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Original Contribution |

A Pedigree With a Novel Presenilin 1 Mutation at a Residue That Is Not Conserved in Presenilin 2 FREE

Minoru Yasuda, MD; Kiyoshi Maeda, MD; Mamoru Hashimoto, MD; Hikari Yamashita, MA; Yoshitaka Ikejiri, MD; Thomas D. Bird, MD; Chikako Tanaka, PhD; Gerard D. Schellenberg, PhD
[+] Author Affiliations

From the Hyogo Institute for Aging Brain and Cognitive Disorders, Himeji, Japan (Drs Yasuda, Maeda, Hashimoto, Ikejiri, Bird, and Tanaka and Mr Yamashita); Geriatric Research Education Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, Wash (Drs Yasuda and Schellenberg); Department of Psychiatry, Osaka University Medical School, Osaka, Japan (Dr Ikejiri); and Department of Neurology (Drs Bird and Schellenberg) and Division of Gerontology and Geriatric Medicine, Department of Pharmacology (Dr Schellenberg), University of Washington, Seattle.


Arch Neurol. 1999;56(1):65-69. doi:10.1001/archneur.56.1.65.
Text Size: A A A
Published online

Objective  To disclose a novel mutation of the presenilin 1 (PS1) gene responsible for early-onset Alzheimer disease and to clarify genotype-phenotype correlation that should help to establish the function of this protein.

Background  The PS1 and presenilin 2 (PS2) genes carry missense mutations in families with Alzheimer disease. The PS1 and PS2 proteins have similar structures, and all presently known mutations are in nucleotides coding for amino acids that are conserved between the 2 presenilins.

Methods  Sequence and restriction fragment length polymorphism analyses of PS1 gene of DNA from a pedigree with early-onset Alzheimer disease.

Results  Sequence analysis disclosed a novel PS1 mutation in a pedigree of Japanese origin with early-onset Alzheimer disease. This mutation, which is predicted to cause a missense substitution of lysine for glutamic acid, occurred at codon 123 of PS1 that was not a conserved residue in PS2. The 2 patients of this pedigree shared an early clinical phenotype consisting of later-onset, progressive aphasia, but preserved visuospatial ability, which was indistinguishable from those of other PS1-associated Alzheimer disease cases.

Conclusion  These results demonstrate that a missense mutation in a region not conserved between PS1 and PS2 can cause Alzheimer disease.

Figures in this Article

THE MAJORITY of known pedigrees of early-onset familial Alzheimer disease (AD) are linked to mutations in the presenilin 1 (PS1) gene on chromosome 14.1 At present, 47 missense mutations at 36 different codons and a point mutation upstream of a splice acceptor site that results in an in-frame deletion have been described in the PS1 gene in patients with early-onset AD.2,3 A further autosomal dominant locus for familial AD in Volga German kindreds was demonstrated on chromosome 1,4,5 and the responsible gene is now called the presenilin 2 (PS2) gene. PS1 and PS2 share overall amino acid sequence identity of 63%.4,5 The presenilins also share substantial sequence homologies with the Caenorhabditis elegansSEL-12.6 In addition, a recent study showed that both PS1 and PS2 can functionally replace C elegans SEL-12, confirming that SEL-12 is a bona fide presenilin.7 Protein topology studies of PS1 and SEL-12 confirmed that presenilins are integral membrane proteins with 6 to 8 transmembrane domains.8,9 Most PS1 mutations documented so far occur at residues that are conserved in the presenilin family. All presently known mutations of PS1 and PS2 are in nucleotides coding for amino acids that are conserved between the 2 presenilins, suggesting a functional significance of these residues.

We report in the present study the detection of a novel mutation, which is predicted to cause a missense substitution at codon 123 in the first hydrophilic loop of PS1 in a pedigree with early-onset AD of Japanese origin. This mutation is the first to be identified at a residue that is not conserved in PS2. The 2 patients of this pedigree shared a dementia syndrome compatible with AD. These results provide evidence that a missense mutation at an amino acid that is not conserved between PS1 and PS2 can cause AD.

PROBAND

The pedigree designated as ABCD-2 family was ascertained through the Hyogo Institute for Aging Brain and Cognitive Disorders, Himeji, Japan. All investigations were performed with the written informed consent of participating family members or next of kin.

The proband (Figure 1), a 57-year-old factory worker, was admitted to the hospital of the Hyogo Institute for Aging Brain and Cognitive Disorders with a 1-year history of progressive memory problems and personality changes. He showed severe amnesia, disorientation in time and place, and word-finding difficulty, but his visuospatial ability was preserved. Magnetic resonance imaging showed severe atrophy in the bilateral medial temporal lobes and moderate atrophy in the bilateral parietal lobes. Positron emission tomography demonstrated hypoperfusion in the bilateral temporal and parietal lobes.

