Progressive Supranuclear Palsy-like Syndrome Research Articles

Mutations in bassoon in individuals with familial and sporadic progressive supranuclear palsy-like syndrome

Clinical diagnosis of progressive supranuclear palsy (PSP) is sometimes difficult because various phenotypes have been identified. Here, we report a mutation in the bassoon (BSN) gene in a family with PSP-like syndrome. Their clinical features resembled not only those of PSP patients but also those of individuals with multiple system atrophy and Alzheimer’s disease. The neuropathological findings showed a novel three + four repeat tauopathy with pallido-luysio-nigral degeneration and hippocampal sclerosis. Whole-exome analysis of this family identified a novel missense mutation in BSN. Within the pedigree, the detected BSN mutation was found only in affected individuals. Further genetic analyses were conducted in probands from four other pedigrees with PSP-like syndrome and in 41 sporadic cases. Three missense mutations in BSN that are very rarely listed in databases of healthy subjects were found in four sporadic cases. Western blot analysis of tau following the overexpression of wild-type or mutated BSN revealed the possibility that wild-type BSN reduced tau accumulation, while mutated BSN lost this function. An association between BSN and neurological diseases has not been previously reported. Our results revealed that the neurodegenerative disorder associated with the original proband’s pedigree is a novel tauopathy, differing from known dementia and parkinsonism syndromes, including PSP.

Mutations in bassoon in individuals with familial and sporadic progressive supranuclear palsy-like syndrome

Mutations in bassoon in individuals with familial and sporadic progressive supranuclear palsy-like syndrome

Role of Niemann-Pick Type C Disease Mutations in Dementia.

Several neurological and systemic diseases can cause dementia, beyond Alzheimer's disease. Rare genetic causes are often responsible for dementia with atypical features. Recently, mutations causative for Niemann-Pick type C disease (NPC) have also been implicated in neurodegenerative diseases. NPC is an autosomal recessive lipid storage disorder caused by mutations in NPC1 and NPC2 genes. In adults, clinical presentation mimicking other neurodegenerative diseases makes diagnosis difficult. Recent evidence suggests that heterozygous mutations in NPC genes may take on etiological significance. To investigate the presence of NPC1 and NPC2 mutations in adults affected by neurodegenerative dementia plus. We performed a genetic screening on 50 patients using a wide clinical and biochemical approach to characterize the phenotype of mutated patients. Sequencing analysis revealed four different and known heterozygous mutations in NPC1 and NPC2 genes. Patient 1 carried the p. F284LfsX26 in NPC1 and was affected by progressive supranuclear palsy-like syndrome. The remaining three patients showed a corticobasal syndrome and harbored the c.441+1G>A variant of NPC2 (patient 2), the missense p.N222 S mutation associated with the c.1947+8G>C variant in the splice region of intron 12 in NPC1 (patient 3), and the p.V30M mutation in NPC2 (patient 4), respectively. Filipin staining was abnormal in patients 1 and 2. mRNA analysis revealed an altered splicing of the NPC2 gene in patient 2. Heterozygous mutations of NPC1 and NPC2 genes could contribute to dementia plus, at least in a subset of patients. We highlight the occurrence of NPC1 and NPC2 heterozygous variants in dementia-plus as pathological event.

Functional Magnetic Resonance Imaging (MRI) and MRI Tractography in Progressive Supranuclear Palsy-Like Syndrome

ABSTRACTAn 18-year-old woman underwent an uneventful ascending aortic aneurysm repair then developed progressive supranuclear palsy-like syndrome. Extensive neuroimaging including contrasted fat-suppressed cranial and orbital magnetic resonance imaging (MRI), MRI tractography, and functional MRI (fMRI) revealed no clear radiographic involvement except for a single tiny hypoechoic midbrain dot on the T2*-weighted gradient-echo imaging, which is not considered sufficient to account for the patient’s deficits. This case attests to the occult nature of this rare and devastating syndrome.

The evolution of primary progressive apraxia of speech.

