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of Neurogenetics, Imperial College School of Medicine,. London WC1N ..... with several practical skills such as simple motor car ..... early in the course of Alzheimer's disease? .... as a trained instrument mechanic, but had been downgraded.
Brain (2000), 123, 894–907

Alzheimer’s disease due to an intronic presenilin-1 (PSEN1 intron 4) mutation A clinicopathological study J. C. Janssen,1 M. Hall,1 N. C. Fox,1 R. J. Harvey,1 J. Beck,2 A. Dickinson,2 T. Campbell,2 J. Collinge,2 P. L. Lantos,3 L. Cipolotti,4 J. M. Stevens5 and M. N. Rossor1 1Dementia

Research Group, Institute of Neurology and Division of Neurosciences, 2MRC Prion Unit, Department of Neurogenetics, Imperial College School of Medicine, 3Department of Neuropathology, Institute of Psychiatry and Departments of 4Clinical Neuropsychology and 5Radiology, National Hospital for Neurology and Neurosurgery, London, UK

Correspondence to: Professor M. N. Rossor, Dementia Research Group, Institute of Neurology, Queen Square, London WC1N 3BG, UK

Summary We describe 21 affected individuals from a kindred with early-onset autosomal dominant familial Alzheimer’s disease caused by an intronic presenilin-1 mutation (in intron 4). Mean age at onset of symptoms was 37.4 years [95% confidence interval (CI): 36.6–38.2 years], mean age at death was 44.7 years (95% CI: 43.1–46.3 years) and mean duration of illness was 7.3 years (95% CI: 5.9–8.7 years). Myoclonus and seizures were prominent features of this pedigree. In the four cases for whom neuropsychometric data were available, verbal memory impairment preceded visual memory deficits; naming was relatively preserved until late in the disease. One of these four cases underwent serial volumetric MRI scans

demonstrating in vivo brain tissue loss of 3.9% (38.9 ml, annualized rate of atrophy: 1.7%) over 22 months of follow-up. The four individuals who had necropsies demonstrated the neuropathological hallmarks of Alzheimer’s disease. Apolipoprotein E (APOE) status was assessed in five individuals: the case with the youngest age at onset at 33 years of age was found to be homozygous ε4/ε4, > 1 SD below the mean age of onset for those of known APOE genotype (36.4 ⍨ 2.3 years, mean ⍨ SD), and > 2 SDs below the mean age of onset for the pedigree as a whole (37.4 ⍨ 1.7 years, mean ⍨ SD). APOE genotype may therefore modulate age at onset in this pedigree.

Keywords: Alzheimer’s disease; familial Alzheimer’s disease; presenilin-1; apolipoprotein E Abbreviations: Aβ ⫽ amyloid β peptide; APOE ⫽ apolipoprotein E gene; APP ⫽ amyloid precursor protein; CI ⫽ confidence interval; MMSE ⫽ Mini-Mental State Examination; PSEN1 ⫽ presenilin-1; WAIS(-R) ⫽ Wechsler Adult Intelligence Scale(—Revised)

Introduction Alzheimer’s disease is the most common cause of dementia and is primarily a disease of old age. However, it can present as early as the fourth decade when it is usually associated with an autosomal dominant family history. Three genetic loci have been identified in autosomal dominant familial Alzheimer’s disease: the amyloid precursor protein (APP) gene on chromosome 21, the presenilin-1 (PSEN1) gene on chromosome 14 and the presenilin-2 gene on chromosome 1 (Hardy, 1997). The majority of early-onset familial Alzheimer’s disease © Oxford University Press 2000

cases (55%) are associated with PSEN1 mutations (Cruts et al., 1996). More than 40 missense point mutations have now been identified, and about half of these occur in exons 5 and 8. PSEN1 intron 4, the first intronic PSEN1 mutation, was first reported in two individuals from a series of 40 cases of autopsy-confirmed early-onset Alzheimer disease that were all unselected for family history (Tysoe et al., 1998). It has since been demonstrated in four additional early-onset familial Alzheimer’s disease pedigrees including F105/160 (De

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Fig. 1 Family tree for family 105. Solid symbols are affected members, open symbols are unaffected members, squares are males and circles are females. For reasons of anonymity, the current generation is represented by diamonds, and their ‘at risk’ offspring are not shown.

Jonghe et al., 1999). We report the detailed clinical and neuropathological features of 21 affected individuals from family 105/160.

Method Family 105/160 is a kindred of British origin. The family tree is shown in Fig. 1. Whenever possible, the history was verified by an independent interview with the primary carer. Age at onset was defined as the age at which an individual first demonstrated signs of memory loss or personality change and was estimated from the reports of family members and hospital records. Following ethics committee approval and individual informed consent, blood specimens were collected and stored at –70°C until the time of DNA extraction.

Neuropsychology Three cases (V.16, V.17 and VI.08) underwent neuropsychological assessment. Case IV.15 had only been assessed on the Wechsler Adult Intelligence Scale (WAIS, Wechsler, 1955).

PSEN1 intron 4 genotyping DNA from four affected members (cases V.10, V.16, V.17 and VI.08) and one unaffected member of F105/160 was screened by restriction digest and sequencing of all coding exons. In addition, two unaffected members and three nonconsanguineous spouses were screened by restriction digest alone. Normal controls (n ⫽ 111) were screened by restriction digest, and one of these was also screened by sequencing all coding exons.

Apolipoprotein E (APOE) genotype determination DNA from the same four affected cases was processed according to previously published protocols and APOE genotype was determined (Mullan et al., 1993). In one further deceased individual (case IV.15), it was possible to infer the APOE genotype from the APOE status of first-degree relatives.

Neuropathology Neuropathological examinations were carried out in two affected members of the family (cases V.10 and VI.08), and details of a further two necropsies performed previously (cases IV.11 and IV.15) were also obtained. Blocks of tissue from the brains of cases V.10 and VI.08 were taken from the frontal, temporal (with the hippocampus and the amygdala), parietal and occipital lobes, the basal ganglia (to include the caudate nucleus, the lentiform nucleus, the claustrum and the nucleus basalis of Meynert), the thalamus with the subthalamic nucleus, midbrain, pons, medulla oblongata and from the cerebellar hemisphere and vermis. The sections were stained with haematoxylin and eosin, impregnated with silver according to the modified Bielschowsky method, and luxol fast blue and cresyl violet (on selected sections). Antibodies were used to immunostain β-amyloid (Aβ), glial fibrillary acidic protein, tau protein (all from DAKO, Ely, Cambridgeshire, UK) and α-synuclein (kindly provided by Professor B. H. Anderton, Institute of Psychiatry, London).

