubMed2004

Voxel-based morphometry in tau-positive and tau-negative frontotemporal lobar degenerations.

BACKGROUND: The identification of specific, diagnostically useful predictors of protein dysfunction in the frontotemporal lobar degenerations (FTLD) is a problem of great clinical and biological interest. Correlations between regional patterns of tissue loss and specific proteinopathies have not been established. OBJECTIVE: Specific brain imaging correlates of protein tau dysfunction were sought using voxel-based morphometry in FTLD subgroups with and without tau pathology. METHODS: Seventeen patients with pathologically or genetically confirmed diagnoses of FTLD who had undergone volumetric brain magnetic resonance imaging (MRI) were identified retrospectively and tau-positive (n = 9) and tau-negative (n = 8) subgroups were defined. MRI data were compared with healthy age- and sex-matched controls using voxel-based morphometry implemented in a statistical parametric mapping software package. RESULTS: Compared with controls, tau-positive and tau-negative subgroups had extensive common areas of regional brain atrophy predominantly affecting the frontal and anterior temporal lobes. No specific brain imaging features were identified for either subgroup. CONCLUSION: Patterns of frontotemporal atrophy do not predict the presence or absence of tau pathology; conversely, different immunohistochemical profiles are associated with similar patterns of regional vulnerability to neuronal loss in FTLD.

Dementia↗

PubMed2003

Change in rates of cerebral atrophy over time in early-onset Alzheimer's disease: longitudinal MRI study.

The extent to which cerebral atrophy in Alzheimer's disease changes with time is unknown. We used multiple MRI scans to measure progression of cerebral atrophy in 12 patients with Alzheimer's disease who were followed up from a presymptomatic stage through to moderately severe dementia. Analysis with hierarchical regression models with quadratic terms in time provided evidence of increasing yearly percentage losses in brain volume. At the time when patients were judged to have mild dementia (mini-mental state examination score MMSE=23), mean yearly loss of brain volume was 2.8% (95% CI 2.3-3.3), which rose by 0.32% per year (0.15-0.50). Our findings reinforce the need for early diagnosis and therapeutic intervention in Alzheimer's disease.

Alzheimer Disease↗

PubMed2003

A longitudinal study of brain volume changes in normal aging using serial registered magnetic resonance imaging.

OBJECTIVE: To investigate the effect of age on global and regional brain volumes and rates of atrophy, and to compare directly results based on cross-sectional and longitudinal data. METHODS: Thirty-nine healthy control subjects (age range, 31-84 years) underwent serial magnetic resonance imaging assessments. Measurements included the whole-brain, temporal lobe, hippocampal, and ventricular volumes at baseline and for repeat scans. RESULTS: We found significant decreases in cross-sectional whole-brain (P<.001), temporal lobe (P<.001), and hippocampal (P =.003) volumes and a significant increase in ventricular volume (P<.001) with increasing age. Cross-sectional and longitudinal estimates of atrophy rates were similar. We also found directional evidence of acceleration in atrophy rates with increasing age in all analyses, with the most marked changes occurring after 70 years of age. This increase in rates after 70 years of age was particularly marked in the ventricles (P<.001) and the hippocampi (P =.01). CONCLUSIONS: We found a significant age-associated decrease in global and regional brain volumes. Some evidence indicates that this decline in brain volumes may be due to a nonlinear acceleration in rates of atrophy with increasing age. A better understanding of this process may help to discriminate normal age-related changes from neurodegenerative diseases.

Adult↗