One of the difficulties in diagnosing patients with PCA is that, although they complain about problems with their vision, descriptions of their symptoms are often difficult for the non-specialist to analyze. They may just say they cannot see, describe their vision as blurry, or may refer to difficulties performing specific tasks such as driving or reading. Only a detailed examination may uncover the specific deficit(s) leading to functional impairment. In the following sections the most important visual deficits in PCA are described.

Simultanagnosia refers to the failure to perceive multiple visual locations simultaneously or to shift attention from one object to another, which results in a very restricted effective visual field (22). A patient may miss an object he or she has just seen or report that objects seem to appear or disappear from view. Simultanagnosia has been consistently demonstrated as the most frequent deficit in PCA, occurring in above 90% of the patients in several series (7, 15–17). It is a pervasive deficit that may be associated with some unusual behavior including the reverse-size phenomenon. This describes patients preferring to look at objects at distance, in order to appreciate them globally, or finding it easier to read small than large letters—such as the text rather than the headlines of a newspaper (23). In severe cases of simultanagnosia, perception of even a single, large object may be impaired, and sometimes an individual part of it may be mistaken for a different object [so-called “partonomic” error (24)].

Tasks relying on visual integration are used to test for simultanagnosia. Established tests include interpretation of a complex visual scene (25), such as the Boston cookie-theft picture, and reading fragmented letters. Failure to read the Ishihara pseudoisochromatic plates despite preserved color perception is a conspicuous feature in many patients with simultanagnosia (24, 26). The latter is often the only abnormality seen in the basic visual assessment of a PCA patient and its usefulness to raise the diagnostic suspicion cannot be overemphasized, although it is usually misinterpreted as a color deficit. However, the patients have as much trouble with the first (control) plate, which does not require color vision as do the subsequent plates. In its purest form simultanagnosia is considered due to impaired visual attention, which can be considered both in terms of shifts of attention to regions within the visual field and also shifts of attention related to the scale of the object to be processed. The former will be mirrored in impairment of ocular motor behavior but the latter may not be. However, it has also been argued that the attentional deficit may be object based resulting in failure to identify overlapping figures (objects at the same spatial location), or collocated objects where linking features have been weakened [such identifying correctly a star of David where the two component triangles are the same but not different colors (27)]. It should also be considered that the perception of illusory contours is a very early process in object identification and may occur as early as V2: this is likely related to the synthesis of partially occluded objects (28). Impairment of this early function in the identification of surfaces, which has been reported in simultanagnosia (29) would certainly seriously impair the identification of fragmented images.

Simultanagnosia may occur in isolation or may be associated with optic ataxia and ocular apraxia, constituting the Bálint syndrome. Optic ataxia—lack of eye-hand coordination—refers to impaired reaching to objects when guided by vision with the preserved ability to do so when the object is accessed by means of other sensory modalities, e.g., sound (22), while ocular apraxia is a disorder of fixation, with the patient failing to fixate a specific object within the visual field in the absence of any ocular motor deficit (30). In PCA, the Bálint syndrome is often incomplete. Silmultanagnosia is thought to be an early finding, initially presenting in isolation or associated with ocular apraxia, with optic ataxia developing later in the course of disease (17). Bálint syndrome is classically seen in the context of biparietal damage due to vascular disorders; however, it has been associated with PCA so often that its occurrence in a progressive manner should raise suspicion of the diagnosis.

Visual agnosia is a visuoperceptual disorder. It is defined as the inability to recognize objects presented visually, in the absence of any ocular or semantic deficit that could otherwise account for it (31). It is further divided into apperceptive and associative, according to the defective process being in the perceptual analysis of the object or in attributing a meaning to it, respectively. In PCA, the apperceptive subtype predominates (16, 32), demonstrated by the patient failing to copy a figure or match a figure with a sample (33). A particular form of visual agnosia affects the recognition of faces (prosopagnosia), a deficit that is a source of great social embarrassment. As with global visual agnosia, prosopagnosia in PCA is thought to be perceptual rather than agnosic in nature (17).

Trouble reading is one of the most frequent and disabling deficits for which PCA patients seek help. It can be due to acquired primary alexia (34), but most often reading impairment in PCA results from a combination of deficits including simultanagnosia, ocular apraxia, visual crowding (16, 24) and potentially homonymous visual field defects.