Results Family overview Table 1 summarizes the clinical features of family members. The mean age at onset was 37.4 years [95% confidence

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Table 1 Summary of the clinical features of family 105 Subject Age (years) Age (years) Duration of Autopsy ApoE NINCDSat onset at death illness (years) genotype ADRDA

First symptom

Other symptoms

Neurological Seizures features

II.1 II.3 III.1 III.2 III.7 III.8 IV.04 IV.08 IV.09 IV.10 IV.11 IV.15 V.07 V.08 V.09 V.10

– – 37 37 39 38 38 37 37 38 36 38 – 40 36 39

46 – 40 42 47 44 47 45 45 48 41 45 41 44 43 54

– – 3 5 8 6 9 8 8 10 5 7 – 4 7 15

No No No No No No No No Yes No Yes Yes – No – Yes

– – – – – – – – – – – 34 – – – 33

– – – – – – – – Probable Probable Definite Definite – Probable – Definite

– – – – – – – – Memory loss Memory loss Depression Memory loss – Memory loss – Memory loss

– – – – – – – – Myoclonus 0 0 Myoclonus – Myoclonus – Myoclonus

– – – – – – – – Yes Yes No Yes – No – Yes

V.12

40

45

5

No



Probable

Memory loss

Myoclonus

Yes

V.16

33

N/A

12

N/A

44

Probable

Memory loss

Myoclonus

Yes

V.17

36

N/A

5

N/A

33

Probable

0

No

VI.08

36

43

7

Yes

33

Definite

Repetitive conversation Mental slowness

– – – – – – – – Wandering – – – – – – Personality change Personality change Personality change Memory loss

Memory loss Myoclonus

Yes

N/A ⫽ not applicable; 0 ⫽ absent; – ⫽ unknown; NINCDS-ADRDA ⫽ National Institute of Neurological and Communicative Disorders and Stroke–Alzheimer’s Disease and Related Disorders Association criteria for the clinical diagnosis of Alzheimer’s disease (McKhann et al., 1984).

interval (CI): 36.7–38.2 years]. The mean age at death was 44.7 years (95% CI: 43.1–46.3 years). Disease duration was 7.3 years (95% CI: 5.9–8.7 years). Individuals I.1, II.1 and II.3 are known to have died at home following a dementing illness; no medical records survive. Cases III.1–IV.08, V.07 and V.09 are all known to have died in the same local psychiatric hospital and to have had dementia. Their clinical records were destroyed in a hospital fire. The five cases (IV.15, V.10, V.16, V.17 and VI.08) for whom we have neuropsychology and/or who underwent neuropathological examination are described in detail below; the remaining cases are summarized in Appendix I. Ages at death were obtained from death certificates.

Case reports IV.15 The age at onset of this individual was 38 years and age at death 45 years. She presented to her local neurological hospital with at least a 9 month history of progressive memory impairment. She had difficulty remembering names of familiar people, and mild word finding difficulties were noted. She had considerable insight into her forgetfulness, and found it distressing. For 1 month prior to admission she had been having ‘sudden jerks’ of the limbs.

Lumbar air encephalogram showed evidence of cortical atrophy, with dilatation of the third ventricle and rounding of the lateral ventricles. Routine blood and CSF examination were normal. An EEG was abnormal, with mild alpha activity in the posterior–central regions and theta activity in all regions. Non-focal multiple spike and wave complexes were also seen. As she deteriorated, she developed frequent generalized seizures and was admitted to a psychiatric hospital for full nursing care. She was treated with chlorpromazine, phenobarbitone and phenytoin. Two years later, she died of pneumonia. Pathological examination (1969) revealed a brain weight of 964 g with generalized cerebral atrophy, but relative sparing of the cerebellum and brainstem. Histology showed the characteristic features of Alzheimer’s disease. Recently performed ubiquitin immunostaining demonstrated many neurofibrillary tangles and neuritic plaques.

V.10 The age at onset of this individual was 39 years and age at death 54 years. This university graduate presented when he was made redundant from his teaching job for being unable to maintain discipline and forgetting staff meetings. At presentation, there was a 3-year history of memory loss; he

Alzheimer’s disease due to PSEN1 intron 4 mutation was fully aware of his family history and had preserved insight at the outset. General and neurological examinations were unremarkable; baseline dementia screening blood tests were normal or negative. A CT scan showed minimal cerebral atrophy. EEG was abnormal, with a low amplitude record with a symmetrical, regular and responsive alpha rhythm at 9–11 Hz. In addition, there was a large amount of theta activity, which was maximal anteriorly. He deteriorated gradually, and his wife noted a personality change, with him becoming distrustful, and occasionally violent. There were times when he would not recognize her and thought that she was stealing their car. He became increasingly childlike, and began to wander. He neglected personal hygiene and developed purposeless choreiform movements, particularly affecting the hands and arms, 7 and 8 years, respectively into the disease. He became an inpatient 3 years later, requiring full nursing care. Over the next 18 months, he continued to deteriorate, he became mute and had his first generalized seizure, following which he was started on carbamazepine. Five years later, he died of bronchopneumonia; neuropathological examination confirmed the diagnosis of Alzheimer’s disease with amyloid angiopathy (see Neuropathology section).

V.16 The age at onset of this individual was 33 years. This righthanded woman presented with a 2-year history of impairment in episodic memory and a change in personality; she had become more introverted. She experienced word finding difficulty but otherwise continued to look after her family without significant problems. She initially had been treated for post-natal depression, but had failed to improve on tricyclic antidepressant medication. There was no other past medical history; she did not smoke. Clinical examination revealed cognitive impairment which was confirmed on formal testing (see Neuropsychology section and Table 2), she scored 21/30 on the Mini-Mental State Examination (MMSE) (Folstein et al., 1975). General physical examination was normal. Neurological examination revealed finger myoclonus; a pout and glabellar tap reflex were elicited. Baseline blood and CSF examination were normal or negative. A CT scan showed slight sulcal widening. An EEG revealed sporadic, symmetrical 8–9 Hz alpha rhythm over posterior regions and widespread 5–6 Hz irregular theta activity. An MRI, 1 year later, showed diffuse cortical atrophy with bilaterally small hippocampi. Examination now revealed Gegenhalten and mild dyspraxia. MMSE was 18/30. Two years later, her myoclonus had become more marked and her MMSE had declined to 13/30. She made body part substitution errors during an assessment of praxis and had difficulty copying gestures with the left hand but not the right. She had suffered a single generalized seizure and was started on sodium valproate. Four years after presentation, there was evidence of further

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cognitive decline, with increasing difficulties with speech and comprehension. She was still largely self-caring. Because of increasing difficulty with menstrual toilet, she was started on depo-provera. The following year, she had become increasingly dependent and required full time nursing care.

