Search

Brain magnetic resonance imaging (MRI) studies have demonstrated regional patterns of brain macrostructural atrophy and white matter microstructural alterations separately in the three major subtypes of frontotemporal lobar degeneration (FTLD), which includes behavioral variant frontotemporal dementia (bvFTD), semantic dementia (SD), and progressive nonfluent aphasia (PNFA). This study was to investigate to what extent the pattern of white matter microstructural alterations in FTLD subtypes mirrors the pattern of brain atrophy, and to compare the ability of various diffusion tensor imaging (DTI) indices in characterizing FTLD patients, as well as to determine whether DTI measures provide greater classification power for FTLD than measuring brain atrophy. Twenty-five patients with FTLD (13 with bvFTD, 6 with SD, and 6 with PNFA) and 19 healthy age-matched control subjects underwent both structural MRI and DTI scans. Measurements of regional brain atrophy were based on T1-weighted MRI data and voxel-based morphometry. Measurements of regional white matter degradation were based on voxelwise as well as regions-of-interest tests of DTI variations, expressed as fractional anisotropy, axial diffusivity, and radial diffusivity. Compared to controls, bvFTD, SD, and PNFA patients each exhibited characteristic regional patterns of brain atrophy and white matter damage. DTI overall provided significantly greater accuracy for FTLD classification than brain atrophy. Moreover, radial diffusivity was more sensitive in assessing white matter damage in FTLD than other DTI indices. The findings suggest that DTI in general and radial diffusivity in particular are more powerful measures for the classification of FTLD patients from controls than brain atrophy. [ABSTRACT FROM AUTHOR]

Predicting the progression of dementia is a challenge for clinicians yet this information is highly valued by patients' families. An informally observed 4-stage model of dementia can be helpful in educating caregivers and preparing them for what lies ahead. In the behavioral variant of frontotemporal dementia (bvFTD), this model describes the evolution of behavioral disturbances and is characterized by an inflection point between stage 2 (progressively severe behavioral aberration) and stage 3 (increasing apathy and remission of behavior problems). In this study, we sought evidence for this model using a database of serial Neuropsychiatric Inventory (NPI) scores for 45 patients with FTD and 47 patients with Alzheimer's disease (AD). We transformed the NPI scores into a single variable for each participant that represented the yearly rate of change in total NPI score and used this as the dependent variable in a multivariate linear regression. Age at onset of dementia, NPI score at initial visit, and duration of illness at first NPI all contributed significantly to the regression model in the bvFTD group. Participants with an initial NPI acquired before 6 years of disease duration tended to have a more positive rate of change in NPI total score (representing worsening behavioral disturbances) than those with an initial NPI performed after 6 years. None of the aforementioned variables were significantly associated with yearly change in NPI total score in the AD group. These results support a crescendo-decrescendo trajectory of behavioral symptoms in bvFTD but do not suggest that there is a similar pattern in AD, and further longitudinal data collection is necessary. [ABSTRACT FROM AUTHOR]

Patients with early age-of-onset Alzheimer's disease show more rapid progression, more generalized cognitive deficits and greater cortical atrophy and hypometabolism compared to late-onset patients at a similar disease stage. The biological mechanisms that underlie these differences are not well understood. The purpose of this study was to examine in vivo whether metabolic differences between early-onset and late-onset Alzheimer's disease are associated with differences in the distribution and burden of fibrillar amyloid-beta. Patients meeting criteria for probable Alzheimer's disease (National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's; Disease and Related Disorders Association criteria) were divided based on estimated age at first symptom (less than or greater than 65 years) into early-onset (n = 21, mean age-at-onset 55.2 +/- 5.9 years) and late-onset (n = 18, 72.0 +/- 4.7 years) groups matched for disease duration and severity. Patients underwent positron emission tomography with the amyloid-beta-ligand [(11)C]-labelled Pittsburgh compound-B and the glucose analogue [(18)F]-labelled fluorodeoxyglucose. A group of cognitively normal controls (n = 30, mean age 73.7 +/- 6.4) was studied for comparison. [(11)C]-labelled Pittsburgh compound-B images were analysed using Logan graphical analysis (cerebellar reference) and [(18)F]-labelled fluorodeoxyglucose images were normalized to mean activity in the pons. Group differences in tracer uptake were assessed on a voxel-wise basis using statistical parametric mapping, and by comparing mean values in regions of interest. To account for brain atrophy, analyses were repeated after applying partial volume correction to positron emission tomography data. Compared to normal controls, both early-onset and late-onset Alzheimer's disease patient groups showed increased [(11)C]-labelled Pittsburgh compound-B uptake throughout frontal, parietal and lateral temporal cortices and striatum on voxel-wise and region of interest comparisons (P < 0.05). However, there were no significant differences in regional or global [(11)C]-labelled Pittsburgh compound-B binding between early-onset and late-onset patients. In contrast, early-onset patients showed significantly lower glucose metabolism than late-onset patients in precuneus/posterior cingulate, lateral temporo-parietal and occipital corticies (voxel-wise and region of interest comparisons, P < 0.05). Similar results were found for [(11)C]-labelled Pittsburgh compound-B and [(18)F]-labelled fluorodeoxyglucose using atrophy-corrected data. Age-at-onset correlated positively with glucose metabolism in precuneus, lateral parietal and occipital regions of interest (controlling for age, education and Mini Mental State Exam, P < 0.05), while no correlations were found between age-at-onset and [(11)C]-labelled Pittsburgh compound-B binding. In summary, a comparable burden of fibrillar amyloid-beta was associated with greater posterior cortical hypometabolism in early-onset Alzheimer's disease. Our data are consistent with a model in which both early amyloid-beta accumulation and increased vulnerability to amyloid-beta pathology play critical roles in the pathogenesis of Alzheimer's disease in young patients. [ABSTRACT FROM AUTHOR]

