PMCC PMCC

Search tips
Search criteria

Advanced
Results 1-13 (13)
 

Clipboard (0)
None
Journals
Year of Publication
Document Types
1.  Corticospinal tract degeneration associated with TDP-43 type C pathology and semantic dementia 
Brain  2013;136(2):455-470.
Four subtypes of frontotemporal lobar degeneration with TDP-43 immunoreactive inclusions have been described (types A–D). Of these four subtypes, motor neuron disease is more commonly associated with type B pathology, but has also been reported with type A pathology. We have noted, however, the unusual occurrence of cases of type C pathology having corticospinal tract degeneration. We aimed to assess the severity of corticospinal tract degeneration in a large cohort of cases with type C (n = 31). Pathological analysis included semi-quantitation of myelin loss of fibres of the corticospinal tract and associated macrophage burden, as well as axonal loss, at the level of the medullary pyramids. We also assessed for motor cortex degeneration and fibre loss of the medial lemniscus/olivocerebellar tract. All cases were subdivided into three groups based on the degree of corticospinal tract degeneration: (i) no corticospinal tract degeneration; (ii) equivocal corticospinal tract degeneration; and (iii) moderate to very severe corticospinal tract degeneration. Clinical, genetic, pathological and imaging comparisons were performed across groups. Eight cases had no corticospinal tract degeneration, and 14 cases had equivocal to mild corticospinal tract degeneration. Nine cases, however, had moderate to very severe corticospinal tract degeneration with myelin and axonal loss. In these nine cases, there was degeneration of the motor cortex without lower motor neuron degeneration or involvement of other brainstem tracts. These cases most commonly presented as semantic dementia, and they had longer disease duration (mean: 15.3 years) compared with the other two groups (10.8 and 9.9 years; P = 0.03). After adjusting for disease duration, severity of corticospinal tract degeneration remained significantly different across groups. Only one case, without corticospinal tract degeneration, was found to have a hexanucleotide repeat expansion in the C9ORF72 gene. All three groups were associated with anterior temporal lobe atrophy on MRI; however, the cases with moderate to severe corticospinal tract degeneration showed right-sided temporal lobe asymmetry and greater involvement of the right temporal lobe and superior motor cortices than the other groups. In contrast, the cases with no or equivocal corticospinal tract degeneration were more likely to show left-sided temporal lobe asymmetry. For comparison, the corticospinal tract was assessed in 86 type A and B cases, and only two cases showed evidence of corticospinal tract degeneration without lower motor neuron degeneration. These findings confirm that there exists a unique association between frontotemporal lobar degeneration with type C pathology and corticospinal tract degeneration, with this entity showing a predilection to involve the right temporal lobe.
doi:10.1093/brain/aws324
PMCID: PMC3572926  PMID: 23358603
TDP-43 type C; corticospinal tract; MRI; semantic dementia; right temporal lobe
2.  Imaging and acetylcholinesterase inhibitor response in dementia with Lewy bodies 
Brain  2012;135(8):2470-2477.
