Background
Corticobasal degeneration (CBD), a sporadic neurodegenerative 4-repeat tauopathy, is a pathologically defined entity associated with several clinical phenotypes. The most common phenotype—corticobasal syndrome (CBS)—is defined by progressive dementia and typically asymmetric parkinsonism unresponsive to dopaminergic therapy, dystonia, limb apraxia, and myoclonus, but these may occur as a result of a number of other pathologic entities. The most characteristic are frontotemporal degeneration spectrum disorders, but Alzheimer disease and rare disorders such as Creutzfeldt–Jakob disease, CNS Whipple disease, and Niemann–Pick disease type C can be associated with corticobasal syndrome. CBD can also present clinically as progressve supranuclear palsy (there is significant clinical and some neuropathological overlap between these entities), a frontal behavioral-spatial syndrome, primary progressive aphasia [1] , or (rarely) as posterior cortical atrophy. [2]
The diagnosis of syndromes associated with CBD pathology is based on history and physical examination, while imaging, serum, and cerebrospinal fluid studies serve an ancillary role. As noted above, CBS is a heterogeneous disorder that can present as a primary tau-related neurodegeneration or could be secondary to other proteinopathies (including amyloid, TAR DNA-binding protein 43, alpha-synuclein (in Lewy bodies) or prion proteins). [3] In an attempt to sort out this heterogeneity of clinical and pathological presentations of CBD, Armstrong et al. proposed new diagnostic criteria for CBD in 2013 based on a review of 267 CBD cases from published reports (1950–2012) with pathological confirmation across five different brain banks. [1] They defined four clinical phenotypes associated with CBD pathology based on these data: (1) Corticobasal syndrome, (2) Frontal behavioral-spatial syndrome (FBS), (3) Nonfluent/agrammatic variant of primary progressive aphasia (naPPA), and (4) Progressive supranuclear palsy syndrome (PSPS). Based on the above phenotypes, they suggested two separate criteria for Probable CBD (at least one CBS feature, however, the differential could include FBS or naPPA) and Possible CBD (more inclusive of other tau disorders including PSPS) intended to be applied during a patient's lifetime. [1]
However, in 2014 Alexander et al. disputed the utility of the above criteria after they applied them to their cohort of 33 patients followed longitudinally between 1990 and 2013. [4] While the Armstrong et al. criteria did help to identify patients with CBS, they were not specific enough to identify which of these patients had CBD pathology on post-mortem examination; that is, not all patients with a CBD diagnosis clinically were found to have CBD-related pathology (4R tau in a specific distribution in neurons and glia). They found 14 patients with possible or probable CBD according to the Armstrong criteria who were found to have non-CBD pathology (CBD mimics, which included 10 patients with AD pathology, 2 with FTLD, and 2 with mixed AD and Lewy body pathology). [4] In this study, no particular symptom was present more often in the 19 cases with CBD pathology vs. the 14 cases with non-CBD pathology to accurately make a diagnosis of CBD pathology on a clinical basis. [4] Thus, current diagnostic criteria lack specificity in identifying CBD pathology clinically (ante-mortem) and the main utility of the Armstrong et al. criteria lies in formally defining the clinical syndromes associated with CBD pathology. Future studies on biomarkers and imaging will likely be helpful in predicting CBD pathology more accurately.
There is no disease-modifying therapy for CBD to date, but a number of symptomatic treatments can be useful, particularly botulinum toxin injections for dystonia and several other indications. Lifelong rehabilitation of these patients with physical, occupational, speech, and swallow therapy focused on maximizing daily function is crucial to limit deconditioning and potentially slow decline.