The occurrence of visual field defects in PCA has been a controversial subject, mainly due to the eloquence of the higher order visuospatial deficits that may arguably compromise the interpretation of visual field tests (35). Indeed, early PCA series dismissed visual field defects as exceptional in this condition (15). However, homonymous hemianopia or quadrantanopia was found in almost 50% of the patients in another series (7) and prevalence is even higher in groups of PCA patients who have visual fields performed as part of the workup (36–38), suggesting this deficit may be overlooked if not routinely searched for. Homonymous visual field defects are increasingly recognized as an early sign in PCA (39), and their occurrence may, remarkably, precede the higher order visual disorder (40, 41). Figure 1 shows a typical visual field test result in a patient with PCA. The inferior quadrants are possibly more affected in the visual variant of AD (4, 42); this would imply involvement of the underlying optic radiations as occurs with bilateral occipitoparietal infarction, but this needs confirmation.

Besides these major, well-characterized deficits, patients with PCA have been reported to complain of a variety of visual problems, including perceived motion of static stimuli, visual crowding, color washout, and prolonged color afterimages (23, 24). In addition, related deficits previously documented in AD patients and attributed to visual cortical pathology, e.g., abnormal contrast sensitivity and loss of color discrimination, particularly affecting short wave length (blue) stimuli (43), may apply to PCA as well. Basic visual skills, such as form detection and discrimination, color perception, and motion coherence were more recently highlighted as possibly contributing to the higher order visual deficits classically reported in PCA (19). A specific dysfunction of the magnocellular (M) pathway in AD, associated with impairment of motion perception and loss of achromatic contrast, has been proposed (44).

Non-visual deficits in PCA are mainly represented by disturbances of numeracy and literacy. These deficits may occur as part of a Gerstmann syndrome (agraphia, acalculia, left-right disorientation, and finger agnosia) or may be isolated. Attentional disorders may occur as visual (16, 45) or spatial neglect (46) or a combination of the two. Ideomotor apraxia is not rare, but it is usually mild in early stages, and if prominent should raise the suspicion of an alternative diagnosis, such as CBD. The same can be said if features of asymmetric parkinsonism are found. Poly-mini-myoclonus has been suggested to be an overlooked sign in PCA, present in a majority of patients (17). Visual hallucinations and REM-sleep behavior disorder have been occasionally observed in PCA, and are also thought to indicate an underlying non-AD pathology, namely DLB (17). Depression is common and is thought to be mainly reactional (35).

It should be noted that dressing and constructional apraxias, which are very common in PCA (7, 47), do not constitute apraxia in its proper definition, but rather visuospatial deficits (48).

Several clinical criteria for PCA have been published (7, 15, 16, 18), which are highly consistent in their definition of PCA. They all emphasize a higher visual disorder of insidious onset, manifesting with deficits of the dorsal and/or ventral stream, and which occurs with relative preservation of more anterior functions, such as memory and language. Some variability exists though in the delimitation of the syndrome. Remarkably, the Tang-Wai criteria (Box 1) introduce visual field defects as a core feature of PCA, given the same importance as simultanagnosia, constructional dyspraxia, environmental disorientation, and any element of the Gerstmann syndrome; at the same time, early parkinsonism and visual hallucinations, meant to distinguish LBD—a disease that may present with posterior cortical deficits but usually shows concomitant or fast developing involvement of other cortical and subcortical regions—are deemed exclusion criteria. Such phenotypic refinement may understandably impact on the specificity of these criteria.

Indeed, by excluding patients with specific LBD features, Tang-Wai et al. aimed to rule out LBD as a distinct condition from PCA; however, thereby, PCA caused by LBD or mixed (LBD-AD) pathologies are likely to be excluded as well (6, 7). Another conflicting issue is the inclusion of patients with PCA due CBD. Asymmetric parkinsonism and apraxia are suggested to distinguish PCA-CBD from PCA-AD, but these features are not addressed in a structured manner. In fact, if parkinsonism develops early in the course of disease, patients with PCA-CBD will be excluded. Therefore, while these criteria were not designed for the etiological diagnosis of PCA, they may be more specific for AD. On one hand, this characteristic has been critical for the very recognition of PCA as a variant of AD, on the other hand, a vacuum is left on how to classify those patients with a progressive posterior cortical dysfunction whose clinical features extend beyond the PCA typical phenotype.