Acetylcholinesterase inhibitors are commonly used to treat patients with dementia with Lewy bodies. Hippocampal atrophy on magnetic resonance imaging and amyloid-β load on positron emission tomography are associated with the Alzheimer’s disease-related pathology in patients with dementia with Lewy bodies. To date, few studies have investigated imaging markers that predict treatment response in patients with dementia with Lewy bodies. Our objective was to determine whether imaging markers of Alzheimer’s disease-related pathology such as hippocampal volume, brain amyloid-β load on 11C Pittsburgh compound B positron emission tomography predict treatment response to acetylcholinesterase inhibitors in patients with dementia with Lewy bodies. We performed a retrospective analysis on consecutive treatment-naive patients with dementia with Lewy bodies (n = 54) from the Mayo Clinic Alzheimer’s Disease Research Centre who subsequently received acetylcholinesterase inhibitors and underwent magnetic resonance imaging with hippocampal volumetry. Baseline and follow-up assessments were obtained with the Mattis Dementia Rating Scale. Subjects were divided into three groups (reliable improvement, stable or reliable decline) using Dementia Rating Scale reliable change indices determined previously. Associations between hippocampal volumes and treatment response were tested with analysis of covariance adjusting for baseline Dementia Rating Scale, age, gender, magnetic resonance field strength and Dementia Rating Scale interval. Seven subjects underwent 11C Pittsburgh compound B imaging within 12 weeks of magnetic resonance imaging. Global cortical 11C Pittsburgh compound B retention (scaled to cerebellar retention) was calculated in these patients. Using a conservative psychometric method of assessing treatment response, there were 12 patients with reliable decline, 29 stable cases and 13 patients with reliable improvement. The improvers had significantly larger hippocampi than those that declined (P = 0.02) and the stable (P = 0.04) group. An exploratory analysis demonstrated larger grey matter volumes in the temporal and parietal lobes in improvers compared with those who declined (P < 0.05). The two patients who had a positive 11C Pittsburgh compound B positron emission tomography scan declined and those who had a negative 11C Pittsburgh compound B positron emission tomography scan improved or were stable after treatment. Patients with dementia with Lewy bodies who do not have the imaging features of coexistent Alzheimer’s disease-related pathology are more likely to cognitively improve with acetylcholinesterase inhibitor treatment.
doi:10.1093/brain/aws173
PMCID: PMC3407425  PMID: 22810436
dementia with Lewy bodies; acetylcholinesterase inhibitors; MRI; PiB; PET; amyloid
3.  Neuropathological features of corticobasal degeneration presenting as corticobasal syndrome or Richardson syndrome 
Brain  2011;134(11):3264-3275.
Patients with corticobasal degeneration can present with several different clinical syndromes, making ante-mortem diagnosis a challenge. Corticobasal syndrome is the clinical phenotype originally described for corticobasal degeneration, characterized by asymmetric rigidity and apraxia, cortical sensory deficits, dystonia and myoclonus. Some patients do not develop these features, but instead have clinical features consistent with the Richardson syndrome presentation of progressive supranuclear palsy, characterized by postural instability, early unexplained falls, vertical supranuclear gaze palsy, symmetric motor disability and dysphagia. The aim of this study was to identify differences in corticobasal degeneration presenting with corticobasal syndrome (n = 11) or Richardson syndrome (n = 15) with respect to demographic, clinical and neuropathological features. Corticobasal degeneration cases were also compared with patients with pathologically proven progressive supranuclear palsy with Richardson syndrome (n = 15). Cases with corticobasal degeneration, regardless of presentation, shared histopathological and tau biochemical characteristics, but they had differing densities of tau pathology in neuroanatomical regions that correlated with their clinical presentation. In particular, those with corticobasal syndrome had greater tau pathology in the primary motor and somatosensory cortices and putamen, while those with Richardson syndrome had greater tau pathology in limbic and hindbrain structures. Compared with progressive supranuclear palsy, patients with corticobasal degeneration and Richardson syndrome had less neuronal loss in the subthalamic nucleus, but more severe neuronal loss in the medial substantia nigra and greater atrophy of the anterior corpus callosum. Clinically, they had more cognitive impairment and frontal behavioural dysfunction. The results suggest that Richardson syndrome can be a clinicopathological presentation of corticobasal degeneration. Atrophy of anterior corpus callosum may be a potential neuroimaging marker to differentiate corticobasal degeneration from progressive supranuclear palsy in patients with Richardson syndrome.
doi:10.1093/brain/awr234
PMCID: PMC3212714  PMID: 21933807
pathology; immunocytochemistry; progressive supranuclear palsy; tau protein; corticobasal degeneration
4.  Sensitivity of revised diagnostic criteria for the behavioural variant of frontotemporal dementia 
Brain  2011;134(9):2456-2477.
