The influence of culture and cognitive reserve on the clinical presentation of behavioural-variant frontotemporal dementia.

Characterisation of the clinical profile of behavioural-variant frontotemporal dementia (bvFTD) has predominantly been based on Western samples. Some small studies have suggested that the clinical profile may differ in culturally and linguistically diverse populations. Additionally, there is evidence that patients from non-English speaking backgrounds may have more cognitive reserve, allowing them to tolerate more disease pathology before clinical symptoms emerge. This study aims to characterise the clinical profiles of patients with bvFTD from culturally diverse backgrounds. BvFTD patients were classified as Australian-born (Australian) or Culturally and Linguistically Diverse-English-speaking (CALD-English) and Culturally and Linguistically Diverse-Language Other Than English (CALD-LOTE). Clinical features, cognitive test performance and cognitive reserve were compared between groups. Voxel-based morphometry was used to examine the neural correlates of cognitive reserve. 107 patients with bvFTD (53 Australian, 36 CALD-English, 18 CALD-LOTE) and 51 controls were included. Analysis of neuropsychiatric features revealed more elation in Australian patients compared to CALD-English patients, with trends for CALD-LOTE patients to report more irritability. CALD-LOTE patients also had higher cognitive reserve and showed relatively greater verbal than non-verbal cognitive impairment. Neuroimaging analyses revealed that higher cognitive reserve was associated with lower integrity in the frontal-temporal regions associated with typical disease pathology in bvFTD. Our findings support the hypothesis that cognitive reserve may delay early cognitive decline in culturally and linguistically diverse patients, although these patients may still show poor verbal performance due to cultural testing biases. Clinically, these results highlight the need to consider cultural and linguistic background to inform the assessment of dementia.

Utility of the Addenbrooke's Cognitive Examination III online calculator to differentiate the primary progressive aphasia variants.

The Addenbrooke's Cognitive Examination III is a brief cognitive screening tool that is widely used for the detection and monitoring of dementia. Recent findings suggest that the three variants of primary progressive aphasia can be distinguished based on their distinct profiles on the five subdomain scores of this test. Here, we investigated the utility of the Addenbrooke's Cognitive Examination III to differentiate the primary progressive aphasia variants based on their item-by-item performance profiles on this test. From these results, we created an interactive primary progressive aphasia Addenbrooke's Cognitive Examination III calculator which predicts the variant based on a patient's unique item-by-item profile. Twenty-eight logopenic variant, 25 non-fluent variant and 37 semantic variant primary progressive aphasia patients and 104 healthy controls completed the Addenbrooke's Cognitive Examination III at first clinical presentation. Multinomial regression analyses were conducted to establish performance profiles among groups, and R Shiny from RStudio was used to create the interactive Addenbrooke's Cognitive Examination III diagnostic calculator. To verify its accuracy, probability values of the regression model were derived based on a 5-fold cross-validation of cases. The calculator's accuracy was then verified in an independent sample of 17 logopenic, 19 non-fluent and 13 semantic variant primary progressive aphasia patients and 68 Alzheimer's disease patients who had completed the Addenbrooke's Cognitive Examination III (or an older version of this test: Revised) and had in vivo amyloid-PET imaging and/or brain autopsy pathological confirmation. Cross-validation of cases in the calculator model revealed different rates of sensitivity in classifying variants: semantic = 100%, non-fluent = 80.6% and logopenic = 79.9%; healthy controls were distinguished from primary progressive aphasia patients with 100% sensitivity. Verification of in vivo amyloid and/or autopsy-confirmed patients showed that the calculator correctly classified 10/13 (77%) semantic variant, 3/19 (16%) non-fluent variant and 4/17 (24%) logopenic variant patients. Importantly, for patients who were not classified, diagnostic probability values mostly pointed toward the correct clinical diagnosis. Furthermore, misclassified diagnoses of the primary progressive aphasia cohort were rare (1/49; 2%). Although 22 of the 68 Alzheimer's disease patients (32%) were misclassified with primary progressive aphasia, 19/22 were misclassified with the logopenic variant (i.e. falling within the same neuropathological entity). The Addenbrooke's Cognitive Examination III primary progressive aphasia diagnostic calculator demonstrates sound accuracy in differentiating the variants based on an item-by-item Addenbrooke's Cognitive Examination III profile. This calculator represents a new frontier in using data-driven approaches to differentiate the primary progressive aphasia variants.

Predictors of survival and progression in behavioural variant frontotemporal dementia.

