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1.  Rates of cerebral atrophy differ in different degenerative pathologies 
Brain : a journal of neurology  2007;130(Pt 4):1148-1158.
Neurodegenerative disorders are pathologically characterized by the deposition of abnormal proteins in the brain. It is likely that future treatment trials will target the underlying protein biochemistry and it is therefore increasingly important to be able to distinguish between different pathologies during life. The aim of this study was to determine whether rates of brain atrophy differ in neurodegenerative dementias that vary by pathological diagnoses and characteristic protein biochemistry. Fifty-six autopsied subjects were identified with a clinical diagnosis of dementia and two serial head MRI. Subjects were subdivided based on pathological diagnoses into Alzheimer's disease (AD), dementia with Lewy bodies (DLB), mixed AD/DLB, frontotemporal lobar degeneration with ubiquitin-only-immunoreactive changes (FTLD-U), corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP). Twenty-five controls were matched by age, gender, and scan interval, to the study cohort. The boundary-shift integral was used to calculate change over time in whole brain (BBSI) and ventricular volume (VBSI). All BSI results were annualized by adjusting for scan interval. The rates of whole brain atrophy and ventricular expansion were significantly increased compared to controls in the AD, mixed AD/DLB, FTLD-U, CBD and PSP groups. However, atrophy rates in the DLB group were not significantly different from control rates of atrophy. The largest rates of atrophy were observed in the CBD group which had a BBSI of 2.3% and VBSI of 16.2%. The CBD group had significantly greater rates of BBSI and VBSI than the DLB, mixed AD/DLB, AD and PSP groups, with a similar trend observed when compared to the FTLD-U group. The FTLD-U group showed the next largest rates with a BBSI of 1.7% and VBSI of 9.6% which were both significantly greater than the DLB group. There was no significant difference in the rates of atrophy between the AD, mixed AD/DLB and PSP groups, which all showed similar rates of atrophy; BBSI of 1.1, 1.3 and 1.0% and VBSI of 8.3, 7.2 and 10.9% respectively. Rates of atrophy therefore differ according to the pathological diagnoses and underlying protein biochemistry. While rates are unlikely to be useful in differentiating AD from cases with mixed AD/DLB pathology, they demonstrate important pathophysiological differences between DLB and those with mixed AD/DLB and AD pathology, and between those with CBD and PSP pathology.
PMCID: PMC2752409  PMID: 17347250
magnetic resonance imaging; Alzheimer's disease; dementia with Lewy bodies; frontotemporal lobar degeneration; progressive supranuclear palsy
2.  3D Maps from Multiple MRI Illustrate Changing Atrophy Patterns as Subjects Progress from MCI to AD 
Brain : a journal of neurology  2007;130(Pt 7):1777-1786.
Mild cognitive impairment (MCI), particularly the amnestic subtype (aMCI), is considered as a transitional stage between normal aging and a diagnosis of clinically probable Alzheimer's disease (AD). The aMCI construct is particularly useful as it provides an opportunity to assess a clinical stage which in most subjects represents prodromal AD. The aim of this study was to assess the progression of cerebral atrophy over multiple serial MRI during the period from aMCI to conversion to AD. Thirty-three subjects were selected that fulfilled clinical criteria for aMCI and had three serial MRI scans: the first scan approximately three years before conversion to AD, the second scan approximately one year before conversion, and the third scan at the time of conversion from aMCI to AD. A group of 33 healthy controls were age and gender-matched to the study cohort. Voxel-based morphometry (VBM) was used to assess patterns of grey matter atrophy in the aMCI subjects at each time-point compared to the control group. Customized templates and prior probability maps were used to avoid normalization and segmentation bias. The pattern of grey matter loss in the aMCI subject scans that were three years before conversion was focused primarily on the medial temporal lobes, including the amygdala, anterior hippocampus and entorhinal cortex, with some additional involvement of the fusiform gyrus, compared to controls. The extent and magnitude of the cerebral atrophy further progressed by the time the subjects were one year before conversion. At this point atrophy in the temporal lobes spread to include the middle temporal gyrus, and extended into more posterior regions of the temporal lobe to include the entire extent of the hippocampus. The parietal lobe also started to become involved. By the time the subjects had converted to a clinical diagnosis of AD the pattern of grey matter atrophy had become still more widespread with more severe involvement of the medial temporal lobes and the temporoparietal association cortices and, for the first time, substantial involvement of the frontal lobes. This pattern of progression fits well with the Braak and Braak neurofibrillary pathological staging scheme in AD. It suggests that the earliest changes occur in the anterior medial temporal lobe and fusiform gyrus, and that these changes occur at least three years before conversion to AD. These results also suggest that 3-dimensional patterns of grey matter atrophy may help to predict the time to conversion in subjects with aMCI.
PMCID: PMC2752411  PMID: 17533169
Alzheimer's disease; mild cognitive impairment; longitudinal; magnetic resonance imaging; voxel-based morphometry
3.  Clinicopathologic and Imaging Correlates of Progressive Aphasia and Apraxia of Speech 
Brain : a journal of neurology  2006;129(Pt 6):1385-1398.
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 neurologic disease. In this study we determined 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 reclassified independently by two speech-language pathologists — blinded to pathologic 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 six, corticobasal degeneration in five, frontotemporal lobar degeneration with ubiquitin-only-immunoreactive changes in five, and Pick’s disease in one. Voxel-based morphometry and SPECT were completed, blinded to the clinical diagnoses, and clinico-imaging and clinico-pathological associations were then sought. Interjudge clinical classification reliability was 87% (κ =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. Voxel-based morphometry 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 behavioral, pathological, and imaging correlations.
