Olof Lindberg

CSF Aβ42/Aβ40 and Aβ42/Aβ38 ratios : better diagnostic markers of Alzheimer disease

The diagnostic accuracy of cerebrospinal fluid (CSF) biomarkers for Alzheimers disease (AD) must be improved before widespread clinical use. This study aimed to determine whether CSF Aβ42/Aβ40 and Aβ42/Aβ38 ratios are better diagnostic biomarkers of AD during both predementia and dementia stages in comparison to CSF Aβ42 alone.

Caudate Nucleus Volumes in Frontotemporal Lobar Degeneration: Differential Atrophy in Subtypes

BACKGROUND AND PURPOSE: Frontostriatal circuits involving the caudate nucleus have been implicated in frontotemporal lobar degeneration (FTLD). We assessed caudate nucleus volumetrics in FTLD and subtypes: frontotemporal dementia (FTD, n = 12), semantic dementia (SD, n = 13), and progressive nonfluent aphasia (PNFA, n = 9) in comparison with healthy controls (n = 27) and subjects with Alzheimer disease (AD, n = 19). MATERIALS AND METHODS: Diagnoses were based on accepted clinical criteria. Manual volume measurement of the head and body of the caudate, excluding the tail, was conducted on T1-weighted brain MR imaging scans, using a published protocol, by a single analyst blinded to the diagnosis. RESULTS: Paired t tests (P < .05) showed that the right caudate nucleus volume was significantly larger than the left in controls and PNFA. No hemispheric asymmetry was found in AD, FTD, and SD. Across the groups, there was a positive partial correlation between the left caudate nucleus volume and Mini-Mental State Examination (MMSE) scores (r = 0.393, n = 76, P = .001) with higher left caudate volumes associated with higher MMSE scores. Multivariate analysis of covariance was used to assess the statistical significance between the subject groups (AD, FTD, SD, PNFA, and controls) as independent variables and raw right/left caudate volumes at the within-subject level (covariates: age and intracranial volume; P < .05). Control volume was largest, followed by AD (93% of control volume), SD (92%), PNFA (79%), and FTD (75%). CONCLUSIONS: Volume of the head and body of the caudate nucleus differs in subtypes of FTLD, due to differential frontostriatal dysfunction in subtypes being reflected in structural change in the caudate, and is correlated with cognition.

Volumetrics of the caudate nucleus: Reliability and validity of a new manual tracing protocol

Our aim was to develop a reliable and valid manual segmentation protocol for tracing the caudate nucleus in MRI for volumetric and, potentially, shape analysis of the caudate. Using the protocol, two inter- and intra-rater reliability studies were conducted using five different raters on two different image analysis platforms (ANALYZE, Mayo Biomedical Imaging Resource, Rochester MN, USA, and HERMES, Nuclear Diagnostics AB, Stockholm, Sweden). Reference images for the detailed protocol are described. Two studies were performed. In study 1, the intra-rater class correlation ICC(1,1) for an experienced rater (JCLL) using this protocol for caudate nucleus volumes was evaluated by repeating right and left caudate measurements on 10 scans (20 comparisons) and was 0.972. The inter-rater class correlation ICC(1,k) with OL was 0.922 on 5 scans (10 comparisons) and with BL was 0.960 on 5 scans (10 comparisons). In study 2, VT obtained an intra-rater class correlation of 0.9 on 5 scans (involving 10 comparisons, e.g. right and left caudate). The inter-rater class correlation ICC(1,k) was 0.988 on 5 scans (again involving 10 comparisons) with EM. We therefore developed a novel, reliable and reference image-based, method of outlining the caudate nucleus on axial MRI scans, usable in two different image analysis laboratories, across two different sets number of tracers reliably, and across software platforms. This method is therefore potentially usable for any image analysis package capable of displaying and measuring outlined voxels from MRI brain scans.

Cortical Morphometric Subclassification of Frontotemporal Lobar Degeneration

BACKGROUND AND PURPOSE: Frontotemporal lobar degeneration (FTLD) is a primary neurodegenerative disease comprising 3 clinical subtypes: frontotemporal dementia (FTD), semantic dementia (SD), and progressive nonfluent aphasia (PNFA). The subdivision is primarily based on the characteristic clinical symptoms displayed by each subtype. We hypothesized that these symptoms would be correlated to characteristic patterns of brain atrophy, which could be indentified and used for subclassification of subjects with FTLD. MATERIALS AND METHODS: Volumes of 9 cortical regions were manually parcellated and measured on both hemispheres on 27 controls, 12 patients with FTD, 9 patients with PNFA, and 13 patients with SD. The volumetric data were analyzed by traditional t tests and by a multivariate discriminant analysis (partial least squares discriminant analysis). RESULTS: The ensemble or pattern of atrophy was a good discriminator in pair-wise comparison between the subtypes: FTD compared with SD (sensitivity 100% [12/12], specificity 100% [13/13]); FTD compared with PNFA (sensitivity 92% [11/12], specificity 89% [8/9]); and SD compared with PNFA (sensitivity 86% [11/13], specificity 100% [9/9]). Temporal-versus-frontal atrophy was the most important pattern for discriminating SD from the other 2 subtypes. Right-sided versus left-sided atrophy was the most important pattern for discriminating between subjects with FTD and PNFA. CONCLUSIONS: FTLD subtypes generally display a characteristic pattern of atrophy, which may be considered in diagnosing patients with FTLD.

