Can We Make an Accurate Diagnosis of Patients with Posterior Cortical Atrophy?

Abstract & Commentary

By Michael Lin, MD, Associate Professor of Neurology and Neuroscience, Weill Cornell Medical College. Dr. Lin reports no financial relationships relevant to this field of study.

Synopsis: The use of biomarkers from the CSF, as well as newer PET imaging ligands, allow for an accurate diagnosis in patients who have a syndrome of posterior cortical atrophy.

Sources: Seguin J, et al. CSF biomarkers in posterior cortical atrophy. Neurology 2011;76:1782-1788. Rosenbloom MH, et al. Distinct clinical and metabolic deficits in PCA and AD are not related to amyloid distribution. Neurology 2011;76:1789-1796.

Posterior cortical atrophy (PCA) is a clinical syndrome that can be the initial presentation of several different neurodegenerative diseases. Initial clinical features typically are referable to occipitoparietal dysfunction, including components of the Balint syndrome (simultanagnosia, ocular apraxia, optic ataxia) or of the Gerstmann syndrome (dysgraphia, dyscalculia, right-left confusion, finger agnosia) or apraxia. In such cases, MRI or FDG-PET will show atrophy or hypometabolism in posterior brain regions. Eventually, other brain regions become involved, depending on the specific underlying disease. The most common pathology underlying PCA is Alzheimer's disease (AD), but corticobasal ganglionic degeneration (CBGD), dementia with Lewy bodies (DLB), and Creutzfeldt-Jakob disease (CJD) also can cause the PCA syndrome and must be considered. Short of brain biopsy, how can one improve diagnostic accuracy in life? In the May 24 issue of Neurology, two back-to-back articles demonstrate the usefulness of CSF and imaging biomarkers specific for AD in achieving an etiologic diagnosis for PCA.

CSF levels of Aβ42 are decreased in AD, while levels of tau and phosphotau are increased. When both Aβ and tau are changed appropriately, the results are highly specific for AD. When only one marker is abnormal, the results may still be consistent with AD, although with less certainty. When neither is abnormal, the underlying condition is unlikely to be AD.

Commentary

Seguin and colleagues examined CSF levels of tau, phosphotau, and Aβ42 in patients with clinical diagnoses of PCA (n = 22), AD (n = 160), DLB (n = 69), and frontotemporal degeneration (FTD, n = 68). Overall, the CSF profile of PCA was not different from AD, but clearly was distinct from the other dementias. Of the 22 PCA cases, eight had isolated visual deficits and 11 had visual deficits with memory loss; of these 19 cases, all had abnormalities of both Aβ and tau (n = 16), or abnormalities in only one biomarker (n = 3), consistent with AD as the underlying pathology. The remaining three PCA cases were characterized by asymmetric dystonia, parkinsonism, or apraxia, and were clinically felt to be due to CBGD. Indeed, two of these three cases had normal levels of CSF Aβ and tau, consistent with a non-AD diagnosis. However, in the remaining case both CSF Aβ and tau were abnormal, highly suggestive that AD was the underlying pathology, despite the clinical presentation suspicious for CBGD. Thus, CSF biomarkers were helpful in differential diagnosis.

Rosenbloom and colleagues examined the distribution of amyloid pathology and glucose hypometabolism using PET with the amyloid binding Pittsburgh B compound (PiB) and fluorodeoxyglucose (FDG) in patients with clinical diagnoses of PCA (n = 12), AD (n = 14), and elderly control subjects (n = 30). As expected, subjects with PCA showed greater deficits in glucose metabolism in occipital regions than subjects with AD or normal controls. However, the pattern of PiB binding in PCA was indistinguishable from that in AD. These results are similar to those in which AD presents as a different focal cortical syndrome, primary progressive aphasia (PPA): Although neurodegeneration in PPA is highly asymmetric and preferentially involves the language network, the distribution of PiB binding in AD-associated cases is symmetric and indistinguishable from that in typical AD.

One weakness of both studies is the lack of neuropathologic confirmation. However, both illustrate the potential usefulness of AD biomarkers in discerning the pathophysiologic process underlying PCA. They are very timely, given the recent publication of revised diagnostic criteria for AD by the National Institute on Aging and the Alzheimer's Association. The major advance in these revised criteria is the inclusion of biomarkers in increasing ante-mortem confidence in AD as the correct diagnosis. Biomarker testing may be particularly useful when the clinical presentation is something other than the usual memory-predominant presentation, such as PCA or PPA. In such cases, alternative diagnoses such as CBGD, DLB, or FTD must be considered as well as AD. Adding biomarkers to the diagnostic arsenal will help in correct classification, allowing formerly questionable cases to be entered into clinical trials, and, with the eventual development of more effective therapies, assisting in targeting correct treatment.

One additional research point is raised by the Rosenbloom study. The dissociation between PiB and FDG-PET results indicates that the distribution of fibrillar amyloid does not adequately explain the distribution of neurodegeneration and clinical symptomatology. Determining the other pathogenetic factors involved in focal AD presentations, such as PCA or PPA, may be useful in understanding AD in general.