PMCID: PMC2748312  PMID: 16613895
Premotor cortex; supplementary motor cortex; progressive supranuclear palsy; apraxia of speech; aphasia
4.  Focal atrophy in Dementia with Lewy Bodies on MRI: a distinct pattern from Alzheimer's disease 
Brain : a journal of neurology  2007;130(Pt 3):708-719.
Dementia with Lewy Bodies (DLB) is the second most common cause of degenerative dementia after Alzheimer's disease (AD). However, unlike in AD the patterns of cerebral atrophy associated with DLB have not been well established. The aim of this study was to identify a signature pattern of cerebral atrophy in DLB and to compare it to the pattern found in AD. Seventy-two patients that fulfilled clinical criteria for probable DLB were age and gender-matched to 72 patients with probable AD and 72 controls. Voxel-based morphometry (VBM) was used to assess patterns of grey matter atrophy in the DLB and AD groups, relative to controls, after correction for multiple comparisons (p<0.05). Study specific templates and prior probability maps were used to avoid normalization and segmentation bias. Region-of-interest (ROI) analyses were also performed comparing loss of the midbrain, substantia innominata (SI), temporoparietal cortex and hippocampus between the groups. The DLB group showed very little cortical involvement on VBM with regional grey matter loss observed primarily in the dorsal midbrain, SI and hypothalamus. In comparison, the AD group showed a widespread pattern of grey matter loss involving the temporoparietal association cortices and the medial temporal lobes. The SI and dorsal midbrain were involved in AD however they were not identified as a cluster of loss discrete from uninvolved surrounding areas, as observed in the DLB group. On direct comparison between the two groups, the AD group showed greater loss in the medial temporal lobe and inferior temporal regions than the DLB group. The ROI analysis showed reduced SI and midbrain grey matter in both the AD and DLB groups. The SI grey matter was reduced more in AD than DLB, yet the midbrain was reduced more in DLB than AD. The hippocampus and temporoparietal cortex showed significantly greater loss in the AD group compared to the DLB group. A pattern of relatively focused atrophy of the midbrain, hypothalamus and SI, with a relative sparing of the hippocampus and temporoparietal cortex, is therefore suggestive of DLB and may aid in the differentiation of DLB from AD. These findings support recent pathological studies showing an ascending pattern of Lewy Body progression from brainstem to basal areas of the brain. Damage to this network of structures in DLB may affect a number of different neurotransmitter systems which in turn may contribute to a number of the core clinical features of DLB.
PMCID: PMC2730778  PMID: 17267521
Dementia with Lewy Bodies; Alzheimer's disease; voxel-based morphometry; magnetic resonance imaging; neurotransmitter systems
5.  11C PiB and Structural MRI Provide Complementary Information in Imaging of AD and Amnestic MCI 
Brain : a journal of neurology  2008;131(Pt 3):665-680.
Twenty cognitively normal (CN), 17 amnestic mild cognitive impairment (aMCI), and 8 subjects with probable Alzheimer's disease (AD) were imaged with both magnetic resonance imaging (MRI) and the amyloid labeling ligand 11C Pittsburgh Compound B (PiB). PiB retention was quantified as the ratio of uptake in cortical regions of interest (ROIs) to the uptake in the cerebellar ROI in images acquired 40-60 minute post injection. A global cortical PiB retention summary measure was derived from six cortical ROIs. Statistical parametric mapping (SPM) and voxel-based morphometry (VBM) were used to evaluate PiB retention and grey matter loss on a 3D voxel-wise basis.
AD subjects had high global cortical PiB retention and low hippocampal volume; most CN subjects had low PiB retention and high hippocampal volume; and on average aMCI subjects were intermediate on both PiB and hippocampal volume. A target-to-cerebellar ratio of 1.5 was used to designate subjects as high vs. low PiB cortical retention. All AD subjects fell above this ratio as did 6/20 CN subjects and 9/17 MCI subjects, indicating bi-modal PiB retention in CN and aMCI. Interestingly, we found no consistent differences in learning and memory performance between high vs. low PiB CN subjects or high vs. low aMCI subjects.
The SPM/VBM voxel-wise comparisons of AD vs. CN subjects provided complementary information in that clear and meaningful similarities and differences in topographic distribution of amyloid deposition and grey matter loss were shown. The frontal lobes had high PiB retention with little grey matter loss. Anteromedial temporal areas had low PiB retention with significant grey matter loss. Lateral temporoparietal association cortex displayed both significant PiB retention and grey matter loss.
A voxel-wise SPM conjunction analysis of PiB uptake revealed that subjects with high PiB retention (high CN, high aMCI, and AD) shared a common PiB retention topographic pattern regardless of clinical category, and this PiB topographic pattern matched that of amyloid plaque distribution that has been established in autopsy studies of AD.
Both global cortical PiB retention and hippocampal volumes demonstrated significant correlation in the expected direction with cognitive testing performance; however, correlations were stronger with MRI than PiB. Pair-wise inter-group diagnostic separation was significant for all group-wise pairs for both PiB and hippocampal volume with the exception of CN vs. aMCI which was not significant for PiB. PiB and MRI provided complementary information such that clinical diagnostic classification with both, in combination, was superior to either alone.
PMCID: PMC2730157  PMID: 18263627
Alzheimer's disease; Mild Cognitive Impairment; Pittsburgh Compound B; amyloid imaging; Magnetic Resonance Imaging; hippocampus

Results 1-5 (5)