Binary reversals: a diagnostic sign in primary progressive aphasia.

BACKGROUND: Binary reversals (exemplified by 'yes'/'no' confusions) have been described in patients with primary progressive aphasia (PPA) but their diagnostic value and phenotypic correlates have not been defined. METHODS: We conducted a retrospective cohort study analysing demographic, clinical, neuropsychological, linguistic and behavioural data from patients representing all major PPA syndromes (non-fluent/agrammatic variant, nfvPPA; logopenic variant, lvPPA; semantic variant, svPPA) and behavioural variant frontotemporal dementia (bvFTD). The prevalence of binary reversals and behavioural abnormalities, illness duration, parkinsonian features and neuropsychological test scores were compared between neurodegenerative syndromes, and the diagnostic predictive value of binary reversals was assessed using logistic regression. RESULTS: Data were obtained for 83 patients (21 nfvPPA, 13 lvPPA, 22 svPPA, 27 bvFTD). Binary reversals occurred in all patients with nfvPPA, but significantly less frequently and later in lvPPA (54%), svPPA (9%) and bvFTD (44%). Patients with bvFTD with binary reversals had significantly more severe language (but not general executive or behavioural) deficits than those without reversals. Controlling for potentially confounding variables, binary reversals strongly predicted a diagnosis of nfvPPA over other syndromes. CONCLUSIONS: Binary reversals are a sensitive (though not specific) neurolinguistic feature of nfvPPA, and should suggest this diagnosis if present as a prominent early symptom.

Symptom-based staging for logopenic variant primary progressive aphasia.

BACKGROUND AND PURPOSE: Logopenic variant primary progressive aphasia (lvPPA) is a major variant presentation of Alzheimer's disease (AD) that signals the importance of communication dysfunction across AD phenotypes. A clinical staging system is lacking for the evolution of AD-associated communication difficulties that could guide diagnosis and care planning. Our aim was to create a symptom-based staging scheme for lvPPA, identifying functional milestones relevant to the broader AD spectrum. METHODS: An international lvPPA caregiver cohort was surveyed on symptom development under an 'exploratory' survey (34 UK caregivers). Feedback from this survey informed the development of a 'consolidation' survey (27 UK, 10 Australian caregivers) in which caregivers were presented with six provisional clinical stages and feedback was analysed using a mixed-methods approach. RESULTS: Six clinical stages were endorsed. Early symptoms included word-finding difficulty, with loss of message comprehension and speech intelligibility signalling later-stage progression. Additionally, problems with hearing in noise, memory and route-finding were prominent early non-verbal symptoms. 'Milestone' symptoms were identified that anticipate daily-life functional transitions and care needs. CONCLUSIONS: This work introduces a new symptom-based staging scheme for lvPPA, and highlights milestone symptoms that could inform future clinical scales for anticipating and managing communication dysfunction across the AD spectrum.

Comprehension of acoustically degraded speech in Alzheimer's disease and primary progressive aphasia.

