Pathologically proven frontotemporal dementia presenting with severe a
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《大脑学杂志》
1 MRC Cognition and Brain Sciences Unit,2 University Department of Neurology, Addenbrooke's Hospital
3 Department of Neuropathology, Addenbrooke's Hospital, Cambridge, UK,4 Prince of Wales Medical Research Institute, University of New South Wales, Randwick, New South Wales, Australia
5 Centre for Education and Research on Ageing, University of Sydney, Concord Hospital, Concord, New South Wales, Australia
Summary
Early and severe memory impairment is generally held to be an exclusion criterion for the clinical diagnosis of frontotemporal dementia (FTD). However, clinical experience suggests that some patients with otherwise typical FTD can be amnesic from presentation, or even present solely with amnesia. A review of severe amnesia at presentation in patients with pathologically proven FTD is therefore warranted. The present study examined the records of all patients in the joint Cambridge–Sydney neuropathological series of patients with dementia and a pathological diagnosis of FTD to identify those for whom memory complaints were dominant at presentation. Eight of 71 patients met these criteria. For two patients, memory loss was the only complaint; for one patient, memory loss was accompanied by personality change; for two patients, memory loss was accompanied by prominent dysexecutive symptoms; and for three patients, memory loss was accompanied by apathy but no other behavioural changes. In seven patients local specialist teams initially diagnosed Alzheimer's disease; four patients entered anticholinesterase drug trials. All eight later developed behavioural features: in four, the diagnosis was revised to FTD, while in four the diagnosis of FTD was made only on neuropathological examination after death. In conclusion, severe amnesia at presentation in FTD is commoner than previously thought and the clinical consensus criteria for the diagnosis of FTD may need to be revised. The underlying basis of the memory impairments in patients with FTD may be heterogeneous, with different explanations in different subgroups.
Key Words: frontotemporal dementia; episodic memory
Abbreviations: FTD = frontotemporal dementia; FTD-MND = frontotemporal dementia with motor neuron inclusions; fvFTD = frontal or behavioural variant frontotemporal dementia; MMSE = Mini-Mental State Examination
Introduction
Frontotemporal dementia (FTD), the second most common neurodegenerative cause of dementia in patients younger than 65 years (Ratnavalli et al., 2002; Harvey et al., 2003), is a disorder characterized by a progressive deterioration of behaviour, personality and cognition in association with prominent frontal and temporal lobar atrophy. Three main clinical presentations of FTD are recognized (Hodges and Miller, 2001): frontal or behavioural variant FTD (fvFTD), in which the initial clinical picture is of insidious behavioural and personality changes, accompanied by frontal lobe atrophy; semantic dementia (SD), in which the initial presentation is of anomia and impaired comprehension secondary to loss of semantic knowledge, accompanied by anterior temporal lobe atrophy; and, less commonly, progressive non-fluent aphasia (PNFA), in which the predominant impairment is a profound disturbance of expressive language, accompanied by left perisylvian atrophy and anterior insular hypometabolism (Grossman et al., 1996; Nestor et al., 2003).
A range of pathological processes underlies these overlapping clinical syndromes. Three broad types of neuropathology are recognized depending on the profile of immunohistochemical staining and the pattern of intracellular inclusions (Jackson and Lowe, 1996; Dickson, 1998; McKhann et al., 2001; Hodges et al., 2003). These are: (i) cases with tau-positive pathology, which can in turn be divided into a number of subtypes; (ii) cases with tau-negative, ubiquitin-positive inclusions in the dentate gyrus and brainstem motor nuclei (FTD with motor neuron inclusions or FTD-MND); and (iii) dementia lacking distinctive histology. The clinical presentation of FTD appears to depend on the locus of initial pathology rather than the precise cellular pathology, although presentation with PNFA is more likely to be associated with underlying tau-positive pathology (Hodges et al., 2004).
Based on the clinical features of FTD, two sets of clinical criteria have been proposed for diagnosis: the Lund–Manchester consensus clinical criteria (Brun et al., 1994; Neary et al., 1998) and the McKhann criteria (McKhann et al., 2001). Examining the validity of the consensus clinical criteria, a recent review of 30 pathologically proven FTD cases and 30 pathologically proven Alzheimer's disease cases demonstrated a close correspondence between clinical and neuropathological diagnoses (Rosen et al., 2002a). Some aspects of the consensus clinical criteria remain, however, controversial. For example, while ‘early, severe amnesia’ is an exclusion criterion for the diagnosis of FTD, clinical experience suggests that some patients with otherwise typical FTD can be amnesic from presentation, while in other patients memory disturbance may even be the presenting feature. Patients with FTD commonly complain of memory loss and memory underperformance (Binetti et al., 2000; Rosen et al., 2002b) and many patients with FTD also meet the NINCDS-ADRDA criteria for possible or probable Alzheimer's disease (Varma et al., 1999). In a recent review of clinicopathological correlations in a cohort of 61 patients with pathologically proven FTD, five patients (8%) presented with memory loss as their leading complaint (Hodges et al., 2004). Of a subsequent 10 cases of pathologically proven FTD seen in Cambridge, three have presented with memory loss as their leading complaint. From this overall cohort of 71 patients, we present individual clinical and pathological information for a total of eight cases (11%) in whom early and severe memory impairment was the major presenting clinical feature and yet the pathological diagnosis was FTD.
Subjects and methods
Three patients were under the care of the Memory Clinic at Addenbrooke's Hospital, Cambridge, UK; five were studied at Concord or Westmead Hospitals, Sydney, Australia. All patients presented with memory difficulties as their main or only complaint; these difficulties were confirmed by neuropsychological testing. Cases 1 and 2 are described in detail: case 1 as an example of a patient with FTD presenting with severe amnesia as their main symptom, and case 2 as an example of a patient with behaviourally typical FTD that was accompanied by severe amnesia at an early stage. Cases 3–8 are presented in tabular form for reasons of space. With the exception of case 4 (Henderson et al., 2001), the clinical details of these patients have not been previously reported.