V.17 The age at onset of this individual was 38 years. This righthanded woman was referred to the clinic with a 2-year history of memory impairment. Her family commented that initially her conversation had become repetitive and she had increasing difficulties with remembering errands and telephone messages. Subsequently, her culinary skills and the standard of her housekeeping had declined and she had started using lists to help organize her day’s chores. Her MMSE was 27/ 30 (see Neuropsychology section and Table 3 for cognitive profile). There was no past medical history of note. She was a non-smoker. Physical and neurological examinations were normal. Volumetric MRI brain scan was reported as normal (Fig. 2A). A diagnosis of Alzheimer’s disease was made. Repeat MRI brain scan 13 months later (Fig. 2B) remained normal. When she was re-assessed at 24 months, her MMSE had declined to 25/30 and she had become more dependent in household activities. Volumetric MRI brain scan was repeated at 22 months (Fig. 2C) and was again regarded as being within normal limits; however, comparison with earlier scans showed that ventricular enlargement had occurred. The difference images in Fig. 2E and F were obtained using a previously published registration protocol (Freeborough et al., 1996). Over the initial interval of 13 months (between Fig. 2A and B, interval 1), quantification revealed brain atrophy of 13.2 ml, which equates to 1.3% brain tissue loss (Fox and Freeborough, 1997). Over the longer interval of 22 months (between Fig. 2A and C, interval 2), brain atrophy was 38.9 ml, which equates to 3.9% brain tissue loss since baseline. Annualized rates of brain tissue loss were 1.3 and 1.7%, respectively for intervals 1 and 2 (normal range 0.2 ⫾ 0.4%).

VI.08 The age at onset of this individual was 36 years and age at death 43 years. This left-handed man, who had left school at the age of 16 years without formal qualifications, presented at the age of 38 years with at least an 18-month history of a progressive loss of mental agility. He had lost his job as a driver 2.5 years previously, which was probably as a result of difficulties at work. There had been deterioration in episodic memory and in particular with remembering the content of messages. More recently, he had great difficulty with several practical skills such as simple motor car maintenance. His family denied problems with route finding, faces or names. He was said to be independent in his activities of daily living. He had lost interest in reading, and spontaneous conversation was noted to be minimal.

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Table 2 Neuropsychology data IV.15

V.16

V.17

VI.08

Assessments: Time (months):

1st 0

2nd 10

3rd 21

1st 0

2nd 12

3rd 23

4th 48

1st 0

2nd 24

1st 0

WAIS-R VIQ WAIS-R PIQ Scaled scores Digit span Vocabulary Arithmetic Similarities Picture completion Picture arrangement Block design Digit symbol Object assembly RMT words RMT faces G NT NART GDST GDAT

70 ⬍56

66 ⬍56

⬍54 ⬍56

92 76

84 73

82 65

81 57

110 116

103 86

64 59

1 10 5 8 6 NT 0 0 2 NT NT NT NT NT NT

4 8 5 5 3 NT 0 0 2 NT NT NT NT NT NT

0 7 2 3 2 NT 0 0 0 NT NT NT NT NT NT

10 9 8 9 6 6 6 NT NT ⬍5th 25th 75–90th ⬎75th NT NT

7 8 8 7 8 5 4 NT NT ⬍5th 25th NT ⬎75th ⬎75th 5th

8 8 5 7 5 5 3 NT NT ⬍5th 10th 90th ⬎75th ⬎75th ⬍1st

4 8 4 10 4 2 2 NT NT NT ⬍5th** 75–90th ⬎75th 50th ⬍1st

14 11 10 12 15 12 9 NT NT ⬍5th 10th 95th ⬎75th ⬎75th ⬎75th

12 10 9 12 9 9 7 NT NT ⬍5th 25th 95th NT ⬎75th 75th

2 7 4 4 5 3 0 NT NT ⬍5th* ⬍5th* ⬍1st 10–25th ⬍1st ⬍1st

NT NT NT

NT NT NT

NT NT NT

NT Pass Pass

25th NT Pass

10–25th NT Fail

5–10th NT NT

⬎75th NT Pass

⬎75th NT Pass

NT Fail NT

VOSP scores Silhouettes (%) Fragmented letters† Cube analysis†

NT ⫽ not tested; WAIS-R ⫽ Wechsler Adult Intelligence Scale—Revised (Wechsler, 1981); VIQ ⫽ verbal IQ; PIQ ⫽ performance IQ; RMT⫽ Recognition Memory Test (Warrington 1986); GNT ⫽ Graded Naming Test (McKenna and Warington, 1986); NART ⫽ National Adult Reading Test (Nelson, 1991); GDST ⫽ Graded Difficulty Spelling Test (Baxter and Warrington, 1994); GDAT ⫽ Graded Difficulty Arithmetic Test (Jackson and Warrington, 1986); VOSP ⫽ Visual Perceptual and Space Perception Battery (Warrington and James, 1991). */**Shortened/shortened and easy version of the RMT, respectively; †5% cutoff used to determine pass/fail.

On examination, his MMSE was 9/30; he was disorientated in time and place (see Neuropsychology section and Table 2 for details). General physical and neurological examination was normal. Baseline blood investigations were normal or negative. MRI brain scan showed diffuse cerebral atrophy. EEG was abnormal with marked generalized slow alpha (2–3 Hz) and theta (4–6 Hz) activity. There was modest attenuation of the slower components with eye opening. Over the next year, he deteriorated further, with evidence of visual disorientation and finger myoclonus; he also developed generalized seizures, which were controlled with carbamazepine. He became increasingly aggressive. He was found wandering by the police, and admitted to his local psychiatric hospital where he remained an in-patient until his death 18 months later. He underwent neuropathological examination (see Neuropathology section).

Molecular genetics PSEN1 mutation scan results The PSEN1 intron 4 mutation (Tysoe et al., 1998) was found to co-segregate with the disease. It was absent from family members tested who had remained asymptomatic and were older than the anticipated age at onset. Linkage studies gave

a LOD (log of the odds) score of 3.72 and the mutation is thought to be fully penetrant.

APOE results The APOE data are listed in Table 1. In the absence of DNA, case IV.15 was postulated to be heterozygous ε3/ε4 as her two children were, respectively, homozygous ε3/ε3 and ε4/ε4.

Neuropsychology The neuropsychological assessments of four cases (IV.15, V.16, V.17 and VI.08) are summarized in Table 2.

General intellectual function To obtain a measure of current intellectual functioning, a shortened version of the WAIS—Revised (WAIS-R; Wechsler, 1981) was administered to all patients, except case IV.15, who had been assessed on a shortened version of the WAIS. The WAIS IQ scores were converted into WAIS-R scores for comparison. The patients’ premorbid optimum levels were estimated with the National Adult Reading Test (Nelson and Willison, 1991). The discrepancy between the National Adult

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Fig. 2 Subject V.17’s MRI brain scans. Registered coronal T1-weighted brain MRIs taken respectively at (A) presentation, (B) 13 months and (C) 22 months later. (D) Sagittal T1-weighted brain MRI demonstrating the level at which coronal slices shown in A–C have been taken. (E) A difference image obtained by comparing the registered images A and B; black shading corresponds to tissue loss. (F) A difference image obtained comparing the registered images A and C, and showing further tissue loss.