Based on the recent literature and collective experience, an international consortium developed revised guidelines for the diagnosis of behavioural variant frontotemporal dementia. The validation process retrospectively reviewed clinical records and compared the sensitivity of proposed and earlier criteria in a multi-site sample of patients with pathologically verified frontotemporal lobar degeneration. According to the revised criteria, ‘possible’ behavioural variant frontotemporal dementia requires three of six clinically discriminating features (disinhibition, apathy/inertia, loss of sympathy/empathy, perseverative/compulsive behaviours, hyperorality and dysexecutive neuropsychological profile). ‘Probable’ behavioural variant frontotemporal dementia adds functional disability and characteristic neuroimaging, while behavioural variant frontotemporal dementia ‘with definite frontotemporal lobar degeneration’ requires histopathological confirmation or a pathogenic mutation. Sixteen brain banks contributed cases meeting histopathological criteria for frontotemporal lobar degeneration and a clinical diagnosis of behavioural variant frontotemporal dementia, Alzheimer’s disease, dementia with Lewy bodies or vascular dementia at presentation. Cases with predominant primary progressive aphasia or extra-pyramidal syndromes were excluded. In these autopsy-confirmed cases, an experienced neurologist or psychiatrist ascertained clinical features necessary for making a diagnosis according to previous and proposed criteria at presentation. Of 137 cases where features were available for both proposed and previously established criteria, 118 (86%) met ‘possible’ criteria, and 104 (76%) met criteria for ‘probable’ behavioural variant frontotemporal dementia. In contrast, 72 cases (53%) met previously established criteria for the syndrome (P < 0.001 for comparison with ‘possible’ and ‘probable’ criteria). Patients who failed to meet revised criteria were significantly older and most had atypical presentations with marked memory impairment. In conclusion, the revised criteria for behavioural variant frontotemporal dementia improve diagnostic accuracy compared with previously established criteria in a sample with known frontotemporal lobar degeneration. Greater sensitivity of the proposed criteria may reflect the optimized diagnostic features, less restrictive exclusion features and a flexible structure that accommodates different initial clinical presentations. Future studies will be needed to establish the reliability and specificity of these revised diagnostic guidelines.
doi:10.1093/brain/awr179
PMCID: PMC3170532  PMID: 21810890
behavioural variant frontotemporal dementia; diagnostic criteria; frontotemporal lobar degeneration; FTD; pathology
5.  Neuroimaging signatures of frontotemporal dementia genetics: C9ORF72, tau, progranulin and sporadics 
Brain  2012;135(3):794-806.
A major recent discovery was the identification of an expansion of a non-coding GGGGCC hexanucleotide repeat in the C9ORF72 gene in patients with frontotemporal dementia and amyotrophic lateral sclerosis. Mutations in two other genes are known to account for familial frontotemporal dementia: microtubule-associated protein tau and progranulin. Although imaging features have been previously reported in subjects with mutations in tau and progranulin, no imaging features have been published in C9ORF72. Furthermore, it remains unknown whether there are differences in atrophy patterns across these mutations, and whether regional differences could help differentiate C9ORF72 from the other two mutations at the single-subject level. We aimed to determine the regional pattern of brain atrophy associated with the C9ORF72 gene mutation, and to determine which regions best differentiate C9ORF72 from subjects with mutations in tau and progranulin, and from sporadic frontotemporal dementia. A total of 76 subjects, including 56 with a clinical diagnosis of behavioural variant frontotemporal dementia and a mutation in one of these genes (19 with C9ORF72 mutations, 25 with tau mutations and 12 with progranulin mutations) and 20 sporadic subjects with behavioural variant frontotemporal dementia (including 50% with amyotrophic lateral sclerosis), with magnetic resonance imaging were included in this study. Voxel-based morphometry was used to assess and compare patterns of grey matter atrophy. Atlas-based parcellation was performed utilizing the automated anatomical labelling atlas and Statistical Parametric Mapping software to compute volumes of 37 regions of interest. Hemispheric