David Foxe

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.

Verbal and Visuospatial Span in Logopenic Progressive Aphasia and Alzheimer's Disease

Logopenic progressive aphasia (LPA) is a form of primary progressive aphasia (PPA) characterized by hesitant speech with marked impairment in naming and repetition. LPA is associated with brain atrophy in the left temporal and inferior parietal cortices and is predominantly associated with Alzheimer’s disease (AD) pathology. In contrast to LPA, ‘‘typical’’ AD is commonly associated with episodic memory disturbance and bilateral medial temporal lobe atrophy. Recent evidence suggests verbal short-term memory is more impaired than visuospatial short-term memory in LPA. This study investigated verbal and visuospatial short-term memory in 12 LPA and 12 AD patients matched for disease severity, and in 12 age- and education-matched healthy controls. Overall, both patient groups showed significantly reduced verbal and visuospatial spans compared with controls. In addition, LPA patients performed significantly worse than AD patients on both forward and backward conditions of the Digit Span task. In contrast, no difference was present between patient groups on either version of the Spatial Span task. Importantly, LPA patients showed better visuospatial than verbal span whereas AD patients and controls did not differ across modality. This study demonstrates the specificity of the short-term memory disturbance in LPA, which arises from a breakdown of the phonological system.

Grief and joy: emotion word comprehension in the dementias.

OBJECTIVE Word comprehension deficits in neurodegenerative conditions are most striking in the syndrome of semantic dementia. Tests of word comprehension typically examine concrete and abstract nonemotion words. Whether or not understanding of words describing emotion concepts (e.g., insulted, fascinated) is also impaired in the dementias has not been systematically investigated. METHOD Patients with semantic dementia (SD; n = 8), behavioral-variant frontotemporal dementia (bvFTD; n = 8), Alzheimers disease (AD; n = 12), as well as healthy controls (n = 15) completed newly designed emotion word comprehension tasks. Participants also undertook the Graded Synonyms Test, an abstract and concrete nonemotion word comprehension measure. RESULTS Degradation of knowledge about negative and positive emotion words was most impaired in SD. Correlation analyses in the SD group also showed that knowledge of emotion words correlated with the understanding of abstract nonemotion words. The bvFTD group was impaired only when making associations for emotion words. The AD cohort did not differ from controls on any measures of word comprehension. CONCLUSIONS Impairment in word knowledge is greatest in the syndrome of SD, compared with bvFTD and AD, and includes concrete words, abstract words as well as emotion words. Importantly, word comprehension deficits affect positive and negative emotions.

Cognitive and Behavioral Symptoms in ALSFTD Detection, Differentiation, and Progression

Brief screening tools that detect and differentiate patients with amyotrophic lateral sclerosis and frontotemporal dementia (ALSFTD) from those more subtle cognitive or behavioral symptoms (ALS plus) and motor symptoms only (ALS pure) is pertinent in a clinical setting. The utility of 2 validated and data-driven tests (Mini-Addenbrooke’s Cognitive Examination [M-ACE] and Motor Neuron Disease Behavioral Scale [MiND-B]) was investigated in 70 ALS patients (24 ALSFTD, 19 ALS plus, and 27 ALS pure). More than 90% of patients with ALSFTD scored at or below the cutoff on the M-ACE, whereas this was seen in only about 20% of ALS patients without dementia. The MiND-B differentiated between ALS pure and ALS plus diagnostic categories. Rasch modeling of M-ACE and MiND-B items revealed early cognitive (fluency, memory recall) and behavioral (apathy) symptoms in ALSFTD. The combined use of the M-ACE and MiND-B detects patients with ALSFTD, differentiates along the ALS continuum, and offers insight into the progression of nonmotor symptomatology in ALSFTD.

Pronounced Impairment of Everyday Skills and Self-Care in Posterior Cortical Atrophy.

Posterior cortical atrophy (PCA) is a neurodegenerative syndrome characterized by progressive visual dysfunction and parietal, occipital, and occipitotemporal atrophy. The aim of this study was to compare the impact of PCA and typical Alzheimers disease (tAD) on everyday functional abilities and neuropsychiatric status. The Cambridge Behavioural Inventory-Revised was given to carers of 32 PCA and 71 tAD patients. PCA patients showed significantly greater impairment in everyday skills and self-care while the tAD group showed greater impairment in aspects of memory and orientation, and motivation. We suggest that PCA poses specific challenges for those caring for people affected by the condition.

