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EU RO PE AN JOUR NAL OF MED I CAL RE SEARCH Eur J Med Res (2008) 13: 579-584 I. Holzapfel Publishers 2008 THREE-YEAR FOLLOW-UP OF A PATIENT WITH EARLY-ONSET ALZHEIMER'S DISEASE WITH PRESENILIN-2 N141I MUTATION G. Nikisch1, A. Hertel2, B. Kießling1, Th. Wagner1, D. Krasz1, E. Hofmann3, G. Wiedemann1 1Department of Psychiatry and Psychotherapy (Chief of Department: Prof. Dr. med. Georg Wiedemann ), 2Department of Nuclear Medicine, (Chief of Department: Assistant Prof. Dr. med. Andreas Hertel), 3Department of Neuroradiology, (Chief of Department: Prof. Dr. med. Erich Hofmann), Abstract
early onset (onset < 65 years) demonstrate a faster pro- Autosomal dominant early-onset Alzheimer disease gression and a more severe clinical presentation than (EOAD) is a heterogeneous condition that has been those with a late onset (onset > 65 years), despite being associated with mutations in 3 different genes: the younger. Autosomal dominant early-onset Alzheimer amyloid precursor protein (APP), presenilin 1 disease (EOAD) is a heterogeneous condition caused (PSEN1), and presenilin 2 (PSEN2) genes. Most cases by different genetic defects. Familial studies, in early- are due to mutations in the PSEN1 gene, whereas mu- onset cases, indicate molecular heterogeneity and have tations in the APP and PSEN2 genes are rare. Muta- linked EOAD to mutations in at least three genes: the tion analysis of the APP, PSEN1 and PSEN2 genes amyloid precursor protein gene (APP) located on chro- was performed. We herein report the case of a Ger- mosome 21 (Mullan and Crawford 1993) and the pre- man EOAD patient with a family history of dementia senilin 1 and 2 (PSEN-1 and PSEN-2, respectively) and a missense mutation at codon 141 (N141I) of the genes located on chromosome 14 and 1 (Levy-Lahad et PSEN2 gene. To our knowledge, this is the first Ger- al. 1995; Sherrington et al. 1995), respectively. Muta- man EOAD patient without a Volga-German ancestry tions in these genes account for approximately half of and a positive family history for dementia carries the the EOAD (Rosenberg 2000). Although more than 166 mutation PSEN-2 N141I. The patient came to our mutations in the PSEN1 gene have been associated clinic for the first time when she was 47 years old.
with autosomal dominant EOAD, only 13 such muta- During the following 3 years, her Mini-Mental State tions have been found in the PSEN2 gene (Finckh et Examination (MMSE) score dropped from 28 to 0.
al. 2005). Mutations in the PSEN2 gene on chromo- Mild cognitive impairment (MCI) was an early symp- some 1 are the second most frequent form of familial tom that was already present during the first consulta- EOAD (age at onset 45-65 years) and have mainly been tion. The concentration in cerebrospinal fluid (CSF) described in large kindreds of Volga-Germans in the of tau-protein (1151 pg/ml) was increased, whereas U.S. (Levy-Lahad et al. 1995; Mann et al. 1997).
the concentration of beta-amyloid protein (Aß1-42) It has been reported that 10-15% of patients with was decreased (335 pg/ml). Magnetic resonance imag- mild cognitive impairment (MCI) develop Alzheimer’s ing (MRI) revealed only slight changes in the early disease (AD) within 1 year (Peterson et al. 1999). Evi- stage of the disease and positron emission tomogra- dence shows that these pathological changes are de- phy with [18F] fluoro-2-deoxy-D-glucose (18F-FDG tectable before the onset of clinical dementia (Morris PET) demonstrated glucose reduction left parietal and and Price 2001). As clinically mildly demented AD pa- in the precuneus region. Follow-up MRI and 18F- tients show elevated tau-protein levels (Galasko 1998; FDG PET studies showed progression of atrophy of Riemenschneider et al. 1996) and decreased Aß1-42 the left entorhinal cortex with relative sparing of the levels (Andreasen et al. 1999; Galasko 1998; Motter et hippocampus and progressive hypometabolism of al. 1995) in cerebrospinal fluid (CSF) compared to both temporoparietal lobes and left frontal lobe. controls. CSF tau protein and Aß1-42 have been pro- posed as putative early diagnostic markers in MCI sub- Key words: MCI; early-onset Alzheimer disease; prese- jects. Patients who converted from MCI to AD showed significantly higher tau-protein levels at base- line compared to healthy individuals (Arai et al. 1997).