A different (lumpers) approach to the diagnosis of PCA has recently been suggested (52). While preserving the core clinical description of the primary PCA syndrome (Box 2), the newly developed classification provides a solution on how to deal with atypical features, including them into a stratified framework to the etiological diagnosis (Figure 2): at the first level, the presence of the PCA clinico-radiological syndrome is established; the second level consists in of deciding whether PCA occurs in isolation (PCA-pure) or whether criteria for another neurodegenerative condition (e.g., visual hallucinations for LBD) are also met (PCA-plus); at the third level, these phenotypical categories are combined with the presence of pathology-specific biomarkers to yield a disease-level PCA description. Ideally, at this level, the patient will be given a diagnosis of PCA-AD, PCA-LBD, PCA-CBD, PCA-prion, and others. If a patient has PCA-pure and positive biomarkers for AD, the definitive diagnosis of PCA-AD may be given in vivo. However, since disease biomarkers are available only for AD and prion, and AD may manifest with such diverse phenotypes, diagnosis of PCA-LBD and PCA-CBD are currently presumptive and dependent on negativity to AD biomarkers. For instance, when patients fulfill criteria for both PCA and CBD and AD biomarkers are negative, the diagnosis of probable PCA-CBD may be appropriate. Alternatively, if a patient with PCA-plus tests positive for AD biomarkers, the diagnosis of AD may be given, although as disease-specific markers are not available for the second clinical suspected condition, the possibility of a dual pathology is still reasonable. These criteria take into account the suggested diagnostic criteria for AD (10) in their comprehensive approach of phenotype and disease-specific biomarkers. Their novelty is to include under the term PCA patients with posterior cortical dysfunction whom would otherwise not be given a unified diagnosis. Only further pathological studies will confirm the accuracy of these criteria. An expected consequence is an increment in the proportion of patients with non-AD pathologies in PCA cohorts. In the clinic the major priority is to recognize the syndrome and manage appropriately whatever the underlying pathology might be. Predictors of whether AD is the underlying pathology or not will not affect management materially until features of the other conditions are clinically apparent.

In the following sections, the imaging studies that support PCA as a clinico-radiological syndrome are reviewed, as well as in vivo pathological biomarkers for AD. In the particular case of LBD, to which no disease-specific biomarker is available, metabolic studies that are associated with the disease are also mentioned.

The syndrome of PCA can manifest without any detectable gray or white matter volume loss at MRI (24), but more commonly patients present with marked atrophy in the occpitoparietal and occipitotemporal regions bilaterally, but often more severe in the right hemisphere (15, 53, 54) (Figure 3). Although the disparate posterior volume loss is used to distinguish PCA from typical AD at imaging, it is not rare for patients with PCA to present coexisting atrophy in the mesial temporal regions, including the hippocampi (54). However, when directly compared, studies have generally shown only subtle differences in levels of atrophy between PCA and AD, with PCA patients showing greater atrophy in the right visual association cortex, while left hippocampal atrophy predominates in amnestic AD (53, 54). Millington et al. (38) used multimodal MR imaging to investigate structural and functional brain changes in a cohort of patients with PCA, all with visual field defects. Compared with healthy controls, cortical activation was reduced in the occipital lobes, with no significant lateralization, while gray matter loss was greater in extrastriate occipital regions, but more marked in the hemisphere contralateral to the visual field deficit (Figure 4). Likewise, reduction in white matter integrity, which was widespread, was lateralized to the hemisphere originating the hemianopia but in the occipital lobes only.

Functional imaging is used as evidence of neurodegeneration in PCA, being particularly useful when MRI is considered normal. When examined with FDG-PET, patients with PCA show hypometabolism that is more marked in the occipitoparietal regions, sometimes with involvement of the frontal eye fields, but with relative sparing of the mesial regions of the frontal and temporal lobes (55–57). Directly compared with amnestic AD, PCA patients present more severe occipitoparietal and/or occipital hypometabolism in the right hemisphere (47, 55, 57, 58).