All cases underwent standardized pathological screening as described elsewhere (Hodges et al., 2003). Cases with significant senile plaques or other contributing dementia-related neuropathologies were excluded. Written informed consent for post-mortem examination of brain tissue was obtained for all subjects and the study was approved by the Research Ethics Committees in both Cambridge and Sydney.
Case reports
Patient 1
This 63-year-old retired laboratory technician with 12 years of education was referred to the Memory Clinic at Addenbrooke's Hospital in September 1996 for the assessment of worsening memory problems over the previous 2 years.
His past medical history consisted of hypertension, hypercholesterolaemia and depression. He drank 8–10 units of alcohol a week and was an ex-smoker of 20 years. His only medication was a lipid-lowering agent. There was no family history of note.
The patient himself lacked insight into his memory problems. His wife had first noticed forgetfulness 2 years previously when they had enrolled on a computer course and he had been unable to retain new information. Since then his memory had steadily deteriorated, with increasing forgetfulness and a tendency to repetitive conversation. Additionally, he had developed difficulties with previously trivial practical tasks, such as changing a light bulb or rewiring a plug; on one or two occasions he had got lost in the local area. Of note was the absence of any stereotypic behaviours, personality change or alteration in food preference.
General physical and neurological examination was unremarkable. On bedside cognitive testing he recalled none of seven elements in a name and address after 5 min and his verbal fluencies were reduced to both letter and category. His language and visuospatial functioning were unimpaired.
A detailed neuropsychological assessment was performed, including tests of general intellectual function, language, memory, executive ability and visuospatial function (Table 1).
His performance on tests of memory was globally poor, encompassing verbal and visual material tested by recall and recognition. On tests of delayed recall he scored at floor level. His language skills were intact with normal naming and comprehension. His performance on the Visual Object and Space Processing battery (VOSP; Warrington and James, 1991) was also satisfactory. The Wisconsin Card Sorting Test (Heaton et al., 1993) was abandoned, however, because of continual perseveration on the first category obtained and on assessment of verbal fluency he scored only 16 for phonemic fluency on the letters F, A and S.
He underwent a comprehensive work-up for causes of early-onset dementia. Full blood count, erythrocyte sedimentation rate, biochemistry profile, thyroid function tests, vitamin B12 and folate levels and an autoantibody screen were all unremarkable. An echocardiogram and EEG were both normal. An MRI scan with the acquisition of sagittal T1, fluid-attenuated inversion recovery, fast spin-echo and coronal multiplanar gradient-recalled sequences revealed diffuse cortical involutional changes, without any regional accentuation of atrophy, together with marked volume loss of both hippocampi, left more than right (Fig. 1). An HMPAO-SPECT ([99mTc]-hexamethyl propyleneamine oxime single photon emission computed tomography) scan demonstrated reduced perfusion in both frontal lobes and parietal lobes.
A diagnosis of Alzheimer's disease was made and he was placed on treatment with rivastigmine. Towards the end of 1997 he developed tonic–clonic generalized seizures. Rivastigmine was therefore withdrawn and carbamazepine was started. Because of continuing seizures, carbamazepine was subsequently replaced by lamotrigine.
In August 2000 a marked physical decline was noted. He attended clinic in a wheelchair, displayed a prominent grasp reflex bilaterally and was mildly parkinsonian. He scored 14/30 on the Mini-Mental State Examination (MMSE; Folstein et al., 1975) and 50/100 on the Addenbrooke's Cognitive Examination, with a global profile of impairments. The possibility of dementia with Lewy bodies was raised but there was no evidence of any fluctuations or visual hallucinations.
His condition steadily deteriorated; by December 2001 he required placement in a residential home. Hyperoral behaviour then emerged; he began continually chewing his left thumb, which in June 2002 required surgical debridement. By October 2002 he was mute and bed-bound. He was admitted to hospital with difficulty in swallowing, developed an aspiration pneumonia and died 2 weeks after admission.
At autopsy the whole brain weighed 1080 g. On external inspection there was a moderate degree of cerebral gyral atrophy involving the frontal lobes, particularly the frontal poles, and the right temporal pole. Coronal slices showed atrophy of the hippocampi with sparing of the parahippocampal regions. Microscopic pathology detected no tau-positive or -synuclein-positive inclusions. Ubiquitinated cytoplasmic inclusions were seen in the nerve cell bodies of the inferior olive and throughout the temporal neocortex (but not in the dentate fascia). The pathological diagnosis was frontotemporal dementia with ubiquitinated (motor neuron type) inclusions (Fig. 2).
Patient 2
This 53-year-old ex-secretary and cleaner was referred to the Memory Clinic at Addenbrooke's Hospital in November 1999 for the assessment of increasingly poor memory and personality change over the previous 3 years.
Her past medical history was unremarkable. Her husband reported a 10-year history of increasing alcohol intake. She had also been a smoker of 15 cigarettes a day since early adult life but recently had begun to smoke more heavily. There was no family history of note.
The patient herself was without insight into her difficulties. On direct questioning she felt that her memory was as good as it ever had been. Her husband had first noticed memory problems two and a half years previously. These initially took the form of mild forgetfulness for events and phone calls. Memory problems then steadily progressed: her conversations became extremely repetitive and she developed a number of fixed routines and preoccupations, such as counting her cigarettes over and over again. There were no other changes in behaviour, food preferences or social conduct.
General physical and neurological examination was unremarkable except for symmetrical difficulty with alternating hand movements and the Luria three-step task. On bedside cognitive testing she scored 23/30 on the MMSE and 63/100 on the Addenbrooke's Cognitive Examination. With regard to her profile of impairments, she recalled none of the three MMSE items and none of seven elements in a name and address. Verbal fluencies were greatly reduced; she produced only four words beginning with ‘P’ and 12 animals in the allotted 1-min period. On assessment of language she was mildly anomic, with surface dyslexia. Visuospatial function was satisfactory.
