Elvira Jimenez

Neuropsychological and neuroimaging markers in early versus late-onset Alzheimer's disease.

Background: Early-onset Alzheimer’s disease (EOAD) has been overshadowed by the more common late-onset AD (LOAD). Yet, the literature indicates EOAD may have less hippocampal-memory presentations and more focal neocortical localization early in the disease. Objective: To evaluate these proposed differences between these 2 forms of AD and to explore what they inform about differences in AD pathophysiology. Methods: In all, 21 patients with EOAD and 24 patients with LOAD matched for disease progression and severity were compared on neurocognitive measures and resting state fluorodeoxy-glucose positron–emission tomography (FDG-PET). Results: Patients with EOAD had worse executive functions with greater hypometabolism in the parietal regions; whereas patients with LOAD had worse confrontation naming and verbal recognition memory with greater hypometabolism in inferior frontotemporal regions. Conclusions: In addition to highlighting significant differences between EOAD and LOAD, these results reveal dissociation between executive deficits in AD and frontal hypometabolism, suggesting early disturbances of the parietal–frontal network in EOAD.

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.

An advanced white matter tract analysis in frontotemporal dementia and early-onset Alzheimer’s disease

Cortical and subcortical nuclei degenerate in the dementias, but less is known about changes in the white matter tracts that connect them. To better understand white matter changes in behavioral variant frontotemporal dementia (bvFTD) and early-onset Alzheimer’s disease (EOAD), we used a novel approach to extract full 3D profiles of fiber bundles from diffusion-weighted MRI (DWI) and map white matter abnormalities onto detailed models of each pathway. The result is a spatially complex picture of tract-by-tract microstructural changes. Our atlas of tracts for each disease consists of 21 anatomically clustered and recognizable white matter tracts generated from whole-brain tractography in 20 patients with bvFTD, 23 with age-matched EOAD, and 33 healthy elderly controls. To analyze the landscape of white matter abnormalities, we used a point-wise tract correspondence method along the 3D profiles of the tracts and quantified the pathway disruptions using common diffusion metrics – fractional anisotropy, mean, radial, and axial diffusivity. We tested the hypothesis that bvFTD and EOAD are associated with preferential degeneration in specific neural networks. We mapped axonal tract damage that was best detected with mean and radial diffusivity metrics, supporting our network hypothesis, highly statistically significant and more sensitive than widely studied fractional anisotropy reductions. From white matter diffusivity, we identified abnormalities in bvFTD in all 21 tracts of interest but especially in the bilateral uncinate fasciculus, frontal callosum, anterior thalamic radiations, cingulum bundles and left superior longitudinal fasciculus. This network of white matter alterations extends beyond the most commonly studied tracts, showing greater white matter abnormalities in bvFTD versus controls and EOAD patients. In EOAD, network alterations involved more posterior white matter – the parietal sector of the corpus callosum and parahipoccampal cingulum bilaterally. Widespread but distinctive white matter alterations are a key feature of the pathophysiology of these two forms of dementia.

Observation of social behavior in frontotemporal dementia.

Background: The most characteristic manifestations of behavioral variant frontotemporal dementia (bvFTD) are abnormalities in social behavior. However, distinguishing bvFTD based on social behavior can be difficult in structured clinical settings. Methods: Using a Social Observation Inventory, 10 patients with bvFTD and 10 patients with Alzheimer’s disease (AD) were compared to their caregiver interlocutors on 1-hour mealtime, in-home videotaped segments. Results: Compared to caregivers and patients with AD, patients with bvFTD were significantly disturbed in social behavior. In contrast, patients with AD were indistinguishable from their caregivers. The lack of “you” comments and decreased tact and manners distinguished 92.6% of the patients with bvFTD from patients with AD and caregivers. The Social Observation Inventory scores correlated with scores on frontal-executive tests and socioemotional scales. Conclusions: The systematic observation of social behavior during routine activities may be one of the best ways to distinguish patients with bvFTD from normal individuals and from patients with other dementias.