Successful communication in daily life depends on accurate decoding of speech signals that are acoustically degraded by challenging listening conditions. This process presents the brain with a demanding computational task that is vulnerable to neurodegenerative pathologies. However, despite recent intense interest in the link between hearing impairment and dementia, comprehension of acoustically degraded speech in these diseases has been little studied. Here we addressed this issue in a cohort of 19 patients with typical Alzheimer's disease and 30 patients representing the three canonical syndromes of primary progressive aphasia (non-fluent/agrammatic variant primary progressive aphasia; semantic variant primary progressive aphasia; logopenic variant primary progressive aphasia), compared to 25 healthy age-matched controls. As a paradigm for the acoustically degraded speech signals of daily life, we used noise-vocoding: synthetic division of the speech signal into frequency channels constituted from amplitude-modulated white noise, such that fewer channels convey less spectrotemporal detail thereby reducing intelligibility. We investigated the impact of noise-vocoding on recognition of spoken three-digit numbers and used psychometric modelling to ascertain the threshold number of noise-vocoding channels required for 50% intelligibility by each participant. Associations of noise-vocoded speech intelligibility threshold with general demographic, clinical and neuropsychological characteristics and regional grey matter volume (defined by voxel-based morphometry of patients' brain images) were also assessed. Mean noise-vocoded speech intelligibility threshold was significantly higher in all patient groups than healthy controls, and significantly higher in Alzheimer's disease and logopenic variant primary progressive aphasia than semantic variant primary progressive aphasia (all P < 0.05). In a receiver operating characteristic analysis, vocoded intelligibility threshold discriminated Alzheimer's disease, non-fluent variant and logopenic variant primary progressive aphasia patients very well from healthy controls. Further, this central hearing measure correlated with overall disease severity but not with peripheral hearing or clear speech perception. Neuroanatomically, after correcting for multiple voxel-wise comparisons in predefined regions of interest, impaired noise-vocoded speech comprehension across syndromes was significantly associated (P < 0.05) with atrophy of left planum temporale, angular gyrus and anterior cingulate gyrus: a cortical network that has previously been widely implicated in processing degraded speech signals. Our findings suggest that the comprehension of acoustically altered speech captures an auditory brain process relevant to daily hearing and communication in major dementia syndromes, with novel diagnostic and therapeutic implications.

Symptom-led staging for semantic and non-fluent/agrammatic variants of primary progressive aphasia.

INTRODUCTION: Here we set out to create a symptom-led staging system for the canonical semantic and non-fluent/agrammatic variants of primary progressive aphasia (PPA), which present unique diagnostic and management challenges not well captured by functional scales developed for Alzheimer's disease and other dementias. METHODS: An international PPA caregiver cohort was surveyed on symptom development under six provisional clinical stages and feedback was analyzed using a mixed-methods sequential explanatory design. RESULTS: Both PPA syndromes were characterized by initial communication dysfunction and non-verbal behavioral changes, with increasing syndromic convergence and functional dependency at later stages. Milestone symptoms were distilled to create a prototypical progression and severity scale of functional impairment: the PPA Progression Planning Aid ("PPA-Squared"). DISCUSSION: This work introduces a symptom-led staging scheme and functional scale for semantic and non-fluent/agrammatic variants of PPA. Our findings have implications for diagnostic and care pathway guidelines, trial design, and personalized prognosis and treatment for PPA. HIGHLIGHTS: We introduce new symptom-led perspectives on primary progressive aphasia (PPA). The focus is on non-fluent/agrammatic (nfvPPA) and semantic (svPPA) variants. Foregrounding of early and non-verbal features of PPA and clinical trajectories is featured. We introduce a symptom-led staging scheme for PPA. We propose a prototype for a functional impairment scale, the PPA Progression Planning Aid.

Primary progressive aphasia: ReADing the clinical GRANularity.

Primary progressive aphasia remains a diagnostic challenge despite (or even because of) the increasing availability of ancillary tests and biomarkers. We present a 67-year-old man with apparently sporadic logopenic aphasia and positive Alzheimer biomarkers who was subsequently found also to have a pathogenic mutation in the progranulin gene. This was signalled by early atypical features (mild expressive agrammatism and behavioural change, rapid clinical deterioration) around the core logopenic aphasia syndrome. Each of the canonical progressive aphasia syndromes has a 'halo' of less typical variants that may herald alternative or additional pathologies. The accurate diagnosis of primary progressive aphasia depends on careful clinical analysis to direct investigations appropriately.

Associations between hypoxia parameters in obstructive sleep apnea and cognition, cortical thickness, and white matter integrity in middle-aged and older adults.

