Megan Quimby

Topography of dilated perivascular spaces in subjects from a memory clinic cohort

Objective: To investigate whether the topography of dilated perivascular spaces (DPVS) corresponds with markers of particular small-vessel diseases such as cerebral amyloid angiopathy and hypertensive vasculopathy. Methods: Patients were recruited from an ongoing single-center prospective longitudinal cohort study of patients evaluated in a memory clinic. All patients underwent structural, high-resolution MRI, and had a clinical assessment performed within 1 year of scan. DPVS were rated in basal ganglia (BG-DPVS) and white matter (WM-DPVS) on T1 sequences, using an established 4-point semiquantitative score. DPVS degree was classified as high (score > 2) or low (score ≤ 2). Independent risk factors for high degree of BG-DPVS and WM-DPVS were investigated. Results: Eighty-nine patients were included (mean age 72.7 ± 9.9 years, 57% female). High degree of WM-DPVS was more frequent than low degree in patients with presence of strictly lobar microbleeds (45.5% vs 28.4% of subjects). High BG-DPVS degree was associated with older age, hypertension, and higher white matter hyperintensity volumes. In multivariate analysis, increased lobar microbleed count was an independent predictor of high degree of WM-DPVS (odds ratio [OR] 1.53 [95% confidence interval (CI) 1.06–2.21], p = 0.02). By contrast, hypertension was an independent predictor of high degree of BG-DPVS (OR 9.4 [95% CI 1–85.2], p = 0.04). Conclusions: The associations of WM-DPVS with lobar microbleeds and BG-DPVS with hypertension raise the possibility that the distribution of DPVS may indicate the presence of underlying small-vessel diseases such as cerebral amyloid angiopathy and hypertensive vasculopathy in patients with cognitive impairment.

Focal temporal pole atrophy and network degeneration in semantic variant primary progressive aphasia

A wealth of neuroimaging research has associated semantic variant primary progressive aphasia with distributed cortical atrophy that is most prominent in the left anterior temporal cortex; however, there is little consensus regarding which region within the anterior temporal cortex is most prominently damaged, which may indicate the putative origin of neurodegeneration. In this study, we localized the most prominent and consistent region of atrophy in semantic variant primary progressive aphasia using cortical thickness analysis in two independent patient samples (n = 16 and 28, respectively) relative to age-matched controls (n = 30). Across both samples the point of maximal atrophy was located in the same region of the left temporal pole. This same region was the point of maximal atrophy in 100% of individual patients in both semantic variant primary progressive aphasia samples. Using resting state functional connectivity in healthy young adults (n = 89), we showed that the seed region derived from the semantic variant primary progressive aphasia analysis was strongly connected with a large-scale network that closely resembled the distributed atrophy pattern in semantic variant primary progressive aphasia. In both patient samples, the magnitude of atrophy within a brain region was predicted by that region’s strength of functional connectivity to the temporopolar seed region in healthy adults. These findings suggest that cortical atrophy in semantic variant primary progressive aphasia may follow connectional pathways within a large-scale network that converges on the temporal pole.

Flortaucipir tau PET imaging in semantic variant primary progressive aphasia

Objective The semantic variant of primary progressive aphasia (svPPA) is typically associated with frontotemporal lobar degeneration (FTLD) with longTAR DNA-binding protein (TDP)-43-positive neuropil threads and dystrophic neurites (type C), and is only rarely due to a primary tauopathy or Alzheimer’s disease. We undertook this study to investigate the localisation and magnitude of the presumed tau Positron Emission Tomography (PET) tracer [18F]Flortaucipir (FTP; also known as T807 or AV1451) in patients with svPPA, hypothesising that most patients would not show tracer uptake different from controls. Methods FTP and [11C]Pittsburgh compound B PET imaging as well as MRI were performed in seven patients with svPPA and in 20 controls. FTP signal was analysed by visual inspection and by quantitative comparison to controls, with and without partial volume correction. Results All seven patients showed elevated FTP uptake in the anterior temporal lobe with a leftward asymmetry that was not observed in healthy controls. This elevated FTP signal, largely co-localised with atrophy, was evident on both visual inspection and quantitative cortical surface-based analysis. Five patients were amyloid negative, one was amyloid positive and one has an unknown amyloid status. Conclusions In this series of patients with clinical profiles, structural MRI and amyloid PET imaging typical for svPPA, FTP signal was unexpectedly elevated with a spatial pattern localised to areas of atrophy. This raises questions about the possible off-target binding of this tracer to non-tau molecules associated with neurodegeneration. Further investigation with autopsy analysis will help illuminate the binding target(s) of FTP in cases of suspected FTLD-TDP neuropathology.