Moreover, it has been demonstrated that subjects with MCI who later developed AD were identified by the Alzheimer disease (AD) is characterized by memory combination of decreased CSF concentrations of loss and declining cognitive functions. Patients with an Aß1-42 and increased levels of tau-protein (Andreasen et al. 1999; Riemenschneider et al. 2002). These find- frontotemporal theta wave activity. The EEG at the ings suggest that tau-protein and Aß1-42 in CSF may age of 51 years showed delta-theta wave activity with be valuable to detect the preclinical stages of AD.
paroxysmal activation of frontal sharp and slow waves.
Up to now only two cases of EOAD due to muta- tions in the PSEN2 gene have been identified in Ger- many (Finckh et al. 2005). We describe the clinical course of a patient with the N141I mutation of The analysis of CSF revealed normal cell count and protein content. There were no oligoclonal bands.
NSE and protein 14-3-3 were within the normal range.
Tau-protein was elevated 1151 pg/ml (normal range: The patient was admitted to our psychiatric clinic for 47-225 pg/ml) and Aß1-42 decreased 335 pg/ml (nor- the first time at the age of 48 years. From the age of 47 years she had started to complain about deficits in her short-term memory. There was no previous histo- ry of severe or chronic illnesses. The patient had no evidence or history of neurological signs or symptoms Our patient received a standardized clinical MRI scan of cerebrovascular disease. Her orientation in person, protocol with T1- weighted and T2- weighted se- situation and time were adequate. She was unable to quences to visualized structural brain changes as vol- date biographical events of the few years and she was ume reductions (i.e., atrophy). A PET scan, which im- aware of her cognitive deficits. Physical examination ages regional brain metabolism with the use of 18F- and laboratory test was normal (including Vitamin FDG, was obtained. At the first presentation MRI B12, TSH, and TPHA). The patient had completed scanning showed slightly changes at the age of 48 and secondary school and education as an industrial clerk.
18F-FDG PET images already showed reduction of She married at the age of 18, and gave birth to one cortical glucose metabolism in the left parietal and precuneus cortex (Fig. 2A). Follow-up MRI and 18F- The family history revealed that the father (II-2) FDG PET studies showed progression of atrophy of and the grandmother (I-1) of the index patient suf- the left entorhinal cortex with relative sparing of the fered from AD (Fig. 1A). The grandmother died at age hippocampus and progressive hypometabolism of bi- 52 years after a clinical course of approximately 5 laterally temporoparietal lobes with additional frontal years on the sequelae of pneumonia with an onset at hypometabolism more apperent on the left lobe three 48 years. The index patient’s father showed first mild cognitive impairments at age of 64 years and died at age 76 years. The 77-year old mother (II-1) of the in- dex patient, and her three siblings aged 52, 50 and 46 (III-1, 3, 4, respectively) are asymptomatic at the time After gaining written informed consent, a blood sam- of clinical examination and genetic data were not col- ple for genetic analysis was obtained from the lected. The healthy son (IV-1) of the index patient re- proband. The DNA was isolated according to stan- ported here has a 50% chance of being a carrier of dard procedures. The coding regions of the PSEN1, the N141I mutation. Predictive testing was not per- PSEN2, and APP (exons 2, 16 and 17) were amplified using specific primers, as described previously (Cruts et al. 1998; Mullan et al.) A heterozygote missense mu- tation resulting in a substitution of asparagine at posi- tion 141 by isoleucine (N141I) in exon 5 of PSEN2 The Mini-Mental-State-Examination (MMSE), the Hamburg-Wechsler-Intelligence Test for Adults (HAWIE) and the Hamilton Depression Scale (HAM- The patient showed progressive mental decline. Neu- D) were used to determine the patient’s cognitive abili- ropsychological assessment, approximately 2 years af- ties. At the first presentation the patient reached a ter disease onset, shows marked intellectual loss. All score of 28 points on the MMSE. The HAWIE measures of auditory and visual memory for immedi- showed a total IQ of 93 with a relevant discrepancy ate and delayed recall were severely impaired (below between the verbal IQ of 101 and the performance IQ the first percentile). Acetylcholinesterase inhibitor and of 84. This is mainly due to the inability of the patient a NMDA receptor antagonist were prescribed to distinguish between important and less important (donepezil, followed by memantine) but were not ben- information of the serial picture stories used in these eficial; one year after presentation MMSE had IQ subtests. The HAM-D showed a mildly elevated dropped to 14 and to 0 two years later. The neuropsy- chological profile was consistent with AD. When the patient was 50 years old she was no longer able to take care of herself. She became dependent with activities such as shopping and housekeeping. At the age of 51 At the first presentation the electroencephalogram years, the patient was unable to repeat words or to fol- (EEG) at the age of 48 years showed a slow alpha low instructions. She spoke only single words which rhythm (6/s) with paroxysmal activation of irregular were remotely connected to the actual situation.
to cosegregate in an autosomal dominant way with EOAD in Volga-Germans in the U.S. (Levy-Lahad et This case is unique in many respects. Although the symptoms, signs, investigations, progress, and family history are consistent with familial EOAD, the neu- ropsychological follow-up changes of her affected rel- atives – who shared a similar presentation – showed the changes seen most often in MCI (Peterson et al.
