Brain TDP‐43 pathology in corticobasal degeneration: topographical correlation with neuronal loss

Abstract Background Neurodegenerative disorders are characterized by insidious progression with poorly-delineated long latent period. Antecedent clinical insult could rarely unmask latent neurodegenerative disorders. Here, we report an autopsy-proven case of corticobasal degeneration which was preceded by a lacunar infarction. Case presentation A 58-year-old man presented with acute ataxia associated with a lacunar infarction in the right paramedian pons. His ataxia persisted with additional progressive gait difficulty and left arm clumsiness. Six months later, a follow-up neurological examination showed asymmetrical bradykinesia, apraxia, dystonic posturing, postural instability, and mild ataxia of the left limbs. Cognitive examination revealed frontal executive dysfunction and visuospatial difficulties. Dopamine transporter imaging scan demonstrated bilateral reduced uptakes in mid-to-posterior putamen, more prominent on the right side. Levodopa-unresponsive parkinsonism, asymmetric limb dystonia, and ideomotor apraxia became more conspicuous, while limb ataxia gradually vanished. The patient became unable to walk without assistance after 1 year, and died 4 years after the symptom onset. Autopsy findings showed frontoparietal cortical atrophy, ballooned neurons, and phosphorylated tau-positive astrocytic plaques and neuropil threads with gliosis and neuronal loss, confirming the corticobasal degeneration. Conclusions The case illustrates that precedent clinical events such as stroke might tip a patient with subclinical CBS into overt clinical manifestations.

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Mechanisms of Neurodegeneration in Various Forms of Parkinsonism—Similarities and Differences

Cells ◽

10.3390/cells10030656 ◽

2021 ◽

Vol 10 (3) ◽

pp. 656

Author(s):

Dariusz Koziorowski ◽

Monika Figura ◽

Łukasz M. Milanowski ◽

Stanisław Szlufik ◽

Piotr Alster ◽

...

Keyword(s):

Neurodegenerative Diseases ◽

Tau Protein ◽

Protein Gene ◽

Clinical Presentation ◽

Neuronal Loss ◽

Corticobasal Degeneration ◽

Inflammatory Factors ◽

Parkinsonian Disorders ◽

Genetic Features ◽

The Brain

Parkinson's disease (PD), dementia with Lewy body (DLB), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD) and multiple system atrophy (MSA) belong to a group of neurodegenerative diseases called parkinsonian syndromes. They share several clinical, neuropathological and genetic features. Neurodegenerative diseases are characterized by the progressive dysfunction of specific populations of neurons, determining clinical presentation. Neuronal loss is associated with extra- and intracellular accumulation of misfolded proteins. The parkinsonian diseases affect distinct areas of the brain. PD and MSA belong to a group of synucleinopathies that are characterized by the presence of fibrillary aggregates of α-synuclein protein in the cytoplasm of selected populations of neurons and glial cells. PSP is a tauopathy associated with the pathological aggregation of the microtubule associated tau protein. Although PD is common in the world's aging population and has been extensively studied, the exact mechanisms of the neurodegeneration are still not fully understood. Growing evidence indicates that parkinsonian disorders to some extent share a genetic background, with two key components identified so far: the microtubule associated tau protein gene (MAPT) and the α-synuclein gene (SNCA). The main pathways of parkinsonian neurodegeneration described in the literature are the protein and mitochondrial pathways. The factors that lead to neurodegeneration are primarily environmental toxins, inflammatory factors, oxidative stress and traumatic brain injury.

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Tauopathies: A Distinct Class of Neurodegenerative Diseases

Balkan Journal of Medical Genetics ◽

10.2478/v10034-008-0001-5 ◽

2007 ◽

Vol 10 (2) ◽

pp. 3-14 ◽

Cited By ~ 1

Author(s):

M Ozansoy ◽

A Başak

Keyword(s):

Neurodegenerative Diseases ◽

Neurofibrillary Tangles ◽

Neuronal Loss ◽

Corticobasal Degeneration ◽

Chromosome 17 ◽

Cell Degeneration ◽

Distinct Class ◽

Postencephalitic Parkinsonism ◽

Tau Isoforms ◽

Niemann Pick

Tauopathies: A Distinct Class of Neurodegenerative DiseasesNeurodegenerative diseases are characterized by neuronal loss and intraneuronal accumulation of fibrillary materials, of which, neurofibrillary tangles (NFT) are the most common. Neurofibrillary tangles also occur in normal aging and contain the hyperphosphorylated microtubule-associated protein tau. A detailed presentation is made of the molecular bases of Alzheimer's disease (AD), postencephalitic parkinsonism, amyotrophic lateral sclerosis/parkinsonism-dementia complex (ALS/PDC) of Guam, progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), Pick's disease, frontotemporal dementia (FTD), Down's syndrome, myotonic dystrophy (DM) and Niemann-Pick Type C (NPC) disease, which are considered to be common tauopathies. The unique human tau gene extends over 100 kb of the long arm of chromosome 17 and contains 16 exons. The human brain contains six tau isoforms that contain from 352 to 441 amino acids. To date, 34 pathogenic tau mutations have been described among 101 families affected by FTD with parkinsonism linked to chromosome 17 (FTDP-17). These mutations may involve alternative splicing of exon 10 that lead to changes in the proportion of 4-repeat- and 3-repeat-tau isoforms, or may modify tau interactions with microtubules. Tau aggregates differ in degree of phosphorylation and in content of tau isoforms. Five classes of tauopathies have been defined depending on the type of tau aggregates. The key event in tauopathies is the disorganization of the cytoskeleton, which is based on mutations/polymorphisms in the tau gene and lead to nerve cell degeneration. In this review, tauopathies as a distinct class of neurodegenerative diseases are discussed with emphasis on their molecular pathology and genetics.

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All tangled up: Tau-dependent neurodegeneration

The Biochemist ◽

10.1042/bio03202010 ◽

2010 ◽

Vol 32 (2) ◽

pp. 10-13

Author(s):

Ceri Lyn-Adams ◽

Kevin Moffat ◽

Calum Sutherland ◽

Bruno G. Frenguelli

Keyword(s):

Neurodegenerative Diseases ◽

Progressive Supranuclear Palsy ◽

Neurofibrillary Tangles ◽

Neuronal Loss ◽

Corticobasal Degeneration ◽

Chromosome 17 ◽

Phosphorylated Tau ◽

Brain Correlates ◽

Severity Of Dementia ◽

The Brain

Currently, there are 30 million people worldwide suffering from dementia. This number is predicted to rise to 100 million if effective treatments aren't developed rapidly. Alzheimer's disease (AD) is the most common form of dementia and is also the most prevalent of a group of neurodegenerative diseases known as tauopathies. Tauopathies are characterized by intraneuronal inclusions (pretangles) composed of aggregates of highly phosphorylated tau in the form of paired helical or straight filaments (PHFs), and neuronal loss. As the load of PHFs increases, they will aggregate and eventually form neurofibrillary tangles (NFTs) which fill the whole cell. The number of tau tangles present in the brain correlates well with the severity of dementia. Tau tangles are routinely found in AD, frontotemporal dementia linked to chromosome 17 with parkinsonism (FTDP-17), progressive supranuclear palsy, Pick's disease, corticobasal degeneration, head trauma and Down's syndrome to name but a few.

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