BackgroundMultiple neurodegenerative diseases are characterized by the abnormal accumulation of FUS protein including various subtypes of frontotemporal lobar degeneration with FUS inclusions (FTLD-FUS). These subtypes include atypical frontotemporal lobar degeneration with ubiquitin-positive inclusions (aFTLD-U), basophilic inclusion body disease (BIBD) and neuronal intermediate filament inclusion disease (NIFID). Despite considerable overlap, certain pathologic features including differences in inclusion morphology, the subcellular localization of inclusions, and the relative paucity of subcortical FUS pathology in aFTLD-U indicate that these three entities represent related but distinct diseases. In this study, we report the clinical and pathologic features of three cases of aFTLD-U and two cases of late-onset BIBD with an emphasis on the anatomic distribution of FUS inclusions.ResultsThe aFTLD-U cases demonstrated FUS inclusions in cerebral cortex, subcortical grey matter and brainstem with a predilection for anterior forebrain and rostral brainstem. In contrast, the distribution of FUS pathology in late-onset BIBD cases demonstrated a predilection for pyramidal and extrapyramidal motor regions with relative sparing of cerebral cortex and limbic regions.ConclusionsThe topography of FUS pathology in these cases demonstrate the diversity of sporadic FUS inclusion body diseases and raises the possibility that late-onset motor neuron disease with BIBD neuropathology may exhibit unique clinical and pathologic features.

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Increasingly, it has been recognized that in order to affect underlying neurodegeneration in Parkinson's disease (PD), individuals must be identified before onset of the classic motor symptoms. Thus, for research purposes, a redefinition of PD has been proposed into preclinical, premotor, and motor phases. In the preclinical phase, no clinical signs or symptoms of PD are present. In the premotor phase, nonmotor manifestations are detectable. These include olfactory, neuropsychiatric, sleep, gastrointestinal, and autonomic changes. A multi-modal approach is needed to maximize both sensitivity and specificity of any assessment of the premotor phase. To that end, several objective markers, such as dopaminergic imaging and electrophysiologic techniques, exist and are of potential utility. This review discusses the candidate nonmotor features and potential objective measures that may be used to define the premotor phase of PD.In the nearly 200 years since Parkinson's disease (PD) was first described, extensive clinical characterization of the signs and symptoms, along with clinicopathological correlation, have allowed for the establishment of robust clinical criteria for diagnosis. 1 However, it is becoming increasingly clear, in the face of multiple failed disease-modification trials, that it is essential that we detect PD earlier, before motor manifestations are present. Thus, for research purposes, a redefinition of PD into three phases, particularly on research grounds, has been put forth. 2,3 These three phases include preclinical, premotor, and motor phases (Table 1). Whether some of the premotor manifestations result from neurodegeneration or are truly premorbid (preceding onset of neurodegeneration), is unclear, though, at least in some cases, evidence suggests the former, as detailed below. Note that the three phases do not necessarily occur in the same chronological order in individual PD patients, and not all may be present. 3 Thus, extensive characterization of each phase is essential. Exciting data have begun to emerge from the cohorts of individuals thought to be "at risk" of PD that have been assembled by us and others to achieve this goal. 4 This review will focus on the premotor phase of PD, namely, the phase of PD in which nonmotor signs and symptoms are present, and are hypothesized to result from extranigral pathology (Table 1). These include various clinical, imaging, and electrophysiological features (Table 2). We will then discuss the need for multimodal biomarkers to further characterize the premotor syndrome and discuss advances in imaging and other tools for identifying premotor PD. Olfactory DysfunctionOver 90% of patients with PD have olfactory dysfunction, 5 manifesting as deficits of odor identification, discrimination, and threshold. [26][27][28] There are extensive data to support the incorporation of olfactory loss as a feature of premotor PD. One of the most robust lines of evidence comes from the Honolulu-Asia Aging Study (HAAS). 8 In this longitudinal study of 2,267 men w...

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