Emotional blunting and abnormal processing of rewards and punishments represent early features of frontotemporal lobar degeneration (FTLD). Better understanding of the physiological underpinnings of these emotional changes can be facilitated by the use of classical psychology approaches. Fear conditioning (FC) is an extensively used paradigm for studying emotional processing that has rarely been applied to the study of dementia. We studied FC in controls (n = 25), Alzheimer's disease (n = 25) and FTLD (n = 25). A neutral stimulus (coloured square on a computer screen) was repeatedly paired with a 1 s burst of 100 db white noise. Change in skin conductance response to the neutral stimulus was used to measure conditioning. Physiological-anatomical correlations were examined using voxel-based morphometry (VBM). Both patient groups showed impaired acquisition of conditioned responses. However, the basis for this deficit appeared to differ between groups. In Alzheimer's disease, impaired FC occurred despite normal electrodermal responses to the aversive stimulus. In contrast, FTLD patients showed reduced skin conductance responses to the aversive stimulus, which contributed significantly to their FC deficit. VBM identified correlations with physiological reactivity in the amygdala, anterior cingulate cortex, orbitofrontal cortex and insula. These data indicate that Alzheimer's disease and FTLD both show abnormalities in emotional learning, but they suggest that in FTLD this is associated with a deficit in basic electrodermal response to aversive stimuli, consistent with the emotional blunting described with this disorder. Deficits in responses to aversive stimuli could contribute to both the behavioural and cognitive features of FTLD and Alzheimer's disease. Further study of FC in humans and animal models of dementia could provide a valuable window into these symptoms. [ABSTRACT FROM AUTHOR]

Alzheimer's disease and frontotemporal dementia (FTD) can be difficult to differentiate clinically because of overlapping symptoms. Distinguishing the two dementias based on volumetric measurements of brain atrophy with MRI has been only partially successful. Whether MRI measurements of cortical thinning improve the differentiation between Alzheimer's disease and FTD is unclear. In this study, we measured cortical thickness using a set of automated tools (Freesurfer) to reconstruct the brain's cortical surface from T1-weighted structural MRI data in 22 patients with Alzheimer's disease, 19 patients with FTD and 23 cognitively normal subjects. The goals were to detect the characteristic patterns of cortical thinning in these two types of dementia, to test the relationship between cortical thickness and cognitive impairment, to determine if measurement of cortical thickness is better than that of cortical volume for differentiating between these dementias and normal ageing and improving the classification of Alzheimer's disease and FTD based on neuropsychological scores alone. Compared to cognitively normal subjects, Alzheimer's disease patients had a thinner cortex primarily in bilateral, frontal, parietal, temporal and occipital lobes (P < 0.001), while FTD patients had a thinner cortex in bilateral, frontal and temporal regions and some thinning in inferior parietal regions and the posterior cingulate (P < 0.001). Compared to FTD patients, Alzheimer's disease patients had a thinner cortex (P < 0.001) in parts of bilateral parietal and precuneus regions. Cognitive impairment was negatively correlated with cortical thickness of frontal, parietal and temporal lobes in Alzheimer's disease, while similar correlations were not significant in FTD. Measurement of cortical thickness was similar to that of cortical volume in differentiating between normal ageing, Alzheimer's disease and FTD. Furthermore, cortical thickness measurements significantly improved the classification between Alzheimer's disease and FTD based on neuropsychological scores alone, including the Mini-Mental State Examination and a modified version of the Trail-Making Test. In conclusion, the characteristic patterns of cortical thinning in Alzheimer's disease and FTD suggest that cortical thickness may be a useful surrogate marker for these types of dementia. [ABSTRACT FROM AUTHOR]