A more detailed neuropsychological assessment was performed, including tests of general intellectual function, language, memory, executive ability and visuospatial function. Her performance on tests of both verbal and visual memory was extremely poor. She was unable to reproduce any part of a short story immediately after hearing it. She recalled none of a list of 10 words after five presentations, and on recognition testing endorsed every item, including all distractors, as having been on the learnt list. Although her copy of the Rey figure was well planned and coherent, she recalled little after a 30-min delay. Striking impairments were also noted on assessment of language. She had great difficulty with the Graded Naming Test, scoring only 4/30. Assessment of semantic function revealed mild deficits: her score on the Pyramids and Palm Trees Test (pictures) was a little reduced at 45/52. Visuospatial function was good, as evidenced by her Rey figure copy. On assessment of executive function she performed surprisingly well, having no difficulty with the alternation required in Part B of the Trails task or in the incongruent condition of the Stroop task.
The initial differential diagnosis was of Alzheimer's disease with prominent language deficits or FTD with a prominent memory disturbance. Investigations performed to exclude alternative causes for an early-onset dementia were all negative. An MRI head scan demonstrated prominent sulci throughout the brain, most marked at the left temporal pole. An HMPAO-SPECT scan showed moderate hypoperfusion of the left temporal lobe and posterior parietal region bilaterally.
The investigation results were felt to be more consistent with the diagnosis of FTD. Over the next year her behavioural disturbance became pronounced. She was reported to the police for an assault on her social worker and the local postmistress, and was detained for shoplifting. In March 2001 she scored 22/30 on the MMSE and 56/100 on the Addenbrooke's Cognitive Examination. Three years after her first assessment she attended clinic with extreme weight loss and some shortness of breath. Examination detected dullness at the right lung base and a chest X-ray demonstrated a mass at the right hilum with right lower lobe collapse. The appearances were highly suggestive of a carcinoma of the bronchus and a supportive and symptomatic management plan was agreed. She was referred to her local palliative care services and died shortly afterwards.
At autopsy the brain weighed 1120 g. On external inspection there was a moderate degree of cerebral gyral atrophy involving the frontal lobes; temporal lobe atrophy was severe. Coronal slices confirmed the frontotemporal atrophy. The hippocampal formation was severely atrophic anteriorly but relatively spared posteriorly. Microscopic pathology revealed marked neuronal loss and gliosis involving the entorhinal and perirhinal cortices and the temporal neocortex. Sections from the hippocampus showed moderate neuronal loss in CA-1. Tau immunohistochemistry showed very numerous Pick bodies in the surviving neuronal perikarya, together with several diffusely tau-positive ballooned neurons in temporal cortex. The pathological diagnosis was Pick body positive FTD.
Summary data for all patients
A summary of the clinical and pathological information for all eight patients is presented in tabular form (Table 2). Men (n = 4) and women (n = 4) were equally represented. The mean age at diagnosis was 58 years (range 44–77) and the mean age at death was 65 years (range 52–89). For two patients, memory loss was the only complaint; for one patient, memory loss was accompanied by personality change; for two patients, memory loss was accompanied by prominent dysexecutive symptoms; and for three patients, memory loss was accompanied by apathy, but no other behavioural changes. In all eight patients neuropsychological assessment (performed by different clinicians) confirmed substantial memory deficits. Since different standardized neuropsychological tasks were used in the two centres (Cambridge and Sydney), we have converted the patients' scores to overall grades, as follows: 0 = within normal range (within 1 standard deviation of control mean); 1 = below average (between 1 and 2 standard deviations below control mean); 2 = impaired (more than 2 standard deviations below control mean); 3 = very impaired, but able to complete task; 4 = too impaired to complete task. As shown in Table 2 all patients showed substantial episodic memory deficits (grade 2 or worse). All patients were assessed with one or both of the following tests of memory: the Wechsler Memory Scale, Logical Memory and Visual Reproduction subscales (Wechsler, 1987) or the Rey Auditory Verbal Learning Test (Schmidt, 1996). In seven patients local specialist teams initially diagnosed Alzheimer's disease (Alzheimer's disease); four patients entered anticholinesterase drug trials. All eight later developed behavioural features suggestive of FTD: in four, the diagnosis was revised to FTD, while in four the diagnosis of FTD was made only on neuropathological examination after death. A broad range of underlying pathologies were found: FTD with Pick bodies in three; FTD lacking distinctive histology in three; FTD-MND in one; and corticobasal degeneration in one.
Discussion
These eight cases demonstrate that severe episodic memory impairment can be a presenting feature in FTD. This finding has practical and theoretical implications. In seven cases impairment of episodic memory was so prominent that the initial clinical diagnosis was Alzheimer's disease; in the eighth case (patient 2) the initial diagnosis was FTD with prominent memory symptoms. Patient 1 was the most striking case, presenting with a virtually pure amnesic syndrome. His initial neuropsychological evaluation was entirely consistent with early Alzheimer's disease, with severe impairment of episodic memory alongside executive dysfunction but intact language and visuospatial skills. This diagnosis was also supported by his MRI scan, which showed bilateral hippocampal atrophy together with generalized cortical involutional changes. His final clinical assessment raised the possibility of dementia with Lewy bodies, but further behavioural features suggestive of a frontal syndrome (such as his hyperorality) emerged only at a very late stage of his disease.
