Approach Considerations
All patients require brain MR imaging and a serum workup for reversible/effectively treatable etiologies (although CBS and other CBD presentations are not diagnoses of exclusion). FDG-PET may be useful in selected cases. [28] Emerging tau PET ligands can image tau pathology in vivo and are currently available on a research basis.
Laboratory Studies
See the list below:
-
Serum copper and ceruloplasmin to evaluate for Wilson disease
-
Workup for reversible systemic causes of cognitive deficits:
Serum vitamin B12 level
Thyroid function tests, and consider thyroid autoantibody screening
Consider rapid plasma reagin (RPR) or Venereal Disease Research Laboratory (VDRL) test, which may be falsely negative in patients older than 65 years, to rule out neurosyphilis [29]
Electrolytes
CBC with differential and platelets
If appropriate or other evidence of systemic disease - Rheumatologic workup, including antinuclear antibody (ANA), erythrocyte sedimentation rate (ESR), liver function tests, and ammonia level
Manual smear for acanthocytes or genetic testing for Huntington disease if the patient presents with chorea
Can consider CSF biomarkers of neurodegeneration:
-
14-3-3 protein, neuron-specific enolase and RT-QuIC to test for prionopathies such as CJD in rapidly progressive cases
-
Amyloid beta-42, phosphorylated tau and total tau levels to assess for AD pathology
-
Neurofilament light chain (NFL) protein elevation, while not specific to CBD, can differentiate atypical parkinsonian disorders from Parkinson disease on a group level [30] ; this remains a research tool to date
Imaging Studies
MRI
Structural MR imaging has shown more asymmetric atrophy of frontal and parietal lobes in corticobasal degeneration (CBD). Recent MRI Quantitative Susceptibility mapping (QSM) of cerebral gyri has shown that CBD has a distinct three-layered pattern of signal density in the cerebral cortex: a higher susceptibility layer in superficial gray matter (layer 3), a lower susceptibility layer, and another higher susceptibility layer in corticomedullary junction. The areas of higher susceptibility were due to ferritin accumulation in microglia, confirmed by histopathology. This MRI finding was thought to be specific for CBD. [31]
MRI is helpful in evaluating the size and appearance of the midbrain if any disturbance of vertical eye movements is noted and progressive supranuclear palsy is being considered. Midbrain size should be relatively normal in typical CBD.
Cortical atrophy usually occurs, and this can be more localized to the central sulci/supplementary motor area (SMA) and superior frontal gyrus than to the temporal/parietal cortex (the latter pattern is classically seen in AD). [6]
Abnormal signal in basal ganglia can occur with metal deposition in Wilson disease or the spectrum of neurodegeneration with brain iron accumulation.
Functional brain imaging is not generally needed, but it can be helpful in some patients to document that cognitive changes are neurological and not psychological in origin.
PET and SPECT
Position emission tomography (PET) and single-photon emission computed tomography (SPECT) reveal asymmetric activity in both cortical (frontal-parietal) and subcortical (basal ganglia) regions. Recent FDG-PET studies in CBD presenting as CBS have shown marked asymmetric hypometabolism of the contralateral frontoparietal cortex (including the superior, middle and inferior frontal gyri, pre- and post-central gyri, superior parietal lobule and supramarginal gyrus), as well as the thalamus and caudate nuclei. In the ipsilateral hemisphere, a smaller cluster of hypometabolism involving the precentral gyrus, superior frontal gyrus and caudate have been demonstrated. [28]
Dopamine transporter (DAT SPECT) imaging can confirm presence of a neurodegenerative parkinsonian disorder, but does not differentiate between parkinsonian syndromes and can be normal early in the course of CBS (as many as 39% of cases in one longitudinal study of CBS without autopsy confirmation). [32]
Tau PET is currently available on a research basis only; the tau ligands studied thus far lack the ability to accurately discriminate between neurodegenerative syndromes on a single patient level, partly due to off-target binding in the basal ganglia (eg, to monoamine oxidase-B). Longitudinal 18F-AV-1451 (the tracer used in the largest patient cohorts thus far) tau imaging in individual patients with CBS has shown an increase in tracer binding with disease progression. [33] Newer ligands that lack off target binding issues are under investigation. [34]
Other Tests
Neuropsychological testing and/or evaluation of cognition and cortical signs by a cognitive neurologist with advanced training and experience with neurodegenerative disorders is recommended. This can be useful to differentiate the more common patients with concomitant parkinsonism and Alzheimer disease, who also can be apraxic but should not have as severe a motor coordination deficit or alien limb phenomena.
Electroencephalography (EEG) can be considered in cases of rapid decline
Somatosensory evoked potentials are not generally a part of the clinical workup.
Procedures
In patients with prominent segmental myoclonus (especially if involving the face); eye movement disorder; and history of celiac sprue, chronic diarrhea, or unexplained arthritis, consider further workup to rule out the diagnosis of CNS Whipple disease.
-
Lumbar puncture (LP) may be done to examine cerebrospinal fluid (CSF) for cells and elevated protein as well as markers of neurodegeneration: amyloid beta-42, total tau, phosphorylated tau (evaluation for AD); neurofilament light chain; and prionopathy testing in rapidly progressive cases < 2 years' duration: RT-QuIC or neuron-specific enolase or 14-3-3); the polymerase chain reaction (PCR) test for the organism Tropheryma whipplei should be considered in select cases (eg, presence of oculomasticatory myorthythmia).
-
Consider jejunal biopsy; it can show changes characteristic of Whipple disease in the gut.
-
In cases with atypical features (eg, rapid course but negative CSF prionopathy testing), consider brain biopsy.
Histologic Findings
(See Overview.) Cortical findings include frontoparietal atrophy and astrogliosis, chracteristic astrocytic plaques containing hyperphosphorylated 4-repeat tau, neuropil threads, and occasionally neurofibrillary tangles and presence of swollen achromatic neurons (ballooned neurons or pale bodies). Argyrophilic tau-immunoreactive inclusion bodies can be found subcortically in the substantia nigra, where neuronal loss can also occur, as well as the basal ganglia and dentato-rubro-thalamic tracts. Although this description is different from that of progressive supranuclear palsy, tau-positive inclusions of CBD may be coiled and thus they can be confused with tau-positive neurofibrillary tangles. Some cases of CBD may thus be difficult to distinguish pathologically from progressive supranuclear palsy.
Staging
An autopsy study of multiple tau disorders that included 40 cases of corticobasal degeneration (CBD) found a characteristic progression of CBD astrocytic plaque pathology: Stage 1 involving the frontal and parietal cortices; Stage 2 involving temporal and occipital cortices (stage 2); Stage 3 involving the striatum and amygdala; and Stage 4 involving the brainstem. [7]