asymmetry was calculated. Penalized multinomial logistic regression was utilized to create a prediction model to discriminate among groups using regional volumes and asymmetry score. Principal component analysis assessed for variance within groups. C9ORF72 was associated with symmetric atrophy predominantly involving dorsolateral, medial and orbitofrontal lobes, with additional loss in anterior temporal lobes, parietal lobes, occipital lobes and cerebellum. In contrast, striking anteromedial temporal atrophy was associated with tau mutations and temporoparietal atrophy was associated with progranulin mutations. The sporadic group was associated with frontal and anterior temporal atrophy. A conservative penalized multinomial logistic regression model identified 14 variables that could accurately classify subjects, including frontal, temporal, parietal, occipital and cerebellum volume. The principal component analysis revealed similar degrees of heterogeneity within all disease groups. Patterns of atrophy therefore differed across subjects with C9ORF72, tau and progranulin mutations and sporadic frontotemporal dementia. Our analysis suggested that imaging has the potential to be useful to help differentiate C9ORF72 from these other groups at the single-subject level.
doi:10.1093/brain/aws001
PMCID: PMC3286334  PMID: 22366795
frontotemporal dementia; magnetic resonance imaging; C9ORF72; tau; progranulin
6.  Characterization of frontotemporal dementia and/or amyotrophic lateral sclerosis associated with the GGGGCC repeat expansion in C9ORF72 
Brain  2012;135(3):765-783.
Numerous kindreds with familial frontotemporal dementia and/or amyotrophic lateral sclerosis have been linked to chromosome 9, and an expansion of the GGGGCC hexanucleotide repeat in the non-coding region of chromosome 9 open reading frame 72 has recently been identified as the pathogenic mechanism. We describe the key characteristics in the probands and their affected relatives who have been evaluated at Mayo Clinic Rochester or Mayo Clinic Florida in whom the hexanucleotide repeat expansion were found. Forty-three probands and 10 of their affected relatives with DNA available (total 53 subjects) were shown to carry the hexanucleotide repeat expansion. Thirty-six (84%) of the 43 probands had a familial disorder, whereas seven (16%) appeared to be sporadic. Among examined subjects from the 43 families (n = 63), the age of onset ranged from 33 to 72 years (median 52 years) and survival ranged from 1 to 17 years, with the age of onset <40 years in six (10%) and >60 in 19 (30%). Clinical diagnoses among examined subjects included behavioural variant frontotemporal dementia with or without parkinsonism (n = 30), amyotrophic lateral sclerosis (n = 18), frontotemporal dementia/amyotrophic lateral sclerosis with or without parkinsonism (n = 12), and other various syndromes (n = 3). Parkinsonism was present in 35% of examined subjects, all of whom had behavioural variant frontotemporal dementia or frontotemporal dementia/amyotrophic lateral sclerosis as the dominant clinical phenotype. No subject with a diagnosis of primary progressive aphasia was identified with this mutation. Incomplete penetrance was suggested in two kindreds, and the youngest generation had significantly earlier age of onset (>10 years) compared with the next oldest generation in 11 kindreds. Neuropsychological testing showed a profile of slowed processing speed, complex attention/executive dysfunction, and impairment in rapid word retrieval. Neuroimaging studies showed bilateral frontal abnormalities most consistently, with more variable degrees of parietal with or without temporal changes; no case had strikingly focal or asymmetric findings. Neuropathological examination of 14 patients revealed a range of transactive response DNA binding protein molecular weight 43 pathology (10 type A and four type B), as well as ubiquitin-positive cerebellar granular neuron inclusions in all but one case. Motor neuron degeneration was detected in nine patients, including five patients without ante-mortem signs of motor neuron disease. While variability exists, most cases with this mutation have a characteristic spectrum of demographic, clinical, neuropsychological, neuroimaging and especially neuropathological findings.
doi:10.1093/brain/aws004
PMCID: PMC3286335  PMID: 22366793
frontotemporal dementia; amyotrophic lateral sclerosis; motor neuron disease; TDP-43; neurogenetics; chromosome 9
7.  Predicting functional decline in behavioural variant frontotemporal dementia 
Brain  2011;134(2):432-448.
