Pavlov's Orienting Response in Frontotemporal Dementia.

Behavioral variant frontotemporal dementia (bvFTD) is a neurodegenerative disorder with initial disturbances in socioemotional behavior in the absence of a sensitive diagnostic test. This study evaluated Pavlov's "orienting response" (OR) or "what is it?" reflex as a measure of their ability to refocus attention on socioemotional stimuli and as a potentially distinguishing measure for bvFTD. Ten patients with bvFTD were compared with 18 normal controls (NC) on ORs (defined as initial heart rate [HR] deceleration) to different pictures based on social and emotional (valence) differences from the International Affective Picture Stimuli. HR was measured while participants viewed pleasant-nonsocial (e.g., food), unpleasant-nonsocial (e.g., garbage), pleasant-social (e.g., babies), and unpleasant-social (e.g., violence) pictures. Participants watched each picture for 6 seconds, and the study examined HR changes during the first 2-second OR interval. The results showed significant differences in valence (pleasant-unpleasant) and valence-group interactions, but no effects of nonsocial-social. Whereas the NCs showed the expected HR deceleration (OR) to unpleasant stimuli, the bvFTD patients showed increased HRs without an initial refocusing. Decreased HR slowing to stimuli among the bvFTD patients correlated with increased scores on an emotional blunting scale. These findings suggest that decreased socioemotional behavior in bvFTD may be associated with decreased appreciation of emotional aspects of stimuli as evidenced by decreased ORs to emotional stimuli, regardless of social content. These findings also suggest further investigation of the OR in bvFTD as an early diagnostic measure for this disorder.

Evaluation of emotional blunting in behavioral variant frontotemporal dementia compared to Alzheimer's disease.

BACKGROUND: Emotional blunting is a major clinical feature of behavioral variant frontotemporal dementia (bvFTD). Assessing the change in emotional blunting may facilitate the differential diagnosis of this disorder and can quantify a major source of distress for the patients' caregivers and families. METHODS: We evaluated investigator ratings on the Scale for Emotional Blunting (SEB) for 13 patients with bvFTD versus 18 patients with early-onset Alzheimer's disease (AD). The caregivers also performed SEB ratings for both the patients' premorbid behavior (before dementia onset) and the patients' behavior on clinical presentation (after dementia onset). RESULTS: Before the onset of dementia, the caregivers reported normal SEB scores for both dementia groups. After the onset of dementia, both caregivers and investigators reported greater SEB scores for the bvFTD patients compared to the AD patients. The patients were rated to be much more emotionally blunted by the bvFTD caregivers than by the investigators. A change of ≥15 in the caregiver SEB ratings suggests bvFTD. The change in caregiver SEB ratings was positively correlated with bifrontal hypometabolism on FDG-PET scans. CONCLUSIONS: Changes in the caregiver assessment of emotional blunting with dementia onset can distinguish patients with bvFTD from those with AD, and they may better reflect the impact of emotional blunting than similar assessments made by clinicians/investigators.

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 Alzheimer's 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.

Eye hand coordination in children with cerebral palsy.

Reaching to grasp an object of interest requires complex sensorimotor coordination involving eye, head, hand and trunk. While numerous studies have demonstrated deficits in each of these systems individually, little is known about how children with cerebral palsy (CP) coordinate multiple motor systems for functional tasks. Here we used kinematics, remote eye tracking and a trunk support device to examine the functional coupling of the eye, head and hand and the extent to which it was constrained by trunk postural control in 10 children with CP (6-16 years). Eye movements in children with CP were similar to typically developing (TD) peers, while hand movements were significantly slower. Postural support influenced initiation of hand movements in the youngest children (TD & CP) and execution of hand movements in children with CP differentially depending on diagnosis. Across all diagnostic categories, the most robust distinction between TD children and children with CP was in their ability to isolate eye, head and hand movements. Results of this study suggest that deficits in motor coordination for accurate reaching in children with CP may reflect coupled eye, head, and hand movements. We have previously suggested that coupled activation of effectors may be the default output for the CNS during early development.

Initial Heart Rate Reactivity to Socioemotional Pictures in Early-Onset Alzheimer's Disease.