1999). Cognitive deficits became obvious when she was 47 years old with an onset of dementia in her family at 48 years and 64 years. MCI was an early symptom that was already present during the first con- sultation. Our patient’s genetic analysis showed a het- Fig. 1. (A): Pedigree of the German FAD family carrying the erozygote missense mutation resulting in a substitu- N141I mutation in PSEN2. Black symbols indicate affected tion of asparagine at position 141 by isoleucine in probands. The index patient is marked by an arrow. (B): DNA sequence chromatogram of part of PSEN2 exon 5, Although we were not able to analyse the PSEN-2 showing the heterozygous A to T transversion in the index gene in the other two affected relatives, the detected patient (III-2). Corresponding reading frame and amino acid PSEN-2 mutation strongly suggests a genetic origin of EOAD in the other members of this family.
Linkage of PSEN-2 mutations with the autosomal transmission of familial EOAD has been shown for 13 different positions in the PSEN-2 gene (Table 1).
Estimations of the frequency of occurrence of muta- tions in the PSEN-2 gene in pedigrees with suspected familial EOAD vary between 3-5%. Whether there are significant differences in clinical symptomatology be- Table 1. Known mutations of the PSEN-2 gene on chromo- some 1 associated with early-onset Alzheimer’s disease (EOAD). http://www.molgen.ua.ac.be/ADMutations/ 1 Arg 62 His 4 / N -Term Cruts et al. 1998 2 Ala 85 Val 4 / N -Term Piscopo et al. 2005 3 Thr 122 Pro 5 / HL - I Finckh et al. 2000 4 Thr 122 Arg 5 / HL - I Binetti et al. 2003 5 Ser 130 Leu 5 / HL - I Sorbi et al. 2002 6 Asn 141 Ile 5 / TM - II Levy-Lahad et al. 1995 7 Val 148 Ile 5 / TM - II Beyer et al. 1998 Fig. 2. MRI scans shown atrophy of the left entorhinal cor- 8 Gln 228 Leu 7 / TM - V Zekanowski et al. 2003 tex with relative sparing of the hippocampus.18F-FDG PET scans showing progressive hypometabolism of both tem- 9 Met 239 Val 7 / TM - V Rogaev et al. 1995 poroparietal lobes and left frontal lobe between May 2005, al- ready beginning in the left parietal cortex (A) and February 10 Met 239 Ile 7 / TM - V Finckh et al. 2000 11 Pro 334 Arg 10 / HL - VI b Lleo et al. 2002 12 Thr 430 Met 12 / TM - IX Lleo et al. 2002 Herein we document clinical and apperative findings in a German patient with early-onset Alzheimer de- 13 Asp439Ala 12 / C - Term Lleo et al. 2001 mentia (EOAD) and with a mutation at codon 141 in the PSEN-2 gene. The same mutation has been shown tween different mutations of the PSEN-2 gene awaits measurements of CSF-tau and CSF-Aß1-42 have been further investigation. Some of these families show a suggested to increase the diagnostic precision of AD wide range in age at onset, and cases of nonpene- (Galasko 1998; Hulstaert et al. 1999). As part of the trance have been found (Cruts et al. 1998; Finckh et al.
clinical routine, these markers have been found to be 2005; Levy-Lahad et al. 1995; Tomaino et al. 2007).
highly sensitive and specific (Andreasen et al. 1998; In our family, there was an almost 15-year gap be- tween the proband and parent in age at disease onset.
Hampel et al. (2004) studied 52 patients with MCI, Although a longer follow-up period is needed, the 93 AD patients, and 10 healthy controls (HC). The presence of a cognitively healthy mutation carrier MCI group was composed of 29 patients who had could indicate the existence of incomplete penetrance.
converted to AD during follow-up, and of 23 patients Nevertheless, we can not rule out that this individual is who showed no cognitive decline. The levels of CSF at risk for EOAD. The variation in age at onset ob- tau-protein were increased, whereas levels of Aß1-42 served in this family confirms that PSEN2 mutations were decreased in MCI subjects. Aß1-42 predicted AD are associated with variable clinical expression. This in converted MCI with a sensitivity of 59% and a fact has important consequences for genetic-testing specificity of 100% compared to HC. Tau-protein and genetic-counseling programs; it may determine yielded a greater sensitivity of 83% and a specificity of the type of information given to these families.