The neural correlates of auditory and visuospatial span in logopenic progressive aphasia and Alzheimer's disease

INTRODUCTION Logopenic progressive aphasia (lv-PPA) is a form of primary progressive aphasia and is predominantly associated with Alzheimers disease (AD) pathology. The neuropsychological profiles of lv-PPA and typical clinical AD are, however, distinct. In particular, these two syndromes differ on attention span measures, where auditory attention span is more impaired in lv-PPA than in AD and visuospatial span appears more impaired in AD than in lv-PPA. The neural basis of these span profiles, however, remains unclear. METHOD Sixteen lv-PPA and 21 AD matched patients, and 15 education-matched healthy controls were recruited. All participants were assessed by a neurologist and completed a neuropsychological assessment that included the Wechsler Memory Scale-III Digit and Spatial Span tasks, and underwent a high-resolution structural brain MRI to conduct cortical thickness analyses. RESULTS Patient groups were impaired on all span tasks compared to Controls. In addition, performance on Digit Span Forward (DSF) was significantly lower in the lv-PPA than the AD group, while Spatial Span Forward (SSF) was significantly lower in the AD than the lv-PPA group. No differences were found between patient groups on the Digit or Spatial Span Backward tasks. Neuroimaging analyses revealed that reduced DSF performance correlated to thinning of the left superior temporal gyrus in the lv-PPA group, whereas reduced SSF performance was related to bilateral precentral sulcus and parieto-occipital thinning in the AD group. Analyses of the backward span tasks revealed that reduced Spatial Span Backward (SSB) performance in the lv-PPA group related to cortical thinning of the left superior parietal lobule. CONCLUSIONS This study demonstrates that while lv-PPA and AD commonly share the same underlying neuropathology, their span profiles are distinct and are mediated by divergent patterns of cortical degeneration.

Clinical heterogeneity of the C9orf72 genetic mutation in frontotemporal dementia

The C9orf72 genetic mutation represents the most common cause of familial frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Studies over the last 2 years have revealed a number of key features of this mutation in the fields of clinical neurology, imaging, pathology, and genetics. Despite these efforts, the clinical phenotype appears to extend beyond FTD and ALS into the realm of psychiatric disease, and while highly variable survival rates have been reported, the clinical course of carriers remains relatively unexplored. This report describes two contrasting C9orf72 cases, one with a protracted indolent course dominated by neuropsychiatric features and the other with a rapidly progressive dementia. In both cases, initial structural brain imaging was relatively normal.

FRONTIER Executive Screen: a brief executive battery to differentiate frontotemporal dementia and Alzheimer's disease

Background and objective Executive dysfunctions are a key clinical feature of behavioural-variant frontotemporal dementia (bvFTD). Such deficits are also found in Alzheimers disease (AD), making the differentiation between these two diseases difficult at times, particularly in the absence of extensive cognitive assessments. To address this issue, we developed the FRONTIER Executive Screen (FES), which combines three abbreviated measures of verbal fluency, inhibitory control and working memory. Methods We administered the FES to 28 patients with dementia (14 bvFTD, 14 AD) matched for disease severity and 33 age-matched and education-matched healthy controls. We also administered traditional tests of executive function to establish the concurrent validity of the FES. Results Both patient groups obtained lower FES scores (total and subscores) compared to controls. Correct classification into patient or control groups was reached in over 90% of study participants based on the FES total score. Only two patients with bvFTD obtained FES scores within 2 SDs of the control group. Receiver operating characteristic analyses on the patient groups showed that a cut-off FES total score of 7/15 achieved 71% sensitivity and 73% specificity for a diagnosis of bvFTD. In addition, the FES showed high correlations with traditional measures of executive function. Conclusions The FES is a brief (5–10 min) bedside screening measure which is simple to administer and score, and demonstrates good discriminative validity to differentiate bvFTD from AD. It is a useful addendum to general cognitive screening measures and can help with the differential diagnosis of dementia.

All Is Not Lost: Positive Behaviors in Alzheimer's Disease and Behavioral-Variant Frontotemporal Dementia with Disease Severity.

Background: Anecdotal evidence indicates that some patients with dementia exhibit novel or increased positive behaviors, such as painting or singing, after the disease onset. Due to the lack of objective measures, however, the frequency and nature of these changes has not been formally investigated. Objective: This study aimed to systematically identify changes in these behaviors in the two most common younger-onset dementia syndromes: Alzheimer’s disease (AD) and behavioral-variant frontotemporal dementia (bvFTD). Methods: Sixty-three caregivers of patients with dementia (32 caregivers of AD patients and 31 caregivers of bvFTD patients) participated in the study. Caregivers rated the presence and frequency of positive and negative behavior changes after the onset of dementia using the Hypersensory and Social/Emotional Scale (HSS) questionnaire, focusing on three domains: sensory processing, cognitive skills, and social/emotional processing. Six composites scores were obtained reflecting these three domains (two composite scores for each domain). Differences across scores and ratios of increased and decreased behaviors were analyzed between AD and bvFTD, at different disease severity levels. Results: After disease onset, significant changes in the sensory processing domain were observed across disease severity levels, particularly in AD. Composite scores of the other domains did not change significantly. Importantly, however, some novel or increased positive behaviors were present in between 10% (Music activities) and 70% (Hypersensitivity) of AD and bvFTD patients, regardless of disease severity. Conclusions: We provide the first systematic investigation of positive behaviors in AD and bvFTD. The newly developed HSS questionnaire is a valid measure to characterize changes and progression of positive behaviors in patients with dementia.