Putaminal Volume in Frontotemporal Lobar Degeneration and Alzheimer Disease: Differential Volumes in Dementia Subtypes and Controls

BACKGROUND AND PURPOSE: Frontostriatal (including the putamen) circuit–mediated cognitive dysfunction has been implicated in frontotemporal lobar degeneration (FTLD), but not in Alzheimer disease (AD) or healthy aging. We sought to assess putaminal volume as a measure of the structural basis of relative frontostriatal dysfunction in these groups. MATERIALS AND METHODS: We measured putaminal volume in FTLD subtypes: frontotemporal dementia (FTD, n = 12), semantic dementia (SD, n = 13), and progressive nonfluent aphasia (PNFA, n = 9) in comparison with healthy controls (n = 25) and patients with AD (n = 18). Diagnoses were based on accepted clinical criteria. We conducted manual volume measurement of the putamen blinded to the diagnosis on T1 brain MR imaging by using a standardized protocol. RESULTS: Paired t tests (P < .05) showed that the left putaminal volume was significantly larger than the right in all groups combined. Multivariate analysis of covariance with a Bonferroni correction was used to assess statistical significance among the subject groups (AD, FTD, SD, PNFA, and controls) as independent variables and right/left putaminal volumes as dependent variables (covariates, age and intracranial volume; P < .05). The right putamen in FTD was significantly smaller than in AD and controls; whereas in SD, it was smaller compared with controls with a trend toward being smaller than in AD. There was also a trend toward the putamen in the PNFA being smaller than that in controls and in patients with AD. Across the groups, there was a positive partial correlation between putaminal volume and Mini-Mental State Examination (MMSE). CONCLUSIONS: Right putaminal volume was significantly smaller in FTD, the FTLD subtype with the greatest expected frontostriatal dysfunction; whereas in SD and PNFA, it showed a trend towards being smaller, consistent with expectation, compared to controls and AD; and in SD, compared with AD and controls. Putaminal volume weakly correlated with MMSE.

Hippocampal Shape Analysis in Alzheimer's Disease and Frontotemporal Lobar Degeneration Subtypes

Hippocampal pathology is central to Alzheimers disease (AD) and other forms of dementia such as frontotemporal lobar degeneration (FTLD). Autopsy studies have shown that certain hippocampal subfields are more vulnerable than others to AD and FTLD pathology, in particular the subiculum and cornu ammonis 1 (CA1). We conducted shape analysis of hippocampi segmented from structural T1 MRI images on clinically diagnosed dementia patients and controls. The subjects included 19 AD and 35 FTLD patients [13 frontotemporal dementia (FTD), 13 semantic dementia (SD), and 9 progressive nonfluent aphasia (PNFA)] and 21 controls. Compared to controls, SD displayed severe atrophy of the whole left hippocampus. PNFA and FTD also displayed atrophy on the left side, restricted to the hippocampal head in FTD. Finally, AD displayed most atrophy in left hippocampal body with relative sparing of the hippocampal head. Consistent with neuropathological studies, most atrophic deformation was found in CA1 and subiculum areas in FTLD and AD.

Acceleration of hippocampal atrophy in a non-demented elderly population : the SNAC-K study

BACKGROUND Brain atrophy in Alzheimers disease (AD) includes not only AD-specific brain atrophy but also the atrophy induced by normal aging. Atrophy of the hippocampus has been one diagnostic marker of AD, but it was also found to emerge in healthy adults, along with increasing age. It was reported that the important age when age-related shrinkage of the hippocampus starts was around the mid-40s. The aim is to study the aging atrophy speed and acceleration of brain atrophy in a cross-sectional database, to identify the age at which acceleration of hippocampal atrophy starts in non-demented elderly persons. METHODS 544 subjects (aged 60-97 years; 318 female and 226 male) were recruited into the MRI study by using a subsample of an epidemiological sample of 3363 healthy non-demented elderly people (over 60 years of age). Hippocampus and ventricle sizes were measured. RESULTS The normalized volumes (by intracranial volume, ICV) of the hippocampus in males were smaller than those in females. The right hippocampus was larger than the left. The expansion of the lateral ventricles (2.80% per year in males, 2.95% in females) and third ventricle (1.58% and 2.28%, respectively) was more marked than the hippocampal shrinkage (0.68% and 0.79%, respectively). The suggested age at which acceleration of hippocampal atrophy starts is 72 years. CONCLUSIONS Males present smaller hippocampus volumes (normalized by ICV) than females; however, females are more vulnerable to hippocampal atrophy in a non-demented elderly population. An acceleration of hippocampal atrophy may emerge and start around 72 years of age in a non-demented elderly population.