BACKGROUND AND PURPOSE: Predicting the course of behavioural variant frontotemporal dementia (bvFTD) remains a major clinical challenge. This study aimed to identify factors that predict survival and clinical progression in bvFTD. METHODS: Consecutive patients with clinically probable bvFTD were prospectively followed up over an 8-year period. Baseline neuropsychological variables, presence of a known pathogenic frontotemporal dementia gene mutation and a systematic visual magnetic resonance imaging assessment at baseline were examined as candidate predictors using multivariate modelling. RESULTS: After screening 121 cases, the study cohort consisted of 75 patients with probable bvFTD, with a mean age of 60.8 ± 8.5 years, followed up for a mean duration of 7.2 ± 3.5 years from symptom onset. Median survival time from disease onset was 10.8 years and median survival, prior to transition to nursing home, was 8.9 years. A total of 25 of the 75 patients died during the study follow-up period. Survival without dependence was predicted by shorter disease duration at presentation (hazard ratio, 0.49, P = 0.001), greater atrophy in the anterior cingulate cortex (hazard ratio, 1.75, P = 0.047), older age (hazard ratio, 1.07, P = 0.026) and a higher burden of behavioural symptoms (hazard ratio, 1.04, P = 0.015). In terms of disease progression, presence of a known pathogenic frontotemporal dementia mutation (ß = 0.46, P < 0.001) was the strongest predictor of progression. Deficits in letter fluency (ß = -0.43, P = 0.017) and greater atrophy in the motor cortex (ß = 0.51, P = 0.03) were also associated with faster progression. CONCLUSIONS: This study provides novel clinical predictors of survival and progression in bvFTD. Our findings are likely to have an impact on prognostication and care planning in this difficult disease.

The behavioural variant frontotemporal dementia phenocopy syndrome is a distinct entity - evidence from a longitudinal study.

BACKGROUND: This study aimed to i) examine the frequency of C9orf72 expansions in a cohort of patients with the behavioural variant frontotemporal dementia (bvFTD) phenocopy syndrome, ii) observe outcomes in a group of phenocopy syndrome with very long term follow-up and iii) compare progression in a cohort of patients with the phenocopy syndrome to a cohort of patients with probable bvFTD. METHODS: Blood was obtained from 16 phenocopy cases. All met criteria for possible bvFTD and were labeled as phenocopy cases if they showed no functional decline, normal cognitive performance on the Addenbrooke's Cognitive Examination-Revised (ACE-R) and a lack of atrophy on brain imaging, over at least 3 years of follow-up. In addition, we obtained very long term follow-up data in 6 cases. A mixed model analysis approach determined the pattern of change in cognition and behaviour over time in phenocopy cases compared to 27 probable bvFTD cases. RESULTS: All 16 patients were screened for the C9orf72 expansion that was present in only one (6.25%). Of the 6 cases available for very long-term follow-up (13 - 21 years) none showed progression to frank dementia. Moreover, there was a decrease in the caregiver ratings of behavioural symptoms over time. Phenocopy cases showed significantly slower rates of progression compared to probable bvFTD patients (p < 0.006). CONCLUSION: The vast majority of patients with the bvFTD phenocopy syndrome remain stable over many years. An occasional patient can harbor the C9orf72 expansion. The aetiology of the remaining cases remains unknown but it appears very unlikely to reflect a neurodegenerative syndrome due to lack of clinical progression or atrophy on imaging.

The midbrain-to-pons ratio distinguishes progressive supranuclear palsy from non-fluent primary progressive aphasias.

BACKGROUND AND PURPOSE: To determine the clinical utility of the midbrain-to-pons (M/P) ratio as a clinical biomarker of progressive supranuclear palsy (PSP) in patients with non-fluent primary progressive aphasia syndromes. METHODS: Patients with PSP, progressive non-fluent aphasia (PNFA) and logopenic progressive aphasia (LPA) were recruited. Patients were diagnosed clinically, but pathological confirmation was available in a proportion of patients. Midbrain and pons areas were measured using Osirix Lite, a free DICOM viewer. The M/P ratio and Magnetic Resonance Parkinsonism Index were calculated and their diagnostic utility compared. RESULTS: A total of 72 participants were included (16 PSP, 18 PNFA, 16 LPA and 22 controls). Patients with PSP had motor features typical of the syndrome. Both the M/P ratio and Magnetic Resonance Parkinsonism Index differed significantly in PSP compared with controls. The M/P ratio was disproportionately reduced in PSP compared with PNFA and LPA (PSP, 0.182 ± 0.043; PNFA, 0.255 ± 0.034; LPA, 0.258 ± 0.033; controls, 0.292 ± 0.031; P < 0.001). An M/P ratio of ≤0.215 produced a positive predictive value of 77.8% for the diagnosis of PSP syndrome. Pathological examination revealed Alzheimer's disease in three cases (all LPA), pathological PSP in two cases (one clinical PSP and one PNFA) and corticobasal degeneration in one case (PNFA). The M/P ratio was ≤0.215 in both pathological cases of PSP. CONCLUSIONS: The M/P ratio was disproportionately reduced in PSP, suggesting its potential as a clinical marker of the PSP syndrome. Larger studies of pathologically confirmed cases are needed to establish the M/P ratio as a biomarker of PSP pathology.