Place holder to copy figure label and caption
Figure 1.

The pedigree of the ABCD-2 family. The proband is indicated by an arrow. Persons known to be demented are indicated by black symbols. Present age or age at death (in years) is indicated in parentheses under each symbol. Children and grandchildren at risk for dementia are living in more recent generations but are not included in the figure.

Graphic Jump Location
AFFECTED FAMILY MEMBERS

The elder brother of the proband, a 65-year-old security guard, was admitted to the hospital of Hyogo Institute for Aging Brain and Cognitive Disorders for examination with a 3-year history of progressive memory problems and speech impediment. He was disoriented in time and place and his memory for recent events was very poor. He showed a marked word-finding difficulty and his arithmetic skills were poor, but his ability to copy a complex figure was well preserved. Magnetic resonance imaging demonstrated that diffuse cerebral cortical atrophy was more marked in the bilateral medial temporal lobes. Positron emission tomography showed biparietal, bitemporal, and bifrontal hypoperfusion.

The proband and his brother had the same mother and father. The mother died of peritonitis at the age of 33 years. The father remarried and had 2 more children, who were not affected (ages 52 and 50 years). The father remained healthy without any cognitive decline until he died at the age of 80 years. The mother of the proband had 5 siblings, 3 of whom (cases II-4, II-5, and II-6) died young of pneumonitis, war, and measles, respectively, and showed no signs of dementia. However, 1 of her brothers (case II-3) and her father had had neuropsychiatric disorders of unknown types and died at 56 and 65 years of age, respectively, several years after the onset. Therefore, the mutant allele may have been inherited from the proband's maternal grandfather.

NEUROPSYCHOLOGICAL ASSESSMENT

Family members were investigated with a battery of tests to measure intellectual, language, visuospatial, executive, and memory abilities, and to ascertain their general level of cognitive functioning. The assessments were performed while the subjects were free of neuroleptic and neurotropic agents and not in an episode of confusion. The battery included the Wechsler Adult Intelligence Scale–Revised,10 Western Aphasia Battery,11 Wechsler Memory Scale–Revised,12 Alzheimer's Disease Assessment Scale–Cognitive subscale,13 and the Mini-Mental State Examination.14 In addition to the total score of the Mini-Mental State Examination, Alzheimer's Disease Assessment Scale–Cognitive subscale, Western Aphasia Battery (aphasia quotient), and Wechsler Adult Intelligence Scale–Revised (full-scale IQ, verbal IQ, and performance IQ) were separately analyzed. Orientation was assessed by using the temporal and locational orientation subtests of the Mini-Mental State Examination.14 The Alzheimer's Disease Assessment Scale–Cognitive subscale recall subtest is inherent in a verbal learning test, in which the registration of a list of 10 written high-imagery words was measured by free immediate recall after each of 3 learning trials. The recall score was expressed as the mean number of words not recalled in 3 trials. The Alzheimer's Disease Assessment Scale–Cognitive subscale total score was analyzed as another index of severity of dementia in terms of overall cognitive impairment.

MOLECULAR GENETIC STUDIES

Genomic DNA was extracted from peripheral leukocytes as described previously.15 The target PS1 gene was amplified by the polymerase chain reaction with the use of primers derived from intronic sequences as described previously.16 The amplified DNA was ligated with the vector pCR2.1 (Original TA Cloning kit; Invitrogen Corp, Carlsbad, Calif) according to the manufacturer's protocol. Plasmid DNA from 5 positive clones was isolated and purified by the alkaline-lysis mini-prep method (AIA tip-20 kit; Qiagen, Hilden, Germany), and completely sequenced (both alleles) by applying the T7 autoread sequencing protocol (Pharmacia, Uppsala, Sweden). The M13 (−40) forward and reverse primers were used for sequencing clones containing fragment inserts of the target genes. Sequencing was performed electrophoretically with the Alfred Sequencer apparatus (Pharmacia). Mutations were identified by comparison of sequences with GenBank sequence data (National Center for Biotechnology Information, Bethesda, Md; available at: http://www.ncbi.nlm.nih.gov/). In addition, we screened 100 controls and 104 patients with late-onset AD for the presence of the mutation by restriction fragment length polymorphism.

