Jeffrey S. Phillips

Multimodal evaluation demonstrates in vivo 18 F-AV-1451 uptake in autopsy-confirmed corticobasal degeneration

in vivo evaluations of F-AV-1451 in patients with pathological confirmation. We report a multimodal evaluation of a 58-year-old male with autopsy-confirmed CBD. He participated in in vivo baseline (15 months pre-death) clinical, F-AV-1451 PET, F-florbetapir PET, MRI, and DTI and longitudinal (5 months pre-death) F-AV-1451 PET research studies (Online Resource 1). When enrolled in research, the patient met clinical criteria for progressive supranuclear palsy (Online Resource 2). Baseline F-AV-1451 (Fig. 1a) revealed the highest retention in deep grey matter areas commonly associated with CBD pathology [1], including bilateral substantia nigra, globus pallidus, and midbrain. Follow-up F-AV1451 revealed more visible retention in bilateral frontal and posterior temporal cortical regions along with midbrain and pons (Fig. 1b). A direct assessment of annualized change revealed a 1–9 % increase in F-AV-1451 retention, which was highest in the pons, medulla, and midbrain along with bilateral frontal and right temporo-parietal cortices (Fig. 1c). Baseline MRI (Fig. 2a) revealed predominantly reduced cortical grey matter in bilateral frontal cortex and right angular gyrus along with deep grey structures, including the midbrain, putamen, right globus pallidus, right caudate, and left hippocampus. White matter revealed increased mean diffusivity (a measure of white matter integrity) in the corpus callosum, bilateral tapetum, pontine crossing fibres, and right lateralized corticospinal tract, and posterior corona radiata. These observations are consistent with previously reported distributions of disease in CBD [6]. Spearman correlations revealed inverse associations between baseline F-AV-1451 and grey matter volume (rs = −0.209; p = 0.016; Fig. 2b) and mean diffusivity (rs = −0.329; p = 0.032; Fig. 2c). Furthermore, we Corticobasal degeneration (CBD) is characterized by 4-repeat misfolded tau (4Rtau) including astrocytic plaques, threads, and neuronal tangles [1]. F-AV-1451 is a PET radioligand that achieves in vivo binding in Alzheimer’s disease (AD) [8] and autoradiographic evidence of binding to paired helical filaments (PHFs) composed of 3-repeat misfolded tau (3Rtau) and 4Rtau characteristic of AD histopathology [4, 5, 7]. However, autoradiographic studies of F-AV-1451 on CBD postmortem tissue failed to demonstrate binding in cortical regions [5, 7], though there was minimal pathology in one study (<1.1 % tau-load) [7]. Another study suggests minimal, but present, autoradiographic binding of F-AV-1451 for 4Rtau [4]. Given mixed autoradiographic evidence in CBD, there is a need for

Left Posterior Parietal Cortex Participates in Both Task Preparation and Episodic Retrieval

Optimal memory retrieval depends not only on the fidelity of stored information, but also on the attentional state of the subject. Factors such as mental preparedness to engage in stimulus processing can facilitate or hinder memory retrieval. The current study used functional magnetic resonance imaging (fMRI) to distinguish preparatory brain activity before episodic and semantic retrieval tasks from activity associated with retrieval itself. A catch-trial imaging paradigm permitted separation of neural responses to preparatory task cues and memory probes. Episodic and semantic task preparation engaged a common set of brain regions, including the bilateral intraparietal sulcus (IPS), left fusiform gyrus (FG), and the pre-supplementary motor area (pre-SMA). In the subsequent retrieval phase, the left IPS was among a set of frontoparietal regions that responded differently to old and new stimuli. In contrast, the right IPS responded to preparatory cues with little modulation during memory retrieval. The findings support a strong left-lateralization of retrieval success effects in left parietal cortex, and further indicate that left IPS performs operations that are common to both task preparation and memory retrieval. Such operations may be related to attentional control, monitoring of stimulus relevance, or retrieval.