Diffusion Tensor Tractography versus Volumetric Imaging in the Diagnosis of Behavioral Variant Frontotemporal Dementia

MRI diffusion tensor imaging (DTI) studies of white matter integrity in behavioral variant frontotemporal dementia have consistently shown involvement of frontal and temporal white matter, corresponding to regional loss of cortical volume. Volumetric imaging has a suboptimal sensitivity as a diagnostic tool and thus we wanted to explore if DTI is a better method to discriminate patients and controls than volumetric imaging. We examined the anterior cingulum bundle in 14 patients with behavioral variant frontotemporal dementia and 22 healthy controls using deterministic manual diffusion tensor tractography, and compared DTI parameters with two measures of cortical atrophy, VBM and cortical thickness, of the anterior cingulate cortex (ACC). Statistically significant changes between patients and controls were detected in all DTI parameters, with large effect sizes. ROC-AUC was for the best DTI parameters: 0.92 (fractional anisotropy) to 0.97 (radial diffusivity), 0.82 for the best cortical parameter, VBM of the ACC. Results from the AUC were confirmed with binary logistic regression analysis including demographic variables, but only for fractional anisotropy and mean diffusivity. Ability to classify patient/nonpatient status was significantly better for mean diffusivity vs. VBM (p=0.031), and borderline significant for fractional anisotropy vs. VBM (p=0.062). The results indicate that DTI could offer advantages in comparison with the assessment of cortical volume in differentiating patients with behavioral variant frontotemporal dementia and controls.

Shape analysis of the neostriatum in frontotemporal lobar degeneration, Alzheimer's disease, and controls

BACKGROUND AND PURPOSE Frontostriatal circuit mediated cognitive dysfunction has been implicated in frontotemporal lobar degeneration (FTLD), but not Alzheimers disease, or healthy aging. We measured the neostriatum (caudate nucleus and putamen) volume in FTLD (n=34), in comparison with controls (n=27) and Alzheimers disease (AD, n=19) subjects. METHODS Diagnoses were based on international consensus criteria. Manual bilateral segmentation of the caudate nucleus and putamen was conducted blind to diagnosis by a single analyst, on MRI scans using a standardized protocol. Intra-cranial volume was calculated via a stereological point counting technique and was used for scaling the shape analysis. The manual segmentation binaries were analyzed using UNC Shape Analysis tools (University of North Carolina) to perform comparisons among FTLD, AD, and controls for global shape, local p-value significance maps, and mean magnitude of shape displacement. RESULTS Shape analysis revealed that there was significant shape difference between FTLD, AD, and controls, consistent with the predicted frontostriatal dysfunction and of significant magnitude, as measured by displacement maps. There was a lateralized difference in shape for the left caudate for FTLD compared to AD; non-specific global atrophy in AD compared to controls; while FTLD showed a more specific pattern in regions relaying fronto- and corticostriatal circuits. CONCLUSIONS Shape analysis shows regional specificity of atrophy, manifest as shape deflation, with implications for frontostriatal and corticostriatal motoric circuits, in FTLD, AD, and controls.

Caudate volumes in public transportation workers exposed to trauma in the Stockholm train system

The caudate nucleus is a structure implicated in the neural circuitry of psychological responses to trauma. This study aimed to quantify the volume of the caudate in persons exposed to trauma. Thirty-six subjects under 65 were recruited from transport workers in Stockholm who reported having been unintentionally responsible for a person-under-the-train accident or among employees having experienced an assault in their work (1999-2001) between 3 months and 6 years before MRI scanning. In those exposed to the trauma, a DSM-IV diagnosis of post-traumatic stress disorder (PTSD) was made by an independent psychiatrist, with subjects being classified as PTSD or no PTSD. MRI data were analyzed blindly to all clinical information by an experienced rater using a standardized manual tracing protocol to quantify the volume of the caudate. Within-group comparisons of PTSD (n=19) and no PTSD (n=17) found the right caudate nucleus to be significantly (9%) larger than the left: a right hemisphere baseline asymmetry. A multivariate analysis of covariance (MANCOVA) was conducted to assess the volume of the caudate nucleus (right and left) in relation to the diagnosis of no PTSD (n=17) or PTSD (n=19). After adjustment for the covariates (age, sex, intracranial volume, years since trauma, and number of trauma episodes), there was a significant difference in raw right caudate nucleus volume between subjects with PTSD compared with those without PTSD. Volume of the left caudate nucleus was not significantly different between the PTSD and no PTSD groups. The right caudate volume in the PTSD group was 9% greater compared with the no PTSD group. There is a larger right hemisphere volume of the caudate within those exposed to trauma with active PTSD compared with those without PTSD, superimposed upon a baseline caudate asymmetry.