Supplementary Material – Case Histories and Tables
Case histories
Patient 1 – FUS pathology, aFTLD-U sub-type
At 42 years, this man developed obsessional preoccupations and rituals such as counting his money repeatedly, counting his fingers and watching the same children’s videos repeatedly. He became withdrawn, avoided social contact, and he spent prolonged periods staring blankly. He communicated little. He ate voraciously. He had no insight into his altered behaviour. There was no relevant previous medical history and no family history of dementia. However, his sister suffered from parkinsonism.
Six years after symptom onset he had a flexed posture, a fixed, staring appearance, he was dishevelled and his clothes were stained. He had reduced eye movements, slowed tongue movements and dysarthric, dysprosodic and stuttering speech. There was moderate nuchal rigidity and minor limb rigidity. Power was normal. There was a postural tremor. Reflexes were brisk. On cognitive examination, responses were slowed and economical. He had difficulty grasping task requirements, and he was slow to establish and switch mental set. He performed extremely poorly on executive tasks requiring abstraction (e.g. proverb interpretation), organisation and sequencing (e.g. picture arrangement), generation (e.g. verbal fluency) and mental manipulation of information (e.g. mental arithmetic). However, there were no frank ‘cortical’ features of aphasia, agnosia, apraxia or spatial disorientation. Despite the paucity of his speech output he made no grammatical or paraphasic errors. He copied line drawings accurately. He was fully oriented in time and place and, notwithstanding inefficiences in open-ended recall, he was not clinically amnesic. The cognitive profile was interpreted as indicative of subcortical-frontal dysfunction. A CT scan showed mild generalised atrophy. A SPECT scan and EEG were reported to be normal.
Over the following year his repetitive behaviours and stereotypies increased, causing substantial problems in his management. He wandered, emptied ashtrays repeatedly, set fire to objects and repeatedly spat on the floor. He ate his own sputum and his budgerigar’s bird seed. His speech output became increasingly sparse and hypophonic, culminating in mutism. There was a virtual total loss of voluntary upgaze and convergence, with limited pursuit gaze. There was generalised hypokinesia, rigidity and pyramidal signs. He died aged 50 years, 8 years after onset of symptoms.
At post mortem, the brain weighed 1290g. The major cerebral blood vessels appeared normal. The brain was moderately and symmetrically atrophied, especially in frontal, anterior parietal and temporal regions, with relative sparing of posterior parietal and occipital lobes. The brainstem and cerebellum appeared externally normal.
On coronal section, the lateral ventricles were grossly enlarged, including the temporal lobe. The frontal, anterior parietal and temporal cortex all showed gross atrophy though the posterior parietal and occipital cortex appeared normal. The hippocampus and amygdala were moderately atrophic. The caudate nucleus and putamen were grossly atrophied, the globus pallidus and thalamus less so. The corpus callosum was thinned at all levels. The substantia nigra was well pigmented. The cerebellum and brainstem appeared normal.
Histologically, the frontal cortex, anterior temporal cortex (including middle and inferior temporal gyri), anterior insular cortex and anterior cingulate gyrus, all showed mild to moderate, sometimes patchy, microvacuolation within layer II. There was severe loss of pyramidal cells from layer III, with moderate loss and atrophy of those in layer V, with moderate astrocytosis at the junction of the grey and white matter. Immunohistochemistry showed no deposits of β-amyloid protein or tau-immunopositive neurofibrillary tangles or Pick bodies. No β-crystallin positive (Pick) cells) or α-synuclein pathology was present. Similar, though less severe, changes were seen in the posterior parts of the temporal lobe (but sparing the superior temporal gyrus) and parietal cortex. The hippocampus showed severe hippocampal sclerosis and the amygdala showed patchy loss of nerve cells and moderate to heavy astrocytosis. The dentate granule cells contained many ubiquitin positive inclusions.