Dynamic Sensorimotor Planning during Long-Term Sequence Learning: The Role of Variability, Response Chunking and Planning Errors

Many everyday skills are learned by binding otherwise independent actions into a unified sequence of responses across days or weeks of practice. Here we looked at how the dynamics of action planning and response binding change across such long timescales. Subjects (N = 23) were trained on a bimanual version of the serial reaction time task (32-item sequence) for two weeks (10 days total). Response times and accuracy both showed improvement with time, but appeared to be learned at different rates. Changes in response speed across training were associated with dynamic changes in response time variability, with faster learners expanding their variability during the early training days and then contracting response variability late in training. Using a novel measure of response chunking, we found that individual responses became temporally correlated across trials and asymptoted to set sizes of approximately 7 bound responses at the end of the first week of training. Finally, we used a state-space model of the response planning process to look at how predictive (i.e., response anticipation) and error-corrective (i.e., post-error slowing) processes correlated with learning rates for speed, accuracy and chunking. This analysis yielded non-monotonic association patterns between the state-space model parameters and learning rates, suggesting that different parts of the response planning process are relevant at different stages of long-term learning. These findings highlight the dynamic modulation of response speed, variability, accuracy and chunking as multiple movements become bound together into a larger set of responses during sequence learning.

18F-Flortaucipir PET/MRI Correlations in Nonamnestic and Amnestic Variants of Alzheimer Disease

Nonamnestic Alzheimer disease (AD) variants, including posterior cortical atrophy and the logopenic variant of primary progressive aphasia, differ from amnestic AD in distributions of tau aggregates and neurodegeneration. We evaluated whether 18F-flortaucipir (also called 18F-AV-1451) PET, targeting tau aggregates, detects these differences, and we compared the results with MRI measures of gray matter (GM) atrophy. Methods: Five subjects with posterior cortical atrophy, 4 subjects with the logopenic variant of primary progressive aphasia, 6 age-matched patients with AD, and 6 control subjects underwent 18F-flortaucipir PET and MRI. SUV ratios and GM volumes were compared using regional and voxel-based methods. Results: The subgroups showed the expected 18F-flortaucipir–binding patterns. Group effect sizes were generally stronger with 18F-flortaucipir PET than with MRI volumes. There were moderate-to-high correlations between regional GM atrophy and 18F-flortaucipir uptake. 18F-flortaucipir binding and GM atrophy correlated similarly to cognitive test performance. Conclusion: 18F-flortaucipir binding corresponds to the expected neurodegeneration patterns in nonamnestic AD, with potential for earlier detection of pathology than is possible with MRI atrophy measures.

Using precise word timing information improves decoding accuracy in a multiband-accelerated multimodal reading experiment

ABSTRACT The blood-oxygen-level-dependent (BOLD) signal measured in functional magnetic resonance imaging (fMRI) experiments is generally regarded as sluggish and poorly suited for probing neural function at the rapid timescales involved in sentence comprehension. However, recent studies have shown the value of acquiring data with very short repetition times (TRs), not merely in terms of improvements in contrast to noise ratio (CNR) through averaging, but also in terms of additional fine-grained temporal information. Using multiband-accelerated fMRI, we achieved whole-brain scans at 3-mm resolution with a TR of just 500 ms at both 3T and 7T field strengths. By taking advantage of word timing information, we found that word decoding accuracy across two separate sets of scan sessions improved significantly, with better overall performance at 7T than at 3T. The effect of TR was also investigated; we found that substantial word timing information can be extracted using fast TRs, with diminishing benefits beyond TRs of 1000 ms.

Is the Link from Working Memory to Analogy Causal? No Analogy Improvements following Working Memory Training Gains

Analogical reasoning has been hypothesized to critically depend upon working memory through correlational data [1], but less work has tested this relationship through experimental manipulation [2]. An opportunity for examining the connection between working memory and analogical reasoning has emerged from the growing, although somewhat controversial, body of literature suggests complex working memory training can sometimes lead to working memory improvements that transfer to novel working memory tasks. This study investigated whether working memory improvements, if replicated, would increase analogical reasoning ability. We assessed participants’ performance on verbal and visual analogy tasks after a complex working memory training program incorporating verbal and spatial tasks [3], [4]. Participants’ improvements on the working memory training tasks transferred to other short-term and working memory tasks, supporting the possibility of broad effects of working memory training. However, we found no effects on analogical reasoning. We propose several possible explanations for the lack of an impact of working memory improvements on analogical reasoning.

