Variability in Corticobasal Degeneration – A Frontally Dominant Disorder?

Abstract & Commentary

By Claire Henchcliffe, MD, Associate Professor of Neurology and Neuroscience, Weill Cornell Medical College. Dr. Henchcliffe reports she is on the speakers bureau and advisory board for Allergan and Teva; speakers bureau for Boehringer-Ingelheim, GlaxoSmithKline, and Novartis; advisory board for Merz; and is a consultant for Gerson Lehman Group and Guidpoint Global.

Synopsis: Cases of autopsy-proven corticobasal degeneration examined in a U.S. academic center presented with frontal-predominant behavioral or cognitive deficits, with a movement disorder following later in the majority.

Source: Lee SE, et al. Clinicopathological correlations in corticobasal degeneration. Ann Neurol 2011;70:327-340.

In this retrospective case series from a san francisco dementia center, subjects were retrieved from a database and included those with autopsy-proven corticobasal degeneration (CBD; n = 18) based on tau pathology, and also those who met clinical criteria for possible or probable corticobasal syndrome (CBS; n = 40) and subsequently underwent autopsy or brain biopsy (n = 1). Upon chart review of the 18 within the CBD cohort, only 5/18 met clinical CBS criteria at the first visit, and 14/18 at later visits (although 13/13 with long-term follow-up finally met these clinical criteria). Of the 40 with clinically identified CBS, subsequent diagnoses based upon pathology were: CBD (n = 14), Alzheimer's disease (AD; n = 9), progressive supranuclear palsy (PSP; n = 5), frontotemporal lobar dementia with TDP-43 protein inclusions (FTLD-TDP; n = 5), mixed (n = 5), Picks' disease (n = 1), and multiple system tau-opathy without argyrophilia (n = 1). Clinically, the autopsy-confirmed CBD cohort fell into four syndromes: executive motor (n = 7), progressive nonfluent aphasia (n = 5), behavioral variant frontotemporal dementia (n = 5), and posterior cortical atrophy (n = 1). There was no difference in survival between the groups. Detailed genetic testing also was performed in a subset of patients, revealing absence of MAPT mutations (8 CBD, 13 CBS) but homozygous presence of the MAPT H1 haplotype in all with CBD (6) and most with CBS (18/19). One patient (mixed FTLD-TDP and AD pathology) had a progranulin mutation. APOE E4 alleles were rare (1/8 CBD). Voxel-based morphometry of brain MRIs demonstrated cortical atrophy in CBD vs controls in the bilateral frontal cortex (including supplementary motor, dorsolateral prefrontal, and pre- and postcentral gyri), as well as the striatum and brainstem. This involvement could be further broken down by syndrome, for example, in executive motor-CBD cell loss focused on perirolandic cortex and striatum, in comparison with posterior cortical atrophy-CBD, which involved temporal and occipital cortical regions, the fusiform gyri, and the left hippocampus.

Commentary

Corticobasal degeneration is a rare progressive neurodegenerative disorder commonly diagnosed on the basis of asymmetric, non-levodopa responsive parkinsonism, often accompanied by apraxia, dystonia, and myoclonus, as well as cognitive dysfunction, and is considered to be one of the "Parkinson's-Plus" syndromes. Unfortunately it often is mistaken for Parkinson's disease and other neurodegenerative disorders early in its course, leading to difficulties achieving optimal care in the clinic. Cognitive deficits have been well-described previously.1 Here, however, the authors expand our understanding of CBD cognitive features, propose a preliminary set of subgroups that may aid in recognition in the clinic, and examine correlations with objective neuroimaging measures. Although some referral bias might be present in this academic dementia center, the authors clearly demonstrate that current CBS clinical criteria have unsatisfactory sensitivity and specificity. It therefore remains the case that many individuals with CBD are misdiagnosed, leading to erroneous counseling, and exposure to the risk of medications that have no proven benefit in CBD. In the clinical arena, the clinical descriptions in this publication therefore may aid in earlier and more accurate diagnosis by raising awareness of these varied (although frontal-predominant) cognitive presentations. In the research arena, one question is whether neuroimaging could have an impact as a diagnostic marker and/or surrogate marker of disease progression. Lack of either currently remains a challenge in clinical trial design. The present study certainly suggests (although does not examine specifically) that MRI data may provide pointers to diagnosis, and it would be fascinating to have long-term data examining performance as a potential biomarker of progression. Finally, should we be lumping or splitting care for our patients with CBD? Many of the "misdiagnoses" are tau-opathies (FTLD, PSP). Some have long-argued that these are variations of a common disease process. Splitting helps dissect the enormous complexity of the disease process itself, and also aids us in the current era of symptom-based interventions for patient management. However, as new treatments become available based upon etiopathogenesis, future treatments conceivably could address tau-opathies as a whole and this may change our way of thinking about these disorders.

Reference

1. Kertesz A, McMonagle P. Behavior and cognition in corticobasal degeneration and progressive supranuclear palsy. J Neurol Sci 2010;289:138-143.