2-(4--(methylamino)phenyl)-6-hydroxybenzothiazole and Supranuclear-Palsy--Progressive

Corticobasal degeneration (CBD) was first described by Rebeiz et al. in 1967, and was called corticodentatonigral degeneration with neuronal achromasia [1]. Since then, our knowledge of the clinical features and underlying tau pathology has grown tremendously. Clinical antemortem diagnosis of CBD pathology remains challenging and has led to the development of revised diagnostic criteria. As various clinical phenotypes may have CBD pathology, accurate prevalence studies are lacking. Recently, pooled prevalence of fronto-temporal lobar degeneration, PSP and CBS was reported as 10.6 per 100,000 [2]. Although rare, CBD is an important disease to understand because it provides a model of a specific proteinopathy (tauopathy) and, therefore, opportunity to study pathophysiology of tauopathies and efficacy of tau-directed therapies. In the past few years, identification of tau specific ligands has advanced neuroimaging of tauopathies such as CBD and progressive supranuclear palsy. However, clinical prediction of CBD pathology remains challenging and an active are of research. In this review, we highlight key emerging issues in CBD pathophysiology, genetics and novel neuroimaging techniques with tau ligands.

Topics: Aniline Compounds; Basal Ganglia; Carbolines; Cerebral Cortex; Dopamine Agents; History, 20th Century; Humans; Levodopa; Neurodegenerative Diseases; Positron-Emission Tomography; Supranuclear Palsy, Progressive; Thiazoles

Little is known about Alzheimer's disease molecular proteins, beta-amyloid and paired helical filament (PHF) tau, in progressive supranuclear palsy (PSP). Recent techniques have been developed to allow for investigations of these proteins in PSP. We determined the frequency of beta-amyloid deposition in PSP, and whether beta-amyloid deposition in PSP is associated with PHF-tau deposition pattern, or clinical features.. Thirty probable PSP participants underwent MRI, [. Twelve subjects (40%) showed beta-amyloid deposition. Higher PiB SUVR correlated with older age but not with AV-1451 SUVR in the AD- or PSP-related regions. Higher AV-1451 SUVR in AD-related regions was associated with higher AV-1451 SUVR in PSP-related regions. We found little evidence for beta-amyloid related differences in clinical metrics, proportion of APOE e4 carriers, pattern of AV-1451 uptake, or pattern of atrophy.. Beta-amyloid deposition occurs in a relatively high proportion of PSP subjects. Unlike in Alzheimer's disease, however, there is little evidence that beta-amyloid, and PHF-tau, play a significant role in neurodegeneration in PSP.

Topics: Aged; Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Apolipoprotein E4; Brain; Carbolines; Female; Humans; Male; Middle Aged; Pathology, Molecular; Positron-Emission Tomography; Supranuclear Palsy, Progressive; tau Proteins; Thiazoles

Alzheimer's disease and progressive supranuclear palsy (PSP) represent neurodegenerative tauopathies with predominantly cortical versus subcortical disease burden. In Alzheimer's disease, neuropathology and atrophy preferentially affect 'hub' brain regions that are densely connected. It was unclear whether hubs are differentially affected by neurodegeneration because they are more likely to receive pathological proteins that propagate trans-neuronally, in a prion-like manner, or whether they are selectively vulnerable due to a lack of local trophic factors, higher metabolic demands, or differential gene expression. We assessed the relationship between tau burden and brain functional connectivity, by combining in vivo PET imaging using the ligand AV-1451, and graph theoretic measures of resting state functional MRI in 17 patients with Alzheimer's disease, 17 patients with PSP, and 12 controls. Strongly connected nodes displayed more tau pathology in Alzheimer's disease, independently of intrinsic connectivity network, validating the predictions of theories of trans-neuronal spread but not supporting a role for metabolic demands or deficient trophic support in tau accumulation. This was not a compensatory phenomenon, as the functional consequence of increasing tau burden in Alzheimer's disease was a progressive weakening of the connectivity of these same nodes, reducing weighted degree and local efficiency and resulting in weaker 'small-world' properties. Conversely, in PSP, unlike in Alzheimer's disease, those nodes that accrued pathological tau were those that displayed graph metric properties associated with increased metabolic demand and a lack of trophic support rather than strong functional connectivity. Together, these findings go some way towards explaining why Alzheimer's disease affects large scale connectivity networks throughout cortex while neuropathology in PSP is concentrated in a small number of subcortical structures. Further, we demonstrate that in PSP increasing tau burden in midbrain and deep nuclei was associated with strengthened cortico-cortical functional connectivity. Disrupted cortico-subcortical and cortico-brainstem interactions meant that information transfer took less direct paths, passing through a larger number of cortical nodes, reducing closeness centrality and eigenvector centrality in PSP, while increasing weighted degree, clustering, betweenness centrality and local efficiency. Our results have wide-ranging implications,

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Aniline Compounds; Brain Mapping; Carbolines; Connectome; Female; Humans; Image Processing, Computer-Assisted; Magnetic Resonance Imaging; Male; Middle Aged; Neural Pathways; Oxygen; Positron-Emission Tomography; Rest; Supranuclear Palsy, Progressive; tau Proteins; Thiazoles

Recent positron emission tomography (PET) studies have demonstrated the accumulation of tau PET tracer in the affected region of progressive supranuclear palsy (PSP) cases. To confirm the binding target of radiotracer in PSP, we performed an imaging-pathology correlation study in two autopsy-confirmed PSP patients who underwent [