Cognition and eating behavior in amyotrophic lateral sclerosis: effect on survival.

It is increasingly recognized that metabolic factors influenced by eating behavior, may affect disease progression in neurodegeneration. In frontotemporal dementia (FTD), which shares a significant overlap with Amyotrophic lateral sclerosis (ALS), patients are well known to develop changes in eating behavior. Whether patients with pure ALS and those with cognitive and behavioral changes associated with ALS also develop similar changes is not known. The current study aimed to examine caloric intake, eating behavioral changes, body mass index, and using cox regression analyses survival across the spectrum of 118 ALS-FTD patients (29 pure ALS, 12 ALS-plus and 21 ALS-FTD, 56 behavioral variant FTD), compared with 25 control subjects. The current study found contrary to previous assumptions eating changes are not restricted to FTD, but a spectrum of eating behavioral changes occur in ALS, present in those with pure ALS and worsening as patients develop cognitive changes. ALS patients with cognitive impairment exhibited changes in food preference, with caloric intake and BMI increasing with the development of cognitive/behavioral changes. Both pure ALS and those with cognitive impairment demonstrated increased saturated fat intake. Survival analyses over the mean patient follow-up period of 6.9 years indicated that increasing eating behavioral changes were associated with an improved survival (threefold decrease risk of dying). Changes in eating behavior and metabolism occur in ALS in association with increasing cognitive impairment, perhaps exerting a protective survival influence. These changes provide insights into the common neural networks controlling eating and metabolism in FTD and ALS and provide potential targets to modify disease prognosis and progression.

Motor function and behaviour across the ALS-FTD spectrum.

BACKGROUND: Behavioural/functional disturbances, characteristic of frontotemporal dementia (FTD), are also a feature of amyotrophic lateral sclerosis (ALS) and patients with combined ALS and FTD (FTD-ALS). AIM OF THE STUDY: To investigate the progression of behavioural disturbances in ALS and FTD using the FTD functional rating scale (FTDFRS). METHODS: Patients with ALS, FTD-ALS and FTD were recruited from specialist clinics. Baseline assessments included the FTDFRS and the ALS functional rating scale-revised (ALSFRS-R). Baseline assessments were included, as were longitudinal assessments in a proportion of patients. RESULTS: In total, 21 ALS, 12 FTD-ALS and 14 behavioural variant FTD (bvFTD) patients were included in the study. Moderate or severe behavioural disturbance was common in patients with ALS at baseline (47.6%), although less frequent than in bvFTD patients; patients with FTD-ALS displayed intermediate impairment. The ALSFRS-R showed the opposite pattern and did not correlate with the FTDFRS. During the follow-up period, significant (P < 0.05) behavioural deterioration was demonstrated in patients with bvFTD and FTD-ALS, with a trend for decline in patients with ALS (P = 0.06). CONCLUSION: Motor disturbance is the primary marker of disease severity in ALS, but behavioural and functional impairment are common, and may decline independently of motor function. As such, the FTDFRS may provide valuable information in the assessment and monitoring of ALS.

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 Alzheimer's 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.

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.

Body mass index delineates ALS from FTD: implications for metabolic health.