The caudate nucleus and putamen both showed subtotal neuronal loss with extensive astrocytosis. The claustrum and external globus pallidus showed moderate to severe reactive astrocytosis, with loss of neurones from the caudate nucleus particularly. The thalamus subthalamic nucleus and substantia nigra were all normal: no Lewy bodies or other inclusions were seen in the latter region. The rest of the brainstem and cerebellum was normal.
Patient 2 - FUS pathology, aFTLD-U subtype
The clinical case history is provided in the main manuscript.
At post mortem, the brain weighed 1160g. The major cerebral blood vessels appeared normal. The brain was grossly and symmetrically atrophied, especially in frontal, anterior parietal and temporal regions, with relative sparing of posterior parietal and occipital lobes. The brainstem and cerebellum appeared externally normal.
On coronal section, the lateral ventricles were grossly and symmetrically enlarged, as was the temporal horns, III and IV ventricles and aqueduct (Figure 1, upper panel. The frontal and temporal lobes showed gross atrophy but with relative sparing of the superior temporal gyrus. The anterior parietal cortex, cingulate gyrus and anterior insular cortex were also much atrophied; though posterior parietal and occipital cortex appeared normal. The hippocampus and amygdala were severely atrophic. The caudate nucleus and putamen were grossly atrophied, the former adopting a concave profile and was discoloured brown. The globus pallidus and thalamus were also atrophied. The corpus callosum was thinned anteriorly and in mid portion. The substantia nigra was reasonably well pigmented. The cerebellum and brainstem appeared normal.
Histologically, the frontal and anterior temporal cortex (including middle and inferior temporal gyri) showed mild to moderate atrophy with loss of pyramidal cells from layer III, whereas those in layer V were only shrunken. Similar, though less severe, changes were seen in the posterior parts of the temporal lobe (but sparing the superior temporal gyrus) and parietal cortex. Other cortical regions appeared normal. Immunohistochemistry showed no deposits of β-amyloid protein or tau-immunopositive neurofibrillary tangles or Pick bodies. No β-crystallin positive (Pick) cells) or α-synuclein pathology was present. The hippocampus showed severe hippocampal sclerosis, but the dentate granule cells contained only a few ubiquitin positive inclusions. The amygdala showed severe loss of nerve cells and moderate to heavy astrocytosis, especially from basolateral nuclei.
The caudate nucleus (especially) and putamen showed moderate to severe reactive astrocytosis, with subtotal loss of neurones from the caudate nucleus. The globus pallidus, thalamus and subthalamic nucleus were normal except for mild astrocytosis within medial thalamus. There was a severe loss of nerve cells from the substantia nigra with heavy reactive astrocytosis, but no Lewy bodies or other inclusions were seen. The rest of the brainstem and cerebellum was normal.
Patient 3 – FUS pathology, aFTLD-U subtype
At 37 years this man developed a number of obsessional behaviours and rituals. He amassed pornographic literature, made obscene telephone calls repeatedly and masturbated in public. He became gluttonous and crammed food. He became generally apathetic and would stare vacantly ahead. He showed no sympathy or interest in his family. He did not initiate speech spontaneously and his utterances consisted of stereotyped phrases. He became slowed down physically. There was no relevant previous medical history. A maternal aunt was said to have mental problems.
Neurological examination two years after onset of symptoms revealed reduced eye movements, rigidity of the limbs, extensor plantar responses and bilateral grasp reflexes. Neuropsychological test performance was coloured by apathy, economy of effort, cursory responding, and difficulty establishing ‘mental set’. He spoke little. Production was hypophonic, dysprosodic and dysarthric, and characterised by echolalia, verbal stereotypies and perseverations. However, he made no grammatical, semantic or phonological errors to suggest a primary aphasia. There was also no evidence of primary perceptual, spatial or praxic disorder, sporadic errors being attributable to his perfunctory mode of response and lack of concern for accuracy. He copied line drawings accurately. Formal memory performance was inefficient and disorganised, but he was not clinically amnesic. He was well oriented in time and place and he gave an accurate account of personally relevant events. Performance was profoundly impaired on frontal executive tests: he showed very poor generation (verbal fluency), abstraction and set shifting (card sorting) and organisational skills (picture sequencing). The cognitive profile was indicative of impaired frontal lobe functioning.