Patients with Alzheimer's disease (AD) often have generalized anxiety, particularly in early-onset AD (EOAD) or the first stages of their disease. This increased anxiety could be associated with decreased sensorimotor gating with increased attention to significant stimuli from AD pathology in the entorhinal cortex. We investigated whether widening initial attention to socioemotional stimuli was association with anxiety among 16 patients with first stage EOAD compared to 19 normal controls (NCs). The participants underwent assessment of their initial heart rate deceleration ("orienting response"; OR), a measure of attentional refocusing, to pictures (International Affective Picture Stimuli) varying in pleasant-unpleasant valence and social-nonsocial content. The results showed group differences; the EOAD patients had significantly larger ORs than the NCs across conditions, with larger ORs in each valence and social condition. In addition, the EOAD patients, but not the NCs, showed ORs to normally less threatening stimuli, particularly pleasant, but also less significantly, social stimuli. On the Neuropsychiatric Inventory, the ORs among the EOAD patients significantly correlated with anxiety scores. Together, these findings suggest that anxiety in mild EOAD may be associated with widening attentional refocusing to socioemotional stimuli, possibly reflecting decreased sensorimotor gating in the entorhinal cortex. This finding could be a potential biomarker for the first stages of AD.

White Matter Changes Associated with Resting Sympathetic Tone in Frontotemporal Dementia vs. Alzheimer's Disease.

BACKGROUND: Resting sympathetic tone, a measure of physiological arousal, is decreased in patients with apathy and inertia, such as those with behavioral variant frontotemporal dementia (bvFTD) and other frontally-predominant disorders. OBJECTIVE: To identify the neuroanatomical correlates of skin conductance levels (SCLs), an index of resting sympathetic tone and apathy, among patients with bvFTD, where SCLs is decreased, compared to those with Alzheimer's disease (AD), where it is not. METHODS: This study analyzed bvFTD (n = 14) patients and a comparison group with early-onset AD (n = 19). We compared their resting SCLs with gray matter and white matter regions of interest and white matter measures of fiber integrity on magnetic resonance imaging and diffusion tensor imaging. RESULTS: As expected, bvFTD patients, compared to AD patients, had lower SCLs, which correlated with an apathy measure, and more gray matter loss and abnormalities of fiber integrity (fractional anisotropy and mean diffusivity) in frontal-anterior temporal regions. After controlling for group membership, the SCLs were significantly correlated with white matter volumes in the cingulum and inferior parietal region in the right hemisphere. CONCLUSION: Among dementia patients, SCLs, and resting sympathetic tone, may correlate with quantity of white matter, rather than with gray matter or with white matter fiber integrity. Loss of white matter volumes, especially involving a right frontoparietal network, may reflect chronic loss of cortical axons that mediate frontal control of resting sympathetic tone, changes that could contribute to the apathy and inertia of bvFTD and related disorders.

Hippocampal and mesial temporal sclerosis in early-onset frontotemporal lobar degeneration versus Alzheimer's disease.

Hippocampal sclerosis (HS) and mesial temporal sclerosis (MTS) may occur with frontotemporal lobar degeneration (FTLD) and Alzheimer's disease (AD) as well as with normal aging. Prior studies suggest that HS/MTS may be more closely associated with FTLD but have not directly compared the prevalence and clinical characteristics of HS/MTS between neuropathologically confirmed early-onset (age ≤ 65) cohorts of FTLD and AD. We identified patients with early-onset FTLD (n = 136) and AD (n = 267) from National Alzheimer's Center Consortium databases and compared neuropathological and clinical data between these 2 groups. The FTLD group had a significantly higher prevalence of HS/MTS than that of the AD group. However, HS/MTS was associated with increasing age and memory impairment in the AD group but not in the FTLD group. These findings are consistent with the hypothesis that HS/MTS in FTLD occurs as part of the primary pathological process, rather than as a secondary, nonspecific effect of aging on memory and hippocampal function.

Rich club network analysis shows distinct patterns of disruption in frontotemporal dementia and Alzheimer's disease.

Diffusion imaging and brain connectivity analyses can reveal the underlying organizational patterns of the human brain, described as complex networks of densely interlinked regions. Here, we analyzed 1.5-Tesla whole-brain diffusion-weighted images from 64 participants - 15 patients with behavioral variant frontotemporal (bvFTD) dementia, 19 with early-onset Alzheimer's disease (EOAD), and 30 healthy elderly controls. Based on whole-brain tractography, we reconstructed structural brain connectivity networks to map connections between cortical regions. We examined how bvFTD and EOAD disrupt the weighted 'rich club' - a network property where high-degree network nodes are more interconnected than expected by chance. bvFTD disrupts both the nodal and global organization of the network in both low- and high-degree regions of the brain. EOAD targets the global connectivity of the brain, mainly affecting the fiber density of high-degree (highly connected) regions that form the rich club network. These rich club analyses suggest distinct patterns of disruptions among different forms of dementia.