Primary progressive apraxia of speech is a recently described neurodegenerative disorder in which patients present with an isolated apraxia of speech and show focal degeneration of superior premotor cortex. Little is known about how these individuals progress over time, making it difficult to provide prognostic estimates. Thirteen subjects with primary progressive apraxia of speech underwent two serial comprehensive clinical and neuroimaging evaluations 2.4 years apart [median age of onset = 67 years (range: 49-76), seven females]. All underwent detailed speech and language, neurological and neuropsychological assessments, and magnetic resonance imaging, diffusion tensor imaging and (18)F-fluorodeoxyglucose positron emission tomography at both baseline and follow-up. Rates of change of whole brain, ventricle, and midbrain volumes were calculated using the boundary-shift integral and atlas-based parcellation, and rates of regional grey matter atrophy were assessed using tensor-based morphometry. White matter tract degeneration was assessed on diffusion-tensor imaging at each time-point. Patterns of hypometabolism were assessed at the single subject-level. Neuroimaging findings were compared with a cohort of 20 age, gender, and scan-interval matched healthy controls. All subjects developed extrapyramidal signs. In eight subjects the apraxia of speech remained the predominant feature. In the other five there was a striking progression of symptoms that had evolved into a progressive supranuclear palsy-like syndrome; they showed a combination of severe parkinsonism, near mutism, dysphagia with choking, vertical supranuclear gaze palsy or slowing, balance difficulties with falls and urinary incontinence, and one was wheelchair bound. Rates of whole brain atrophy (1.5% per year; controls = 0.4% per year), ventricular expansion (8.0% per year; controls = 3.3% per year) and midbrain atrophy (1.5% per year; controls = 0.1% per year) were elevated (P ≤ 0.001) in all 13, compared to controls. Increased rates of brain atrophy over time were observed throughout the premotor cortex, as well as prefrontal cortex, motor cortex, basal ganglia and midbrain, while white matter tract degeneration spread into the splenium of the corpus callosum and motor cortex white matter. Hypometabolism progressed over time in almost all subjects. These findings demonstrate that some subjects with primary progressive apraxia of speech will rapidly evolve and develop a devastating progressive supranuclear palsy-like syndrome ∼ 5 years after onset, perhaps related to progressive involvement of neocortex, basal ganglia and midbrain. These findings help improve our understanding of primary progressive apraxia of speech and provide some important prognostic guidelines.

Diagnosis and Treatment of Corticobasal Degeneration

Corticobasal degeneration is a pathologic entity. Presenting clinical phenotypes include corticobasal syndrome (CBS), frontal behavioral spatial syndrome, aphasia, progressive supranuclear palsy-like syndrome (PSPS), and a predominantly cognitive phenotype often mistaken for Alzheimer's disease (AD). Treatment of CBD is symptomatic, particularly given recently negative neuroprotective studies. Given the relentless progression in CBD, all interested patients should be offered the opportunity to enroll in clinical neuroprotective trials as they arise. For symptomatic therapy, treatment options are necessarily based on evidence from other disorders given the lack of studies in CBD. In patients with CBS and PSPS, parkinsonism is treated with levodopa/carbidopa. This generally has modest and transient benefits at best and often results in no improvement. Botulinum toxin injections are the treatment of choice for limb dystonia. Clonazepam and levetiracetam are commonly used for myoclonus. Physical therapy is an important part of motor treatment, particularly for fall prevention strategies and assist device assessment. Whether medications such as cholinesterase inhibitors or memantine have any role in CBD is unclear given the various responses described in related phenotypes and diseases. Treating the behavioral symptoms associated with CBD is critical in an attempt to treat symptoms for which we have good pharmacologic interventions and to hopefully improve quality of life. General supportive care is important, including assessing for sores related to dystonia or immobility, monitoring dysphagia, and identifying needs for support services. Finally, as with other relentlessly progressive neurodegenerative diseases, it is critical to provide family and caregiver support and to assess for when palliative care services will serve the patient best.

Progressive supranuclear palsy-like syndrome after aortic aneurysm repair: a case series.

The syndrome of progressive supranuclear palsy-like syndrome is a rare complication of ascending aortic aneurysm repair. We report two patients with videos and present a table of prior reported cases. To our knowledge there is no previously published video of this syndrome. The suspected mechanism is brainstem injury though neuroimaging is often negative for an associated infarct. We hope our report will increase recognition of this syndrome after aortic surgery, especially in patients with visual complaints.

Progressive Supranuclear Palsy-Like Syndrome After Aortic Aneurysm Repair: A Case Series

The syndrome of progressive supranuclear palsy-like syndrome is a rare complication of ascending aortic aneurysm repair. We report two patients with videos and present a table of prior reported cases. To our knowledge there is no previously published video of this syndrome. The suspected mechanism is brainstem injury though neuroimaging is often negative for an associated infarct. We hope our report will increase recognition of this syndrome after aortic surgery, especially in patients with visual complaints.

Is progressive upper-body apraxia a corticobasal syndrome?

Corticobasal degeneration (CBD) is characterized by various clinical manifestations including corticobasal syndrome, progressive supranuclear palsy-like syndrome and frontotemporal dementia. Focal cortical atrophy syndrome as the initial manifestation rarely occurs in CBD. Here, we present a 62-year-old man and a 70-year-old man who were admitted due to clumsiness in the arms. On initial neurological examination, they showed asymmetric limb apraxia without parkinsonism or global cognitive dysfunction. Brain MRI showed focal atrophy in the frontal and prefrontal cortices, and brain positron emission tomography scan revealed decreased metabolism in these same brain locations. Although these patients developed parkinsonism and dystonia within several years, the neurological signs were limited to the arms for a long period. “Progressive upper-body apraxia” may be a rare clinical manifestation of CBD which shows a benign clinical outcome. The patients described may enhance our understanding of the clinical heterogeneity of this disease.