The N141I mutation is located in exon 5 of the Regarding its potential role in AD, studies with PSEN2 gene, near the D439A mutation and the C-ter- transfected cell lines and transgenic animals expressing minal end of the protein. The presenilin 2 protein is mutant PSEN-2 showed an alteration in amyloid pro- an integral transmembrane protein normally processed cessing leading to a higher production of Aß1-42 /1- by proteolytic cleavage. Interestingly, the C-terminus is 43 (Citron et al. 1997; Tomita et al. 1997).
a critical region for endoproteolytic processing and possibly for the pathologic function of the protein demonstrated that the missense mutation at codon (Shirontani et al. 2000) Thus; the N141I mutation 141 of the PSEN2 gene, the MCI present during the could disrupt the endoproteolytic process and inter- first consultation and the elevated tau-protein levels fere with the normal function of the protein.
and decreased Aß1-42 levels in CSF interact in their The diagnosis of primary degenerative dementia effect on brain metabolism in specific brain areas. Our disorders such as AD is made largely by excluding oth- findings are interesting as several 18F-FDG PET stud- er causes of dementia. The search for biochemical di- ies have been published predicting the decline from agnostic markers that could be used for an early diag- normal to MCI. This studies showed that reduced nosis of AD has led to the suggestion that the con- baseline metabolic levels in the entorhinal cortex, centrations of tau-protein and the 42-amino acid form which is part of the medial temporal lobes (MTL, i.e., of Aß1-42 in cerebrospinal fluid (CSF) have a diag- hippocampus, transentorhinal and entorhinal cortices, nostic value (Andreasen et al. 2001; Hulstaert et al.
and parahippocampal gyrus), predict an MCI diagnosis 3 years later (de Leon et al. 2001; Gary et al. 2000) The Tau-protein is a normal axonal protein, which by baseline metabolic reduction predicted decline to MCI binding to tubulin in microtubules promotes their as- with 83% sensitivity and 85% specificity. No cortical sembly and stability (Goedert 1993). An increase in regions showed preclinical effects. Moreover, progres- CSF-tau-protein in AD has been found in numerous sive metabolic reductions in the entorhinal cortex and studies (Arai et al. 1997; Blennow et al. 1995; Jensen et in the left lateral temporal lobe paralleled the onset of al. 1995; Vandermeeren et al. 1993), which probably MCI, which is of interest, as an ideal biomarker for reflects the neuronal and axonal degeneration EOAD must correlate with disease progression. (Blennow et al. 1995; Vanmechelen et al. 1996), or possibly the successive accumulation of neurofibrillary tangles in AD (Tapiola et al. 1997). The sensitivity of CSF-tau-protein for AD in several studies has been Although mutations in the genes for PSEN-1, PSEN- high, often 80-90% (Andreasen et al. 1998, Andreasen 2 and APP cause familial EOAD, it must be remem- et al. 1999; Galasko 1998). The specificity has also bered that the majority of EOAD is not genetically been relatively high because most patients with other determined but belongs to the sporadic type of AD.
dementias, chronic neurologic disorders (e.g., Parkin- EOAD due to a mutation in the PSEN-2 gene seems son disease), or psychiatric diagnoses (e.g., depressive to be rare in Germany. Our findings support the no- pseudo-dementia) have physiologic CSF tau-protein tion that CSF tau-protein, Aß1-42 and structural and values (Blennow et al. 1995; Mecocci et al. 1998; Sjö- functional neuroimanging (MRI, 18F-FDG PET) may be useful biomarkers in the early identification of AD Aß1-42 has been implicated in the pathogenesis of AD and is the core peptide that accumulates in senile plaques (Tamaoka et al. 1995). Several studies have found that CSF- Aß1-42 is decreased in AD (An- dreasen et al. 1999; Galasko et al. 1997; Motter et al.
1995; Sjögren et al. 2000). A high sensitivity (80-90%) Acknowledgements: We thanks Ulrich Müller and Dagmar for CSF- Aß1-42 as a marker for AD has been found Nolte (Institute of Human Genetics at the University of (Andreasen et al. 1999; Galasko 1998), whereas the Gießen/Marburg, Germany) for the critical, stimulating and specificity has to be investigated further. Concomitant motivating comments on the final version of the article.
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