Phenocopy or variant: a longitudinal study of very slowly progressive frontotemporal dementia

Abstract

Frontal variant frontotemporal dementia (fvFTD) can present with a range of social and cognitive impairments. Complicating this clinical picture is a group of non-progressive or ‘phenocopy’ patients. We present a patient and his father with very slowly progressive fvFTD over decades. Stable MRI and positron emission tomography (PET) imaging abnormalities were present in the presenting patient, with serial neuropsychological assessments that showed no significant change over 15 years. His father also had a 20-year history of functional decline, associated with neuropsychological evidence of change. Neuropathological confirmation of the condition of his father became available. This revealed gross bilateral frontal atrophy and spongiosis in the frontal cortical regions with mild neuronal loss and rounded ubiquitinated perinuclear inclusions, consistent with early stage frontotemporal lobar degeneration with ubiquitin by current neuropathological criteria. The phenotype of frontal variant FTD is broad. Many patients present with frontal networks dysfunction. We present evidence that some patients with a very slow clinical progression do have FTD.

Background

We often see patients in cognitive clinics with features consistent with frontal networks dysfunction, but a history of FTD depends on progression. Sometimes, it is difficult to ascertain this history, particularly if the patient's family members state that there is a long history over many years, especially in the face of stable or minimal change neuropsychological change, hence the concept of the FTD phenocopy. Yet some patients are declining, albeit very slowly, and at a rate that does not fit with the normal clinic 2-year to 4-year model. The presence of FTD pathology—fortuitously—in the patient's father suggests that some of these people do have a forme fruste FTD presentation, expanding our understanding of these puzzling syndromes.

Introduction

Frontal variant frontotemporal dementia (fvFTD) can present with a range of social and cognitive impairments. Considerable variation in clinical course is reported, with a median of 5–7 years from symptom onset to death,¹ even shorter with motor neuron disease (MND).^{2 3} This wide phenotypic variability appears determined by pathological and genetic determinants.⁴

Complicating this clinical picture is a group of non-progressive or ‘phenocopy’ patients. These people present with fvFTD features but a particularly slowly progressive clinical course, with minimal or absent brain atrophy. Davies et al described 31 patients with otherwise typical features of fvFTD but absent brain atrophy on initial MRI. They demonstrated significantly longer survival than those with atrophy.⁵ Progressive and non-progressive groups were difficult to differentiate on first presentation, even with agreed diagnostic criteria.⁶ They suggested a number of ways to distinguish between non-progressive patients early in their disease course, concluding that these patients may not have a neurodegenerative disease.⁷

A ‘phenocopy’ can be defined as a non-genetically produced phenotype that mimics or resembles the genetically produced one, or identical phenotypes caused by genetic variants of a main mutation. There has been a debate about the FTD phenocopy, perhaps caused by the effects of ageing on an unusual personality, or alternatively as a slowly progressive variant of FTD.⁸ Here, we present two relatives supporting the latter position.

Case report

In 1997, KD, a 52-year-old right-handed secondary school teacher, presented with his wife, who described 8 years of insidious, slowly progressive cognitive decline. Professionally, he had difficulty controlling student conduct, demotion to part-time work and eventual retirement on sickness benefits. Around 5 years into his illness, his wife reported that he was unable to perform simple repair tasks around the house, remember his bank personal codes, pay bills or even remember to bring his wallet. He was forgetting discussions, directions and timings to pick up his children, and was frequently taking wrong turns while driving. Sertraline and later low-dose fluoxetine improved his mood and reduced his irritability, but not his cognition.

He was alert, oriented and euthymic: MMSE 29/30. Neurological examination was normal. Neuropsychological examination estimated premorbid intellectual abilities to be in the superior range, but inefficient memory and fluctuating attention with mild psychomotor slowing and high-level visuoperceptual difficulties. MRI revealed mild biparietal atrophy with no hippocampal atrophy; 18-FDG-PET scanning revealed mild biparietal hypometabolism. The possibility of an underlying neurodegenerative process was raised.

He was reviewed over a further 15 years. Two repeat PET scans and three MRI scans were unchanged. Repeated neuropsychological assessments revealed no systematic cognitive deterioration in any domain.

On review in 2012 (23 years after initial symptoms), he reported no functional change except for a greater need for sleep. He continued to work part-time as a parcel courier in his son's business. His wife again reported a continuing slow but significant functional decline.

He had a paternal uncle who had died of MND in his sixties. A paternal grandmother had dementia in her 70s. His wife stated that they had a remote Danish ancestry. His father (MD) had had slowly progressive personality change for 20 years prior to his death at the age of 75 years. His medical history was also available and the relevant details are reported here.

Paternal history

MD's initial symptoms were very slowly progressive forgetfulness and personality change. He had been a ‘bubbly and outgoing man’ who had become progressively quieter and more withdrawn. He had had three episodes of altered consciousness, each associated with an accident and physical injury: at age 15 while riding a bicycle, and at the age of 37 and 52 while driving. There was never any associated aura, witnessed tonic-clonic movements, tongue-biting or incontinence.

At the age of 74, he was a pedestrian struck by the side mirror of a passing truck, sustaining a right frontal skull fracture with frontoparietal subarachnoid haemorrhage. Police eyewitness accounts state that he ‘ran out into oncoming traffic’. A neuropsychological assessment documented tangential and repetitive speech, severe attention, recent memory, planning and executive deficits and slowing of information processing. Digit span was four forwards and three backwards. Recent and delayed memory was impaired, with poor acquisition, failure to retain information, distractibility and poor verbal fluency. Poor executive and organisational skills were evident on visuospatial and constructional tasks, particularly in his right hemispace.