Topics: Aged; Aged, 80 and over; Aminopyridines; Aniline Compounds; Astrocytes; Autopsy; Autoradiography; Correlation of Data; Female; Globus Pallidus; Humans; Magnetic Resonance Imaging; Male; Mesencephalon; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Nerve Tissue Proteins; Picolinic Acids; Positron-Emission Tomography; Quinolines; Supranuclear Palsy, Progressive; tau Proteins; Thiazoles

Participants underwent magnetic resonance imaging and positron emission tomography for amyloid-β (. Clinical PSP patients showed bilaterally elevated

Topics: Aged; Aniline Compounds; Brain; Brain Mapping; Carbolines; Case-Control Studies; Cognition Disorders; Diagnosis; Female; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Neuropsychological Tests; Parkinson Disease; Positron-Emission Tomography; Severity of Illness Index; Supranuclear Palsy, Progressive; tau Proteins; Thiazoles

Visualization of pathogenic protein aggregates is crucial to elucidate pathomechanisms and to make an accurate diagnosis in many neurodegenerative conditions. Aggregates of the microtubule-binding protein, tau, are one of the most important pathogenic molecules in neurodegenerative disorders. Progressive supranuclear palsy (PSP) is characterized by the deposition of tau proteins in some specific area such as the basal ganglia and brainstem. We tried to detect tau lesions in the brains of living patients with PSP with a novel positron emission tomography (PET) tracer, [. Paraffin-embedded brain sections of the patients with PSP were used for autoradiography with [. Autoradiography in the brain sections of patients with PSP demonstrated [. We conclude that [

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Aniline Compounds; Brain; Female; Humans; Male; Positron-Emission Tomography; Supranuclear Palsy, Progressive; tau Proteins; Thiazoles

Corticobasal syndrome (CBS) and progressive supranuclear palsy syndrome (PSPS) are atypical parkinsonian syndromes that are both associated with white matter tract degeneration. However, little is known about how patterns of degeneration compare across these two syndromes.. Twenty-seven subjects, nine with CBS and eighteen with probable or definite PSPS (9 pathologically confirmed) were prospectively recruited and underwent 3.0 T diffusion tensor imaging. A whole-brain voxel-based analysis was performed on fractional anisotropy (FA) and mean diffusivity (MD) images to compare both groups to each other and to 50 healthy controls.. The two syndromes showed overlapping regions of reduced FA and increased MD in the body of the corpus callosum, middle cingulum bundle, and premotor and prefrontal white matter, with reduced FA also observed in the superior cerebellar peduncles in both syndromes. However, CBS showed a more supratentorial and posterior pattern of degeneration with greater involvement of the splenium of the corpus callosum, premotor, motor and parietal lobes than PSPS. Findings in CBS were also highly asymmetric. Conversely, PSPS showed a more symmetric and infratentorial pattern of degeneration, with greater involvement of the superior cerebellar peduncles and midbrain than CBS.. CBS and PSPS are both associated with striking white matter tract degeneration. Despite differences in the supratentorial and infratentorial distribution of degeneration, and in asymmetry, both tend to target a common structural network. Measurements of white matter tract diffusion could therefore be useful disease biomarkers in both of these syndromes.

Topics: Aged; Aniline Compounds; Anisotropy; Brain; Diffusion Tensor Imaging; Female; Humans; Imaging, Three-Dimensional; Magnetic Resonance Imaging; Male; Middle Aged; Neurodegenerative Diseases; Positron-Emission Tomography; Supranuclear Palsy, Progressive; Thiazoles; White Matter

Core pathologies of Alzheimer's disease (AD) are aggregated amyloid-β peptides (Aβ) and tau, and the latter is also characteristic of diverse neurodegenerative tauopathies. These amyloid lesions provoke microglial activation, and recent neuroimaging technologies have enabled visualization of this response in living brains using radioligands for the peripheral benzodiazepine receptor also known as the 18 kDa translocator protein (TSPO). Here, we elucidated contributions of Aβ and tau deposits to in vivo TSPO signals in pursuit of mechanistic and diagnostic significance of TSPO imaging in AD and other tauopathies. A new antibody to human TSPO revealed induction of TSPO-positive microgliosis by tau fibrils in tauopathy brains. Emergence of TSPO signals before occurrence of brain atrophy and thioflavin-S-positive tau amyloidosis was also demonstrated in living mice transgenic for mutant tau by positron emission tomography (PET) with two classes of TSPO radioligands, [(11)C]AC-5216 and [(18)F]fluoroethoxy-DAA1106. Meanwhile, only modest TSPO elevation was observed in aged mice modeling Aβ plaque deposition, despite the notably enhanced in vivo binding of amyloid radiotracer, [(11)C]Pittsburgh Compound-B, to plaques. In these animals, [(11)C]AC-5216 yielded better TSPO contrasts than [(18)F]fluoroethoxy-DAA1106, supporting the possibility of capturing early neurotoxicity with high-performance TSPO probes. Furthermore, an additional line of mice modeling intraneuronal Aβ accumulation displayed elevated TSPO signals following noticeable neuronal loss, unlike TSPO upregulation heralding massive neuronal death in tauopathy model mice. Our data corroborate the utility of TSPO-PET imaging as a biomarker for tau-triggered toxicity, and as a complement to amyloid scans for diagnostic assessment of tauopathies with and without Aβ pathologies.

Topics: Acetamides; Alzheimer Disease; Amyloid beta-Protein Precursor; Aniline Compounds; Animals; Autoradiography; Brain; Humans; Immunohistochemistry; Isotope Labeling; Magnetic Resonance Imaging; Mice; Mice, Inbred C57BL; Neuritis; Neuroglia; Pick Disease of the Brain; Plaque, Amyloid; Positron-Emission Tomography; Purines; Radiopharmaceuticals; Receptors, GABA; Supranuclear Palsy, Progressive; tau Proteins; Thiazoles