Reading Test and the WAIS-R IQ scores provides a measure of the severity of intellectual deterioration. At the time of their first assessment, both IV.15 and V.16 presented with intellectual deterioration, affecting non-verbal IQ to a greater extent than verbal IQ. On subsequent assessments, both patients showed increasing deterioration, affecting non-verbal functions to a greater extent. However, patient IV.15 presented a severe generalized decline on her third assessment. Patient V.17 showed mild intellectual decline on both measures, verbal scores being lower than performance scores. Patient VI.08 presented with global intellectual decline. Inspection of the cohort’s age-scaled scores reveals that, in the verbal domain, the arithmetic and digit span subtests showed the greatest impairment in all cases, except V.17. In summary, all patients had verbal IQs that were higher than performance IQs. In the verbal domain, the arithmetic and digit span subtests were more affected than the vocabulary and similarities subtests.

Memory skills At the time of her first assessment, patient IV.15 already had a severe and global memory impairment, which prevented formal assessment. Verbal and visual memory functions were

assessed with the Recognition Memory Test (Warrington, 1984) and the Easy Recognition Memory Test (Clegg and Warrington, 1994) in patients V.16 and V.17, and with the shortened version of the Recognition Memory Test (Warrington, 1996) in patient VI.08. At first assessment, both patients V.16 and V.17 presented with selective verbal memory impairment. Subsequently, patient V.16’s memory functions became globally and severely impaired. In contrast, case V.17 continued to present a selective verbal memory impairment. Case VI.08 presented with a severe and global memory impairment.

Naming skills Naming skills were assessed with the Graded Naming Test (McKenna and Warrington, 1983). Throughout assessments, they remained well preserved in patients V.16 and V.17. Patient VI.08 obtained a poor score on the Graded Naming Test; however, on the Oldfield Picture Naming Test (Oldfield and Wingfield, 1965), he obtained a creditable score (22/30) in the context of his modest premorbid verbal functioning. Thus, naming skills were well preserved in all patients across the assessments.

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Literacy skills Reading skills were assessed on the National Adult Reading Test, spelling skills were assessed with the Graded Difficulty Spelling Test (Baxter and Warrington, 1994) and calculation skills were assessed with the Graded Difficulty Arithmetic Test (Jackson and Warrington, 1986). All patients demonstrated intact reading skills, which remained remarkably stable across assessments. In patients V.16 and V.17, spelling skills were preserved and did not deteriorate across assessments. Patient VI.08 obtained a poor score in the Graded Difficulty Spelling Test which, in the context of his modest reading skills and relatively poor education, cannot be taken to indicate unambiguously a spelling impairment. Calculation skills were found to be severely impaired in all patients, with the exception of V.17. In summary, reading and spelling skills were remarkably well preserved in two patients (V.16 and V.17), and did not deteriorate as the disease progressed. In contrast, calculation skills were impaired in two patients (VI.08 and V.16).

Perceptual and spatial skills Three subtests of the Visual Object and Space Perception Battery (Warrington and James, 1991) were administered to obtain a measure of perceptual (fragmented letters and silhouettes) and spatial skills (cube analysis). At first assessment, patients V.16 and V.17 presented with preserved perceptual and spatial skills. Perceptual skills were found to be gravely impaired in patient VI.08.

Frontal executive functions Frontal ‘executive’ functions were assessed using the Weigl Test (Weigl, 1941), the Wisconsin Card Sorting Test (Nelson, 1976) and Verbal Fluency tests (Spreen and Strauss, 1998). Patients V.16 and VI.08 failed these tests. Patient V.17 completed the Wisconsin Card Sorting Test competently at her first assessment, but had become mildly impaired at her second assessment.

Neuropathology The brain weight of case V.10 was 963 g, and the weight of the brainstem and the cerebellum 174 g. The leptomeninges were thickened and the large cerebral arteries showed a few atherosclerotic plaques with up to 50% narrowing of lumina. In case VI.08, the brain weighed 1051 g and the cerebellum with the brainstem 162 g. The leptomeninges were normal, but there were occasional small atherosclerotic plaques in the large cerebral vessels. The remaining neuropathology was identical for both cases which are described together. The cranial nerves were normal. There was severe diffuse tissue loss affecting all lobes, but it was more pronounced in the frontotemporal region: the gyri here were considerably narrowed and the intervening sulci widened. The lateral

ventricles were greatly enlarged, with rounding of the angle. Both the substantia nigra and the locus coeruleus were paler than usual. The histological sections showed many neurofibrillary tangles, neuropil threads and neuritic plaques throughout the neocortex (Fig. 3). In places, there was superficial status spongiosus accompanied by astrocytosis, indicating neuronal loss. The hippocampus showed neuronal loss from the CA1 area, many neurofibrillary tangles, senile plaques, granulovacuoles and Hirano bodies (Fig. 4). The nucleus basalis of Meynert was depopulated and many of the surviving neurons contained neurofibrillary tangles (Fig. 5). A few neurofibrillary tangles were also seen in the caudate nucleus, in the lentiform nucleus, in the claustrum and in the subthalamic nucleus, and several more were noted in the thalamus. The substantia nigra and the locus coeruleus showed neuronal loss, extraneuronal pigment and neurofibrillary tangles. These were also seen in the raphe nuclei and in the periaqueductal grey matter. There was slight focal Purkinje cell loss in the cerebellum with accompanying mild to moderate astrocytosis of Bergmann glia. The walls of the small and medium sized cerebral and leptomeningeal blood vessels were thickened, and often appeared homogeneously eosinophilic with occasional double barrelling, particularly in case V.10. The enlarged perivascular space contained mononuclear cells including lymphocytes and pigmentbearing macrophages. Immunohistochemistry for βA4 amyloid showed extensive deposition in the grey matter (Fig. 6) as well as in the leptomeningeal and parenchymatous blood vessels. In the cerebellum, the Aβ deposition was more severe in the blood vessels than in the parenchyma. Tau immunostaining confirmed all the cytoskeletal abnormalities, while reaction for α-synuclein was negative in VI.08, but revealed several Lewy bodies in the substantia nigra, the locus coeruleus, the frontal and insular cortices, and in the parahippocampal gyrus of case V.10. Glial fibrillary acidic protein highlighted astrocytosis in the cortex, subcortical white matter and, to a lesser extent, in the deep grey structures. In conclusion, both cases showed severe Alzheimer’s disease fulfilling the CERAD (Consortium to Establish a Registry for Alzheimer’s Disease) as well as the more recent National Institute of Aging and Reagan Institute criteria for the diagnosis of definite Alzheimer’s disease (Hyman and Trojanowski, 1997), with extensive deposition of Aβ both in the grey matter and in the cerebral blood vessels.