ABCD-2 FAMILY

The members of ABCD-2 family are Japanese (Figure 1). There are no known links between this pedigree and other Japanese pedigrees associated with PS1 mutations. Clinical, neuroradiological, and neurophysiological examinations of the proband and his affected brother were consistent with the diagnosis of probable AD.17 The proband had an apolipoprotein E ϵ3/ϵ3 genotype, and his brother had an apolipoprotein E ϵ2/ϵ3 genotype.

MUTATION ANALYSIS

The nucleotide and exon numberings described herein are in accordance with those of GenBank No. L76518-76528. Complete sequencing of the PS1 gene of the proband (III-2) in family ABCD-2 disclosed a new missense mutation (G to A) in 1 allele at nucleotide 615 in exon 6, which is predicted to cause a glutamic acid–to-lysine missense substitution at codon 123 (E123K) in the first hydrophilic loop of PS1. The substitution of G to A abolishes the restriction site for Alw26I (Figure 2). The polymerase chain reaction–restriction fragment length polymorphism analysis confirmed the heterozygote substitution at nucleotide 615 of the PS1 gene. The same substitution was found in the DNA of the affected brother (III-1) but was not found in 100 healthy control subjects or in 104 patients with sporadic AD.

Place holder to copy figure label and caption
Figure 2.

Alw26I restriction enzyme analysis of the nucleotide 615 (G to A) mutation. The amplification primers (forward, the 2057 primer; reverse, the 911 primer) and polymerase chain reaction conditions were as previously described.16 The normal polymerase chain reaction product was 260 base pairs (bp), which was cleaved to 122-, 93-, and 45-bp fragments after Alw26I digestion. The proband and his brother were heterozygous for a G to A transition that abolishes a restriction enzyme site. When the amplified mutant fragment was digested with Alw26I and resolved on a 10% nondenaturing polyacrylamide gel, a novel band at 215 bp appeared.

Graphic Jump Location
EARLY CLINICAL PHENOTYPE ASSOCIATED WITH THE PS1 CODON 123 MUTATION

The initial prospective neuropsychological assessment of subject III-2 at symptom year 3 showed deficits in several measures of memory, in executive abilities concerning cognitive processing speed, and in attention to complex cognitive sets (Table 1). Reevaluation with the same protocols at symptom year 4 showed both the persistence of these deficits and the acquisition of deficits in concept formation. Neither subject showed deficits in nonmemory language and visuospatial functions. Patient III-1 shared a common phenotype with patient II-2 (Table 1).

Table Graphic Jump LocationTable 1. Neuropsychological Test Scores of the Patients of the ABCD-2 Family*

In the present study, we described a novel E123K mutation in the PS1 gene of 2 patients in the ABCD-2 family with early-onset AD. The E123K mutation is of particular interest, because it alters a residue that is not conserved in PS2. Although PS1 and PS2 share 63% overall amino acid sequence identity, several domains show almost complete identity, especially in the putative transmembrane domains,4,5 where the vast majority of mutations are clustered (Figure 3). Even in the hydrophilic loops, where there is a great sequence divergence in the amino acid sequence between PS1 and PS2, known mutations in PS1 have all occurred at residues that are conserved in PS2. Thus, so far all 36 of the affected residues in PS1 are conserved in PS2. The E123K mutation of the ABCD-2 family is the first to be identified at a residue that is not conserved in PS2. Although any base pair of DNA may be mutated, the residues that are conserved between the presenilins have far more AD-associated mutations than would be expected from a random distribution, which indicates essential functions for the conserved residues. Since PS1 and PS2 appear to be similar in their ability to substitute for SEL-12, they may also have overlapping functions in mammals.7 Recently, a PS1 mutation associated with early-onset AD was described at a site homologous to a PS2 mutation in Volga German kindreds, indicating that the alteration of a common residue can cause AD.18 Therefore, it is likely that the common residues between PS1 and PS2 are important for presenilin function associated with AD. On the contrary, the missense mutations that occur at the nonconserved residues might be expected to be functionally silent, ie, they might be so-called neutral substitutions. However, this possibility seems unlikely, because no substitutions were found in PS1 in individuals who did not have early-onset AD (either controls or patients with late-onset sporadic AD).19

Place holder to copy figure label and caption
Figure 3.

Schematic representation of transmembrane structure of the presenilin 1 protein, modified from Doan et al,8 and its amino acid sequence. The mutated amino acid residues that are so far known are described by white letters. The arrow indicates the glutamic acid (E)–to-lysine (K) missense substitution at codon 123 of the ABCD-2 family in this study. Amino acid residues that are not conserved between human PS1 and PS2 are indicated by an asterisk. All of the PS1 mutations that are so far known have occurred at residues that are conserved in PS2.