FTLD-TDP with motor neuron disease, visuospatial impairment and a progressive supranuclear palsy-like syndrome: broadening the clinical phenotype of TDP-43 proteinopathies. A report of three cases

BackgroundFrontotemporal lobar degeneration with ubiquitin and TDP-43 positive neuronal inclusions represents a novel entity (FTLD-TDP) that may be associated with motor neuron disease (FTLD-MND); involvement of extrapyramidal and other systems has also been reported.Case presentationWe present three cases with similar clinical symptoms, including Parkinsonism, supranuclear gaze palsy, visuospatial impairment and a behavioral variant of frontotemporal dementia, associated with either clinically possible or definite MND. Neuropathological examination revealed hallmarks of FTLD-TDP with major involvement of subcortical and, in particular, mesencephalic structures. These cases differed in onset and progression of clinical manifestations as well as distribution of histopathological changes in the brain and spinal cord. Two cases were sporadic, whereas the third case had a pathological variation in the progranulin gene 102 delC.ConclusionsAssociation of a "progressive supranuclear palsy-like" syndrome with marked visuospatial impairment, motor neuron disease and early behavioral disturbances may represent a clinically distinct phenotype of FTLD-TDP. Our observations further support the concept that TDP-43 proteinopathies represent a spectrum of disorders, where preferential localization of pathogenetic inclusions and neuronal cell loss defines clinical phenotypes ranging from frontotemporal dementia with or without motor neuron disease, to corticobasal syndrome and to a progressive supranuclear palsy-like syndrome.

Narcolepsy, REM Sleep Behavior Disorder, and Supranuclear Gaze Palsy Associated With Ma1 and Ma2 Antibodies and Tonsillar Carcinoma

To describe a patient with diencephalic and mesencephalic presentation of a Ma1 and Ma2 antibody-associated paraneoplastic neurological disorder. Case report. The Colorado Neurological Institute Movement Disorders Center in Englewood, Colorado, and the Mayo Clinic in Rochester, Minnesota. A 55-year-old man with a paraneoplastic neurological disorder characterized by rapid eye movement sleep behavior disorder, narcolepsy, and a progressive supranuclear palsy-like syndrome in the setting of tonsillar carcinoma. Immunotherapy for paraneoplastic neurological disorder, surgery and radiotherapy for cancer, and symptomatic treatment for parkinsonism and sleep disorders. Polysomnography, multiple sleep latency test, and neurological examination. The cancer was detected at a limited stage and treatable. After oncological therapy and immunotherapy, symptoms stabilized. Treatment with modafinil improved daytime somnolence. Rapid onset and progression of multifocal deficits may be a clue to paraneoplastic etiology. Early treatment of a limited stage cancer (with or without immunotherapy) may possibly slow progression of neurological symptoms. Symptomatic treatment may be beneficial.

Magnetic resonance imaging lesion pattern in Guadeloupean parkinsonism is distinct from progressive supranuclear palsy

In the Caribbean island of Guadeloupe, patients with atypical parkinsonism develop a progressive supranuclear palsy-like syndrome, named Guadeloupean parkinsonism. Unlike the classical forms of progressive supranuclear palsy, they develop hallucinations and myoclonus. As lesions associated with Guadeloupean parkinsonism are poorly characterized, it is not known to what extent they differ from progressive supranuclear palsy. The aim of the present study was to determine the structural and metabolic profiles of Guadeloupean parkinsonism compared with progressive supranuclear palsy and controls using combined structural and diffusion magnetic resonance imaging and magnetic resonance spectroscopy. We included 9 patients with Guadeloupean parkinsonism, 10 with progressive supranuclear palsy and 9 age-matched controls. Magnetic resonance imaging examination was performed at 1.5 T and included 3D T(1)-weighted and fluid-attenuated inversion recovery images, diffusion tensor imaging and single voxel magnetic resonance spectroscopy in the lenticular nucleus. Images were analysed using voxel-based morphometry, voxel-based diffusion tensor imaging and brainstem region of interest measurements. In patients with Guadeloupean parkinsonism, structural and diffusion changes predominated in the temporal and occipital lobes, the limbic areas (medial temporal, orbitofrontal and cingulate cortices) and the cerebellum. In contrast to patients with progressive supranuclear palsy, structural changes predominated in the midbrain and the basal ganglia and diffusion abnormalities predominated in the frontocentral white matter, the basal ganglia and the brainstem. Compared with controls, the N-acetylaspartate to creatinine ratio was decreased in patients with progressive supranuclear palsy and to a lesser extent in patients with Guadeloupean parkinsonism. The pattern of structural and diffusion abnormalities differed between progressive supranuclear palsy and Guadeloupean parkinsonism. Widespread cortical atrophy was observed in patients with Guadeloupean parkinsonism who presented marked cognitive changes and hallucinations, whereas midbrain lesions were less severe than in progressive supranuclear palsy. Midbrain (progressive supranuclear palsy) or cortical (Guadeloupean parkinsonism) atrophy was a distinctive neuroimaging feature for differential diagnosis.