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Patients with posterior cortical atrophy (PCA) have difficulty integrating visual scenes, locating objects or recognizing them, and navigating their environment. These higher order visual dysfunctions often occur in the presence of parietal function deficits such as calculating numbers, praxis and reading. In the beginning, patients often have preserved anterograde memory because the pathology spares the hippocampus.
DR. PIERRE KROLAK-SALMON: “The CSF biomarker examination appears relevant to the etiological diagnosis of PCA, since the prevalence of AD pathology is high in this condition…Is it AD or not? CSF biomarkers are good at detecting AD in these patients so that we can think about disease-modifying therapies.”
Now two new studies in the April 27 online edition of Neurology suggest that PCA shares a similar metabolic and pathological signature with AD. These findings are important since some experts have estimated that atypical AD presentations such as PCA may account for up to 15 percent of all AD cases seen in dementia referral centers.
In one study, Gil Rabinovici, MD, assistant professor of neurology at the Memory and Aging Center at the University of California-San Francisco, compared two groups of patients, one with PCA and the other with classical AD, on two different brain scan measures and found intriguing differences that would help in the diagnosis of the condition. In another, a team, led by neurologist Pierre Krolak-Salmon, MD, PhD, professor of geriatrics and director of the Memory Center of Lyon (France), examined a series of CSF biomarkers in PCA and AD patients and reported that PCA patients looked very similar to AD patients.
Both studies confirmed that amyloid deposition is a key feature, even though PCA patients have visual deficits and their memory is relatively spared early in the disease.
“The findings have clinical and scientific significance,” said Dr. Rabinovici. “These studies confirm that PCA is often due to AD, and demonstrate how molecular biomarkers such as amyloid imaging can help confirm that PCA is due to underlying AD pathology.” The other CSF biomarkers tested by the French team also found that 90 percent of the PCA patients studied have CSF levels consistent with AD.
Dr. Rabinovici and his colleagues studied 12 PCA patients, 14 AD patients, and 30 healthy volunteers. After a careful history and neurological testing to assess memory and visual-spatial function, the study participants were scanned with Pittsburgh Compound B (PIB) PET to measure amyloid binding and flurodeoxyglucose (FDG) PET to obtain a snapshot of glucose metabolism. This study was designed to look at patients early in the disease process (the mean age was 58 years old in PCA and AD groups and 73 in the healthy volunteers) to see whether their brains showed the classic early amyloid and tau pathology seen in AD.
They reported that PIB binding appeared in the same regions in patients with PCA and AD but not in the controls. All 12 PCA patients (and all 14 AD patients) showed high PIB binding, confirming that PCA is often related to underlying AD. The PIB binding was diffuse, affecting frontal as well as posterior cortex, visual and non-visual areas alike. On direct comparison, there was no difference in the distribution of amyloid, as measured by PIB, between PCA and typical AD. In contrast, on FDG-PET PCA patients showed more severe hypometabolism in occipital cortex, concordant with their more severe visual dysfunction.
Dr. Rabinovici said that he offers patients with PCA symptomatic AD therapies such as cholinesterase inhibitors and memantine. “That said, the efficacy of these drugs in PCA has never been established in a clinical trial, and their use assumes that therapies that are effective in typical AD will also be effective in PCA due to the common pathology.”
Another important intervention is to offer patients with PCA physical and occupational therapy for the visually impaired, he added. This allows them to maximize function given their visual disability. Some very simple modifications to the home (e.g. greater lighting) can make a big difference, he said.
Dr. Rabinovici also emphasized the discordance that was found between the distribution of amyloid (diffuse in cortex) and the metabolic pattern (focal parietal, posterior and temporal hypometabolism) in PCA. “The pathology literature has suggested this discrepancy, but it has never been clear whether the distribution of plaques at autopsy, which reflects end-stage disease, applies to earlier disease stages. The discrepancy that we found supports the view that amyloid-based therapies may be more successful in pre- or minimally symptomatic disease stages, but may not be effective once patients have developed dementia, since at that point other disease mechanisms (for example, tangle deposition, inflammation) may predominate.”
“We clearly have much to learn in terms of the pathogenesis of PCA and other focal variants of AD,” he added. “We plan to combine molecular imaging with PIB, functional imaging with FDG and fMRI, as well as structural imaging (e.g. DTI) to better understand network degeneration in AD variants, and to identify developmental, environmental and genetic factors that may drive the degenerative phenotype in AD. I believe that atypical AD variants offer important clues about disease pathogenesis that may lead to new therapeutic strategies.”
Dr. Krolak-Salmon and his colleagues in Lyon conducted a prospective observational study of 22 PCA patients who had undergone CSF biomarker analysis of total tau, phosphorylated tau on amino acid 181 and amyloid beta (AB42). The group average was compared to CSF measures on AD patients and other dementia patients. At a group level, they found that the PCA patient biomarker profile was virtually identical to the AD biomarker profile but different from the profiles of the patients with other forms of dementia, such as corticobasal syndrome and Creutzfeldt-Jakob disease.
“The CSF biomarker examination appears relevant to the etiological diagnosis of PCA, since the prevalence of AD pathology is high in this condition,” the investigators wrote in the Neurology paper. “We must do as much as we can to make a diagnosis,” said Dr. Krolak-Salmon, “Is it AD or not? CSF biomarkers are good at detecting AD in these patients so that we can think about disease-modifying therapies.”
DR. GIL RABINOVICI: “The findings have clinical and scientific significance. These studies confirm that PCA is often due to AD, and demonstrate how molecular biomarkers such as amyloid imaging can help confirm that PCA is due to underlying AD pathology.”
The Memory Center of Lyon has been following PCA patients, who show up with progressive high order visual disorders like visuospatial impairment, Balint syndrome, Gertsman syndrome and visual agnosia. What is still not known, he said, “is why these AD patients present with such a particular symptomatology related to focal cortical atrophy.” The team has just completed a neuroimaging study with PIB-PET that will be published in the Journal of Neurology.
In an accompanying editorial in Neurology, David F. Tang-Wai, MD, of the University Health Network Memory Clinic in London, and Neill R. Graff-Radford, MBBCh, of the Mayo Clinic College of Medicine in Jacksonville, FL, wrote that “although it would be easy to dismiss PCA as just a variant of AD, the study of these focal atypical presentations of AD may help illuminate the pathophysiology of the disease. Recognizing PCA accurately and confirming the diagnosis with biomarkers makes us better clinicians and allows patients with PCA entry into therapeutic trials.”
In a telephone interview Dr. Graff-Radford added that these new technologies allow clinicians to look at the brain and differentiate different syndromes. He said that the studies are important “because they nail down the diagnosis of AD in PCA patients. Now researchers can confidently enroll them into AD studies.” His group has a large case study of PCA patients. “These new studies move the field forward,” he added.
Seguin J, Formaglio M, Krolak-Salmon P, et al. Cererospinal fluid biomarkers in posterior cortical atrophy 2011; E-pub 2011 April 27.