Graphic Jump Location

The site of the E123K mutation is also located at an amino acid residue that is conserved in the PS1 of mice and rats, but not in SEL-12. The similarity of murine and human PS1 amino acid sequences is about 92%.1,20 All of the affected residues are conserved in the murine sequence with the exception of a German patient with early-onset AD with the E318G mutation.21 The C elegans SEL-12 gene product displays about 50% amino acid sequence identity to PS1 and PS2.6 Eighty-one percent (29/36) of the affected residues in PS1 are conserved in SEL-12. Therefore, the mutations preferentially occur at residues that are strictly conserved through evolution. The characteristics of PS1 mutations that occur at residues that are not conserved among the presenilin family are listed in Table 2. Seven PS1 mutations that have been identified in patients with early-onset AD occur in residues that are not conserved in SEL-12. These patients had ages at onset that ranged from 32 to 55 years. This range extensively overlaps with the age at onsets in the pedigrees having early-onset AD in which the affected residues in PS1 are ones that are conserved in SEL-12. A patient with a mutation (E318G) occurring at an amino acid residue that is not conserved in the murine sequence had an age at onset of 47 years. Patient III-1 of the ABCD-2 family had an age at onset of 62 years, which is the latest onset in PS1-associated AD reported previously. One exception is an individual who had the I143F mutation, who was reported to be symptom free at the age of 68 years.27

Table Graphic Jump LocationTable 2. Alzheimer Disease−Associated Mutations in Human Presenilin 1 in Nucleotides Coding for an Amino Acid That Is Not Conserved Between Human Presenilin 1 and Other Presenilins*

Since the 2 patients having the E123K mutation shared the phenotypes of later onset, progressive aphasia, and preserved visuospatial ability, it seems likely that the earliest clinical manifestations in this pedigree reflect deficits in memory and a speech impediment. Nonmemory language and visuospatial functions appeared relatively intact. These phenotypic characteristics seem to be consistent with other cases of early-onset PS1 mutation, although patients with PS1-associated AD often have myoclonus, seizure, or extrapyramidal signs earlier in the course of the disease than occurs in sporadic cases. Thus, there may be a common phenotype of the PS1-associated disease. Further genotype-phenotype correlation studies should help to establish the function of this protein.

Accepted for publication April 9, 1998.

Reprints: Minoru Yasuda, MD, Hyogo Institute for Aging Brain and Cognitive Disorders, 520 Saisho-ko, Himeji 670-0981, Japan (e-mail: yasuda@hiabcd.go.jp).

