Michelle Mather

Regional Differences in White Matter Breakdown Between Frontotemporal Dementia and Early-Onset Alzheimer's Disease

BACKGROUND White matter abnormalities have been associated with both behavioral variant frontotemporal dementia (bvFTD) and Alzheimers disease (AD). OBJECTIVE Using MRI diffusion tensor imaging (DTI) measures, we compared white matter integrity between patients with bvFTD and those with early-onset AD and correlated these biomarkers with behavioral symptoms involving emotional blunting. METHODS We studied 8 bvFTD and 12 AD patients as well as 12 demographically-matched healthy controls (NCs). Using four DTI metrics (fractional anisotropy, axial diffusivity, radial diffusivity, and mean diffusivity), we assessed the frontal lobes (FWM) and genu of the corpus callosum (GWM), which are vulnerable late-myelinating regions, and a contrasting early-myelinating region (splenium of the corpus callosum). The Scale for Emotional Blunting Scale (SEB) was used to assess emotional functioning of the study participants. RESULTS Compared to AD patients and NCs, the bvFTD subjects exhibited significantly worse FWM and GWM integrity on all four DTI metrics sensitive to myelin and axonal integrity. In contrast, AD patients showed a numerical trend toward worse splenium of the corpus callosum integrity than bvFTD and NC groups. Significant associations between SEB ratings and GWM DTI measures were demonstrated in the combined bvFTD and AD sample. When examined separately, these relationships remained robust for the bvFTD group but not the AD group. CONCLUSIONS The regional DTI alterations suggest that FTD and AD are each associated with a characteristic distribution of white matter degradation. White matter breakdown in late-myelinating regions was associated with symptoms of emotional blunting, particularly within the bvFTD group.

Skin Conductance Levels May Reflect Emotional Blunting in Behavioral Variant Frontotemporal Dementia

Emotional blunting is a core diagnostic feature of behavioral variant frontotemporal dementia (bvFTD). The authors evaluated skin conductance as a measure of emotional blunting among 10 patients with bvFTD compared with 10 with Alzheimers disease and 14 healthy control subjects. Despite responses to an auditory startle stimulus, skin conductance levels (SCLs) were lower in the patients with bvFTD compared with the other groups. The low SCLs significantly correlated with ratings of emotional blunting. The authors conclude that low SCLs in bvFTD indicate a low resting sympathetic state and low emotional arousal. The measurement of SCLs may be a useful noninvasive diagnostic test for bvFTD.

Neuroanatomical correlates of emotional blunting in behavioral variant frontotemporal dementia and early-onset Alzheimer's disease.

BACKGROUND Emotional blunting is a characteristic feature of behavioral variant frontotemporal dementia (bvFTD) and can help discriminate between patients with bvFTD and other forms of younger-onset dementia. OBJECTIVE We compared the presence of emotional blunting symptoms in patients with bvFTD and early-onset Alzheimers disease (AD), and investigated the neuroanatomical associations between emotional blunting and regional brain volume. METHODS Twenty-five individuals with bvFTD (n = 11) and early-onset AD (n = 14) underwent magnetic resonance imaging (MRI) and were rated on symptoms of emotional blunting using the Scale for Emotional Blunting (SEB). The two groups were compared on SEB ratings and MRI-derived brain volume using tensor-based morphometry. Voxel-wise linear regression was performed to determine neuroanatomical correlates of SEB scores. RESULTS The bvFTD group had significantly higher SEB scores compared to the AD group. On MRI, bvFTD patients had smaller bilateral frontal lobe volume compared to AD patients, while AD patients had smaller bilateral temporal and left parietal volume than bvFTD patients. In bvFTD, SEB ratings were strongly correlated with right anterior temporal volume, while the association between SEB and the right orbitofrontal cortex was non-significant. CONCLUSIONS Symptoms of emotional blunting were more prevalent in bvFTD than early-onset AD patients. These symptoms were particularly associated with right-sided atrophy, with significant involvement of the right anterior temporal region. Based on these findings, the SEB appears to measure symptoms of emotional blunting that are localized to the right anterior temporal lobe.

An investigation of care-based vs. rule-based morality in frontotemporal dementia, Alzheimer's disease, and healthy controls.

Behavioral changes in dementia, especially behavioral variant frontotemporal dementia (bvFTD), may result in alterations in moral reasoning. Investigators have not clarified whether these alterations reflect differential impairment of care-based vs. rule-based moral behavior. This study investigated 18 bvFTD patients, 22 early onset Alzheimers disease (eAD) patients, and 20 healthy age-matched controls on care-based and rule-based items from the Moral Behavioral Inventory and the Social Norms Questionnaire, neuropsychological measures, and magnetic resonance imaging (MRI) regions of interest. There were significant group differences with the bvFTD patients rating care-based morality transgressions less severely than the eAD group and rule-based moral behavioral transgressions more severely than controls. Across groups, higher care-based morality ratings correlated with phonemic fluency on neuropsychological tests, whereas higher rule-based morality ratings correlated with increased difficulty set-shifting and learning new rules to tasks. On neuroimaging, severe care-based reasoning correlated with cortical volume in right anterior temporal lobe, and rule-based reasoning correlated with decreased cortical volume in the right orbitofrontal cortex. Together, these findings suggest that frontotemporal disease decreases care-based morality and facilitates rule-based morality possibly from disturbed contextual abstraction and set-shifting. Future research can examine whether frontal lobe disorders and bvFTD result in a shift from empathic morality to the strong adherence to conventional rules.

