Kimiko Domoto-Reilly

Pathological correlations of [F‐18]‐AV‐1451 imaging in non‐alzheimer tauopathies

Recent studies have shown that positron emission tomography (PET) tracer AV‐1451 exhibits high binding affinity for paired helical filament (PHF)‐tau pathology in Alzheimers brains. However, the ability of this ligand to bind to tau lesions in other tauopathies remains controversial. Our goal was to examine the correlation of in vivo and postmortem AV‐1451 binding patterns in three autopsy‐confirmed non‐Alzheimer tauopathy cases.

Naming impairment in Alzheimer's disease is associated with left anterior temporal lobe atrophy

There is considerable debate about the neuroanatomic localization of semantic memory, the knowledge of culturally shared elements such as objects, concepts, and people. Two recent meta-analyses of functional imaging studies (fMRI and PET) sought to identify cortical regions involved in semantic processing. Binder and colleagues (Binder et al., 2009) identified several regions of interest, widely distributed throughout the frontal, parietal, and temporal cortices. In contrast, Lambon Ralph and colleagues (2010) focused on the anterior temporal lobe, and found that when the potential for signal loss is accounted for (due, for example, to distortion artifact or field of view restriction), significant regional activation is detected. We set out to determine whether the anterior temporal lobe plays a significant role in picture naming, a task which relies on semantic memory. We examined a relatively large sample of patients with early Alzheimers disease (N=145), a multifocal disease process typically characterized in the early stages by problems with episodic memory and executive function. Hypothesis-driven analyses based on regions of interest derived from the meta-analyses as well as exploratory analyses across the entire cerebral cortex demonstrated a highly specific correlation between cortical thinning of the left anterior temporal lobe and impaired naming performance. These findings lend further support to theories that include a prominent role for the anterior temporal lobe in tasks that rely on semantic memory.

The role of phonological and orthographic information in lexical selection

We report the performance of two patients with lexico-semantic deficits following left MCA CVA. Both patients produce similar numbers of semantic paraphasias in naming tasks, but presented one crucial difference: grapheme-to-phoneme and phoneme-to-grapheme conversion procedures were available only to one of them. We investigated the impact of this availability on the process of lexical selection during word production. The patient for whom conversion procedures were not operational produced semantic errors in transcoding tasks such as reading and writing to dictation; furthermore, when asked to name a given picture in multiple output modalities--e.g., to say the name of a picture and immediately after to write it down--he produced lexically inconsistent responses. By contrast, the patient for whom conversion procedures were available did not produce semantic errors in transcoding tasks and did not produce lexically inconsistent responses in multiple picture-naming tasks. These observations are interpreted in the context of the summation hypothesis (Hillis & Caramazza, 1991), according to which the activation of lexical entries for production would be made on the basis of semantic information and, when available, on the basis of form-specific information. The implementation of this hypothesis in models of lexical access is discussed in detail.

Interrater reliability of the new criteria for behavioral variant frontotemporal dementia

Objective: To evaluate the interrater reliability of the new International Behavioural Variant FTD Criteria Consortium (FTDC) criteria for behavioral variant frontotemporal dementia (bvFTD). Methods: Twenty standardized clinical case modules were developed for patients with a range of neurodegenerative diagnoses, including bvFTD, primary progressive aphasia (nonfluent, semantic, and logopenic variant), Alzheimer disease, and Lewy body dementia. Eighteen blinded raters reviewed the modules and 1) rated the presence or absence of core diagnostic features for the FTDC criteria, and 2) provided an overall diagnostic rating. Interrater reliability was determined by κ statistics for multiple raters with categorical ratings. Results: The mean κ value for diagnostic agreement was 0.81 for possible bvFTD and 0.82 for probable bvFTD (“almost perfect agreement”). Interrater reliability for 4 of the 6 core features had “substantial” agreement (behavioral disinhibition, perseverative/compulsive, sympathy/empathy, hyperorality; κ = 0.61–0.80), whereas 2 had “moderate” agreement (apathy/inertia, neuropsychological; κ = 0.41–0.6). Clinician years of experience did not significantly influence rater accuracy. Conclusions: The FTDC criteria show promise for improving the diagnostic accuracy and reliability of clinicians and researchers. As disease-altering therapies are developed, accurate differential diagnosis between bvFTD and other neurodegenerative diseases will become increasingly important.

Use of the Progressive Aphasia Severity Scale (PASS) in monitoring speech and language status in PPA

Background: Primary progressive aphasia (PPA) is a devastating neurodegenerative syndrome involving the gradual development of aphasia, slowly impairing the patient’s ability to communicate. Pharmaceutical treatments do not currently exist and intervention often focuses on speech and language behavioural therapies, although further investigation is warranted to determine how best to harness functional benefits. Efforts to develop pharmaceutical and behavioural treatments have been hindered by a lack of standardised methods to monitor disease progression and treatment efficacy. Aims: Here, we describe our current approach to monitoring progression of PPA, including the development and applications of a novel clinical instrument for this purpose, the Progressive Aphasia Severity Scale (PASS). We also outline some of the issues related to initial evaluation and longitudinal monitoring of PPA. Methods & Procedures: In our clinical and research practice, we perform initial and follow-up assessments of PPA patients using a multifaceted approach. In addition to standardised assessment measures, we use the PASS to rate presence and severity of symptoms across distinct domains of speech, language, and functional and pragmatic aspects of communication. Ratings are made using the clinician’s best judgement, integrating information from patient test performance in the office as well as a companion’s description of routine daily functioning. Outcomes & Results: Monitoring symptom characteristics and severity with the PASS can assist in developing behavioural therapies, planning treatment goals, and counselling patients and families on clinical status and prognosis. The PASS also has potential to advance the implementation of PPA clinical trials. Conclusions: PPA patients display heterogeneous language profiles that change over time given the progressive nature of the disease. The monitoring of symptom progression is therefore crucial to ensure that proposed treatments are appropriate at any given stage, including speech and language therapy and potentially pharmaceutical treatments once these become available. Because of the discrepancy that can exist between a patient’s daily functioning and standardised test performance, we believe a comprehensive assessment and monitoring battery must include performance-based instruments, interviews with the patient and partner, questionnaires about functioning in daily life, and measures of clinician judgement. We hope that our clinician judgement-based rating scale described here will be a valuable addition to the PPA assessment and monitoring battery.