a practical perspective, this finding is important as recent consensus criteria for the diagnosis of FTD emphasize the absence of severe amnesia in this condition (Brun et al., 1994; Neary et al., 1998). To date, however, there have been very few empirical studies of memory in pathologically proven (as opposed to clinically diagnosed) FTD. In a review of the neuropsychological test performance of 14 patients with pathologically proven FTD and 28 patients with pathologically proven Alzheimer's disease (Rascovsky et al., 2002), the FTD group were significantly less impaired than the Alzheimer's disease group on the single measure of memory available for all patients, the memory subscale of the Mattis Dementia Rating Scale. By contrast, in a recent British series that included comprehensive neuropsychological assessment at presentation, four of 12 patients with pathologically verified FTD secondary to the intronic tau+16 mutation had ‘grave global memory impairment’ (Janssen et al., 2002). Evidence for memory problems in FTD also comes from recent Japanese reports, including a single case study of a patient with a novel tau gene mutation and a clinical syndrome of amnesia without personality change (Hayashi et al., 2002). Two of a series of six patients with Pick body-positive FTD also presented with amnesia and received a clinical diagnosis of Alzheimer's disease in life (Tsuchiya et al., 2001).
The findings reported in this paper add to this growing documentation of major memory impairments in some patients with FTD, and suggest that the consensus clinical criteria may need to be revised. By making early severe memory loss an exclusion criterion for the diagnosis of FTD, strict application of the consensus clinical criteria increases the likelihood that only ‘typical’ cases of FTD (with minimal or moderate memory impairment) are selected for follow-up (and eventual neuropathological confirmation of the diagnosis). Some patients diagnosed with Alzheimer's disease or ‘atypical Alzheimer's disease’ in life may in fact have FTD that, without neuropathological examination, remains undetected. Given the much higher incidence of Alzheimer's disease than FTD, their numbers could be substantial. Our findings emphasize the need to follow up and review cases of early-onset dementia even when the initial diagnosis is apparently clear-cut. Acknowledging this diagnostic uncertainty also has important implications for the advice given to patients, families and carers about prognosis and treatment. For example, with the increasing use of cholinesterase inhibitors in the symptomatic management of Alzheimer's disease, patients are being commenced on treatment at an earlier stage of their illness. The benefits of treatment with cholinesterase inhibitors for patients with FTD are not established.
The degree of hippocampal atrophy seen in patient 1 is striking. Early pathological reports suggested that the hippocampi are preserved in FTD (Mann et al., 1993) but hippocampal atrophy is now well described in both pathological (Broe et al., 2003) and imaging studies (Frisoni et al., 1996; Chan et al., 2001; Galton et al., 2001). In a recent case report of a patient with FTD and ubiquitinated inclusions, hippocampal atrophy on MRI was associated with a profound anterograde amnesia at presentation (Caine et al., 2001). Patient 1 also demonstrated ubiquitinated inclusions but the pattern of inclusions was unusual in that no inclusions were seen in the dentate gyrus or brainstem motor nuclei, in contrast to the recognized pattern in FTD-MND. FTD with ubiquitin-positive inclusions but sparing the brainstem motor nuclei and without lower motor neuron involvement has been described with both behavioural (Yaguchi et al., 2003) and semantic (Rossor et al., 2000) presentations.
The finding of severe amnesia in FTD also raises questions as to the nature and underlying neural basis of the memory impairment. Studies of patients with static focal frontal lobe lesions and memory impairments have typically attributed these deficits to poor strategic retrieval as a result of frontal lobe dysfunction (Shimamura et al., 1991; Stuss et al., 1994). However, the findings of the few prospective studies of memory in FTD are mixed. In a study of 12 fvFTD patients, nine FTD patients with a language presentation, and 30 Alzheimer's disease patients, the FTD group showed no evidence for a selective deficit in memory organization and retrieval (Glosser et al., 2002). By contrast in another study of 15 fvFTD patients, 30 Alzheimer's disease patients and 12 healthy controls, the fvFTD group demonstrated genuine memory deficits, but performance on tests of verbal recall was greatly improved by priming, suggesting mainly retrieval difficulties (Pasquier et al., 2001). With regard to the patients described here, those who received a comprehensive neuropsychological assessment were impaired on both recognition and recall tasks, making a deficit based purely on a failure of retrieval unlikely. Memory impairments in patients with FTD may be heterogeneous, with different explanations in different subgroups.
In summary, a retrospective case review of a large multicentre neuropathological series of 71 patients with FTD identified eight (11%) in whom memory loss was either the sole or leading complaint, supported by neuropsychological evidence of genuine memory deficits in each case. The memory loss was sufficiently predominant that in seven of eight patients Alzheimer's disease was the initial clinical diagnosis. In all patients behavioural features suggestive of FTD later developed, but in only four was the diagnosis revised to FTD prior to death. These patients challenge the consensus that early and severe amnesia is an exclusion criterion for the diagnosis of FTD. Indeed, the proportion of patients with FTD presenting with amnesia in this study means that this type of clinical presentation can no longer be considered exceptional or rare in FTD. We suggest that memory impairment in FTD is multifactorial, not only related to frontal and temporal atrophy but also, in some cases, with additional bilateral hippocampal involvement. Overall, with the exception of patients with FTD-MND or corticobasal degeneration, it remains the distribution of pathology, rather than the nature of the underlying pathology, which is the most powerful predictor of the pattern of cognitive impairment in patients with FTD. Further work is required to delineate the memory impairments in patients with FTD more precisely and to relate differing memory deficits to the widely differing patterns of regional atrophy and underlying pathology seen in this condition. Both retrospective and prospective studies are currently under way in an effort to answer these fascinating questions more fully.
Acknowledgements
A. G. and R. D. are supported by the Wellcome Trust as Research Training Fellows. J. H. is supported by the Medical Research Council of the UK. G. H. is supported by the National Health and Medical Research Council of Australia (NHMRC) as a Principal Research Fellow. The NHMRC also provides J. K., H. C. and G. H. with project support for this work (no. 301964). We are grateful to the patients and their families for participation in these studies, to Angela O'Sullivan for her work with the Cambridge Brain Bank cohort, to Melissa Broe for assistance with pathological case classification and to the laboratory staff for tissue and slide preparation.