DISTINCT LONGITUDINAL CORTICAL ATROPHY IN NON-AMNESTIC COMPARED TO AMNESTIC ALZHEIMER’S DISEASE SUGGESTS DIFFERENT PATTERNS OF SPREADING PATHOLOGY

Figure 1. (A) The progression of neurofibrillary tangle (NFT) pathology in the medial temporal lobe in Braak stages I and II. Braak stages III-VI are not shown. NFT pathology starts in trans-entorhinal area (lateral ERC/BA35) and precedes to the ERC and the hippocampus. (B) The two dominant anatomical variants of the medial temporal lobe, defined by the folding patterns of the collateral sulcus (CS). Variant 1 has deep and continuous CS while variant 2 has discontinuous CS. Figure adapted from (Xie et al., 2017; Braak and Braak, 1995; Ding and Van Hosesen, 2010). Fulvio Da Re, Jeffrey S. Phillips, Sharon X. Xie, Carlo Ferrarese, Corey T.McMillan, David J. Irwin, MurrayGrossman, University of Milano-Bicocca, Milan, Italy; School of Medicine and Surgery, Milan Center for Neuroscience, University of Milano-Bicocca, Milan, Italy; Penn Frontotemporal Degeneration Center, University of Pennsylvania, Philadelphia, PA, USA; Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Contact e-mail: dare.fulvio@gmail. com

AMNESTIC AND NON-AMNESTIC PHENOTYPES OF ALZHEIMER'S DISEASE: AN MRI-BASED PHASING ANALYSIS

Fig. 1. Increa tional anisotro FW increase th the AD stage. FAT reduced i it further redu are reported a Mean FW (der (D) Mean FAT sion. ’**’ indic Fig. 2. Free-water (FW) increase and tissue compartment fractional anisotropy (FAT) deterioration correlated with verbal memory deficits. (A)Wholebrain voxel-wise linear regression indicated that increased FW values in widespread brain regions were associated with worse verbal memory. (B) Region-specific FAT reduce was associated with verbal memory deficits AND EXTRACELLULAR FREE-WATER CHANGES ASSOCIATEDWITH COGNITION IN AMNESTIC MILD COGNITIVE IMPAIRMENTAND ALZHEIMER’S DISEASE only in the body of fornix. White matter skeleton is highlighted in green color. All results are reported at the threshold of p< 0.05, TFCE and FWE corrected. Fang Ji, Ofer Pasternak, Siwei Liu, Yng Miin, Saima Hilal, Xin Xu, Narayanaswamy Venketasubramanian, Christopher Chen, Juan Zhou, Duke-NUS Medical School, Singapore, Singapore; Harvard Medical School, Boston, MA, USA; National University of Singapore, Singapore, Singapore; Raffles Neuroscience Centre, Raffles Hospital, Singapore, Singapore. Contact e-mail: james_jifang@foxmail.com

TAU BINDING MEASURED USING PET IN MEDIAL TEMPORAL LOBE CORRELATES WITH SUBREGIONAL ATROPHY AND EPISODIC MEMORY PERFORMANCE IN ALZHEIMER'S DISEASE

TEMPORAL LOBE CORRELATES WITH SUBREGIONAL ATROPHY AND EPISODIC MEMORY PERFORMANCE IN ALZHEIMER’S DISEASE Sandhitsu Das, Jeffrey Phillips, Laura E. M. Wisse, Grace Stockbower, Kylie Ternes, Corey T. McMillan, Paul A. Yushkevich, Murray Grossman, Ilya Nasrallah, David Wolk, University of Pennsylvania, Philadelphia, PA, USA; University of Pennsylvania, Philadelphia, PA, USA. Contact e-mail: sudas@seas.upenn.edu