Mild cognitive impairment of frontotemporal lobar degeneration subtypes: Clinical and imaging characteristics

ined. Results: Her consciousness was alert. Her cognitive function was mildly affected: mini-mental state examination 27/30, frontal assessment battery 12/18, Montreal cognitive assessment 21/30, and geriatric depression scale 10/15. She had severe thermoanesthesia and hypoalgesia in lower limbs. Tendon reflexes showed generalized areflexia. Severe orthostatic hypotensionwas observed with changes of blood pressures from 115/80mmHg (lying) to 59/35mmHg (standing). The brain MRI showed neither cerebral atrophy nor abnormal signal intensities including diffusion weighted image. The NCS showed the compound muscle action potential in tibial nerves and the sensory nerve action potential of the sural nerve were not evoked. The sural nerve biopsy revealed moderate loss of myelinated fibers. The blood gas analysis showed respiratory acidosis with mild metabolic compensation (pH 7.35, PaCO2 57.5mmHg, PaO2 68.9mmHg, HCO331.1mmol/l). The eye drops test showedreduced response indicating the central autonomic failure. The heart-to-mediastinum ratio decreased to 1.99 in the early phase and 1.77 in the delayed phase of the 123I-MIBG scintigraphy. The sweating test showed general anhidrosis. The CSF 14-3-3 and tau proteins were elevated at 1,125̂I1⁄4g/ml and 2,994pg/ml, respectively. The prion gene analysis showed a 2 bp deletion in codon 178 that causes a premature stop codon and additional variable 25 amino acid at C-terminal from the mutation site.Conclusions: A novel prion gene mutation was found in 34-year-old female, which potentially caused the characteristic complex phenotype of the cognitive disturbance, peripheral neuropathy and pan-autonomic failure.

Semantic memory impairment in Alzheimer's disease and frontotemporal dementia is associated with semantic network degradation

Background: Semantic memory deficits in early AD are typically subtle, and overshadowed by other cognitive impairments such as problems with episodic memory. FTD, in contrast, can sometimes cause early, prominent semantic impairment. Ongoing debate regarding the localization of semantic memory has focused on whether there is a distributed set of brain regions with convergence zones in association cortices, or whether the anterior temporal lobes form a “hub” for centralizing conceptual processing. We performed a series of analyses to address this issue. First, we examined ADNI data to determine the correlation between regional cortical atrophy and degree of semantic impairment in early AD. Our group has previously demonstrated that AD affects a “signature set” of cortical regions, overlapping with the default mode network. We hypothesized that, if semantic memory is subserved primarily by a distributed set of brain regions, the degree of semantic impairment in AD would correlate with the degree of atrophy distributed throughout this large-scale network. In contrast, if access to semanticmemory requires a temporal pole hub, patients with greater semantic impairment would have greater atrophy in a pattern more consistent with a temporopolar network. Second, we analyzed FTD patients to identify brain regions associated with prominent semantic impairment. Methods: We extracted Boston Naming Test data from mild AD patients in ADNI. Cortical thickness analysis was performed, identifying areas in which cortical thinning was correlated with naming impairment, controlling for age, sex, education, and MMSE score. We performed a similar analysis of FTD patients (all subtypes).We then compared the thinningmaps associated with semantic impairment between the two diseases. Results: Naming impairment correlated strongly with left-lateralized anterior and lateral temporal cortical thinning, and not with thinning in the overall AD signature. This pattern was very similar in FTD.Conclusions:The basis for naming deficits in early AD appears to be neurodegeneration of temporal regions associated with lexico-semantic abilities. Semantic impairment in FTD follows a similar pattern: atrophy prominently affecting the ventral language network, with relative dorsal sparing. These findings provide further support that neurodegenerative diseases may target specific cognitive-behavioral brain networks, but demonstrate that distinct diseases may affect a single network. P4-094 A SPECIFIC RELATIONSHIP BETWEEN HIPPOCAMPAL CA1 SUBFIELD ATROPHYAND EPISODIC MEMORY ENCODING IN AMNESTIC MILD COGNITIVE IMPAIRMENT Marine Fouquet, B eatrice Desgranges, Renaud La Joie, Denis Rivi ere, Brigitte Landeau, Florence M ezenge, Vincent de La Sayette, Fausto Viader, Jean-François Mangin, Jean-Claude Baron, Francis Eustache, Ga€el Ch etelat, INSERM-EPHE-UCBN U923, Caen, France; CEA LNAO, Gif-sur-Yvette, France; University of Cambridge, Cambridge, United Kingdom.