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3 Department of Neuropathology, Addenbrooke's Hospital, Cambridge, UK,4 Prince of Wales Medical Research Institute, University of New South Wales, Randwick, New South Wales, Australia
5 Centre for Education and Research on Ageing, University of Sydney, Concord Hospital, Concord, New South Wales, Australia
Summary
Early and severe memory impairment is generally held to be an exclusion criterion for the clinical diagnosis of frontotemporal dementia (FTD). However, clinical experience suggests that some patients with otherwise typical FTD can be amnesic from presentation, or even present solely with amnesia. A review of severe amnesia at presentation in patients with pathologically proven FTD is therefore warranted. The present study examined the records of all patients in the joint Cambridge–Sydney neuropathological series of patients with dementia and a pathological diagnosis of FTD to identify those for whom memory complaints were dominant at presentation. Eight of 71 patients met these criteria. For two patients, memory loss was the only complaint; for one patient, memory loss was accompanied by personality change; for two patients, memory loss was accompanied by prominent dysexecutive symptoms; and for three patients, memory loss was accompanied by apathy but no other behavioural changes. In seven patients local specialist teams initially diagnosed Alzheimer's disease; four patients entered anticholinesterase drug trials. All eight later developed behavioural features: in four, the diagnosis was revised to FTD, while in four the diagnosis of FTD was made only on neuropathological examination after death. In conclusion, severe amnesia at presentation in FTD is commoner than previously thought and the clinical consensus criteria for the diagnosis of FTD may need to be revised. The underlying basis of the memory impairments in patients with FTD may be heterogeneous, with different explanations in different subgroups.
Key Words: frontotemporal dementia; episodic memory
Abbreviations: FTD = frontotemporal dementia; FTD-MND = frontotemporal dementia with motor neuron inclusions; fvFTD = frontal or behavioural variant frontotemporal dementia; MMSE = Mini-Mental State Examination
Introduction
Frontotemporal dementia (FTD), the second most common neurodegenerative cause of dementia in patients younger than 65 years (Ratnavalli et al., 2002; Harvey et al., 2003), is a disorder characterized by a progressive deterioration of behaviour, personality and cognition in association with prominent frontal and temporal lobar atrophy. Three main clinical presentations of FTD are recognized (Hodges and Miller, 2001): frontal or behavioural variant FTD (fvFTD), in which the initial clinical picture is of insidious behavioural and personality changes, accompanied by frontal lobe atrophy; semantic dementia (SD), in which the initial presentation is of anomia and impaired comprehension secondary to loss of semantic knowledge, accompanied by anterior temporal lobe atrophy; and, less commonly, progressive non-fluent aphasia (PNFA), in which the predominant impairment is a profound disturbance of expressive language, accompanied by left perisylvian atrophy and anterior insular hypometabolism (Grossman et al., 1996; Nestor et al., 2003).
A range of pathological processes underlies these overlapping clinical syndromes. Three broad types of neuropathology are recognized depending on the profile of immunohistochemical staining and the pattern of intracellular inclusions (Jackson and Lowe, 1996; Dickson, 1998; McKhann et al., 2001; Hodges et al., 2003). These are: (i) cases with tau-positive pathology, which can in turn be divided into a number of subtypes; (ii) cases with tau-negative, ubiquitin-positive inclusions in the dentate gyrus and brainstem motor nuclei (FTD with motor neuron inclusions or FTD-MND); and (iii) dementia lacking distinctive histology. The clinical presentation of FTD appears to depend on the locus of initial pathology rather than the precise cellular pathology, although presentation with PNFA is more likely to be associated with underlying tau-positive pathology (Hodges et al., 2004).
Based on the clinical features of FTD, two sets of clinical criteria have been proposed for diagnosis: the Lund–Manchester consensus clinical criteria (Brun et al., 1994; Neary et al., 1998) and the McKhann criteria (McKhann et al., 2001). Examining the validity of the consensus clinical criteria, a recent review of 30 pathologically proven FTD cases and 30 pathologically proven Alzheimer's disease cases demonstrated a close correspondence between clinical and neuropathological diagnoses (Rosen et al., 2002a). Some aspects of the consensus clinical criteria remain, however, controversial. For example, while ‘early, severe amnesia’ is an exclusion criterion for the diagnosis of FTD, clinical experience suggests that some patients with otherwise typical FTD can be amnesic from presentation, while in other patients memory disturbance may even be the presenting feature. Patients with FTD commonly complain of memory loss and memory underperformance (Binetti et al., 2000; Rosen et al., 2002b) and many patients with FTD also meet the NINCDS-ADRDA criteria for possible or probable Alzheimer's disease (Varma et al., 1999). In a recent review of clinicopathological correlations in a cohort of 61 patients with pathologically proven FTD, five patients (8%) presented with memory loss as their leading complaint (Hodges et al., 2004). Of a subsequent 10 cases of pathologically proven FTD seen in Cambridge, three have presented with memory loss as their leading complaint. From this overall cohort of 71 patients, we present individual clinical and pathological information for a total of eight cases (11%) in whom early and severe memory impairment was the major presenting clinical feature and yet the pathological diagnosis was FTD.
Subjects and methods
Three patients were under the care of the Memory Clinic at Addenbrooke's Hospital, Cambridge, UK; five were studied at Concord or Westmead Hospitals, Sydney, Australia. All patients presented with memory difficulties as their main or only complaint; these difficulties were confirmed by neuropsychological testing. Cases 1 and 2 are described in detail: case 1 as an example of a patient with FTD presenting with severe amnesia as their main symptom, and case 2 as an example of a patient with behaviourally typical FTD that was accompanied by severe amnesia at an early stage. Cases 3–8 are presented in tabular form for reasons of space. With the exception of case 4 (Henderson et al., 2001), the clinical details of these patients have not been previously reported.