OBJECTIVE: This study aimed to investigate the association between each parameter of intermittent hypoxia in obstructive sleep apnea (OSA) and the cognitive profile, cortical thickness, and white matter integrity in middle-aged and older adults. METHODOLOGY: Participants were newly diagnosed with moderate or severe OSA from the King Chulalongkorn Memorial Hospital, Bangkok, Thailand. Respiratory parameters from polysomnography were extracted. Each participant was tested on a battery of neuropsychological tests and underwent an MRI scan of the brain. Cortical thickness analysis and diffusion tensor imaging analysis were performed. Participants were classified as having either severe or mild hypoxia based on parameters of hypoxia, i.e., oxygen desaturation index, lowest oxygen saturation, and the percentage of total sleep time spent below 90% oxygen saturation. RESULTS: Of 17 patients with OSA, there were 8 men (47%). Median age was 57 years and median AHI was 60.6. Comparison of cortical thickness between the severe and the mild group of each hypoxic parameter revealed two clusters of cortical thinning at the right inferior frontal gyrus (p-value = 0.008) and right inferior parietal gyrus (p-value = 0.006) in the severe desaturation group and a cluster of cortical thinning at the superior parietal gyrus (p-value = 0.008) in the high oxygen desaturation index group. There was no difference in cognitive function or white matter integrity between groups. CONCLUSIONS: The magnitude of the degree and frequency of desaturations in OSA are associated with a decrease in cortical thickness at the frontal and parietal regions.

Primary progressive aphasia: six questions in search of an answer.

Here, we review recent progress in the diagnosis and management of primary progressive aphasia-the language-led dementias. We pose six key unanswered questions that challenge current assumptions and highlight the unresolved difficulties that surround these diseases. How many syndromes of primary progressive aphasia are there-and is syndromic diagnosis even useful? Are these truly 'language-led' dementias? How can we diagnose (and track) primary progressive aphasia better? Can brain pathology be predicted in these diseases? What is their core pathophysiology? In addition, how can primary progressive aphasia best be treated? We propose that pathophysiological mechanisms linking proteinopathies to phenotypes may help resolve the clinical complexity of primary progressive aphasia, and may suggest novel diagnostic tools and markers and guide the deployment of effective therapies.

Inappropriate trusting behaviour in dementia.

Background: Inappropriate trusting behaviour may have significant social, financial and other consequences for people living with dementia. However, its clinical associations and predictors have not been clarified. Here we addressed this issue in canonical syndromes of frontotemporal dementia (FTD) and Alzheimer's disease (AD). Methods: In 34 patients with AD and 73 with FTD (27 behavioural variant (bv)FTD, 22 semantic variant primary progressive aphasia (svPPA), 24 nonfluent/agrammatic variant (nfv)PPA) we recorded inappropriate trusting and other abnormal socio-emotional behaviours using a semi-structured caregiver survey. Patients were comprehensively characterised using a general cognitive assessment and the Revised Self-Monitoring Scale (RSMS; an informant index of socioemotional awareness). Results: Inappropriate trusting was more frequent in svPPA (55%) and bvFTD (44%) than nfvPPA (17%) or AD (24%). After adjusting for age, sex, education and Mini-Mental State Examination (MMSE) score, inappropriate trusting was significantly more likely in svPPA (odds ratio 3.61; 95% confidence interval 1.41-8.75) and bvFTD (3.01, 1.23-6.65) than AD. Significant predictors of inappropriate trusting comprised apathy in svPPA, disinhibition and altered pain responsiveness in bvFTD, and lower MMSE and RSMS (self-presentation) scores in AD. Conclusion: Dementia syndromes vary in prevalence and predictors of abnormal trusting behaviour, with implications for clinical counselling and safeguarding.

Association of Long-Term Blood Pressure Variability with Cerebral Amyloid Angiopathy-related Brain Injury and Cognitive Decline.

