Sharpley Hsieh

Validation of the Addenbrooke's Cognitive Examination III in frontotemporal dementia and Alzheimer's disease.

Background/Aims: The aims of this study were to validate the newly developed version of the Addenbrookes Cognitive Examination (ACE-III) against standardised neuropsychological tests and its predecessor (ACE-R) in early dementia. Methods: A total of 61 patients with dementia (frontotemporal dementia, FTD, n = 33, and Alzheimers disease, AD, n = 28) and 25 controls were included in the study. Results: ACE-III cognitive domains correlated significantly with standardised neuropsychological tests used in the assessment of attention, language, verbal memory and visuospatial function. The ACE-III also compared very favourably with its predecessor, the ACE-R, with similar levels of sensitivity and specificity. Conclusion: The results of this study provide objective validation of the ACE-III as a screening tool for cognitive deficits in FTD and AD.

Clinical staging and disease progression in frontotemporal dementia

Objective: We aimed to develop a novel tool capable of staging disease severity in frontotemporal dementia (FTD) based upon functional dependence and behavioral changes, and to assess change over time in the 3 main FTD variants (behavioral variant FTD [bvFTD]; progressive nonfluent aphasia [PNFA]; and semantic dementia [SemD]). Methods: The Frontotemporal Dementia Rating Scale (FRS) was developed in a validation cohort of 77 consecutive clinic attendees (bvFTD = 29; PNFA = 20; SemD = 28) and applied to an independent sample of 75 patients (bvFTD = 28; PNFA = 21; SemD = 26) to establish intergroup differences. Assessments from 42 patients followed up after 12 months were used to determine annual progression. Finally, a combined sample (n = 152) was used to determine length of symptoms in each severity category. Results: Six severity stages were identified and operationalized based upon a 30-item questionnaire (very mild to profound). The cross-sectional study revealed much greater levels of impairment in bvFTD than in the language variants, with limited correlation with general cognitive measures. Patients with SemD showed the closest association between length of symptoms and stage, taking, on average, 10 years to reach the severe stage. Patients with bvFTD appear to move most quickly between stages and patients with PNFA were intermediate. The FRS was capable of detecting functional deterioration in all 3 variants over 12 months. Conclusions: Disease progression differs across frontotemporal dementia (FTD) variants. Patients with behavioral variant FTD progress rapidly whereas those with semantic dementia progress more slowly. The Frontotemporal Dementia Rating Scale can aid in staging and determining disease progression. Length of symptoms and global cognitive assessments alone do not reflect disease severity and progression in FTD.

Distinguishing Subtypes in Primary Progressive Aphasia: Application of the Sydney Language Battery

Background/Aims: Primary progressive aphasia (PPA) comprises three main subtypes, varying in clinical features, patterns of brain atrophy, and underlying pathology. Differentiation of these variants is important for treatment and planning; however, simple, effective cognitive tests to aid diagnosis are lacking. This study introduces a new language battery - the SYDBAT (Sydney Language Battery) - to assist clinicians. Methods: Fifty-seven PPA patients and 54 age- and education-matched healthy controls were compared on naming, repetition, word comprehension, and semantic association subtests. Results: Significant group differences were found for all tasks, reflecting different language profiles for each group. Using discriminative function analysis, 80% of PPA cases were correctly classified from three SYDBAT scores, from which a simple diagnostic algorithm was defined. Conclusion: The SYDBAT is a fast and simple tool which provides a valuable adjunct to clinicians diagnosing PPA.

The impact of dementia severity on caregiver burden in frontotemporal dementia and Alzheimer disease.

Caregiver burden is greater in frontotemporal dementia (FTD) than in Alzheimer disease (AD). However, little is known of the impact of the 3 main clinical variants of FTD— behavioral-variant frontotemporal dementia (bvFTD), semantic dementia (SemDem), and progressive nonfluent aphasia (PNFA)—or the role of disease severity in caregiver burden. The Zarit Burden Inventory was used to measure caregiver burden of bvFTD (n=17), SemDem (n=20), PNFA (n=20), and AD (n=19) patients. Symptom duration, caregiver age, and relationship type were matched across groups. Moreover, a number of caregiver (mood, social network) and patient variables (functional disability, behavioral changes, relationship with caregiver, and dementia stage) were addressed to investigate their impact on caregiver burden. Caregivers of bvFTD patients reported the highest burden, whereas SemDem and PNFA caregivers reported burden similar to AD. A regression analysis revealed that caregiver burden in FTD, regardless of subtype, was explained by a model combining disease staging, relationship changes, and caregiver depression. Burden increased with disease severity in FTD. This study is the first to show that caregivers of SemDem, PNFA, and AD patients show similar burden, while confirming that bvFTD caregivers show higher burden than AD caregivers. More importantly, this study demonstrates that burden worsens with disease progression in FTD.