All cases underwent standardized pathological screening as described elsewhere (Hodges et al., 2003). Cases with significant senile plaques or other contributing dementia-related neuropathologies were excluded. Written informed consent for post-mortem examination of brain tissue was obtained for all subjects and the study was approved by the Research Ethics Committees in both Cambridge and Sydney.
Case reports
Patient 1
This 63-year-old retired laboratory technician with 12 years of education was referred to the Memory Clinic at Addenbrooke's Hospital in September 1996 for the assessment of worsening memory problems over the previous 2 years.
His past medical history consisted of hypertension, hypercholesterolaemia and depression. He drank 8–10 units of alcohol a week and was an ex-smoker of 20 years. His only medication was a lipid-lowering agent. There was no family history of note.
The patient himself lacked insight into his memory problems. His wife had first noticed forgetfulness 2 years previously when they had enrolled on a computer course and he had been unable to retain new information. Since then his memory had steadily deteriorated, with increasing forgetfulness and a tendency to repetitive conversation. Additionally, he had developed difficulties with previously trivial practical tasks, such as changing a light bulb or rewiring a plug; on one or two occasions he had got lost in the local area. Of note was the absence of any stereotypic behaviours, personality change or alteration in food preference.
General physical and neurological examination was unremarkable. On bedside cognitive testing he recalled none of seven elements in a name and address after 5 min and his verbal fluencies were reduced to both letter and category. His language and visuospatial functioning were unimpaired.
A detailed neuropsychological assessment was performed, including tests of general intellectual function, language, memory, executive ability and visuospatial function (Table 1).
His performance on tests of memory was globally poor, encompassing verbal and visual material tested by recall and recognition. On tests of delayed recall he scored at floor level. His language skills were intact with normal naming and comprehension. His performance on the Visual Object and Space Processing battery (VOSP; Warrington and James, 1991) was also satisfactory. The Wisconsin Card Sorting Test (Heaton et al., 1993) was abandoned, however, because of continual perseveration on the first category obtained and on assessment of verbal fluency he scored only 16 for phonemic fluency on the letters F, A and S.
He underwent a comprehensive work-up for causes of early-onset dementia. Full blood count, erythrocyte sedimentation rate, biochemistry profile, thyroid function tests, vitamin B12 and folate levels and an autoantibody screen were all unremarkable. An echocardiogram and EEG were both normal. An MRI scan with the acquisition of sagittal T1, fluid-attenuated inversion recovery, fast spin-echo and coronal multiplanar gradient-recalled sequences revealed diffuse cortical involutional changes, without any regional accentuation of atrophy, together with marked volume loss of both hippocampi, left more than right (Fig. 1). An HMPAO-SPECT ([99mTc]-hexamethyl propyleneamine oxime single photon emission computed tomography) scan demonstrated reduced perfusion in both frontal lobes and parietal lobes.
A diagnosis of Alzheimer's disease was made and he was placed on treatment with rivastigmine. Towards the end of 1997 he developed tonic–clonic generalized seizures. Rivastigmine was therefore withdrawn and carbamazepine was started. Because of continuing seizures, carbamazepine was subsequently replaced by lamotrigine.
In August 2000 a marked physical decline was noted. He attended clinic in a wheelchair, displayed a prominent grasp reflex bilaterally and was mildly parkinsonian. He scored 14/30 on the Mini-Mental State Examination (MMSE; Folstein et al., 1975) and 50/100 on the Addenbrooke's Cognitive Examination, with a global profile of impairments. The possibility of dementia with Lewy bodies was raised but there was no evidence of any fluctuations or visual hallucinations.
His condition steadily deteriorated; by December 2001 he required placement in a residential home. Hyperoral behaviour then emerged; he began continually chewing his left thumb, which in June 2002 required surgical debridement. By October 2002 he was mute and bed-bound. He was admitted to hospital with difficulty in swallowing, developed an aspiration pneumonia and died 2 weeks after admission.
At autopsy the whole brain weighed 1080 g. On external inspection there was a moderate degree of cerebral gyral atrophy involving the frontal lobes, particularly the frontal poles, and the right temporal pole. Coronal slices showed atrophy of the hippocampi with sparing of the parahippocampal regions. Microscopic pathology detected no tau-positive or -synuclein-positive inclusions. Ubiquitinated cytoplasmic inclusions were seen in the nerve cell bodies of the inferior olive and throughout the temporal neocortex (but not in the dentate fascia). The pathological diagnosis was frontotemporal dementia with ubiquitinated (motor neuron type) inclusions (Fig. 2).
Patient 2
This 53-year-old ex-secretary and cleaner was referred to the Memory Clinic at Addenbrooke's Hospital in November 1999 for the assessment of increasingly poor memory and personality change over the previous 3 years.
Her past medical history was unremarkable. Her husband reported a 10-year history of increasing alcohol intake. She had also been a smoker of 15 cigarettes a day since early adult life but recently had begun to smoke more heavily. There was no family history of note.
The patient herself was without insight into her difficulties. On direct questioning she felt that her memory was as good as it ever had been. Her husband had first noticed memory problems two and a half years previously. These initially took the form of mild forgetfulness for events and phone calls. Memory problems then steadily progressed: her conversations became extremely repetitive and she developed a number of fixed routines and preoccupations, such as counting her cigarettes over and over again. There were no other changes in behaviour, food preferences or social conduct.
General physical and neurological examination was unremarkable except for symmetrical difficulty with alternating hand movements and the Luria three-step task. On bedside cognitive testing she scored 23/30 on the MMSE and 63/100 on the Addenbrooke's Cognitive Examination. With regard to her profile of impairments, she recalled none of the three MMSE items and none of seven elements in a name and address. Verbal fluencies were greatly reduced; she produced only four words beginning with ‘P’ and 12 animals in the allotted 1-min period. On assessment of language she was mildly anomic, with surface dyslexia. Visuospatial function was satisfactory.