Changes in personality after mild traumatic brain injury from primary blast vs. blunt forces

Introduction: Injuries from explosive devices can cause blast-force injuries, including mild traumatic brain injury (mTBI). Objective: This study investigated changes in personality from blast-force mTBI in comparison to blunt-force mTBI. Methods: Clinicians and significant others assessed US veterans who sustained pure blast-force mTBI (n = 12), as compared to those who sustained pure blunt-force mTBI (n = 12). Inclusion criteria included absence of any mixed blast–blunt trauma and absence of post-traumatic stress disorder. Measures included the Interpersonal Measure of Psychopathy (IM-P), the Big Five Inventory (BFI), the Interpersonal Adjectives Scale (IAS) and the Frontal Systems Behaviour Scale (FrSBe). Results: There were no group differences on demographic or TBI-related variables. Compared to the Blunt Group, the Blast Group had more psychopathy on the IM-P, with anger, frustration, toughness and boundary violations and tended to more neuroticism on the BFI. When pre-TBI and post-TBI assessments were compared on the IAS and FrSBe, only the patients with blast force mTBI had become more cold-hearted, aloof–introverted and apathetic. Conclusion: These results suggest that blast forces alone can cause negativistic behavioural changes when evaluated with selected measures of personality. Further research on isolated blast-force mTBI should focus on these personality changes and their relationship to blast over-pressure.

Patterns of Brain Atrophy in Clinical Variants of Frontotemporal Lobar Degeneration

Background/Aims: The clinical syndromes of frontotemporal lobar degeneration include behavioral variant frontotemporal dementia (bvFTD) and semantic (SV-PPA) and nonfluent variants (NF-PPA) of primary progressive aphasia. Using magnetic resonance imaging (MRI), tensor-based morphometry (TBM) was used to determine distinct patterns of atrophy between these three clinical groups. Methods: Twenty-seven participants diagnosed with bvFTD, 16 with SV-PPA, and 19 with NF-PPA received baseline and follow-up MRI scans approximately 1 year apart. TBM was used to create three-dimensional Jacobian maps of local brain atrophy rates for individual subjects. Results: Regional analyses were performed on the three-dimensional maps and direct comparisons between groups (corrected for multiple comparisons using permutation tests) revealed significantly greater frontal lobe and frontal white matter atrophy in the bvFTD relative to the SV-PPA group (p < 0.005). The SV-PPA subjects exhibited significantly greater atrophy than the bvFTD in the fusiform gyrus (p = 0.007). The NF-PPA group showed significantly more atrophy in the parietal lobes relative to both bvFTD and SV-PPA groups (p < 0.05). Percent volume change in ventromedial prefrontal cortex was significantly associated with baseline behavioral symptomatology. Conclusion: The bvFTD, SV-PPA, and NF-PPA groups displayed distinct patterns of progressive atrophy over a 1-year period that correspond well to the behavioral disturbances characteristic of the clinical syndromes. More specifically, the bvFTD group showed significant white matter contraction and presence of behavioral symptoms at baseline predicted significant volume loss of the ventromedial prefrontal cortex.

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.

Middle-aged children of Alzheimer parents, a pilot study: stable neurocognitive performance at 20-year follow-up.

The objective of this pilot study on a convenience sample of 25 offspring of Alzheimer patients (mean age 61.5 ± 8.8 years; range, 50-82) was the early detection of neurocognitive decline. This preliminary report appears to be the first one dealing with 20-year follow-up of neurocognitive data of Alzheimer’s disease (AD) children. Digit symbol (Wechsler Adult Intelligence Scale) was the only of 11 neurocognitive measures with a significant decline. And that decline between first and last testing (mean = 19.98 ± 0.30 years) was on raw scores, not scaled scores. Neither parents’ age at onset of AD nor autopsy confirmation or offspring APOE-e4 status influenced neurocognitive results. More robust data than currently available are needed to confirm the findings of this first pilot study and to determine both the trajectory of neurocognitive decline in AD and the risks of developing AD faced by children whose parent had the disease.

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.