Weight loss and catabolic changes are increasingly recognized as factors that influence outcomes in patients with amyotrophic lateral sclerosis (ALS). An association between disease progression and low BMI has been reported in ALS; however, it remains unknown whether low BMI occurs across all forms of ALS and whether BMI changes with the development of cognitive impairment across the spectrum between ALS and frontotemporal dementia (FTD). One hundred and three ALS patients (56 limb predominant, 18 bulbar predominant, 13 ALS plus, 16 ALSFTD) were recruited and compared to 19 behavioral variant FTD (bvFTD) patients and a group of age-matched healthy controls. BMI was measured at the initial clinical visit. Patients were characterized as underweight, normal, overweight or obese, based on the current World Health Organization (WHO) guidelines. Limb and bulbar ALS patients had significantly lower BMI than ALS plus, ALSFTD, and bvFTD patient groups. When BMI was categorized using WHO guidelines the majority of the limb and bulbar ALS patients were either underweight or normal weight, whilst the majority of the ALS plus, ALSFTD and bvFTD patients were either overweight or obese. On follow-up BMI assessment the limb and bulbar groups tended to decline whilst ALS plus, ALSFTD and bvFTD groups remained stable or increased. BMI is significantly higher in ALS individuals with cognitive deficits. The present findings have prognostic implications for disease progression and may help delineate the metabolic profile across the ALSFTD spectrum.

Validation of the new consensus criteria for the diagnosis of corticobasal degeneration.

BACKGROUND: Corticobasal degeneration (CBD) is a complex neurodegenerative disorder. Accurate diagnosis is increasingly important, with the advent of clinical trials of drugs aimed at modifying the underlying tau pathology. CBD often presents with a 'corticobasal syndrome' including impairments of movement and cognition. However, patients with similar corticobasal syndromes can have neurodegenerative pathologies that are not CBD. In addition, patients with CBD may present with aphasia or behavioural change. The clinical diversity of CBD and mimicry by non-CBD pathologies hinders accurate diagnosis. METHODS: We applied the new consensus criteria of Armstrong and colleagues et al 1 to a cohort of patients with detailed longitudinal clinical evaluation and neuropathology. RESULTS: In patients with pathologically confirmed CBD, accuracy of diagnosis was similar under the new and previous criteria: 9/19 (47%) met criteria for probable CBD at presentation, 13/19 (68%) at last clinical assessment. Patients with a corticobasal syndrome but without CBD pathology all (14/14) met the new diagnostic criteria of probable or possible CBD, demonstrating that the new criteria lacks the necessary specificity for an accurate ante mortem clinical diagnosis of CBD. None of the clinical features used in the new criteria were more common in the patients with CBD pathology (n=19) than without (n=14). CONCLUSIONS: The Armstrong criteria usefully broadens the recognised clinical phenotype of CBD but does not sufficiently improve the specificity of diagnosis to increase the power of clinical trials or targeted applications of tau-based disease-modifying therapies. Further work is required to show whether biomarkers could be more effective than clinical signs in the diagnosis of CBD.

Disturbances in melatonin secretion and circadian sleep-wake regulation in Parkinson disease.

OBJECTIVE: Using salivary dim light melatonin onset (DLMO) and actigraphy, our study sought to determine if Parkinson disease (PD) patients demonstrate circadian disturbance compared to healthy controls. Additionally, our study investigated if circadian disturbances represent a disease-related process or may be attributed to dopaminergic therapy. METHODS: Twenty-nine patients with PD were divided into unmedicated and medicated groups and were compared to 27 healthy controls. All participants underwent neurologic assessment and 14 days of actigraphy to establish habitual sleep-onset time (HSO). DLMO time and area under the melatonin curve (AUC) were calculated from salivary melatonin sampling. The phase angle of entrainment was calculated by subtracting DLMO from HSO. Overnight polysomnography (PSG) was performed to determine sleep architecture. RESULTS: DLMO and HSO were not different across the groups. However, the phase angle of entrainment was more than twice as long in the medicated PD group compared to the unmedicated PD group (U = 35.5; P = .002) and was more than 50% longer than controls (U = 130.0; P = .021). The medicated PD group showed more than double the melatonin AUC compared to the unmedicated group (U = 31; P = 0.001) and controls (U = 87; P = .001). There was no difference in these measures comparing unmedicated PD and controls. CONCLUSIONS: In PD dopaminergic treatment profoundly increases the secretion of melatonin. Our study reported no difference in circadian phase and HSO between groups. However, PD patients treated with dopaminergic therapy unexpectedly showed a delayed sleep onset relative to DLMO, suggesting dopaminergic therapy in PD results in an uncoupling of circadian and sleep regulation.

Disability in atypical parkinsonian syndromes is more dependent on memory dysfunction than motor symptoms.