Pathophysiology
Typical autopsy findings in corticobasal degeneration (CBD) include asymmetric frontoparietal cortical atrophy. [5] Both cortical and subcortical abnormalities are seen in CBD, as the name of the disorder suggests. The disorder is classified as a 4-repeat tauopathy, and although tau-immunoreactive neuronal and glial inclusions may be seen in progressive supranuclear palsy (PSP), Alzheimer disease, and Pick disease, these disorders may differ in the proportions of 4-repeat as compared with 3-repeat microtubule-associated tau protein isoforms, with CBD and PSP being the two predominantly 4-repeat tauopathies. The astrocytic plaque containing aberrantly hyperphosphorylated 4-repeat tau is the defining pathological feature of CBD, whereas PSP is characterized by the presence of tufted astrocytes. [2] Ballooned swollen neurons with loss of cytoplasmic staining (ie, achromasia) are a supportive feature when present in the cortex and basal ganglia, but are not a CBD-specific finding. CBD may be associated with both cortical and subcortical neuronal loss, neuronal and glial tau pathology (including astrocytic plaques); cortical loss predominantly affecting motor and premotor regions [6] may distinguish this disorder from PSP. The tau histopathology in CBD is found predominantly in the corpus callosum and parasagittal and paracentral gyri and correlates with areas of cortical atrophy. [5] An autopsy study of multiple tau disorders that included 40 cases of 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]
Tau is a protein involved in axonal transport and stabilization of neuronal microtubules. [2] Abnormal phosphorylation of tau reduces its binding to microtubules and interferes with microtubule function, impairing axonal transport and leading to abnormal tau aggregation. [2, 8] Normal tau in the human brain contains six isoforms that are generated by alternative messenger RNA splicing of a single tau gene on chromosome 17. [2] Alternative splicing of exon 10 results in isoforms with either 3 or 4 repeats (3R or 4R) of the tau microtubule binding domain. [8] The normal ratio of 3R tau and 4R tau is approximately 1:1 and disruption of this ratio is thought to lead to neurodegeneration. [8] Isoforms common to both CBD and PSP are aggregates of the 4R-tau that occur because of splicing of exon 10. [8] The 3R-tau form dominates in the aggregates of some other tau disorders, such as Pick disease. The mechanism behind tau hyperphosphorylation in CBD is currently unknown, although some studies have implicated microglial signaling. [9, 10]
A recent review of neurophysiological studies (quantitative electroencephalography and transcanial magnetic stimulation (TMS)) suggests that pathologic asymmetric hyperexcitability of the motor cortex is present in CBD and may be due to the loss of normal inhibitory inputs from the sensory cortex. [11] Long latency reflexes in these patients are shorter than in cortical reflex myoclonus as seen in myoclonc epilepsies; [11] TMS studies have revealed revealed asymmetric intracortical disinhibition; [11] and somatosensory evoked potential (SEP) studies show reduced N20–P25 amplitudes and absence of giant SEPs. [11]
Understanding of the genetic underpinnings of CBD is limited. Although CBD is thought to arise sporadically in the vast majority of cases, several rare mutations in the microtubule-associated protein tau (MAPT) have been implicated as causative for CBS and CBD. [12] Also, both CBD and PSP are associated with a greater frequency of H1 tau haplotype homozygosity: in one study of 57 CBD cases, the odds ratio (95% CI) of H1/H1 haplotype in CBD versus controls was 3.61(1.85–7.05). [13] A genome-wide association study of CBD identified several new CBD susceptibility loci and demonstrated that CBD and PSP share a genetic risk factor other than MAPT at 3p22 MOBP (myelin-associated oligodendrocyte basic protein). [14]
Epidemiology
Frequency
Data on incidence and prevalence of corticobasal degeneration (CBD) are still being collected. Clinical reports have multiplied geometrically in the last 20 years, suggesting either that clinical evaluation has become more sensitive (most likely) or that the syndrome is appearing more frequently. It is estimated to account for about 5% of cases of parkinsonism seen in clinics that specialize in movement disorders, or 0.62–0.92 per 100,000 per year, with an estimated prevalence of 4.9–7.3 per 100,000. [15] A study in Eastern European and Asian subjects reported an incidence of 0.02 case per 100,000 people. [16]
Demographics
No racial predilection is known.
In several studies, CBD was reported to be more common in women. [15, 17, 18] However, more recent studies have not found this to be the case. [19]
Typically, CBD presents between the ages of 50 and 75 years. The CBD cases from multiple brain banks reviewed as part of the Armstrong et al. diagnostic criteria had mean age of onset of 63 years with a standard deviation of 7 years and range of 45–77 years. [1] No pathologically confirmed case of CBD has been published with onset before 45 years, but the previous author of this article personally reviewed medical records for a man who died with pathologically confirmed CBD whose first symptoms occurred at age 41 years, and a patient with the onset of corticobasal syndrome at age 28 years has been reported. [20]
Mortality/Morbidity
This is a progressive neurodegenerative disorder that causes increasing levels of disability and loss of independence. Individuals with CBD usually die within 10 years of symptom onset from complications of dysphagia (aspiration pneumonia), urinary incontinence (urinary tract infections complicated by urosepsis) and an immobile state (susceptibility to infections).
Prognosis
Prognosis is variable, with several studies indicating mean survival of 6–8 years from symptom onset; multiple cases with survival of >10 years have been reported. [2, 21] One UK study found mean survival of 4.6 years from time of diagnosis. [1] In the large number of CBD cases reviewed for the development of diagnostic criteria by Armstrong et al., mean (standard deviation) disease duration was 6.6(2.4) years with a range of 2.0 to 12.5 years. [1] In their meta-analysis, Kansal et al. estimated the number of years of life lost based on mean survival from three studies at 11.33 years, with 95% confidence interval of 9.60 to 13.06. [22] In a UK cohort comprised of 29 CBS, 35 PSP, 33 primary progressive aphasia, and 27 behavioral variant Frontotemporal degeneration patients, presence of apathy (as assessed from carer reports using the Apathy Evaluation Scale, Neuropsychiatric Inventory, and Cambridge Behavioral Inventory) predicted death at 2.5 years post-assessment and on average was highest for corticobasal syndrome (CBS). [23] Age at assessment, sex, and global cognitive impairment were not significant predictors of survival in this study. [23]
Patient Education
Information for patients and families, guidelines for rehabilitation, virtual support groups specific to CBS/CBD can be found at https://www.psp.org/
Additional information from the Institute for Neurological Disorders and Stroke: https://www.ninds.nih.gov/Disorders/All-Disorders/Corticobasal-Degeneration-Information-Page