Slowed articulation rate is a sensitive diagnostic marker for identifying non-fluent primary progressive aphasia

ABSTRACT Background: Primary progressive aphasia (PPA) is a neurodegenerative aphasic syndrome with three distinct clinical variants: non-fluent (nfvPPA), logopenic (lvPPA), and semantic (svPPA). Speech (non-) fluency is a key diagnostic marker used to aid identification of the clinical variants, and researchers have been actively developing diagnostic tools to assess speech fluency. Current approaches reveal coarse differences in fluency between subgroups, but often fail to clearly differentiate nfvPPA from the variably fluent lvPPA. More robust subtype differentiation may be possible with finer-grained measures of fluency. Aims: We sought to identify the quantitative measures of speech rate – including articulation rate and pausing measures – that best differentiated PPA subtypes, specifically the non-fluent group (nfvPPA) from the more fluent groups (lvPPA, svPPA). The diagnostic accuracy of the quantitative speech rate variables was compared to that of a speech fluency impairment rating made by clinicians. Methods & Procedures: Automatic estimates of pause and speech segment durations and rate measures were derived from connected speech samples of participants with PPA (N = 38; 11 nfvPPA, 14 lvPPA, 13 svPPA) and healthy age-matched controls (N = 8). Clinician ratings of fluency impairment were made using a previously validated clinician rating scale developed specifically for use in PPA. Receiver operating characteristic (ROC) analyses enabled a quantification of diagnostic accuracy. Outcomes & Results: Among the quantitative measures, articulation rate was the most effective for differentiating between nfvPPA and the more fluent lvPPA and svPPA groups. The diagnostic accuracy of both speech and articulation rate measures was markedly better than that of the clinician rating scale, and articulation rate was the best classifier overall. Area under the curve (AUC) values for articulation rate were good to excellent for identifying nfvPPA from both svPPA (AUC = .96) and lvPPA (AUC = .86). Cross-validation of accuracy results for articulation rate showed good generalisability outside the training dataset. Conclusions: Results provide empirical support for (1) the efficacy of quantitative assessments of speech fluency and (2) a distinct non-fluent PPA subtype characterised, at least in part, by an underlying disturbance in speech motor control. The trend towards improved classifier performance for quantitative rate measures demonstrates the potential for a more accurate and reliable approach to subtyping in the fluency domain, and suggests that articulation rate may be a useful input variable as part of a multidimensional clinical subtyping approach.

Relearning and Retaining Personally-Relevant Words using Computer-Based Flashcard Software in Primary Progressive Aphasia

Although anomia treatments have often focused on training small sets of words in the hopes of promoting generalization to untrained items, an alternative is to directly train a larger set of words more efficiently. The current case study reports on a novel treatment for a patient with semantic variant Primary Progressive Aphasia (svPPA), in which the patient was taught to make and practice flashcards for personally-relevant words using an open-source computer program (Anki). Results show that the patient was able to relearn and retain a large subset of her studied words for up to 20 months, the full duration of the study period. At the end of treatment, she showed good retention for 139 words. While only a subset of the 591 studied overall, this is still far more words than is typically targeted in svPPA interventions. Furthermore, she showed evidence of generalization to perceptually distinct stimuli during confrontation naming and temporary gains in semantic fluency, suggesting limited gains in semantic knowledge as a result of training. This case represents a successful example of patient-centered treatment, where the patient used a computer-based intervention independently at home. It also illustrates how data captured from computer-based treatments during routine clinical care can provide valuable “practice-based evidence” for motivating further treatment research.

VERBAL FLUENCY IN ATYPICAL PHENOTYPES OF ALZHEIMER’S DISEASE

lineal model with age as covariate) for the three groups in MMSE1⁄4 MiniMental State Examination; CAMCOG-R1⁄4 Cambridge Cognitive AssessmentRevised; TMT-A1⁄4 Trail Making TestForm A seconds; TMT-B1⁄4 Trail Making TestFormB seconds; BNT1⁄4Boston Naming Test total score; CVLT-SDFR1⁄4 Short Delay Free Recall from California Verbal Learning Test; CVLT-SDCR1⁄4 Short Delay Cued Recall from California Verbal Learning Test; CVLT-LDFR1⁄4 Long Delay Free Recall from California Verbal Learning Test; CVLTLDCR1⁄4LongDelay Cued Recall fromCalifornia Verbal Learning Test; CVLT-Recognition. Poster Presentations: Sunday, July 22, 2018 P537

HARMONIZING TOGETHER: SPEECH AND MUSIC THERAPY AND SUPPORT FOR PATIENTS AND PARTNERS WITH PPA

The Frontotemporal Disorders Unit at Massachusetts General Hospital, Boston, Massachusetts, USA, facilitated an eight-week interdisciplinary therapeutic support group targeted at early stage PPA patients and their care partners. Group goals included providing patients and their care partners with functional communication strategies, decreasing patient isolation, support for caregiver resilience and music therapy to promote utilization of language, social engagement and emotional connections between patients and care partners.