Discussion Clinical features The available clinical information suggests features broadly typical of Alzheimer’s disease. Myoclonus was a particularly marked feature in the individuals on whom we have more detailed medical information. As with other chromosome 14linked or PSEN1 mutation familial Alzheimer’s disease pedigrees (Frommelt et al., 1991; Haltia et al., 1994; Lampe

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Fig. 3 Neuritic plaques, neurofibrillary tangles and neuropil threads against a background of status spongiosus in the superficial parietal cortex. Tau immunohistochemistry (magnification ⫻251).

Fig. 4 Neurofibrillary tangles and neuritic plaques in the hippocampus. Modified Bielschowsky silver impregnation (magnification ⫻251).

et al., 1994; Kennedy et al., 1995), the majority of the cases experienced seizures. As in two families with PSEN1 M139V mutations, myoclonus and seizures were a feature common to all affected individuals, with the myoclonus starting, on average, 3 years before the seizures (Fox et al., 1997). This appears to be a feature of younger onset familial Alzheimer’s disease (Mayeux et al., 1985).

An early age at onset appears to be the key phenotypic difference between this pedigree and other PSEN1 pedigrees. In a review of 38 published pedigrees with 22 different PSEN1 mutations, seven pedigrees had a mean age at onset in the fourth decade of life, 21 had a mean age at onset in the fifth decade and, for 10 families, the mean age at onset was in the sixth decade of life (Cruts et al., 1996).

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Fig. 5 Neurofibrillary tangles in the nucleus basalis of Meynert. Tau immunohistochemistry (magnification ⫻465).

Fig. 6 Extensive deposition of Aβ in the cerebral cortex (magnification ⫻251).

It appears that the age at onset is determined by both the site and nature of the mutation; the small numbers of families with the same mutation have very similar ages at onset. However, there are some families where there are variations in the age at onset. It has been reported that APOE status does not influence age at onset in PSEN1 familial Alzheimer’s disease (Van Broeckhoven et al., 1994), in contrast to APP

mutation cases (Mullan et al., 1993; Hardy, 1995), and further genetic factor(s) have been proposed (Fox et al., 1997). In this pedigree, APOE genotype could only be elucidated for five cases. Patient V.16 (APOE ε4/ε4) had an age at onset of 33 years which was ⬎1 SD below the mean age of onset for those of known APOE genotype (36.4 ⫾ 2.3 years, mean ⫾ SD), and ⬎ 2 SDs below the mean age of onset for

Alzheimer’s disease due to PSEN1 intron 4 mutation the pedigree as a whole (37.4 ⫾ 1.7 years, mean ⫾ SD). APOE ε4 may accelerate the disease process in the absence of normal functioning wild-type PSEN1 alleles. The disease duration varied from 3 to 15 years, mean 7.3 years (95% CI: 5.9–8.7 years), which is consistent with our previously published PSEN1 families (Kennedy et al., 1995; Fox et al., 1997) and with predicted survival in sporadic Alzheimer’s disease cases (Bracco et al., 1994). Survival appears to be increasing in the later generations. Earlier diagnosis and better care undoubtedly contribute to this, but it is unclear in what proportion.

Neuropsychology Patient IV.15 only underwent a limited assessment and presented with a severe global intellectual and memory impairment. Cases V.16, V.17 and VI.08 also showed intellectual and memory deficits at the first assessment, which became more pronounced with disease progression. Intellectual and memory failures often have been reported as a common feature of both familial and sporadic Alzheimer’s disease (Nee et al., 1983; McKhann et al., 1984; Sadovnick et al., 1988; Karlinsky et al., 1991; Lehtovirta et al., 1996; Fox et al., 1997, 1998). In the two less affected cases (V.16 and V.17), verbal memory impairment preceded visual memory impairment. This finding is in accord with the notion that verbal memory is more vulnerable than non-verbal memory in familial Alzheimer’s disease (Newman et al., 1994; Kennedy et al., 1995; Fox et al., 1997, 1998). Cases VI.08 and V.16 presented with cognitive deficits extending beyond intellectual functioning and memory. In both cases, perceptual and spatial skills were more affected than naming skills. In patient VI.16, perceptual and spatial skills deteriorated across assessments whilst naming skills remained static at a superior level. This pattern has been reported previously in a single familial Alzheimer’s disease case, from a chromosome 14-linked pedigree (Newman et al., 1994). Visuospatial and naming impairments have been reported in the context of mild sporadic Alzheimer’s disease (Morris et al., 1991; Hodges and Patterson, 1995; Jacobs et al., 1995; Kaskie and Storandt, 1995). Our findings of relatively wellpreserved naming skills support the notion that this could be a common feature in familial Alzheimer’s disease (Duara et al., 1993; Newman et al., 1994; Kennedy et al., 1995; Fox et al., 1997). In cases V.16 and VI.08, calculation skills were more impaired than reading skills, a finding in accord with previous reports (Nee et al., 1983; Karlinsky et al., 1991; Kennedy et al., 1993, 1995; Fox et al., 1997). In patient V.16, spelling skills remained entirely preserved, whereas a spelling impairment was documented by Newman and colleagues (Newman et al., 1994). It may be that these subtle differences between familial Alzheimer’s disease pedigrees reflect disease severity or genotypic differences.

Neuroimaging Case IV.15 had brain atrophy demonstrated indirectly by means of a lumbar air encephalogram. Cases V.10 and V.16

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had CT scans, which demonstrated brains that were smaller than expected for their age. These cases were already relatively far advanced in the disease process. Case V.17 was imaged early in the disease process when her MMSE was still 27. Her MRI brain scan was reported as normal, as were subsequent MRI brain scans 13 and 22 months later. Quantification of the registered images revealed 1.3 and 3.9% brain tissue loss over these two intervals, providing clear evidence of early cerebral atrophy. Comparable data on young age at onset sporadic Alzheimer’s disease do not exist. There is, however, a significant association between rate of cognitive decline and the rate of tissue loss demonstrated by positional matching and registration (Fox et al., 1999).