Positron emission tomography with fluorodeoxyglucose has also been studied in the differential diagnosis between PCA and LBD, with variable results (57, 59). A common problem is that, in line with overlapping posterior presentations, occipital hypometabolism may occur in both conditions (7, 60). In a comparative study, patients with PCA showed greater hypometabolism in the right temporooccipital cortex, while LBD was distinguished by hypometabolism predominating in the left occipital cortex (57). In another study (59), however, rather than lateralization, it was the degree of asymmetry and anterior extension that best distinguished them: PCA and LBD were both associated with bilateral occipitoparietal hypometabolism, but a higher degree of asymmetry favored PCA, while extension to orbitofrontal and anterior temporal regions was suggestive of LBD. The relative preservation of the posterior cingulate cortex compared with the precuneus and cuneus—a sign that has shown to distinguish LBD from typical AD (61, 62)—was not specific to LBD when compared with PCA (59).

This novel imaging modality is based on the involvement of microglia activation in the pathogenesis of neurodegenerative diseases. The PET tracer ¹¹C-PBR28 binds to the translocator protein-18 kDa, which is overexpressed in activated microglia; therefore, its regional distribution can be interpreted as an effect of local degeneration (63). In ¹¹C-PBR28-PET, patients with PCA showed greater binding in occipital, posterior parietal, and temporal regions compared to controls and were distinguished from amnestic AD patients by higher binding in the occipital cortex bilaterally (64). Despite these encouraging results, TPSO PET imaging still has some limitations, including the existence of non-binders (65).

Albeit not part of PCA routine assessment, this test may be very helpful when the clinical diagnosis of LBD is in the differential, as well as in patients with established PCA who progress with LBD features, e.g., parkinsonism and visual hallucinations. The finding of low dopamine transporter concentration in basal ganglia, measured with PET or single photon emission tomography (SPECT), supports the diagnosis of LBD (60).

Amyloid imaging has a role in the diagnosis of AD, more so in presenile patients—when greater deposition of β-amyloid is not expected—but has no use in distinguishing PCA from amnestic AD, as the same global pattern of deposition is seen (17, 72). This is no surprise, since in pathological studies of PCA, the anterior-posterior gradient refers to the disparate concentration of tau-derived neurofibrillary tangles in posterior regions, while the distribution of β-amyloid is diffuse (7).

Cerebrospinal fluid examination is not required for the diagnosis of PCA, but this test is usually recommended in presenile dementia to exclude treatable causes. Furthermore, in the current diagnostic approach to AD, CSF biomarkers have a positive predictive value when they show low concentrations of amyloid β, increased total tau, and increased phospho-tau (10). As with the PET-amyloid, the application of these tests to PCA patients did not help to distinguish them from amnestic AD (35), although they have a place in the differential diagnosis of AD and alternative underlying pathologies.

Several tau-specific tracers for PET, including ¹⁸F-AV-1451 (Flortaucipir) were recently made available for clinical assessment of various tauopathies (73). Although their affinity for specific tau deposits is still to be established, the application of tau-PET to the diagnosis of AD is promising. Because ¹⁸F-AV-1451 binds to hyperphosphorylated paired helical filament tau and neurofibrillary tangles (73), and tau pathology—but not amyloid—is at disproportionate higher concentration in posterior brain regions in PCA (5, 7), the tau-PET has the additional potential to distinguish PCA from other AD variants. A pattern with localized elevation of ¹⁸F-AV-1451 to posterior regions has indeed been shown to strongly correlate with PCA (74, 75), distinguishing it from amnestic AD (76). Moreover, regional tau-binding mirrors regional patterns of both hypometabolism (74, 75) and atrophy (75) across AD major phenotypes, PCA included. For this reason, it is possible that this test be included as an in vivo imaging biomarker of AD in future (75).

Decrement of peripheral β-amyloid does occur in AD, but later than CSF levels, so that an important effect is observed at the stage of dementia only (77). Plasma levels of Aβ have not been studied in PCA. Markers of neuronal injury, the tau, and neurofilament light (NFL) proteins are elevated in the sera of AD patients, but levels significantly overlap with those of controls and individuals with mild cognitive impairment, although NFL may be more accurate (78). These difficulties have prevented the recognition of a serum signature of AD. Plasma NFL levels further correlate with longitudinal measures of cognition and atrophy in AD and have been suggested as a tool for screening patients at risk of cognitive decline (78); however, NFL is not specific for AD, thus cannot help in the differential diagnosis with other neurodegenerative conditions.