A more detailed neuropsychological assessment was performed, including tests of general intellectual function, language, memory, executive ability and visuospatial function. Her performance on tests of both verbal and visual memory was extremely poor. She was unable to reproduce any part of a short story immediately after hearing it. She recalled none of a list of 10 words after five presentations, and on recognition testing endorsed every item, including all distractors, as having been on the learnt list. Although her copy of the Rey figure was well planned and coherent, she recalled little after a 30-min delay. Striking impairments were also noted on assessment of language. She had great difficulty with the Graded Naming Test, scoring only 4/30. Assessment of semantic function revealed mild deficits: her score on the Pyramids and Palm Trees Test (pictures) was a little reduced at 45/52. Visuospatial function was good, as evidenced by her Rey figure copy. On assessment of executive function she performed surprisingly well, having no difficulty with the alternation required in Part B of the Trails task or in the incongruent condition of the Stroop task.
The initial differential diagnosis was of Alzheimer's disease with prominent language deficits or FTD with a prominent memory disturbance. Investigations performed to exclude alternative causes for an early-onset dementia were all negative. An MRI head scan demonstrated prominent sulci throughout the brain, most marked at the left temporal pole. An HMPAO-SPECT scan showed moderate hypoperfusion of the left temporal lobe and posterior parietal region bilaterally.
The investigation results were felt to be more consistent with the diagnosis of FTD. Over the next year her behavioural disturbance became pronounced. She was reported to the police for an assault on her social worker and the local postmistress, and was detained for shoplifting. In March 2001 she scored 22/30 on the MMSE and 56/100 on the Addenbrooke's Cognitive Examination. Three years after her first assessment she attended clinic with extreme weight loss and some shortness of breath. Examination detected dullness at the right lung base and a chest X-ray demonstrated a mass at the right hilum with right lower lobe collapse. The appearances were highly suggestive of a carcinoma of the bronchus and a supportive and symptomatic management plan was agreed. She was referred to her local palliative care services and died shortly afterwards.
At autopsy the brain weighed 1120 g. On external inspection there was a moderate degree of cerebral gyral atrophy involving the frontal lobes; temporal lobe atrophy was severe. Coronal slices confirmed the frontotemporal atrophy. The hippocampal formation was severely atrophic anteriorly but relatively spared posteriorly. Microscopic pathology revealed marked neuronal loss and gliosis involving the entorhinal and perirhinal cortices and the temporal neocortex. Sections from the hippocampus showed moderate neuronal loss in CA-1. Tau immunohistochemistry showed very numerous Pick bodies in the surviving neuronal perikarya, together with several diffusely tau-positive ballooned neurons in temporal cortex. The pathological diagnosis was Pick body positive FTD.
Summary data for all patients
A summary of the clinical and pathological information for all eight patients is presented in tabular form (Table 2). Men (n = 4) and women (n = 4) were equally represented. The mean age at diagnosis was 58 years (range 44–77) and the mean age at death was 65 years (range 52–89). For two patients, memory loss was the only complaint; for one patient, memory loss was accompanied by personality change; for two patients, memory loss was accompanied by prominent dysexecutive symptoms; and for three patients, memory loss was accompanied by apathy, but no other behavioural changes. In all eight patients neuropsychological assessment (performed by different clinicians) confirmed substantial memory deficits. Since different standardized neuropsychological tasks were used in the two centres (Cambridge and Sydney), we have converted the patients' scores to overall grades, as follows: 0 = within normal range (within 1 standard deviation of control mean); 1 = below average (between 1 and 2 standard deviations below control mean); 2 = impaired (more than 2 standard deviations below control mean); 3 = very impaired, but able to complete task; 4 = too impaired to complete task. As shown in Table 2 all patients showed substantial episodic memory deficits (grade 2 or worse). All patients were assessed with one or both of the following tests of memory: the Wechsler Memory Scale, Logical Memory and Visual Reproduction subscales (Wechsler, 1987) or the Rey Auditory Verbal Learning Test (Schmidt, 1996). In seven patients local specialist teams initially diagnosed Alzheimer's disease (Alzheimer's disease); four patients entered anticholinesterase drug trials. All eight later developed behavioural features suggestive of FTD: in four, the diagnosis was revised to FTD, while in four the diagnosis of FTD was made only on neuropathological examination after death. A broad range of underlying pathologies were found: FTD with Pick bodies in three; FTD lacking distinctive histology in three; FTD-MND in one; and corticobasal degeneration in one.
Discussion
These eight cases demonstrate that severe episodic memory impairment can be a presenting feature in FTD. This finding has practical and theoretical implications. In seven cases impairment of episodic memory was so prominent that the initial clinical diagnosis was Alzheimer's disease; in the eighth case (patient 2) the initial diagnosis was FTD with prominent memory symptoms. Patient 1 was the most striking case, presenting with a virtually pure amnesic syndrome. His initial neuropsychological evaluation was entirely consistent with early Alzheimer's disease, with severe impairment of episodic memory alongside executive dysfunction but intact language and visuospatial skills. This diagnosis was also supported by his MRI scan, which showed bilateral hippocampal atrophy together with generalized cortical involutional changes. His final clinical assessment raised the possibility of dementia with Lewy bodies, but further behavioural features suggestive of a frontal syndrome (such as his hyperorality) emerged only at a very late stage of his disease.
a practical perspective, this finding is important as recent consensus criteria for the diagnosis of FTD emphasize the absence of severe amnesia in this condition (Brun et al., 1994; Neary et al., 1998). To date, however, there have been very few empirical studies of memory in pathologically proven (as opposed to clinically diagnosed) FTD. In a review of the neuropsychological test performance of 14 patients with pathologically proven FTD and 28 patients with pathologically proven Alzheimer's disease (Rascovsky et al., 2002), the FTD group were significantly less impaired than the Alzheimer's disease group on the single measure of memory available for all patients, the memory subscale of the Mattis Dementia Rating Scale. By contrast, in a recent British series that included comprehensive neuropsychological assessment at presentation, four of 12 patients with pathologically verified FTD secondary to the intronic tau+16 mutation had ‘grave global memory impairment’ (Janssen et al., 2002). Evidence for memory problems in FTD also comes from recent Japanese reports, including a single case study of a patient with a novel tau gene mutation and a clinical syndrome of amnesia without personality change (Hayashi et al., 2002). Two of a series of six patients with Pick body-positive FTD also presented with amnesia and received a clinical diagnosis of Alzheimer's disease in life (Tsuchiya et al., 2001).