Neuropathology Neuropathological findings in the two affected individuals studied in detail (V.10 and V1.08) showed features of severe Alzheimer’s disease, including extensive formation of neuritic plaques, neurofibrillary tangles and neuropil threads. The deposition of Aβ was particularly prominent in the cortical ribbon, and amyloid angiopathy was particularly severe in both cases, with the amyloid spreading from the vascular walls into the surrounding cerebral parenchyma to correspond to the classical picture of dyshoric angiopathy. Although the general histological features of sporadic and familial cases of Alzheimer’s disease are the same, recent investigations have revealed differences in the severity of Aβ deposition, depending on the causative gene mutation. In cases due to APP717 mutations, the Aβ plaques are composed predominantly of Aβ1–42(3), with relatively little Aβ1–40 present. The total amount of Aβ1–42(3) is considerably greater than in sporadic Alzheimer’s disease (Mann et al., 1996b). Similarly, in brains with familial Alzheimer’s disease due to PSEN1 mutations, Aβ1–42(3) was the main component of plaques. Moreover, the total amount of Aβ1–42(3) and Aβ1–40 was more than twice the amount deposited in cases of sporadic Alzheimer’s disease of similar duration, although the ratio of the extent of deposition of the two amyloid species was the same as that in patients with sporadic Alzheimer’s disease (Mann et al., 1996a). In a recent study of 10 different PSEN1 and PSEN2 mutations, including one of our cases (V.10), enhanced deposition of total Aβ and Aβ1–42(3), but not Aβ1–40, in the superior temporal gyrus was noted when compared with sporadic cases (Gomez-Isla et al., 1999). Moreover, some of the PSEN1 mutations (M139V, I143F, G209V, R269H and E280A) were also associated with faster rates of neurofibrillary tangle formation and an accelerated neuronal loss when compared with sporadic cases. Case V.10 also had several Lewy bodies in the pigmented nuclei of the brainstem and in restricted areas of the cerebral cortex. This finding is not surprising since a significant proportion of familial Alzheimer’s disease is complicated by some Lewy body pathology. In a recent study, α-synuclein

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immunohistochemistry revealed Lewy bodies in 22% of familial Alzheimer’s disease cases (Lippa et al., 1998).

pathogenic effect of the intron 4 mutation appears to be mediated by increased Aβ42(3) formation which is emerging as a general mechanism in presenilin and APP717 mutation familial Alzheimer’s disease.

Molecular genetics The PSEN1 gene comprises 13 exons, of which exons 3–12 code for a 467 amino acid protein (Alzheimer’s Disease Collaborative Group, 1995; Cruts et al., 1995). The PSEN1 protein has six to eight transmembrane domains and most mutations occur in the regions encoding these domains, especially in transmembrane domain 2. The major cluster of mutations is in exon 8, close to the PSEN1 cleavage site. Remarkably, the mutations in transmembrane domain 2 occur every third or fourth amino acid, suggesting that they line up on the same side of an α-helix, disrupting the structure and hence interfering with the function of PSEN1 (Hardy, 1997). The presenilins are homologous membrane proteins that are found in the endoplasmic reticulum and the Golgi apparatus in mammals. A member of the roundworm Caenorhabditis elegans presenilin family, sel-12, facilitates Notch signalling in development (Levitan and Greenwald, 1995). Wild-type human PSEN1 can rescue the lethal phenotype caused by sel-12 mutations in C. elegans, whereas most familial Alzheimer’s disease mutant PSEN1 molecules result in only partial functional recovery (Levitan et al., 1996; Baumeister et al., 1997). Despite this PSEN1 and sel12 homology, the details of PSEN1 function are not fully understood. However, evidence has emerged recently that suggests a direct involvement of PSEN1 in the γ-secretase cleavage of APP and may even be γ-secretase itself (for a review, see Selkoe, 1999). Previously described PSEN1 mutations have all been missense or in-frame splice mutants and so it has been suggested that these mutations result in disease by the acquisition of novel deleterious functions (Scheuner et al., 1996), either by gain-of-function or dominant-negative mechanisms. In contrast, this PSEN1 intron 4 mutation was thought to result in familial Alzheimer’s disease by haploinsufficiency of full-length PSEN1 (Tysoe et al., 1998). However, it has since been shown that the intron 4 mutation produces three different transcripts, two deletion transcripts (PSEN1 ∆4 and ∆4cryptic) and one insertion transcript (insTAC), by aberrant splicing (De Jonghe et al., 1999). De Jonghe and co-workers demonstrated that the latter transcript was due to the insertion of a TAC triplet between exons 4 and 5 of the PSEN1 gene and resulted in the insertion of a threonine after amino acid 113 (T113–114ins). In contrast to the insertion transcript, the truncated proteins were not detectable in vivo in brain homogenates or lymphoblast lysates of mutation carriers. Similarly, De Jonghe and co-workers demonstrated that in vitro Aβ42 secretion was increased in human embryonic kidney cells (HEK-293) overexpressing the insertion transcript, but not in those overexpressing the deletion transcripts. Increased Aβ42:Aβ40 ratios in brain homogenates were also demonstrated. Thus, in common with previous missense mutations, the

Conclusion We have described an autopsy-confirmed early onset familial Alzheimer’s disease pedigree due to an intronic PSEN1 mutation. The clinical features of this pedigree are remarkably similar to previously described PSEN1 mutation familial Alzheimer’s disease pedigrees and share their early age at onset, the presence of myoclonus and generalized seizures, and a relative preservation of naming skills until late in the disease. The neuropathology is similar to that of other PSEN1 cases and is more severe than sporadic Alzheimer’s disease. In view of the reduced age at onset in case V.16 and APOE ε4/ε4 homozygosity, APOE may modulate the age at onset in this PSEN1 intron 4 familial Alzheimer’s disease pedigree.

Acknowledgements We wish to thank the family members and their attendant physicians, Dr Nigel Cairns for his help and Mrs Heidi Barnes for her skilful technical assistance (both members of the MRC-supported London Neurodegenerative Diseases Brain Bank), Dr S. Al-Sarraj (Institute of Psychiatry and King’s Healthcare NHS Trust) and Dr J. S. Dinnen (County Hospital, Hereford, UK) for performing the post-mortem examination of cases VI.08 and V.10, respectively, Miss Penelope Roques for her help with collecting the blood specimens and family details, and all the staff in the MRI department at St Mary’s Hospital. This study was supported by MRC programme grant G9626876.

References Alzheimer’s Disease Collaborative Group. The structure of the presenilin I (S182) gene and identification of six novel mutations in early onset AD families. Nature Genet 1995; 11: 219–22. Baumeister R, Leimer U, Zweckbronner I, Jakubek C, Grunberg J, Haass C. Human presenilin-1, but not familial Alzheimer’s disease (FAD) mutants, facilitate Caenorhabditis elegans Notch signalling independently of proteolytic processing. Genes Funct 1997; 1: 149–59. Baxter DM, Warrington EK. Measuring dysgraphia: a gradeddifficulty spelling test. Behav Neurol 1994; 7: 107–16. Bielschowsky M. Die silberimpregnation der axonzylinder. Zentralb Neurol 1902; 21: 579. Bracco L, Gallato R, Grigoletto F, Lippi A, Lepore V, Bino G, et al. Factors affecting course and survival in Alzheimer’s disease. Arch Neurol 1994; 51: 1213–9. Clegg F, Warrington EK. Four easy memory tests for older adults. Memory 1994; 2: 167–82.

