CNS nontumor

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• Brain autopsy is the gold standard for CBD diagnosis (see Microscopic (histologic) features description)
• First standardized neuropathological criteria for CBD were published in 2002 (J Neuropathol Exp Neurol 2002;61:935)

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Contributed by Charles L. White, III, M.D.

• CBD is characterized by the accumulation of pathological aggregates of the 4R tau isoform (Prog Neurobiol 2019;180:101644)
• Astrocytic plaques, which are annular clusters of short and stubby processes forming plaque-like lesions, are found in the cortex and basal ganglia
• Ballooned (achromatic) neurons are characterized by swelling of the perikarya and proximal dendrites, along with loss of Nissl substance in pyramidal neurons
  • They are immunoreactive for alpha B crystallin (Neuropathol Appl Neurobiol 1992;18:341)
• Neuronal and glial inclusions are present in the cerebral cortical and subcortical gray matter
• Neuropil threads and coiled bodies are found in both white and gray matter
• Indistinct boundary between white and gray matter is often observed due to the abundance of neuropil threads in both compartments
• Superficial or laminar spongiosis is seen in the cerebral cortex
• Pattern of tau accumulation in the white matter CBD can be used to differentiate it from progressive nuclear palsy and Alzheimer disease (Acta Neuropathol Commun 2021;9:170)

Contributed by Charles L. White, III, M.D.

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• Progressive supranuclear palsy (PSP):
  • Sporadic 4 repeat tauopathy with glial and neuronal involvement, similar to CBD
  • Clinical and neuropathological features can overlap with CBD; some argue that they should be considered part of the same disease spectrum (Neurology 2001;56:1702, Mov Disord Clin Pract 2018;5:141)
  • Midbrain and subthalamic nuclei atrophy are more common than in CBD
  • Cortical involvement is less frequent or less pronounced than in CBD
  • Characteristic glial pathology is in the form of tufted astrocytes, radial arrangement of thin, long, branching aggregates of tau in proximal processes of astrocytes (Neuropathology 2014;34:555)
  • Ballooned neurons are less frequent compared to CBD; when detected, they are usually associated with concurrent argyrophilic grain disease (Acta Neuropathol 2002;104:53)
• Argyrophilic grain disease (AGD):
  • Sporadic 4 repeat tauopathy with glial and neuronal involvement, similar to CBD
  • Clinical and neuropathological features can overlap with CBD (Brain 2008;131:1416)
  • Pathology is mainly limited to medial temporal lobe structures including the amygdala, hippocampus and entorhinal cortex (Neuropathol Appl Neurobiol 1989;15:13)
  • Characteristic pathology is the presence of argyrophilic grains, tau immunoreactive, spindle shaped, rod-like, button-like or round bodies in the neuropil (Brain 2008;131:1416)
  • Ballooned neurons, typically found in amygdala (Neurosci Lett 1998;246:165)
• Globular glial tauopathy (GGT):
  • Sporadic 4 repeat tauopathy with only glial involvement (Acta Neuropathol 2013;126:537)
  • Clinical picture of a frontotemporal dementia syndrome and asymmetric brain atrophy may resemble CBD (Eur J Neurol 2023;30:321)
  • Characterized by globular inclusions in both oligodendrocytes and astrocytes but not in neurons (Psychiatr Clin North Am 2020;43:331)
  • Astrocytic plaques are not seen (Acta Neuropathol 2013;126:537)
• Frontotemporal lobar degeneration (FTLD, tau-):
  • Group of disorders with frontotemporal atrophy and frontotemporal dementia clinical syndrome
  • Subclassified based on the type of proteinopathy (Psychiatr Clin North Am 2020;43:331)
    • TAR DNA binding protein 43 (TDP-43) related FTLD: tau-, TDP-43+ inclusions
    • FTLD fused in sarcoma gene (FUS): tau-, ubiquitin+, p62+ and FUS+ inclusions
• Frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17):
  • Autosomal dominant inherited disorder usually caused by mutations in the MAPT gene, which is located on chromosome 17 (Folia Neuropathol 2005;43:258)
  • Clinical and neuropathological features can overlap with CBD (Folia Neuropathol 2005;43:258)
  • Positive family history and earlier age of onset (average of 45 years) (J Hum Genet 2015;60:281)
• Alzheimer disease (AD):
  • Progressive dementia characterized by amyloid plaques and neurofibrillary tangles (Alzheimers Dement 2012;8:1)
  • Clinical features may overlap with CBD; approximately 1 in 4 clinical CBS cases show postmortem AD pathology instead of CBD (Brain 2010;133:2045)
  • Both 3 repeat and 4 repeat tau isoforms are present (Int J Mol Sci 2022;23:12841)
  • Much more prevalent than CBD (Nat Rev Dis Primers 2015;1:15056, J Neurol 2023;270:4451)
• Pick disease (PiD):
  • Sporadic 3 repeat tauopathy with neuronal and glial involvement (Ann Neurol 2002;51:730)
  • Clinical features can overlap with CBD (Neurology 1997;48:119)
  • Atrophy spares the pre and postcentral gyri (Neurology 2001;56:S16)
  • Characteristic pathology consists of round cytoplasmic neuronal tau inclusions called Pick bodies (Handb Clin Neurol 2008;89:415)
• Alpha synucleinopathies (Lewy body dementia, Parkinson disease, multiple system atrophy, etc.):
  • Alpha-synuclein+, tau- aggregates
  • Cortical atrophy is not as pronounced
  • Atrophy of the cerebellum or putamen (multiple system atrophy)

The above image shows an alpha B crystallin stain of the neocortex. These cells are most characteristic of which neurodegenerative disease?

1. Alzheimer disease
2. Corticobasal degeneration
3. Lewy body disease
4. Pick disease

B. Corticobasal degeneration. These are alpha B crystallin immunoreactive ballooned (achromatic) neurons, which are generally seen in the third, fifth and sixth cortical layers and are considered an important histological feature of CBD. Answers A and D are incorrect because balloon cells are not characteristic for Alzheimer disease or Pick disease, although they can occasionally be seen in these entities. Answer C is incorrect because balloon neurons are not usually seen in Lewy body disease.

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Reference: Corticobasal degeneration

Which of the following is the main component of these lesions, shown in the image above, from a case of corticobasal degeneration (CBD)?

1. 4R tau
2. Alpha-synuclein
3. Amyloid beta
4. TDP-43

A. 4R tau. Astrocytic plaques are a distinct annular array of 4R tau immunoreactive processes that are reminiscent of the senile plaques of Alzheimer disease but lack amyloid beta immunoreactivity, differentiating them from Alzheimer disease associated senile plaques. They are also positive for GFAP, indicating a glial, rather than a neuronal, origin (Neuropathology 2014;34:555). Answer D is incorrect because TDP-43 is negative in CBD but positive in other neurodegenerative diseases, such as frontotemporal lobar degeneration with TDP-43 proteinopathy (FTLD TDP), amyotrophic lateral sclerosis and limbic predominant age related TDP-43 encephalopathy (LATE NC). Answer C incorrect because senile plaques of Alzheimer disease show co-occurring immunoreactivity for both tau and amyloid beta but astrocytic plaques of CBD are positive only for tau. Answer B is incorrect because CBD is a tauopathy, not a synucleinopathy like Lewy body disease or multiple systemic atrophy.

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Reference: Corticobasal degeneration