Prosopagnosia: face blindness and its association with neurological disorders

Abstract

Loss of facial recognition or prosopagnosia has been well-recognized for over a century. It has been categorized as developmental or acquired depending on whether the onset is in early childhood or beyond, and acquired cases can have degenerative or non-degenerative aetiologies. Prosopagnosia has been linked to involvement of the fusiform gyri, mainly in the right hemisphere. The literature on prosopagnosia comprises case reports and small case series. We aim to assess demographic, clinical and imaging characteristics and neurological and neuropathological disorders associated with a diagnosis of prosopagnosia in a large cohort. Patients were categorized as developmental versus acquired; those with acquired prosopagnosia were further subdivided into degenerative versus non-degenerative, based on neurological aetiology. We assessed regional involvement on [¹⁸F] fluorodeoxyglucose-PET and MRI of the right and left frontal, temporal, parietal and occipital lobes. The Intake and Referral Center at the Mayo Clinic identified 487 patients with possible prosopagnosia, of which 336 met study criteria for probable or definite prosopagnosia. Ten patients, 80.0% male, had developmental prosopagnosia including one with Niemann-Pick type C and another with a forkhead box G1 gene mutation. Of the 326 with acquired prosopagnosia, 235 (72.1%) were categorized as degenerative, 91 (27.9%) as non-degenerative. The most common degenerative diagnoses were posterior cortical atrophy, primary prosopagnosia syndrome, Alzheimer's disease dementia and semantic dementia, with each diagnosis accounting for >10% of this group. The most common non-degenerative diagnoses were infarcts (ischaemic and haemorrhagic), epilepsy-related and primary brain tumours, each accounting for >10%. We identified a group of patients with non-degenerative transient prosopagnosia in which facial recognition loss improved or resolved over time. These patients had migraine-related prosopagnosia, posterior reversible encephalopathy syndrome, delirium, hypoxic encephalopathy and ischaemic infarcts. On [¹⁸F] fluorodeoxyglucose-PET, the temporal lobes proved to be the most frequently affected regions in 117 patients with degenerative prosopagnosia, while in 82 patients with non-degenerative prosopagnosia, MRI revealed the right temporal and right occipital lobes as most affected by a focal lesion. The most common pathological findings in those with degenerative prosopagnosia were frontotemporal lobar degeneration with hippocampal sclerosis and mixed Alzheimer's and Lewy body disease pathology. In this large case series of patients diagnosed with prosopagnosia, we observed that facial recognition loss occurs across a wide range of acquired degenerative and non-degenerative neurological disorders, most commonly in males with developmental prosopagnosia. The right temporal and occipital lobes, and connecting fusiform gyrus, are key areas. Multiple different pathologies cause degenerative prosopagnosia.

Keywords: MRI; PET; neurodegenerative; pathology; prosopagnosia.

Graphical Abstract

Figure 1

Flow chart showing prosopagnosia diagnostic categories and neurological diagnoses within category. Of the 333 patients with prosopagnosia included in the study, 11 had developmental prosopagnosia and 322 had an acquired prosopagnosia. Those with acquired prosopagnosia were subcategorized into acquired degenerative prosopagnosia (n = 233) and acquired non-degenerative prosopagnosia (n = 89). FOXG1, foxhead box G1; FTD, frontotemporal dementia; NOS, not otherwise specified; PRES, posterior reversible encephalopathy syndrome.

Figure 2

FDG-PET of hypometabolic areas in patients with neurodegenerative diagnoses. This figure demonstrates regional hypometabolism in patients with neurodegenerative prosopagnosia. Shown for each image are the patient’s sex, age at onset of prosopagnosia and the neurological diagnosis. Colours represent severity/degree of hypometabolism based on Z-score difference in metabolism between the patient’s uptake and mean uptake of a group of age-matched health controls. All patients show some degree of cortical hypometabolism but with different patterns of regional involvement. ADD, Alzheimer’s disease dementia; bvFTD, behavioural-variant frontotemporal dementia; CBS, corticobasal syndrome; CJD, Creutzfeldt–Jakob disease; DLB, dementia with Lewy bodies; HSA, hippocampal sclerosis of aging; LPA, logopenic progressive aphasia; PCA, posterior cortical atrophy; PPS, Progressive apraxia syndrome; SMD, semantic dementia.