Alzheimer’s disease due to PSEN1 intron 4 mutation Cruts M, Backhovens H, Wang SY, Gassen GV, Theuns J, De Jonghe CD, et al. Molecular genetic analysis of familial early-onset Alzheimer’s disease linked to chromosome 14q24.3. Hum Mol Genet 1995; 4: 2363–71. Cruts M, Hendriks L, Van Broeckhoven C. The presenilin genes: a new gene family involved in Alzheimer disease pathology. [Review]. Hum Mol Genet 1996; 5 Spec No: 1449–55. De Jonghe C, Cruts M, Rogaeva EA, Tysoe C, Singleton A, Vanderstichele H, et al. Aberrant splicing in the presenilin-1 intron 4 mutation causes presenile Alzheimer’s disease by increased Aβ42 secretion. Hum Mol Genet 1999; 8: 1529–40. Duara R, Lopez-Alberola RF, Barker WW, Loewenstein DA, Zatinsky M, Eisdorfer CE, et al. A comparison of familial and sporadic Alzheimer’s disease. Neurology 1993; 43: 1377–84. Folstein MF, Folstein SE, McHughs PR. ‘Mini mental state’: a practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975; 12: 189–98. Fox NC, Freeborough PA. Brain atrophy progression measured from registered serial MRI: validation and application to Alzheimer’s disease. J Magn Reson Imaging 1997; 7: 1069–75. Fox NC, Kennedy AM, Harvey RJ, Lantos PL, Roques PK, Collinge J, et al. Clinicopathological features of familial Alzheimer’s disease associated with the M139V mutation in the presenilin 1 gene. Pedigree but not mutation specific age at onset provides evidence for a further genetic factor. Brain 1997; 120: 491–501. Fox NC, Warrington EK, Seiffer AL, Agnew SK, Rossor MN. Presymptomatic cognitive deficits in individuals at risk of familial Alzheimer’s disease. A longitudinal prospective study. Brain 1998; 121: 1631–9. Fox NC, Scahill RI, Crum WR, Rossor MN. Correlation between rates of brain atrophy and cognitive decline in AD. Neurology 1999; 52: 1687–9. Freeborough PA, Woods RP, Fox NC. Accurate registration of serial 3D MR brain images and its application to visualizing change in neurodegenerative disorders. J Comput Assist Tomogr 1996; 20: 1012–22. Frommelt P, Schnabel R, Kuhne W, Nee LE, Polinsky RJ. Familial Alzheimer’s disease: a large multigeneration German kindred. Alzheimer Dis Assoc Disord 1991; 5: 36–43. Gomez-Isla T, Growdon WB, McNamara MJ, Nochlin D, Bird TD, Arango JC, et al. The impact of different presenilin 1 and presenilin 2 mutations on amyloid deposition, neurofibrillary changes and neuronal loss in the familial Alzheimer’s disease brain: evidence for other phenotype-modifying factors. Brain 1999; 122: 1709–19. Haltia M, Viitanen M, Sulkava R, Ala-Hurula V, Poyhonen M, Goldfarb L, et al. Chromosome 14-encoded Alzheimer’s disease: genetic and clinicopathological description. Ann Neurol 1994; 36: 362–7. Hardy J. Apolipoprotein E in the genetics and epidemiology of Alzheimer’s disease. Am J Med Genet 1995; 60: 456–60. Hardy J. Amyloid, the presenilins and Alzheimer’s disease. [Review]. Trends Neurosci 1997; 20: 154–9. Hodges JR, Patterson K. Is semantic memory consistently impaired

905

early in the course of Alzheimer’s disease? Neuroanatomical and diagnostic implications. Neuropsychologia 1995; 33: 441–59. Hyman BT, Trojanowski JQ. Consensus recommendations for the postmortem diagnosis of Alzheimer disease from the National Institute on Aging and the Reagan Institute Working Group on diagnostic criteria for the neuropathological assessment of Alzheimer disease. J Neuropathol Exp Neurol 1997; 56: 1095–7. Jackson M, Warrington EK. Arithmetic skills in patients with unilateral cerebral lesions. Cortex 1986; 22: 611–20. Jacobs DM, Sano M, Dooneief G, Marder K, Bell KL, Stern Y. Neuropsychological detection and characterization of preclinical Alzheimer’s disease. Neurology 1995; 45: 957–62. Karlinsky H, Madrick E, Ridgley J, Berg JM, Becker R, Bergeron C, et al. A family with multiple instances of definite, probable and possible early-onset Alzheimer’s disease. Br J Psychiatry 1991; 159: 524–30. Kaskie B, Storandt M. Visuospatial deficit in dementia of the Alzheimer type. Arch Neurol 1995; 52: 422–5. Kennedy AM, Newman S, McCaddon A, Ball J, Roques P, Mullan M, et al. Familial Alzheimer’s disease. A pedigree with a mis-sense mutation in the amyloid precursor protein gene (amyloid precursor protein 717 valine→glycine). Brain 1993; 116: 309–24. Kennedy AM, Newman SK, Frackowiak RS, Cunningham VJ, Roques P, Stevens J, et al. Chromosome 14 linked familial Alzheimer’s disease: a clinico-pathological study of a single pedigree. Brain 1995; 118: 185–205. Lampe TH, Bird TD, Nochlin D, Nemens E, Risse SC, Sumi SM, et al. Phenotype of chromosome 14-linked familial Alzheimer’s disease in a large kindred. Ann Neurol 1994; 36: 368–78. Lehtovirta M, Soininen H, Helisalmi S, Mannermaa A, Helkala EL, Hartikainen P, et al. Clinical and neuropsychological characteristics in familial and sporadic Alzheimer’s disease: relation to apolipoprotein E polymorphism. Neurology 1996; 46: 413–9. Levitan D, Greenwald I. Facilitation of lin-12-mediated signalling by sel-12, a Caenorhabditis elegans S182 Alzheimer’s disease gene. Nature 1995; 377: 351–4. Levitan D, Doyle TG, Brousseau D, Lee MK, Thinakaran G, Slunt HH, et al. Assessment of normal and mutant human presenilin function in Caenorhabditis elegans. Proc Natl Acad Sci USA 1996; 93: 14940–4. Lippa CF, Fujiwara H, Mann DM, Giasson B, Baba M, Schmidt ML, et al. Lewy bodies contain altered alpha-synuclein in brains of many familial Alzheimer’s disease patients with mutations in presenilin and amyloid precursor protein genes. Am J Pathol 1998; 153: 1365–70. Mann DM, Iwatsubo T, Cairns NJ, Lantos PL, Nochlin D, Sumi SM, et al. Amyloid beta protein (Abeta) deposition in chromosome 14-linked Alzheimer’s disease: predominance of Abeta42(43). Ann Neurol 1996a; 40: 149–56. Mann DM, Iwatsubo T, Ihara Y, Cairns NJ, Lantos PL, Bogdanovic N, et al. Predominant deposition of amyloid-beta 42(43) in plaques in cases of Alzheimer’s disease and hereditary cerebral hemorrhage associated with mutations in the amyloid precursor protein gene. Am J Pathol 1996b; 148: 1257–66.

