This study characterizes the initial clinical presentation of 30 patients meeting criteria for PCA. We used a novel approach incorporating hierarchical cluster analysis to separate the participants with PCA into dorsal and ventral stream subgroups. The dorsal stream subgroup included the majority of the participants, but both groups had similar disease duration and severity. These results suggest that PCA represents neurodegeneration that disproportionately affects the dorsal or ventral visual processing streams and comprise sufficiently distinct syndromes. These findings implicate variations in vulnerability of different neural networks in AD.
There were clear differences between dorsal and ventral subgroups, not only on visual deficits but also on other clinical features. The 2 groups differed on the BNT and functional imaging. The ventral patients had greater naming difficulty due in part to visuoperceptual problems in identifying line drawings. The presence of greater hypofunction in posterior parietal regions in the dorsal, as compared to the ventral subgroup further bolsters the discreteness of these subgroups. The presence of elements of Gerstmann syndrome in 53% of the dorsal patients also corresponds to the greater left parietal hypofunction in the dorsal subgroup as compared to the ventral subgroup. In other functional imaging studies of patients with PCA, investigators have found hemispheric asymmetry in hypometabolism but not consistently on the right-hand or left-hand side.15
Overall, patients with PCA demonstrated deficits in memory retrieval rather than the encoding deficits that are typical of amnestic AD.16
Although PCA is classically characterized by complex visual disturbances, the majority of our participants (67%) had memory complaints. However, the improvement in recognition testing suggests memory retrieval impairment with relative sparing of the medial temporal structures important for memory encoding, as occurs in typical AD. The memory retrieval deficit in these participants could be caused by neurodegeneration of parietal regions, which have been shown to participate in memory retrieval.17
As PCA progresses, visual symptoms worsen, often leading to functional impairment. On the first follow-up visits, which occurred on average 8 months after the initial visit, our PCA patients reported progression of the visual symptoms identified on initial visit without involvement of new visual stream symptoms. The similarities in disease duration and severity between the dorsal and the ventral subgroups argue against previous thinking that ventral symptoms emerge as PCA progresses to the occipitotemporal areas.8
Moreover, other investigators have reported that, as PCA progresses, even in late stages, functional neuroimaging changes remain centered in the posterior regions where they began.18
The 1 patient for whom pathology is available had amyloid plaques and neurofibrillary tangles, which is consistent with prior clinicopathological studies showing AD as the typical underlying etiology for PCA.3,19
Among patients with PCA, recent investigations of cerebrospinal fluid profiles and of in vivo b-amyloid binding with Pittsburgh compound B (PiB), neuroimaging have demonstrated patterns highly consistent with AD.20-23
However, other pathological causes such as corticobasal degeneration, dementia with Lewy bodies, subcortical gliosis, and prion diseases may occasionally present as PCA.4
Interestingly, our PCA patient with pathology had predominantly ventral symptoms along with diffuse amyloid plaques in visual areas. Neurofibrillary tangles, however, were confined to the entorhinal cortex. This observation raises the possibility of neuropathological evidence for discrete PCA syndromes: ventral variant PCA may be a rare pathological presentation of AD, where clinical symptoms are characterized by the spread of amyloid plaques to neocortical areas, but neurofibrillary tangles remain confined to entorhinal cortex. Additional clinicopathological studies are necessary to confirm this hypothesis, and such studies could also help identify factors involved in amyloid protein’s regional selectivity of posterior focal regions in PCA.
Overall, the cohort had disease onset at a mean age of 59.2 years and an average delay between symptom onset and diagnosis of 3.6 years. The delayed time to diagnosis likely reflects the relative rarity of PCA in clinical settings. In a clinicopathological study of 100 cases of focal cortical syndromes, PCA was the clinical premorbid diagnosis in only 7 participants.24
Clinicians and patients may therefore lack awareness for PCA. It is common for patients with PCA to initially seek care from optometrists or ophthalmologists due to the visual symptoms that they experience.5
There are some limitations to the study. Due to the retrospective nature of the study, not all symptoms or signs may have been evaluated as vigorously as a prospective clinical trial, and cognitive and imaging information were not complete for every patient. These factors could limit the generalizability of our conclusions. Nevertheless, the relative availability of cognitive and imaging data was similar between the 2 groups. Since PCA is a rare disorder, the number of participants in the study, particularly in the ventral subgroup, is small, which limits our ability to detect more subtle differences in demographic and cognitive measures between the dorsal and ventral subgroups. Cluster analysis has not been previously used to classify clinical syndromes in patients with PCA. However, our clustering results were consistent with our contingency tables and cognitive testing results (eg, the ventral group performed worse on BNT, a test that relies on the ventral stream processing of object identification). Additionally, even though these patients with PCA were not contrasted with a group of patients with typical AD, the amnestic memory-deficit pattern of patients with typical AD is well characterized and different from the retrieval memory-deficit pattern found in our patients with PCA.13
In conclusion, we present evidence supporting the characterization of PCA as discrete visual stream syndromes in early-onset AD, possibly implicating differences in network vulnerability in AD. The clinical findings support a predominant dorsal variant with early parietal involvement, compared to a ventral variant with greater difficulty in confrontational naming, both of which are distinct from typical amnestic AD. Moreover, with disease progression, the visual symptoms in these subgroups do not appear to overlap within the first year of initial visit but are accompanied by other cognitive manifestations associated with AD.