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 Alzheimer's 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.

Clinicopathologic differences among patients with behavioral variant frontotemporal dementia.

OBJECTIVE: To characterize the presenting symptoms and signs of patients clinically diagnosed with behavioral variant frontotemporal dementia (bvFTD) and who had different neuropathologic findings on autopsy. METHODS: This study reviewed all patients entered as clinical bvFTD in the National Alzheimer's Coordinating Center's database and who had both clinical and neuropathologic data from 2005 to 2011. Among the 107 patients identified, 95 had unambiguous pathologic findings, including 74 with frontotemporal lobar degeneration (bvFTD-FTLD) and 21 with Alzheimer disease (bvFTD-AD). The patients with bvFTD-FTLD were further subdivided into τ-positive (n = 23) or τ-negative (n = 51) histopathology subgroups. Presenting clinical signs and symptoms were compared between these neuropathologic groups. RESULTS: The patients with bvFTD-FTLD were significantly more likely than patients with bvFTD-AD to have initially predominant personality changes and poor judgment/decision-making. In contrast, patients with bvFTD-AD were more likely than patients with bvFTD-FTLD to have memory difficulty and delusions/hallucinations and agitation. Within the bvFTD-FTLD group, the τ-positive subgroup had more patients with initial behavioral problems and personality change than the τ-negative subgroup, who, in turn, had more patients with initial cognitive impairment and speech problems. CONCLUSION: During life, patients with AD pathology may be misdiagnosed with bvFTD if they have an early age at onset and prominent neuropsychiatric features despite having greater memory difficulties and more intact personality and executive functions than patients with bvFTD-FTLD. Among those with FTLD pathology, patients with τ-positive bvFTD were likely to present with behavior/personality changes. These findings offer clues for antemortem recognition of neuropathologic subtypes of bvFTD.

Nonamnestic presentations of early-onset Alzheimer's disease.

Early-onset Alzheimer's disease (EOAD) beginning before the age of 65 may differ from late-onset AD (LOAD) in clinical course and frequency of nonamnestic presentations. In a 10-year retrospective review, 125 patients with EOAD, diagnosed clinically and verified by functional neuroimaging, were compared with 56 patients with LOAD and further classified depending on predominant cognitive difficulty on presentation. Eighty (64%) of the patients with EOAD had a nonamnestic presentation, compared with only 7 (12.5%) of the patients with LOAD. Compared with LOAD, the patients with EOAD had a shorter duration with lower Mini-Mental State Examination scores. The neuroimaging reports among the patients with EOAD showed more hippocampal atrophy with an amnestic presentation, more left parietal changes with impaired language presentations, and more right parietal and occipital changes with impaired visuospatial presentations. These findings indicate that EOAD differs from LOAD in a more aggressive course and in having predominantly nonamnestic presentations that vary in neuropathological location.

Comparison of clinical characteristics between familial and non-familial early onset Alzheimer's disease.

Although familial Alzheimer's disease (FAD) is an early onset AD (EAD), most patients with EAD do not have a familial disorder. Recent guidelines recommend testing for genes causing FAD only in those EAD patients with two first-degree relatives. However, some patients with FAD may lack a known family history or other indications for suspecting FAD but might nonetheless be carriers of FAD mutations. The study was aimed to identify clinical features that distinguish FAD from non-familial EAD (NF-EAD). A retrospective review of a university-based cohort of 32 FAD patients with PSEN1-related AD and 81 with NF-EAD was conducted. The PSEN1 patients, compared to the NF-EAD patients, had an earlier age of disease onset (41.8 ± 5.2 vs. 55.9 ± 4.8 years) and, at initial assessment, a longer disease duration (5.1 ± 3.4 vs. 3.3 ± 2.6 years) and lower MMSE scores (10.74 ± 8.0 vs. 20.95 ± 5.8). Patients with NF-EAD were more likely to present with non-memory deficits, particularly visuospatial symptoms, than were FAD patients. When age, disease duration, and MMSE scores were controlled in a logistical regression model, FAD patients were more likely to have significant headaches, myoclonus, gait abnormality, and pseudobulbar affect than those with NF-EAD. In addition to a much younger age of onset, FAD patients with PSEN1 mutations differed from those with NF-EAD by a history of headaches and pseudobulbar affect, as well as myoclonus and gait abnormality on examination. These may represent differences in pathophysiology between FAD and NF-EAD and in some contexts such findings should lead to genetic counseling and appropriate recommendations for genetic testing for FAD.