906

J. C. Janssen et al.

Mayeux R, Stern Y, Spanton S. Heterogeneity in dementia of the Alzheimer type: evidence of subgroups. Neurology 1985; 35: 453–60. McKenna P, Warrington EK. The Graded Naming Test. Windsor (UK): NFER-Nelson; 1983. McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM. Clinical diagnosis of Alzheimer’s disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer’s Disease. Neurology 1984; 34: 939–44. Morris JC, McKeel DW Jr, Storandt M, Rubin EH, Price JL, Grant EA, et al. Very mild Alzheimer’s disease: informant-based clinical, psychometric and pathological distinction from normal aging. Neurology 1991; 41: 469–78.

Scheuner D, Eckman C, Jensen M, Song X, Citron M, Suzuki N, et al. Secreted amyloid beta-protein similar to that in the senile plaques of Alzheimer’s disease is increased in vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer’s disease. Nature Med 1996; 2: 864–70. Selkoe DJ. Translating cell biology into therapeutic advances in Alzheimer’s disease. Nature 1999; 399 (Suppl): A23–31. Spreen O, Strauss E. A compendium of neuropsychological tests: administration, norms, and commentary. 2nd edn. New York, University Press; 1998. Tysoe C, Whittaker J, Xuereb J, Cairns NJ, Cruts M, Van Broeckhoven C, et al. A presenilin-1 truncating mutation is present in two cases with autopsy-confirmed early-onset Alzheimer disease. Am J Hum Genet 1998; 62: 70–6.

Mullan M, Houlden H, Crawford F, Kennedy A, Rogues P, Rossor M. Age of onset in familial early-onset Alzheimer’s disease correlates with genetic aetiology. Am J Med Genet 1993; 48: 129–30.

Van Broeckhoven C, Backhovens H, Cruts M, Martin JJ, Crook R, Houlden H, et al. APOE genotype does not modulate age of onset in families with chromosome 14 encoded Alzheimer’s disease. Neurosci Lett 1994; 169: 179–80.

Nee LE, Polinsky RJ, Eldridge R, Weingarter H, Smallberg S, Ebert M. A family with histologically confirmed Alzheimer’s disease. Arch Neurol 1983; 40: 203–8.

Warrington EK. Recognition Memory Test. Manual. Windsor (UK): NFER-Nelson; 1984.

Nelson HE. A modified card sorting test sensitive to frontal lobe defects. Cortex 1976; 12: 313–24. Nelson HE, Willison J. The National Adult Reading Test (NART); manual. Windsor (UK): NFER-Nelson; 1991. Newman SK, Warrington EK, Kennedy AM, Rossor MN. The earliest cognitive change in a person with familial Alzheimer’s disease: presymptomatic neuropsychological features in a pedigree with familial Alzheimer’s disease confirmed at necropsy. J Neurol, Neurosurg Psychiatry 1994; 57: 967–72. Oldfield RC, Wingfield A. Response latencies in naming objects. Q J Exp Psychol 1965; 17: 273–81.

Warrington EK. The Camden Memory Tests. Manual. Hove (UK): Psychology Press; 1996. Warrington EK, James M. The Visual Object and Space Perception Battery. Bury St. Edmunds (UK): Thames Valley Test Company; 1991. Wechsler D. Wechsler Adult Intelligence Scale: Manual. New York: Psychological Corporation; 1955. Wechsler D. Wechsler Adult Intelligence Scale: WAIS-R manual. New York: Psychological Corporation; 1981. Weigl E. On the psychology of so-called processes of abstraction. J Abnorm Social Psychol 1941; 36: 3–33.

Sadovnick AD, Tuokko H, Horton A, Baird PA, Beattie BL. Familial Alzheimer’s disease. Can J Neurol Sci 1988; 15: 142–6.

Received August 20, 1999. Revised November 15, 1999. Accepted November 22, 1999

Appendix I Case reports of the family members IV.09

had considerable insight into his condition at the outset. He died in his local psychiatric hospital (records destroyed). Death certificate: Ia status epilepticus, duration two and a half hours; Ib cerebral degeneration; and II pre-senile dementia.

Age at onset 37 years; age at death 45 years. The first symptom was memory loss, followed by personality change and wandering. Frequent jerky movements and occasional generalized seizures were observed, and Huntington’s disease was diagnosed. The baseline blood tests and CSF examination were normal. The cause of death was bronchopneumonia. Fresh brain weight was 1293 g; no further neuropathology data survive.

IV.10 Age at onset 38 years; age at death 48 years. Due to increasing forgetfulness, he was downgraded at work. He

IV.11 Age at onset 36 years; age at death 41 years. She presented with symptoms of depression. EEG was mildly abnormal, but non-specific, with an 8 Hz dominant rhythm and some theta activity. She died of bilateral bronchopneumonia. Macroscopically, the brain was atrophied, which was most marked anteriorly, and ‘internal hydrocephalus’ was noted. Routine staining with haematoxylin and eosin revealed

Alzheimer’s disease due to PSEN1 intron 4 mutation changes consistent with Alzheimer’s disease. Plaques were most numerous in the frontal cortex sections. There was complete loss of the cytoarchitecture of the cortex, and significant neuronal degeneration, with remaining neurons showing chronic degenerative changes, including a few cells with granulovacuolar degeneration.

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‘peculiar type of motor restlessness’, which he tried to disguise by converting it into gesticulation. An EEG was abnormal and a clinical diagnosis of Huntington’s disease was made.

V.12 V.08 Age at onset 40 years; age at death 44 years. He presented with a 2-year history of cognitive decline. He had worked as a trained instrument mechanic, but had been downgraded because of memory and concentration problems. He was disorientated in time and it was noted that he showed a

Age at onset 40 years; age at death 45 years. The onset of symptoms coincided with a deterioration in diabetic control. She had a single generalized seizure associated with a severe hypoglycaemic episode. During the last 2 years of her life, myoclonus was reported in the fingers and arms particularly, but also in the legs and trunk.