Behavioural variant frontotemporal dementia is characterized by a change in comportment. It is associated with considerable functional decline over the course of the illness albeit with sometimes dramatic variability among patients. It is unknown whether any baseline features, or combination of features, could predict rate of functional decline in behavioural variant frontotemporal dementia. The aim of this study was to investigate the effects of different baseline clinical, neuropsychological, neuropsychiatric, genetic and anatomic predictors on the rate of functional decline as measured by the Clinical Dementia Rating Sum of Boxes scale. We identified 86 subjects with behavioural variant frontotemporal dementia that had multiple serial Clinical Dementia Rating Sum of Boxes assessments (mean 4, range 2–18). Atlas-based parcellation was used to generate volumes for specific regions of interest at baseline. Volumes were utilized to classify subjects into different anatomical subtypes using the advanced statistical technique of cluster analysis and were assessed as predictor variables. Composite scores were generated for the neuropsychological domains of executive, language, memory and visuospatial function. Behaviours from the brief questionnaire form of the Neuropsychiatric Inventory were assessed. Linear mixed-effects regression modelling was used to determine which baseline features predict rate of future functional decline. Rates of functional decline differed across the anatomical subtypes of behavioural variant frontotemporal dementia, with faster rates observed in the frontal dominant and frontotemporal subtypes. In addition, subjects with poorer performance on neuropsychological tests of executive, language and visuospatial function, less disinhibition, agitation/aggression and night-time behaviours at presentation, and smaller medial, lateral and orbital frontal lobe volumes showed faster rates of decline. In many instances, the effect of the predictor variables observed across all subjects was also preserved within anatomical subtypes. Furthermore, some of the predictor variables improved our prediction of rate of functional decline after anatomical subtype was taken into account. In particular, age at onset was a highly significant predictor but only after adjusting for subtype. We also found that although some predictor variables, for example gender, Mini-Mental State Examination score, and apathy/indifference, did not affect the rate of functional decline; these variables were associated with the actual Clinical Dementia Rating Sum of Boxes score estimated for any given time-point. These findings suggest that in behavioural variant frontotemporal dementia, rate of functional decline is driven by the combination of anatomical pattern of atrophy, age at onset, and neuropsychiatric characteristics of the subject at baseline.
doi:10.1093/brain/awq348
PMCID: PMC3030765  PMID: 21252111
frontotemporal dementia; behaviour; functional decline; brain volumes; mixed effects models
8.  Distinct anatomical subtypes of the behavioural variant of frontotemporal dementia: a cluster analysis study 
Brain  2009;132(11):2932-2946.