A Scale of Socioemotional Dysfunction in Frontotemporal Dementia

Early social dysfunction is a hallmark symptom of behavioral variant frontotemporal dementia (bvFTD); however, validated measures for assessing social deficits in dementia are needed. The purpose of the current study was to examine the utility of a novel informant-based measure of social impairment, the Socioemotional Dysfunction Scale (SDS) in early-onset dementia. Sixteen bvFTD and 18 early-onset Alzheimers disease (EOAD) participants received standard clinical neuropsychological measures and neuroimaging. Caregiver informants were administered the SDS. Individuals with bvFTD exhibited greater social dysfunction on the SDS compared with the EOAD group; t(32) = 6.32, p < .001. The scale demonstrated preliminary evidence for discriminating these frequently misdiagnosed groups (area under the curve = 0.920, p = <.001) and internal consistency α = 0.977. The SDS demonstrated initial evidence as an effective measure for detecting abnormal social behavior and discriminating bvFTD from EOAD. Future validation is recommended in larger and more diverse patient groups.

What dementia reveals about proverb interpretation and its neuroanatomical correlates

OBJECTIVE Neuropsychologists frequently include proverb interpretation as a measure of executive abilities. A concrete interpretation of proverbs, however, may reflect semantic impairments from anterior temporal lobes, rather than executive dysfunction from frontal lobes. The investigation of proverb interpretation among patients with different dementias with varying degrees of temporal and frontal dysfunction may clarify the underlying brain-behavior mechanisms for abstraction from proverbs. We propose that patients with behavioral variant frontotemporal dementia (bvFTD), who are characteristically more impaired on proverb interpretation than those with Alzheimers disease (AD), are disproportionately impaired because of anterior temporal-mediated semantic deficits. METHODS Eleven patients with bvFTD and 10 with AD completed the Delis-Kaplan Executive Function System (D-KEFS) Proverbs Test and a series of neuropsychological measures of executive and semantic functions. The analysis included both raw and age-adjusted normed data for multiple choice responses on the D-KEFS Proverbs Test using independent samples t-tests. Tensor-based morphometry (TBM) applied to 3D T1-weighted MRI scans mapped the association between regional brain volume and proverb performance. Computations of mean Jacobian values within select regions of interest provided a numeric summary of regional volume, and voxel-wise regression yielded 3D statistical maps of the association between tissue volume and proverb scores. RESULTS The patients with bvFTD were significantly worse than those with AD in proverb interpretation. The worse performance of the bvFTD patients involved a greater number of concrete responses to common, familiar proverbs, but not to uncommon, unfamiliar ones. These concrete responses to common proverbs correlated with semantic measures, whereas concrete responses to uncommon proverbs correlated with executive functions. After controlling for dementia diagnosis, TBM analyses indicated significant correlations between impaired proverb interpretation and the anterior temporal lobe region (left>right). CONCLUSIONS Among two dementia groups, those with bvFTD, demonstrated a greater number of concrete responses to common proverbs compared to those with AD, and this performance correlated with semantic deficits and the volume of the left anterior lobe, the hub of semantic knowledge. The findings of this study suggest that common proverb interpretation is greatly influenced by semantic dysfunction and that the use of proverbs for testing executive functions needs to include the interpretation of unfamiliar proverbs.

Neuropsychological and Neuroanatomical Correlates of the Social Norms Questionnaire in Frontotemporal Dementia Versus Alzheimer’s Disease

Traditional neuropsychological batteries may not distinguish early behavioral variant frontotemporal dementia (bvFTD) from Alzheimer’s disease (AD) without the inclusion of a social behavioral measure. We compared 33 participants, 15 bvFTD, and 18 matched patients with early-onset AD (eAD), on the Social Norms Questionnaire (SNQ), neuropsychological tests and 3-dimensional T1-weighted magnetic resonance imaging (MRI). The analyses included correlations of SNQ results (total score, overendorsement or “overadhere” errors, and violations or “break” errors) with neuropsychological results and tensor-based morphometry regions of interest. Patients with BvFTD had significantly lower SNQ total scores and higher overadhere errors than patients with eAD. On neuropsychological measures, the SNQ total scores correlated significantly with semantic knowledge and the overadhere subscores with executive dysfunction. On MRI analysis, the break subscores significantly correlated with lower volume of lateral anterior temporal lobes (aTL). The results also suggest that endorsement of social norm violations corresponds to the role of the right aTL in social semantic knowledge.

Are we comparing frontotemporal dementia and Alzheimer disease patients with the right measures

BACKGROUND Clinical research studies of behavioral variant frontotemporal dementia (bvFTD) often use Alzheimer disease (AD) as a comparison group for control of dementia variables, using tests of cognitive function to match the groups. These two dementia syndromes, however, are very different in clinical manifestations, and the comparable severity of these dementias may not be reflected by commonly used cognitive scales such as the Mini-Mental State Examination (MMSE). METHODS We evaluated different measures of dementia severity and symptoms among 20 people with bvFTD compared to 24 with early-onset AD. RESULTS Despite similar ages, disease-duration, education, and cognitive performance on two tests of cognitive function, the MMSE and the Montreal Cognitive Assessment (MoCA), the bvFTD participants, compared to the AD participants, were significantly more impaired on other measures of disease severity, including function (Functional Assessment Questionnaire (FAQ)), neuropsychiatric symptoms (Neuropsychiatric Inventory (NPI)), and global dementia stage (Clinical Dementia Rating Scales (CDRs)). However, when we adjusted for the frontotemporal lobar degeneration-CDR (FTLD-CDR) in the analyses, the two dementia groups were comparable across all measures despite significant differences on the cognitive scales. CONCLUSION We found tests of cognitive functions (MMSE and MoCA) to be insufficient measures for ensuring comparability between bvFTD and AD groups. In clinical studies, the FTLD-CDR, which includes additional language and behavior items, may be a better overall way to match bvFTD and AD groups on dementia severity.