The findings reported in this paper add to this growing documentation of major memory impairments in some patients with FTD, and suggest that the consensus clinical criteria may need to be revised. By making early severe memory loss an exclusion criterion for the diagnosis of FTD, strict application of the consensus clinical criteria increases the likelihood that only ‘typical’ cases of FTD (with minimal or moderate memory impairment) are selected for follow-up (and eventual neuropathological confirmation of the diagnosis). Some patients diagnosed with Alzheimer's disease or ‘atypical Alzheimer's disease’ in life may in fact have FTD that, without neuropathological examination, remains undetected. Given the much higher incidence of Alzheimer's disease than FTD, their numbers could be substantial. Our findings emphasize the need to follow up and review cases of early-onset dementia even when the initial diagnosis is apparently clear-cut. Acknowledging this diagnostic uncertainty also has important implications for the advice given to patients, families and carers about prognosis and treatment. For example, with the increasing use of cholinesterase inhibitors in the symptomatic management of Alzheimer's disease, patients are being commenced on treatment at an earlier stage of their illness. The benefits of treatment with cholinesterase inhibitors for patients with FTD are not established.
The degree of hippocampal atrophy seen in patient 1 is striking. Early pathological reports suggested that the hippocampi are preserved in FTD (Mann et al., 1993) but hippocampal atrophy is now well described in both pathological (Broe et al., 2003) and imaging studies (Frisoni et al., 1996; Chan et al., 2001; Galton et al., 2001). In a recent case report of a patient with FTD and ubiquitinated inclusions, hippocampal atrophy on MRI was associated with a profound anterograde amnesia at presentation (Caine et al., 2001). Patient 1 also demonstrated ubiquitinated inclusions but the pattern of inclusions was unusual in that no inclusions were seen in the dentate gyrus or brainstem motor nuclei, in contrast to the recognized pattern in FTD-MND. FTD with ubiquitin-positive inclusions but sparing the brainstem motor nuclei and without lower motor neuron involvement has been described with both behavioural (Yaguchi et al., 2003) and semantic (Rossor et al., 2000) presentations.
The finding of severe amnesia in FTD also raises questions as to the nature and underlying neural basis of the memory impairment. Studies of patients with static focal frontal lobe lesions and memory impairments have typically attributed these deficits to poor strategic retrieval as a result of frontal lobe dysfunction (Shimamura et al., 1991; Stuss et al., 1994). However, the findings of the few prospective studies of memory in FTD are mixed. In a study of 12 fvFTD patients, nine FTD patients with a language presentation, and 30 Alzheimer's disease patients, the FTD group showed no evidence for a selective deficit in memory organization and retrieval (Glosser et al., 2002). By contrast in another study of 15 fvFTD patients, 30 Alzheimer's disease patients and 12 healthy controls, the fvFTD group demonstrated genuine memory deficits, but performance on tests of verbal recall was greatly improved by priming, suggesting mainly retrieval difficulties (Pasquier et al., 2001). With regard to the patients described here, those who received a comprehensive neuropsychological assessment were impaired on both recognition and recall tasks, making a deficit based purely on a failure of retrieval unlikely. Memory impairments in patients with FTD may be heterogeneous, with different explanations in different subgroups.
In summary, a retrospective case review of a large multicentre neuropathological series of 71 patients with FTD identified eight (11%) in whom memory loss was either the sole or leading complaint, supported by neuropsychological evidence of genuine memory deficits in each case. The memory loss was sufficiently predominant that in seven of eight patients Alzheimer's disease was the initial clinical diagnosis. In all patients behavioural features suggestive of FTD later developed, but in only four was the diagnosis revised to FTD prior to death. These patients challenge the consensus that early and severe amnesia is an exclusion criterion for the diagnosis of FTD. Indeed, the proportion of patients with FTD presenting with amnesia in this study means that this type of clinical presentation can no longer be considered exceptional or rare in FTD. We suggest that memory impairment in FTD is multifactorial, not only related to frontal and temporal atrophy but also, in some cases, with additional bilateral hippocampal involvement. Overall, with the exception of patients with FTD-MND or corticobasal degeneration, it remains the distribution of pathology, rather than the nature of the underlying pathology, which is the most powerful predictor of the pattern of cognitive impairment in patients with FTD. Further work is required to delineate the memory impairments in patients with FTD more precisely and to relate differing memory deficits to the widely differing patterns of regional atrophy and underlying pathology seen in this condition. Both retrospective and prospective studies are currently under way in an effort to answer these fascinating questions more fully.
Acknowledgements
A. G. and R. D. are supported by the Wellcome Trust as Research Training Fellows. J. H. is supported by the Medical Research Council of the UK. G. H. is supported by the National Health and Medical Research Council of Australia (NHMRC) as a Principal Research Fellow. The NHMRC also provides J. K., H. C. and G. H. with project support for this work (no. 301964). We are grateful to the patients and their families for participation in these studies, to Angela O'Sullivan for her work with the Cambridge Brain Bank cohort, to Melissa Broe for assistance with pathological case classification and to the laboratory staff for tissue and slide preparation.
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