A CT scan showed cerebral atrophy. A SPECT scan showed hypoperfusion most marked in the frontotemporal lobes.
He became increasingly inert and apathetic, and his parkinsonian features more profound. He exhibited repetitive motor behaviours such as hand rubbing. Echolalia and verbal and motor perseveration gave way ultimately to mutism. No cortical features of aphasia were seen. He died aged 41 years, 4 years after onset of symptoms.
At post mortem, the brain weighed 1201g. The major cerebral blood vessels appeared normal. The brain was grossly and symmetrically atrophied, especially in frontal, anterior parietal and temporal regions, with relative sparing of posterior parietal and occipital lobes. The brainstem and cerebellum appeared externally normal.
On coronal section (Figure 1, lower panel), the lateral ventricle was greatly enlarged especially anteriorly, though posteriorly, and within the temporal lobe, the ventricle was only mildly enlarged. The frontal cortex showed gross atrophy, affecting the grey matter more than the white matter, and involving the orbitofrontal cortex more than the convexity of the cortex. The anterior temporal lobe was also severely affected, this becoming less severe posteriorly with sparing of the superior temporal gyrus. The anterior parietal cortex, cingulate gyrus and anterior insular cortex were much atrophied; though posterior parietal and occipital cortex appeared normal. The hippocampus and amygdala were mildly atrophic. The caudate nucleus and putamen were atrophied, the globus pallidus and thalamus less so. The corpus callosum was thinned at all levels. The substantia nigra was reasonably well pigmented. The cerebellum and brainstem appeared normal.
Histologically, the frontal cortex, anterior temporal cortex (including middle and inferior temporal gyri), anterior insular cortex and anterior cingulate gyrus, all showed mild to moderate, sometimes patchy, microvacuolation within layer II with mild subpial gliosis and a variable reactive astrocytosis at the junction of the grey and white matter. There was severe loss of pyramidal cells from layer III, whereas those in layer V were shrunken. There was mild étatlacunaire with moderate loss of myelin from the deep white matter of the frontal and temporal poles. Immunohistochemistry showed no deposits of β-amyloid protein or tau-immunopositive neurofibrillary tangles or Pick bodies. No β-crystallin positive (Pick) cells) or α-synuclein pathology was present. Similar, though less severe, changes were seen in the posterior parts of the temporal lobe (but sparing the superior temporal gyrus) and parietal cortex. The hippocampus showed severe hippocampal sclerosis. The dentate granule cells did not contain any ubiquitin positive inclusions.
The caudate nucleus (especially), putamen, claustrum and globus pallidus all showed moderate to severe reactive astrocytosis, with loss of neurones from the caudate nucleus particularly. The thalamus and subthalamic nucleus were normal. There was a severe loss of nerve cells from the substantia nigra, especially the ventral tier, with moderate reactive astrocytosis. Much residual melanin was seen in macrophages or freely in the neuropil and grumose bodies are common, but no Lewy bodies or other inclusions were seen. The rest of the brainstem and cerebellum was normal.
Patient 4 – FUS pathology, a-FTLD-U subtype
This man has been described previously [47]. In brief, from the age of 22 years his behaviour became increasingly obsessional. He was obsessive about body image and weight training. He demanded meals at precisely the same time. He gave up work, gradually lost contact with his friends and became increasingly withdrawn. He talked to himself, switched lights on and off repetitively, flushed the toilet again and again, and constantly repeated phrases from television soaps. He was admitted to hospital under section of the Mental Health Act. On admission, he was agitated with mannerisms and markedly stereotyped behaviour. He gave ‘don’t know’ responses to open-ended questions. However, he was oriented and there was no evidence of aphasia, visuospatial impairment or amnesia. Neurological examination was normal. An initial diagnosis was made of schizophrenia. However, he failed to respond to antipsychotic medication. Over subsequent months he became hypersexual, doubly incontinent, and hyperphagic, with ingestion of non-food stuffs including wallpaper, plaster, clothing and his own faeces. Four years later he was mute, aside from occasional verbal stereotypies. He explored the environment continually both manually and orally. EEG was normal. MRI showed marked bilateral frontotemporal atrophy, with cavum septum pellucidum.