Introduction: Long-term systolic blood pressure variability (BPV) has been proposed as a novel risk factor for dementia, but the underlying mechanisms are largely unknown. We aimed to investigate the association between long-term blood pressure variability (BPV), brain injury, and cognitive decline in patients with mild cognitive symptoms and cerebral amyloid angiopathy (CAA), a well-characterized small-vessel disease that causes cognitive decline in older adults. Methods: Using a prospective memory clinic cohort, we enrolled 102 participants, of whom 52 with probable CAA. All underwent a 3-tesla research MRI at baseline and annual neuropsychological evaluation over 2 years, for which standardized z-scores for four cognitive domains were calculated. BPV was assessed using a coefficient of variation derived from serial outpatient BP measurements (median 12) over five years. We measured the peak width of skeletonized mean diffusivity (PSMD) as a marker of white matter integrity, and other neuroimaging markers of CAA, including lacunes and cortical cerebral microinfarcts. Using regression models, we evaluated the association of BPV with microstructural brain injury and whether CAA modified this association. We also examined the association of BPV with subsequent cognitive decline. Results: Systolic BPV was dose-dependently associated with PSMD (estimate=0.22, 95% CI: 0.06, 0.39, p=0.010), independent of age, sex, mean BP, common vascular risk factors, brain atrophy, and CAA severity. The presence of probable CAA strengthened the association between BPV and PSMD (estimate=9.33, 95% CI: 1.32, 17.34, p for interaction = 0.023). Higher BPV correlated with greater ischemic injury (lobar lacunes and cortical cerebral microinfarcts) and a decline in global cognition and processing speed (estimate=-0.30, 95% CI: -0.55, -0.04, p=0.022). Discussion: Long-term BPV has a dose-dependent association with alterations in white matter integrity, lobar lacunes, and cortical cerebral microinfarcts, and predicts cognitive decline. Controlling BPV is a potential strategic approach to prevent cognitive decline, especially in early-stage CAA.

Apathy in Patients With Cerebral Amyloid Angiopathy: A Multimodal Neuroimaging Study.

BACKGROUND AND OBJECTIVE: To analyze the prevalence and associated clinical characteristics of apathy in sporadic cerebral amyloid angiopathy and investigate whether apathy was associated with disease burden and disconnections of key structures in the reward circuit through a structural and functional multimodal neuroimaging approach. METHODS: Thirty-seven participants with probable sporadic cerebral amyloid angiopathy without symptomatic intracranial hemorrhage or dementia (mean age, 73.3 ± 7.2 years, % male = 59.5%) underwent a detailed neuropsychological evaluation, including measures of apathy and depression, and a multimodal MR neuroimaging study. A multiple linear regression analysis was used to assess the association of apathy with conventional small vessel disease neuroimaging markers. A voxel-based morphometry with a small volume correction within regions previously associated with apathy and a whole-brain tract-based spatial statistics were performed to identify differences in the gray matter and white matter between the apathetic and nonapathetic groups. Gray matter regions significantly associated with apathy were further evaluated for their functional alterations as seeds in the seed-based resting-state functional connectivity analysis. Potential confounders, namely, age, sex, and measures of depression, were entered as covariates in all analyses. RESULTS: A higher composite small vessel disease marker score (CAA-SVD) was associated with a higher degree of apathy (standardized coefficient = 1.35 (0.07-2.62), adjusted R2 = 27.90, p = 0.04). Lower gray matter volume of the bilateral orbitofrontal cortices was observed in the apathetic group than in the nonapathetic group (F = 13.20, family-wise error-corrected p = 0.028). The apathetic group demonstrated a widespread decrease in white matter microstructural integrity compared with the nonapathetic group. These tracts connect key regions within and between related reward circuits. Finally, there were no significant functional alterations between the apathetic and nonapathetic groups. DISCUSSION: Our findings revealed the orbitofrontal cortex as a key region in the reward circuit associated with apathy in sporadic cerebral amyloid angiopathy, independent from depression. Apathy was shown to be associated with a higher CAA-SVD score and an extensive disruption of white matter tracts, which suggested that a higher burden of CAA pathology and the disruption in large-scale white matter networks may underlie manifestations of apathy.