The behavioural variant of frontotemporal dementia is a progressive neurodegenerative syndrome characterized by changes in personality and behaviour. It is typically associated with frontal lobe atrophy, although patterns of atrophy are heterogeneous. The objective of this study was to examine case-by-case variability in patterns of grey matter atrophy in subjects with the behavioural variant of frontotemporal dementia and to investigate whether behavioural variant of frontotemporal dementia can be divided into distinct anatomical subtypes. Sixty-six subjects that fulfilled clinical criteria for a diagnosis of the behavioural variant of frontotemporal dementia with a volumetric magnetic resonance imaging scan were identified. Grey matter volumes were obtained for 26 regions of interest, covering frontal, temporal and parietal lobes, striatum, insula and supplemental motor area, using the automated anatomical labelling atlas. Regional volumes were divided by total grey matter volume. A hierarchical agglomerative cluster analysis using Ward's clustering linkage method was performed to cluster the behavioural variant of frontotemporal dementia subjects into different anatomical clusters. Voxel-based morphometry was used to assess patterns of grey matter loss in each identified cluster of subjects compared to an age and gender-matched control group at P < 0.05 (family-wise error corrected). We identified four potentially useful clusters with distinct patterns of grey matter loss, which we posit represent anatomical subtypes of the behavioural variant of frontotemporal dementia. Two of these subtypes were associated with temporal lobe volume loss, with one subtype showing loss restricted to temporal lobe regions (temporal-dominant subtype) and the other showing grey matter loss in the temporal lobes as well as frontal and parietal lobes (temporofrontoparietal subtype). Another two subtypes were characterized by a large amount of frontal lobe volume loss, with one subtype showing grey matter loss in the frontal lobes as well as loss of the temporal lobes (frontotemporal subtype) and the other subtype showing loss relatively restricted to the frontal lobes (frontal-dominant subtype). These four subtypes differed on clinical measures of executive function, episodic memory and confrontation naming. There were also associations between the four subtypes and genetic or pathological diagnoses which were obtained in 48% of the cohort. The clusters did not differ in behavioural severity as measured by the Neuropsychiatric Inventory; supporting the original classification of the behavioural variant of frontotemporal dementia in these subjects. Our findings suggest behavioural variant of frontotemporal dementia can therefore be subdivided into four different anatomical subtypes.
doi:10.1093/brain/awp232
PMCID: PMC2768663  PMID: 19762452
behavioural variant frontotemporal dementia; atrophy; cluster analysis; voxel-based morphometry
9.  Development of methodology for conducting clinical trials in frontotemporal lobar degeneration 
Brain  2008;131(11):2957-2968.
To design clinical trials for the frontotemporal lobar degenerations (FTLD), knowledge about measurement of disease progression is needed to estimate power and enable the choice of optimal outcome measures. The aim here was to conduct a multicentre, 1 year replica of a clinical trial in patients with one of four FTLD syndromes, behavioural variant frontotemporal dementia (bvFTD), progressive nonfluent aphasia (PNFA), progressive logopenic aphasia (PLA) and semantic dementia (SMD). Patients with one of the four FTLD syndromes were recruited from five academic medical centres over a 2 year period. Standard operationalized diagnostic criteria were used. In addition to clinical inclusion and exclusion criteria, patients were required to exhibit focal frontal, temporal or insular brain atrophy or dysfunction by neuroimaging. Patients underwent neuropsychological, functional, behavioural, neurological and MR imaging assessment at baseline and approximately 12 months later. Potential outcome measures were examined for their rates of floor and ceiling values at baseline and end of study, their mean changes and variances. The neuropsychological tests were combined into two cognitive composites—one for language functions and the other for executive functions. There were 107 patients who underwent baseline assessment and 78 who completed a follow-up assessment within 10–16 months. Two global measures, the FTLD-modified Clinical Dementia Rating (FTLD-modified CDR) and the Clinical Global Impression of Change (CGIC) demonstrated decline in the majority of patients. Several cognitive measures showed negligible floor or ceiling scores either at baseline or follow-up. Scores declined at follow-up in the majority of patients. The cognitive, executive and combined composites were shown to be sensitive to change across all FTLD syndromes. Patients improved at follow-up on the behavioural scales—the Frontal Behavioural Inventory (22%) and the Neuropsychiatric Inventory (28%)—suggesting that these instruments may not be ideal for clinical trial use. It was feasible to recruit FTLD patients in a simulated multi-centre trial. There are several candidate outcome measures—including the FTLD-CDR and the cognitive composites— that could be used in clinical trials across the spectrum of FTLD.
doi:10.1093/brain/awn234
PMCID: PMC2725027  PMID: 18829698
frontotemporal dementia; clinical trials; neuropsychology
10.  Rates of cerebral atrophy differ in different degenerative pathologies 
Brain : a journal of neurology  2007;130(Pt 4):1148-1158.