A cerebral biopsy carried out six years after symptom onset demonstrated neuronal loss with marked reactive gliosis but no tau immunopositivity. He died aged 29 years, seven years after symptom onset. The final clinical diagnosis was frontotemporal dementia.
At post mortem, the major cerebral blood vessels appeared normal. The brain showed marked frontal and temporal atrophy, particularly in rostral regions, the inferofrontal gyri being very atrophic. The cerebellar peduncle was atrophic and the ventral surface of the pons being mildly scalloped due to atrophy. The cerebellum and medulla appeared normal.
On coronal section, the frontal ventricle was grossly dilated, extending cm 6-14. There was prominent cavum septum pellucidum, and the third ventricle was grossly enlarged (18mm across). The lateral ventricles were moderately severely enlarged at parietal, occipital and temporal levels. The corpus striatum was severely atrophic – the caudate head and body being represented by a thin strip of tissue (1mm). The globus pallidus was likewise atrophic (reduced to a strip), especially at rostral and middle levels. There was moderate atrophy in the thalamus, in the dorsal nuclei rostrally. The hippocampus was severely atrophic. In the brainstem, the aqueduct was dilated and there was loss of pigmentation from the upper and lower substantia nigra and from the locus coeruleus.
Histologically, the frontal and temporal lobes showed moderate to severe microvacuolation and neuronal loss, respectively associated with gliosis, with moderate to severe myelin loss. The hippocampus showed severe neuronal loss (hippocampal sclerosis) in CA1, subiculum and parahippocampal gyrus with some ubiquitin-positive neuronal intranuclear inclusions in the granule cells of the dentate gyrus. These resembled curved, thick filaments, complete rings or fine granules). Neuronal cytoplasmic inclusions were also present in the granule cells. No TDP-43 immunoreactive changes were seen. Tau-2 immunostaining revealed a prominent microglial reaction in the white matter (but less in cerebral cortex grey matter). No tau or neurofilament pathology was seen.
Patient 5 – FUS pathology, NIFID subtype
This woman was described previously (NIFID-1 in Cairns et al [5]). She presented at the age of 52 years with forgetfulness and apathy. There was no relevant previous medical or family history. A CT scan showed mild generalised atrophy only but a SPECT scan revealed hypoperfusion in both parietal lobes and left frontal region. Her condition deteriorated rapidly. She had become agitated and was no longer able to carry out activities of daily living such as dressing and cooking independently. She was disorientated, dysphasic and dyspraxic. Neurological examination revealed hypomimia and increase in tone. Over ensuing months she became totally dependant, incontinent, hypersomnolent and mute. Extrapyramidal signs increased and there were positive palmomental, grasp and pout reflexes. An MRI scan showed severe bilateral symmetrical cerebral atrophy with atrophy of the caudate heads and to a lesser extent putamen, with preservation of the cerebellum. She died aged 54 years, 3 years after onset of symptoms.
At post mortem the brain weighed 813g. There was marked atrophy of the rostral frontal and inferomedial temporal lobes, and cingulate gyrus. On coronal section, there was severe dilatation of the lateral ventricle, with frontal grey and white matter atrophy in the centrum semiovale, but less atrophy in the posterior frontal gyri. The Sylvian fissure was widened to 6mm, and the temporal pole was severely atrophic, showing no discernable white matter. The temporal horn was greatly enlarged with extreme atrophy of the hippocampus and parahippocampal gyrus. Parietal cortex was atrophic but the occipital cortex appeared unaffected. The caudate head and body were reduced to a linear irregular strip 3mm wide. The corpus callosum was thinned to 3mm. The lentiform nucleus was atrophic and the external globus pallidus was degenerate rostrally. In the brainstem substantia nigra and locus caeruleus showed loss of pigmentation. The cerebellum and appeared normal.