Familial tauopathy with P364S MAPT mutation: clinical course, neuropathology and ultrastructure of neuronal tau inclusions.

AIMS: This report presents the clinical course, neuropathology and ultrastructure of neuronal tau inclusions of four Slovene relatives with P364S MAPT mutation. METHODS: The clinical history of three out of four P364S MAPT mutation carriers was taken. After formalin fixation, thorough sampling of the central nervous system was followed by paraffin embedding, H&E, Gallyas, Bielschowsky and immunostaining with AT8, anti-3R, anti-4R tau, anti-amyloid-ß, anti-TDP43 and anti-alpha-synuclein antibodies. The distribution and density of different types of neuronal tau inclusions were semiquantitatively assessed. In addition, the ultrastructure of neuronal tau inclusions was analysed. RESULTS: Macroscopic examination of the brains was unremarkable. Microscopically, neuronal tau inclusions of almost all known types were widespread and distributed fairly uniformly in all cases. Pick bodies and swollen neurones were found in only one family member. Mutant tau was composed of 3R and 4R isoforms, with a slight predominance of 3R tau. Composite neuronal tau inclusion (CNTI), found in all four relatives, was a hallmark of the P364S MAPT mutation. CNTI showed compartmental differences in H&E and Gallyas staining, tau isoforms immunolabelling and ultrastructure, displaying fuzzy fibrils in the core and paired twisted tubules at the periphery. CONCLUSIONS: P364S MAPT mutation is characterized clinically by a variable combination of frontotemporal dementia, parkinsonism and motor neurone disease of short duration, and neuropathologically by a widespread uniform distribution of all known neuronal tau inclusions in one family member. Two-compartment CNTI is a unique characteristic of the P364S MAPT mutation.

Functional changes of the cortical motor system in hereditary spastic paraparesis.

BACKGROUND: Hereditary spastic paraparesis (HSP) is a heterogeneous group of disorders characterized by progressive bilateral lower limb spasticity. Functional imaging studies in patients with corticospinal tract involvement have shown reorganization of motor circuitry. Our study investigates functional changes in sensorimotor brain areas in patients with HSP. METHODS: Twelve subjects with HSP and 12 healthy subjects were studied. Functional magnetic resonance imaging (fMRI) was used to measure brain activation during right-hand finger tapping. Image analysis was performed using general linear model and regions of interest (ROI)-based approach. Weighted laterality indices (wLI) and anterior/posterior indicies (wAI and wPI) were calculated for predefined ROIs. RESULTS AND DISCUSSION: Comparing patients and controls at the same finger-tapping rate (1.8 Hz), there was increased fMRI activation in patients' bilateral posterior parietal cortex and left primary sensorimotor cortex. No differences were found when comparing patients and controls at 80% of their individual maximum tapping rates. wLI of the primary sensorimotor cortex was significantly lower in patients. Subjects with HSP also showed a relative increase in the activation of the posterior parietal and premotor areas compared with that of the primary sensorimotor cortex. Our findings demonstrate an altered pattern of cortical activation in subjects with HSP during motor task. The increased activation probably reflects reorganization of the cortical motor system.

Muscle activity-resistant acetylcholine receptor accumulation is induced in places of former motor endplates in ectopically innervated regenerating rat muscles.

Expression of acetylcholine receptors (AChRs) in the extrajunctional muscle regions, but not in the neuromuscular junctions, is repressed by propagated electric activity in muscle fibers. During regeneration, subsynaptic-like specializations accumulating AChRs are induced in new myotubes by agrin attached to the synaptic basal lamina at the places of former motor endplates even in the absence of innervation. We examined whether AChRs still accumulated at these places when the regenerating muscles were ectopically innervated and the former synaptic places became extrajunctional. Rat soleus muscles were injured by bupivacaine and ischemia to produce complete myofiber degeneration. The soleus muscle nerve was permanently severed and the muscle was ectopically innervated by the peroneal nerve a few millimeters away from the former junctional region. After 4 weeks of regeneration, the muscles contracted upon nerve stimulation, showed little atrophy and the cross-section areas of their fibers were completely above the range in non-innervated regenerating muscles, indicating successful innervation. Subsynaptic-like specializations in the former junctional region still accumulated AChRs (and acetylcholinesterase) although no motor nerve endings were observed in their vicinity and the cross-section area of their fibers clearly demonstrated that they were ectopically innervated. We conclude that the expression of AChRs at the places of the former neuromuscular junctions in the ectopically innervated regenerated soleus muscles is activity-independent.

Acetylcholinesterase in the neuromuscular junction.

New findings regarding acetylcholinesterase (AChE) in the neuromuscular junction (NMJ), obtained in the last decade, are briefly reviewed. AChE is highly concentrated in the NMJs of vertebrates. Its location remains stable after denervation in mature rat muscles but not in early postnatal muscles. Agrin in the synaptic basal lamina is able to induce sarcolemmal differentiations accumulating AChE even in the absence of a nerve ending. Asymmetric A12 AChE form is the major molecular form of AChE in vertebrate NMJs. Extrajunctional suppression of this form is a developmental phenomenon. Motor nerve is able to reinduce expression of the A12 AChE form in the ectopic NMJs even in muscles with complete extrajunctional suppression of this form. The 'tail' of the A12 AChE form is made of collagen Q. It contains domains for binding AChE to basal lamina with ionic and covalent interactions. Muscle activity is required for normal AChE expression in muscles and its accumulation in the NMJs. In addition, the pattern of muscle activation also regulates AChE activity in the NMJs, demonstrating that the pattern of synaptic transmission is able to modulate one of the key synaptic components.