Neural basis of music knowledge: evidence from the dementias

The study of patients with semantic dementia has revealed important insights into the cognitive and neural architecture of semantic memory. Patients with semantic dementia are known to have difficulty understanding the meanings of environmental sounds from an early stage but little is known about their knowledge for famous tunes, which might be preserved in some cases. Patients with semantic dementia (n = 13), Alzheimers disease (n = 14) as well as matched healthy control participants (n = 20) underwent a battery of tests designed to assess knowledge of famous tunes, environmental sounds and famous faces, as well as volumetric magnetic resonance imaging. As a group, patients with semantic dementia were profoundly impaired in the recognition of everyday environmental sounds and famous tunes with consistent performance across testing modalities, which is suggestive of a central semantic deficit. A few notable individuals (n = 3) with semantic dementia demonstrated clear preservation of knowledge of known melodies and famous people. Defects in auditory semantics were mild in patients with Alzheimers disease. Voxel-based morphometry of magnetic resonance brain images showed that the recognition of famous tunes correlated with the degree of right anterior temporal lobe atrophy, particularly in the temporal pole. This area was segregated from the region found to be involved in the recognition of everyday sounds but overlapped considerably with the area that was correlated with the recognition of famous faces. The three patients with semantic dementia with sparing of musical knowledge had significantly less atrophy of the right temporal pole in comparison to the other patients in the semantic dementia group. These findings highlight the role of the right temporal pole in the processing of known tunes and faces. Overlap in this region might reflect that having a unique identity is a quality that is common to both melodies and people.

Brain correlates of musical and facial emotion recognition: evidence from the dementias.

The recognition of facial expressions of emotion is impaired in semantic dementia (SD) and is associated with right-sided brain atrophy in areas known to be involved in emotion processing, notably the amygdala. Whether patients with SD also experience difficulty recognizing emotions conveyed by other media, such as music, is unclear. Prior studies have used excerpts of known music from classical or film repertoire but not unfamiliar melodies designed to convey distinct emotions. Patients with SD (n = 11), Alzheimers disease (n = 12) and healthy control participants (n = 20) underwent tests of emotion recognition in two modalities: unfamiliar musical tunes and unknown faces as well as volumetric MRI. Patients with SD were most impaired with the recognition of facial and musical emotions, particularly for negative emotions. Voxel-based morphometry showed that the labelling of emotions, regardless of modality, correlated with the degree of atrophy in the right temporal pole, amygdala and insula. The recognition of musical (but not facial) emotions was also associated with atrophy of the left anterior and inferior temporal lobe, which overlapped with regions correlating with standardized measures of verbal semantic memory. These findings highlight the common neural substrates supporting the processing of emotions by facial and musical stimuli but also indicate that the recognition of emotions from music draws upon brain regions that are associated with semantics in language.

Cortical atrophy in ALS is critically associated with neuropsychiatric and cognitive changes

Objective: To characterize the patterns of brain atrophy in patients with amyotrophic lateral sclerosis (ALS) with and without cognitive and neuropsychiatric symptoms, in comparison to controls and patients with ALS–frontotemporal dementia (FTD). Methods: A total of 57 participants (ALS = 22; ALS-FTD = 17; controls = 18) were included, following current ALS and FTD criteria. Patients with ALS were further subclassified into ALS with cognitive and behavioral symptoms (ALS-plus; n = 8) and those without (ALS; n = 14). By definition, ALS-plus did not reach the diagnostic threshold for ALS-FTD. All patients underwent neuropsychological and neuropsychiatric assessments, and underwent a brain MRI. Voxel-based morphometry analysis was conducted to establish patterns of brain atrophy. Results: Cortical atrophy in ALS was linked to neuropsychiatric and cognitive changes (ALS-plus vs ALS). Patients with ALS-plus had significant atrophy across motor and somatosensory as well as adjacent frontal and parietal areas, even after strict multiple comparison correction. By contrast, patients with ALS showed no significant cortical atrophy, and only brainstem atrophy. Importantly, atrophy in ALS-plus was not as widespread as in ALS-FTD, with ALS-plus atrophy mostly confined to motor and somatosensory areas, while atrophy in ALS-FTD also included substantial frontal and temporal atrophy. Conclusions: The present findings establish that cortical atrophy in ALS is highly dependent upon neuropsychiatric and cognitive changes. Previous inconsistent findings of cortical atrophy in ALS likely relate to the inclusion of cognitively affected patients and patients with pure motor ALS.

