Letters to the Editor Related to New Topics Association of Corticobasal Degeneration and Huntington’s Disease: Can Tau Aggregates Protect Huntingtin Toxicity?

A 70-year-old woman developed a mild cerebellar syndrome including hypotonia and moderate postural instability which did not progress with time. Hypotonia related to cerebellar signs was associated with scarce and slight jerky arrhythmic involuntary movements of the arms, which disappeared as the disease progressed. After 1 year, she developed progressive dysarthria and dysphagia associated with bucco-linguofacial apraxia. The cognitive evaluation revealed mild praxis impairment during reflexive movements, but memory and executive testing were normal. Eighteen months after disease onset, she developed signs of spastic face, including jaw jerk and brisk nasopalpebral reflex. She had also reduced tongue protraction, tongue amyotrophy, fasciculations, and progressive swallowing impairment. Complete anarthria was noted 2 years after disease onset. Swallowing apraxia worsened, requiring tube feeding. The disease progressed with left leg spastic paresis and amyotrophy, which extended to other limbs. She died after 3 years of disease duration. Until death, she communicated by writing. All sentences and responses to questions demonstrated that cognitive function was roughly intact. Neither rigidity of the limbs nor limited amplitude of the eye movements was noted. During the follow-up, standard biological results were normal, as well as brain MRI. Technecium 99m SPECT showed bilateral fronto-temporoparietal hypoperfusion. Repeated electromyography showed signs of anterior horn in face muscles only, but never in limbs. She had no familial history of neurodegenerative disorder. Because of scarce and slight jerky arrhythmic involuntary movements of the arms, genetic testing of Huntington’s disease was performed. A CAG repeat corresponding to an expanded allele (40 repeats) was found. The brain weighed 1,265 g. A moderate and diffuse atrophy was noticed, with a mild narrowing of the frontal and temporal gyri. Microscopically, lesions associated neuronal loss, astrocytic gliosis, and superficial spongiosis. They were mainly observed in the frontal and temporal cortices. The basal ganglia were also affected, but the severity of lesions was lower than in cortical areas. Scarce ballooned neurons were found in the frontal cortex. Using anti-Tau antibody, Tau immunoreactivity appeared as neurofibrillary tangles (NFT) and pre-tangles in the hippocampus and in the temporal neocortex, oligodendroglial inclusions (coiled bodies) in the cerebral white matter (Fig. 1A) and thread processes. In subcortical areas, Tau immunostaining was restricted to rare NFT and coiled bodies in the caudate nucleus, the putamen, and the substantia nigra. b-amyloid, a-synuclein, and prion protein immunoreactivities were negative. The neuroanatomical distribution of this Tauopathy was in favor of corticobasal degeneration, as confirmed by biochemical characterization of pathological hyperphosphorylated tau proteins using western blot analysis of paired helical filaments (PHF-tau), mainly in temporal cortex, hippocampus, pallidum, and Meynert nucleus. A typical tau 64, 69 doublet on electrophoresis gave the molecular signature of corticobasal degeneration. An associated Huntington’s disease was suggested by the demonstration of characteristic aggregates. Anti-Huntingtin EM48 antibody showed neuropil inclusions and rare nuclear aggregates (Fig. 1B), which were located in the cerebral cortex and in the striatum. In the same areas, anti-polyglutamine 1C2 antibody stained many neurons. The striatal degenerative changes were dorsally situated, consistent with a Grade 1 according to the Vonsattel classification of Huntington’s disease pathological severity. Double immunofluorescence for Huntingtin and Tau was performed and colocalization was detected in some aggregates by confocal microscopy in our case (Fig. 1C), but no costaining was observed in a corticobasal degeneration case control (Fig. 1D). The association of speech and swallowing apraxia, without cognitive impairment and the progressive involvement of parietal cortex, cerebellum and anterior horn of spinal cord suggested a neurodegenerative disorder which could be corticobasal degeneration. The neuropathological study and the biochemical characterization of pathological hyperphosphorylated tau proteins confirmed the clinical features were related to a corticobasal degeneration type tauopathy. With a CAG repeat size of 40, the expected median age at Huntington’s disease onset is 59. However, asymptomatic carriers of 40 CAG repeats have already been reported with an oldest age at onset of 78 years. The lack of clinical symptoms of Huntington’s disease in this 72-year-woman was then not remarkable. Neuropathological examination of brain and striatum confirmed a low grade in Huntington, but interestingly demonstrated the presence of huntingtin aggregates that colocalize with tau aggregates. Numerous proteins have been demonstrated to interact with huntingtin, modifying mutant hutingtin toxicity. Tau has never been documented to interact with mutant huntingtin. The present observation raises the question to whether or not the level of tau phosphorylation could limit the severity and/or progression of Huntington’s disease.