On review, his wife reported progressive cognitive decline, confusion and disorientation, poor insight, memory impairment and increasing dependency. He was oriented to the year but not to the month or day of the week. Digit span was now three forwards and zero backwards; significant new learning and retrieval difficulties without rapid forgetting were found, with significant super-added left-sided neglect due to his head injury. The testing neuropsychologist reported that while some of his deficits were related to his head injury (neglect), his performance could not be explained by his head injury alone. She postulated an underlying neurodegenerative process. MD continued to decline at home, dying from pneumonia 10 months after this assessment. After autopsy, his death was ruled secondary to ‘tracheobronchitis and bronchopneumonia in a man with impaired cerebral function following a head injury’.

Investigations

Histopathology of MD

Examination of the central nervous system was initially limited, recording a posterior parietal cannula and his patent intraventricular drain. Brain weight was 1405 g. Some frontal lobe atrophy was noted. No further histopathological study was performed at that time. However, the current authors managed to obtain stored formalin-fixed brain material for further neuropathological examination (AB, CM). Microscopic sectioning revealed lamina II spongiosis in the frontal cortical regions associated with mild neuronal loss (figure 1). No amyloid plaques and only 1 tau-positive neurofibrillary tangle were seen. Numerous rounded ubiquitin-positive perinuclear inclusions were seen in the dentate nucleus. TDP-43, p62/sequestosome1 antibody and fused-in sarcoma (FUS) staining were negative. The features were consistent with early stage frontotemporal lobar degeneration with ubiquitin (FTLD-U) by current neuropathological criteria.⁹

Figure 1.

(A) Frontal superficial lamina spongiosis and minor neuronal loss; (B) hippocampal ubiquitinated perinuclear inclusions with numerous neuropil ubiquitin granules; scattered neurons with cytoplasmic diffuse ubiquitin.

Genetic testing

Genomic DNA was extracted from KD's EDTA blood and MD's brain after deparaffinisation. Each exon of granulin, microtubule associated tau, charged-multivesicular-body protein-2B (CHMP2B) genes and exons 14 and 15 of the  FUS gene were sequenced and were compared to published and control sequences. Sequence variants were noted, revealing no pathogenic known mutations. However, KD had one homozygous synonymous CHMP2B variation detected: c.312>T; p. T104T (rs11540913) in exon 3. This has been previously reported as non-pathogenic.^{10 11} Owing to the availability of formalin-preserved specimens, this could not be confirmed (or excluded) in MD. C9ORF72 mutations were not tested for, as the gene was reported after the pathology was known.

Outcome and follow-up

MD has neuropathologically confirmed FTD. KD presents with a similar history, and is still under review.

Discussion

This is the first case report to our knowledge of two first-degree relatives with FTD phenocopy syndromes, with autopsy findings of FTLD-U in a non-progressive patient. Brain imaging abnormalities were present in KD, but biparietally, not frontotemporally, and there was no significant clinical, neuropsychological or radiological progression over 15 years. MD suffered a 20-year decline with initial memory disorder, abulia and impulsive behaviour. Although complicated by undiagnosed blackouts and a serious head injury at age 74, he continued to deteriorate, and brain examination revealed FTLD-U changes. Genetic screening failed to reveal a pathogenic known mutation in either, though a CHMP2B variation was found in the KD.

The existence of a non-progressive group of patients remains problematic. They are usually men, stable or improved over many years, distinguished by minimal executive and neuropsychological deficits and no abnormalities on brain imaging.^{5 6 12 13} Functional impairment is milder and does not deteriorate.¹³ Very long atypical courses have been described in C9ORF72-positive patients.¹⁴ Atypical imaging findings have also been reported, including parietal and cerebellar atrophy, and early parietal lobe atrophy has been described in progranulin mutation carriers.¹⁵

The individual clinical courses were consistent with an intrinsic neurodegenerative condition, yet atypical for the major recognised FTD syndromes. Although the clinical features of KD were different to those of his father, the similarity in the disease course raises the possibility that their conditions are different phenotypes of the same, hitherto undescribed genetic mutation. The possible Danish ancestry and the paternal MND history makes KD's non-pathogenic CHMP2B variant more intriguing. Non-pathogenic variants have also been reported in other FTD syndromes.¹⁶ Mutations of this gene, located on chromosome 3, have been associated with familial MND and fvFTD with FTLD-U pathology in large Danish kindreds.¹⁶ No mutations have yet been reported in patients with an FTD phenocopy syndrome. Unfortunately, we were unable to test MD due to our inability to extract sufficiently preserved DNA from the recovered formalin-fixed brain tissue.

In conclusion, we report the familial occurrence of a father and son with insidious onset and slow impairment of personality, behaviour and cognition. Pathological examination of the father showed FTLD-U. A benign proband CHMP2B mutation was present. This report expands our understanding of the heterogeneity of these complex and interesting diseases. Further genetic and autopsy studies of such patients are required to elucidate the full spectrum of FTD.

Learning points.

• Frontal variant frontotemporal dementia (fvFTD) can present with a range of social and cognitive impairments.

• Most patients show clear evidence of decline over 1–3 years, an important clinical feature in current diagnostic criteria.

• Some patients present with very slow decline, making the diagnosis difficult, and can be labelled FTD phenocopies.

• Some of these people may have a very slowly progressive variant.

• The genetics of these patients still requires clarification.