BACKGROUND: There is a gap in the systematic description and investigation of functional disability in corticobasal syndrome (CBS) and progressive supranuclear palsy (PSP). Additionally, the relations between disability, apraxia, cognitive and behavioural changes are not well understood in atypical parkinsonian syndromes. METHODS: Fifty patients were included in this study (CBS = 18; PSP = 11), including a subgroup of primary progressive aphasia-nonfluent variant (PPA-nfv = 21) who were used as a control group given the clinic-pathological overlap. Functional disability (basic and instrumental activities of daily living), general cognition and behavioural changes were evaluated at baseline, with a subgroup of patients being reassessed after 16 months. RESULTS: The corticobasal syndrome group had the most marked disability in basic activities in comparison to progressive supranuclear palsy and primary progressive aphasia-nonfluent variant. Longitudinal decline was marked for all three groups. In a linear regression examining factors behind functional disability in CBS and PSP, memory dysfunction emerged as the main factor (48.5%), followed by apraxia (14.9%) and atypical parkinsonian symptoms (9.6%). CONCLUSIONS: Memory dysfunction is the most important factor in functional disability in CBS and PSP, which has to be taken into consideration in disease management, prognosis and planning of services to fully address patients' and families' needs.

Neural correlates of activities of daily living in frontotemporal dementia.

BACKGROUND: Little research to date has investigated neural correlates of functional disability in frontotemporal dementia (FTD). METHODS: Activities of daily living (ADL) were covaried against gray matter atrophy regions via Voxel-based morphometry in FTD (n = 52) and contrasted against a dementia control Alzheimer disease (AD) group (n = 20) and healthy age-matched controls (n = 18). RESULTS: Both patient groups had similar ADL scores. However, FTD and AD differed on the gray matter atrophy areas associated with ADL scores. The FTD showed involvement of prefrontal and thalamus regions while AD showed widespread temporal, parietal, frontal, and caudate atrophy correlating with ADL dysfunction. Importantly, only the left superior frontal gyrus was implicated in ADL dysfunction for both FTD and AD. CONCLUSIONS: Differences in underlying neural correlates of ADL impairment have important clinical implications as these differences should be taken into account when interventions are planned. Dementia subtypes might require specifically tailored interventions for functional disability.

Dissociation of explicit and implicit long-term memory consolidation in semantic dementia: a case study.

We report a case study of a semantic dementia patient, whose episodic memory consolidation was tested over a 2-month period. The results reveal that despite early retention of information, the patient lost all explicit information of the newly learnt material after 2 weeks. By contrast, he retained implicit word information even after a 4-week delay. These findings highlight the critical time window of 2-4 weeks in which newly learnt information should be re-encoded in rehabilitations studies. The results also indicate that learnt information can be still accessed with implicit retrieval strategies when explicit retrieval fails.

Longitudinal changes in primary progressive aphasias: differences in cognitive and dementia staging measures.

BACKGROUND/AIMS: The longitudinal course of three primary progressive aphasia (PPA) variants was examined using Addenbrooke's Cognitive Examination-Revised (ACE-R) and the Frontotemporal dementia Rating Scale (FRS). METHODS: Cases with two assessments on the ACE-R and FRS were selected. A total of 220 assessments were obtained on 55 patients: 17 Alzheimer's disease (AD) and 38 PPA [17 semantic variant (svPPA), 12 non-fluent/agrammatic (naPPA) and 9 logopenic variant (lvPPA) cases]. RESULTS: The annualized rate of change was greater in all PPA variants in comparison with the AD group on the ACE-R whereas only the svPPA and naPPA groups differed from AD on the FRS. CONCLUSIONS: The longitudinal profile differs across PPA syndromes on cognitive and functional measures. Findings have theoretical implications and are relevant to the care of patients with dementia.

Activities of daily living in progressive non-fluent aphasia, logopenic progressive aphasia and Alzheimer's disease.

BACKGROUND/AIMS: This study examined functional changes in progressive non-fluent aphasia (PNFA) and logopenic progressive aphasia (LPA) and Alzheimer's disease (AD) and the association between function, cognition and behaviour. METHODS: 59 patients were assessed with the Disability Assessment of Dementia (DAD), Addenbrooke's Cognitive Examination Revised (ACE-R) and the Cambridge Behavioural Inventory Revised (CBI-R). RESULTS: No differences between groups in basic and instrumental activities of daily living (ADLs), and total ACE-R scores were found; there were correlations between total DAD and ACE-R scores for PNFA and LPA. Over 12 months, PNFA showed the marked decline of basic ADLs, whereas all three groups showed marked decline of instrumental ADLs. CONCLUSION: PNFA, LPA and AD appear functionally similar when matched for disease duration. The rate of decline of ADLs depends, however, on disease diagnosis.