Orbitofrontal Dysfunction Discriminates Behavioral Variant Frontotemporal Dementia from Alzheimer's Disease

Background: Behavioral variant frontotemporal dementia (bvFTD) patients show prefrontal cortex dysfunction and atrophy. Methods: We investigated whether executive function in conjunction with prefrontal cortex atrophy discriminates bvFTD and Alzheimer’s disease (AD) patients efficiently at presentation. Results: AD and bvFTD patients were distinguishable by 89.5% on their performance of 3 executive tasks: the Hayling Test of Inhibitory Control, Digit Span Backward and Letter Fluency. Similarly, scan ratings showed that orbitofrontal cortex (OFC) and dorsolateral prefrontal cortex regions distinguish both patient groups. More importantly, employing the Hayling error score in conjunction with the OFC atrophy rating showed that 92% of patients can be correctly classified into bvFTD and AD. Conclusion: A combination of OFC and disinhibition measures appears to be a powerful diagnostic tool in differentiating bvFTD from AD patients in this preliminary study.

Cognitive decline in logopenic aphasia: more than losing words.

Objective: To track cognitive and language changes over time in patients with logopenic (lv-PPA) and semantic (sv-PPA) variants of primary progressive aphasia (PPA). Methods: Thirteen consecutive patients with lv-PPA and 11 patients with sv-PPA underwent yearly evaluation for a mean of 3 years. Nineteen patients (11 lv-PPA, 8 sv-PPA) had Pittsburgh compound B PET scans. Outcome variables included the Mini-Mental State Examination, Addenbrookes Cognitive Examination–revised (ACE-R) with its 5 cognitive subscores, and 3 language tasks based on single word processing. Mixed-models regressions were used to estimate the differential rate of decline between cohorts. Results: Despite equivalent level of baseline impairment, the lv-PPA cohort showed more rapid and generalized cognitive decline that involved nonverbal domains, with the majority of cases meeting criteria for dementia within 12 months. By contrast, cognitive changes in the sv-PPA cohort were slower and remained confined to verbally mediated tasks. Conclusions: Patients with lv-PPA are on the cusp of global dementia that typically develops quite rapidly, contrasting with the long period of circumscribed semantic impairment seen in patients with sv-PPA. The ACE-R appears capable of monitoring decline, which is relevant to therapeutic trials.

One size does not fit all: Face emotion processing impairments in semantic dementia, behavioural-variant frontotemporal dementia and Alzheimer's disease are mediated by distinct cognitive deficits

Patients with frontotemporal dementia (both behavioural variant [bvFTD] and semantic dementia [SD]) as well as those with Alzheimers disease (AD) show deficits on tests of face emotion processing, yet the mechanisms underlying these deficits have rarely been explored. We compared groups of patients with bvFTD (n = 17), SD (n = 12) or AD (n = 20) to an age- and education-matched group of healthy control subjects (n = 36) on three face emotion processing tasks (Ekman 60, Emotion Matching and Emotion Selection) and found that all three patient groups were similarly impaired. Analyses of covariance employed to partial out the influences of language and perceptual impairments, which frequently co-occur in these patients, provided evidence of different underlying cognitive mechanisms. These analyses revealed that language impairments explained the original poor scores obtained by the SD patients on the Ekman 60 and Emotion Selection tasks, which involve verbal labels. Perceptual deficits contributed to Emotion Matching performance in the bvFTD and AD patients. Importantly, all groups remained impaired on one task or more following these analyses, denoting a primary emotion processing disturbance in these dementia syndromes. These findings highlight the multifactorial nature of emotion processing deficits in patients with dementia.