SUMMARY
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.
doi:10.1093/brain/awm021
PMCID: PMC2752409  PMID: 17347250
magnetic resonance imaging; Alzheimer's disease; dementia with Lewy bodies; frontotemporal lobar degeneration; progressive supranuclear palsy
11.  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.
doi:10.1093/brain/awl078
PMCID: PMC2748312  PMID: 16613895
Premotor cortex; supplementary motor cortex; progressive supranuclear palsy; apraxia of speech; aphasia
12.  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.
Summary
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.
doi:10.1093/brain/awm336
PMCID: PMC2730157  PMID: 18263627
Alzheimer's disease; Mild Cognitive Impairment; Pittsburgh Compound B; amyloid imaging; Magnetic Resonance Imaging; hippocampus
13.  Serial PIB and MRI in normal, mild cognitive impairment and Alzheimer's disease: implications for sequence of pathological events in Alzheimer's disease 
Brain  2009;132(5):1355-1365.
The purpose of this study was to use serial imaging to gain insight into the sequence of pathologic events in Alzheimer's disease, and the clinical features associated with this sequence. We measured change in amyloid deposition over time using serial 11C Pittsburgh compound B (PIB) positron emission tomography and progression of neurodegeneration using serial structural magnetic resonance imaging. We studied 21 healthy cognitively normal subjects, 32 with amnestic mild cognitive impairment and 8 with Alzheimer's disease. Subjects were drawn from two sources—ongoing longitudinal registries at Mayo Clinic, and the Alzheimer's disease Neuroimaging Initiative (ADNI). All subjects underwent clinical assessments, MRI and PIB studies at two time points, approximately one year apart. PIB retention was quantified in global cortical to cerebellar ratio units and brain atrophy in units of cm3 by measuring ventricular expansion. The annual change in global PIB retention did not differ by clinical group (P = 0.90), and although small (median 0.042 ratio units/year overall) was greater than zero among all subjects (P < 0.001). Ventricular expansion rates differed by clinical group (P < 0.001) and increased in the following order: cognitively normal (1.3 cm3/year) <  amnestic mild cognitive impairment (2.5 cm3/year) <  Alzheimer's disease (7.7 cm3/year). Among all subjects there was no correlation between PIB change and concurrent change on CDR-SB (r = −0.01, P = 0.97) but some evidence of a weak correlation with MMSE (r =−0.22, P = 0.09). In contrast, greater rates of ventricular expansion were clearly correlated with worsening concurrent change on CDR-SB (r = 0.42, P < 0.01) and MMSE (r =−0.52, P < 0.01). Our data are consistent with a model of typical late onset Alzheimer's disease that has two main features: (i) dissociation between the rate of amyloid deposition and the rate of neurodegeneration late in life, with amyloid deposition proceeding at a constant slow rate while neurodegeneration accelerates and (ii) clinical symptoms are coupled to neurodegeneration not amyloid deposition. Significant plaque deposition occurs prior to clinical decline. The presence of brain amyloidosis alone is not sufficient to produce cognitive decline, rather, the neurodegenerative component of Alzheimer's disease pathology is the direct substrate of cognitive impairment and the rate of cognitive decline is driven by the rate of neurodegeneration. Neurodegeneration (atrophy on MRI) both precedes and parallels cognitive decline. This model implies a complimentary role for MRI and PIB imaging in Alzheimer's disease, with each reflecting one of the major pathologies, amyloid dysmetabolism and neurodegeneration.
doi:10.1093/brain/awp062
PMCID: PMC2677798  PMID: 19339253
Alzheimer's disease; amyloid imaging; magnetic resonance imaging, longitudinal imaging; mild cognitive impairment; Pittsburgh compound B

Results 1-13 (13)