Figure 3

MRI scans of structural abnormalities in patients with a non-degenerative diagnosis. This figure shows a wide range of diverse types of lesions identified on head MRI scan in the patients with non-degenerative prosopagnosia. R, right hemisphere; L, left hemisphere. All images are fluid-attenuated inversion recovery (FLAIR) sequences except for images H and K (diffusion-weighted images), L (T1 + gadolinium) and Q (3D fobl). Epilepsy-related lesions associated with prosopagnosia are shown in panels A, F and M (area of encephalomalacia). Tumour-related lesions associated with prosopagnosia are shown in panels B and C (glioblastoma multiforme), G and L (oligodendroglioma) and O. Other lesion-related prosopagnosias are shown in D (limbic encephalitis), E (stroke), H (mitochondrial encephalopathy, lactic acidosis and stroke-like episodes), I (necrotizing meningoencephalitis), J (post-herpetic encephalomalacia), K (toxic encephalopathy), N (right temporal lesion), O (mass of undermined aetiology), P (post-stroke encephalomalacia), Q (temporal lobe cyst), R and S (post-traumatic encephalomalacia) and T (post-traumatic contusion). All panels show lesions affecting either the right temporal lobe or the right occipital lobe except for C that shows an extensive infiltrative glioblastoma multiforme located primarily in the left hemisphere. All images shown are from adult except for A, which is from an adult patient with developmental prosopagnosia, whose MRI scan at age 7 is shown.

Figure 4

FDG-PET, head MRI, gross and histological findings in a patient with PPS. There is marked to severe hypometabolism of the anterior medial temporal lobes, right > left on FDG-PET (A). MRI (B) and gross pathological images (C) reveal atrophy of anterior medial temporal lobe regions including severe atrophy of the right fusiform gyrus. Histological findings include the presence of neuronal loss and gliosis in the CA1 and subicular regions of the hippocampus (D) as well as TDP-43 immunoreactive small rounded or grain-like inclusions (brown spots) in the dentate gyrus of the right hippocampus (E) and long thin dystrophic neurites (brown thread-like squiggles) in the right temporal neocortex (F) consistent with a pathological diagnosis of FTLD-TDP type C. On MRI, the fusiform gyri are highlighted in red. Black arrows in E point to the dentate granule cells of the hippocampus. TDP-43 immunohistochemistry, with a haematoxylin counter stain, was perform using phosphorylated TDP-43 (pS409/410, mouse monoclonal, 1:5000, Cosmo Bio, Tokyo, Japan).

Figure 5

Radar plots showing regional hypometabolism and lesion location. This figure shows the proportion of patients that showed involvement of eight brain regions: left and right frontal, temporal, parietal and occipital lobes. For the 117 patients with a neurodegenerative disease, the plots show the proportion of patients with moderate-to-severe hypometabolism on FDG-PET in each brain region. The neurodegenerative diseases are split into three groups: Group 1, ‘the Alzheimer’s disease group’, includes logopenic progressive aphasia (LPA), posterior cortical atrophy (PCA) and Alzheimer’s disease dementia (ADD). Group 2, ‘the frontotemporal lobar degeneration group’, includes semantic dementia (SMD), behavioural-variant frontotemporal dementia (bvFTD), primary prosopagnosia syndrome (PPS) and hippocampal sclerosis of aging (HSA). Group 3, ‘the mixed group’, includes dementia with Lewy bodies (DLB), corticobasal syndrome (CBS), Creutzfeldt–Jakob disease (CJD) and dementia not otherwise specified (DEM NOS). For example, in Degenerative group 1, the right parietal lobe showed hypometabolism in >80% of the PCA patients (orange web), while 100% of the LPA patients (blue web) showed hypometabolism of the left temporal and parietal lobes. For the 81 patients with a non-degenerative disease, the plot shows the proportion with a focal lesion on MRI affecting each of the eight brain regions. Lesions were most frequently observed in the right temporal and occipital lobes, with ∼60% of patients having a lesion that affected the right temporal lobe and ∼50% having a lesion that affected the right occipital lobe. Note that a lesion/s could affect multiple regions. For example, a large lesion (e.g. a tumour) could involve both right temporal and right occipital regions and hence would contribute to the frequency of both regions for that one patient.