FLORTAUCIPIR IMAGING IN PRIMARY PROGRESSIVE APHASIA PREDICTS VARIABILITY IN LANGUAGE IMPAIRMENT

Background:[F]MK-6240 is a promising PET radioligand for in vivo detection of neurofibrillary tau tangles in Alzheimer’s disease (AD). Characterization of target and off-target binding features is required to improve the interpretation of the PET signal as it relates to neurofibrillary tau. This work probes spatial and kinetic features of [F]MK-6240 binding in target and off-target regions to determine the optimal imaging parameters in humans ranging from young controls to AD. Methods: Fifty-one participants (3 young controls, 33 older controls, 6 longitudinal cognitive declining, 2 MCI, 7 probable AD) underwent [F]MK-6240 PET and T1-weighted MRI scans. [C]PiB PET scans were acquired to assess amyloid burden (young controls assumed amyloid negative). [F]MK-6240 scans were acquired up to 120 minutes following 10 mCi bolus injection. Parametric SUVR images (70-90 min) were generated and warped to MNI space (inferior cerebellar GM reference region). Mean SUVR images were generated across groups to identify potential off-target binding regions and guide ROI delineation. [F]MK-6240 time-activ-

Geschwind Syndrome in frontotemporal lobar degeneration: Neuroanatomical and neuropsychological features over 9 years

Geschwind Syndrome, a characteristic behavioral syndrome frequently described in patients affected by temporal lobe epilepsy (TLE), consists of the following features: hyper-religiosity, hypergraphia, hyposexuality, and irritability. Here we report the 9-year-clinical course of a case of Geschwind Syndrome that developed as a first and salient clinical expression of right temporal lobe variant of frontotemporal lobar degeneration (FTLD). Only one patient affected by frontotemporal dementia has previously been shown to present with Geschwind Syndrome. MS presented at age 73 with 3 years of personality and behavioral symptoms. Her early symptoms primarily included hyper-religiosity, hypergraphia, and poor emotional regulation (irritability, impulsivity, disinhibition, egocentric behavior). Over nine years, other cognitive functions (word retrieval, memory coding and recall, set-shifting, famous face and building recognition) became affected; however, hyper-religiosity, hypergraphia, and scarce emotional control remained her most prominent deficits. Longitudinal cortical thickness and volumetric analyses revealed early atrophy in the right temporal pole, right amygdala, and right hippocampus, which progressively affected homologous regions in the left hemisphere. The present case describes an unusual clinical picture associated with frontotemporal dementia (FTD), in which the most salient symptoms originated and remained consistent with Geschwind Syndrome.

COMPARISON OF HYPOMETABOLISM AND CORTICAL ATROPHY IN PRIMARY PROGRESSIVE APHASIA

functional magnetic resonance imaging (fMRI). The current study investigated differences in resting-state connectivity between AD patients with and without delusions.Methods:10 AD patients with delusions and 11 AD patients without delusions underwent fMRI scanning in a 3 Tesla scanner. The resting-state functional connectivity was assessed by parcellating the brain using a data-drivenmethod based on kmeans clustering, and measuring functional connectivity for frontal clusters, associated with cognitive control. The presence of delusions was evaluated using the Neuropsychiatric Inventory Questionnaire completed by an informant. Results:There were no significant differences in age, education, or global cognition as measured by the Montreal Cognitive Assessment (MoCA) between delusional and nondelusional groups. None of the delusional patients were on antipsychoticmedication. A single cluster of interest was analyzed, consisting of the superior medial frontal gyrus and the anterior cingulate. A twosample t-test found significantly increased connectivity (p<0.05, cluster size thresholded) between these regions of interest and the superior frontal gyrus in delusional compared to non-delusional patients. Conclusions:Our results suggest that aberrant resting-state connectivity between frontal regions may be related to the pathophysiology of delusions in Alzheimer’s disease. It is possible that altered frontal connectivity may be the brain trying to integrate disorganized neural processes, which can give rise to delusions[1]. The findings resemble resting-state abnormalities observed in patients with schizophrenia with delusions, with reports showing increased connectivity between the anterior cingulate gyrus (ACC) and medial frontal gyrus [2, 3].