Sherrington  RRogaev  EILiang  Y  et al.  Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease. Nature. 1995;375754- 760
Link to Article
Hardy  J Amyloid, the presenilins and Alzheimer's disease. Trends Neurosci. 1997;20154- 159
Link to Article
Rohan de Silva  HAPatel  AJ Presenilins and early-onset familial Alzheimer's disease. Neuroreport. 1997;8i- xii
Levy-Lahad  EWasco  WPoorkaj  P  et al.  Candidate gene for the chromosome 1 familial Alzheimer's disease locus. Science. 1995;269973- 977
Link to Article
Rogaev  EISherrington  RRogaeva  EA  et al.  Familial Alzheimer's disease in kindreds with missense mutations in a gene on chromosome 1 related to the Alzheimer's disease type 3 gene. Nature. 1995;376775- 778
Link to Article
Levitan  DGreenwald  I Facilitation of lin-12-mediated signaling by sel-12, a Caenorhabditis elegans S182 Alzheimer's disease gene. Nature. 1995;377351- 354
Link to Article
Levitan  DDoyle  TGBrousseau  D  et al.  Assessment of normal and mutant human presenilin function in Caenorhabditis elegansProc Natl Acad Sci U S A. 1996;9314940- 14944
Link to Article
Doan  AThinakaran  GBorchelt  DR  et al.  Protein topology of presenilin 1. Neuron. 1996;171023- 1030
Link to Article
Lehmann  SChiesa  RHarris  DA Evidence for a six-transmembrane domain structure of presenilin 1. J Biol Chem. 1997;27212047- 12051
Link to Article
Wechsler  D WAIS-R Manual.  New York, NY Psychological Corp1981;
Kertesz  A The Western Aphasia Battery.  New York, NY Grune & Stratton Inc1982;
Wechsler  D Wechsler Memory Scale–Revised Manual.  San Antonio, Tex Psychological Corp1987;
Mohs  RCRosen  WGDavis  KL The Alzheimer's Disease Assessment Scale: an instrument for assessing treatment efficacy. Psychopharmacol Bull. 1983;19448- 450
Folstein  MFFolstein  SEMcHugh  PR "Mini-Mental State": a practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res. 1975;12189- 198
Link to Article
Yasuda  MMaeda  KIkejiri  YKawamata  TKuroda  STanaka  C A novel missense mutation in the presenilin-1 gene in a familial Alzheimer's disease pedigree with abundant amyloid angiopathy. Neurosci Lett. 1997;23229- 32
Link to Article
Hutton  MBusfield  FWragg  M  et al.  Complete analysis of the presenilin 1 gene in early onset Alzheimer's disease. Neuroreport. 1996;7801- 805
Link to Article
McKhann  GDrachman  DFolstein  MKatzman  RPrice  DStadlan  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;34939- 944
Link to Article
Crook  REllis  RShanks  M  et al.  Early-onset Alzheimer's disease with a presenilin-1 mutation at the site corresponding to the Volga German presenilin-2 mutation. Ann Neurol. 1997;42124- 128
Link to Article
Tsuda  TChi  HLiang  Y  et al.  Failure to detect missense mutations in the S182 gene in a series of late-onset Alzheimer's disease cases. Neurosci Lett. 1995;201188- 190
Link to Article
Taniguchi  THashimoto  TTaniguchi  R  et al.  Cloning of the cDNA encoding rat presenilin-1. Gene. 1997;18673- 75
Link to Article
Sandbrink  RZhang  DSchaeffer  S  et al.  Missense mutations of the PS-1/S182 gene in German early-onset Alzheimer's disease patients. Ann Neurol. 1996;40265- 266
Link to Article
Reznik-Wolf  HTreves  TADavidson  M  et al.  A novel mutation of presenilin 1 in familial Alzheimer's disease in Israel detected by denaturing gradient gel electrophoresis. Hum Genet. 1996;98700- 702
Link to Article
Rossor  MNFox  NCBeck  JCampbell  TCCollinge  J Incomplete penetrance of familial Alzheimer's disease in a pedigree with a novel presenilin-1 gene mutation. Lancet. 1996;3471560
Link to Article
Cruts  MBackhovens  HWang  SY  et al.  Molecular genetic analysis of familial early-onset Alzheimer's disease linked to chromosome 14q24.3. Hum Mol Genet. 1995;42363- 2371
Link to Article
Kamino  KSato  SSakaki  Y  et al.  Three different mutations of presenilin 1 gene in early-onset Alzheimer's disease families. Neurosci Lett. 1996;208195- 198
Link to Article
Wasco  WPettingell  WPJondro  PD  et al.  Familial Alzheimer's chromosome 14 mutations [letter]. Nat Med. 1995;1848
Link to Article
Van Broeckhoven  CCruts  MBackhovens  H  et al.  Estimation of the presenilin-1 mutation frequency in a population-based sample of early-onset Alzheimer's disease [abstract]. Am J Hum Genet. 1996;59A291

Figures

Place holder to copy figure label and caption
Figure 1.

The pedigree of the ABCD-2 family. The proband is indicated by an arrow. Persons known to be demented are indicated by black symbols. Present age or age at death (in years) is indicated in parentheses under each symbol. Children and grandchildren at risk for dementia are living in more recent generations but are not included in the figure.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.

Alw26I restriction enzyme analysis of the nucleotide 615 (G to A) mutation. The amplification primers (forward, the 2057 primer; reverse, the 911 primer) and polymerase chain reaction conditions were as previously described.16 The normal polymerase chain reaction product was 260 base pairs (bp), which was cleaved to 122-, 93-, and 45-bp fragments after Alw26I digestion. The proband and his brother were heterozygous for a G to A transition that abolishes a restriction enzyme site. When the amplified mutant fragment was digested with Alw26I and resolved on a 10% nondenaturing polyacrylamide gel, a novel band at 215 bp appeared.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 3.

Schematic representation of transmembrane structure of the presenilin 1 protein, modified from Doan et al,8 and its amino acid sequence. The mutated amino acid residues that are so far known are described by white letters. The arrow indicates the glutamic acid (E)–to-lysine (K) missense substitution at codon 123 of the ABCD-2 family in this study. Amino acid residues that are not conserved between human PS1 and PS2 are indicated by an asterisk. All of the PS1 mutations that are so far known have occurred at residues that are conserved in PS2.

Graphic Jump Location

Tables

Table Graphic Jump LocationTable 1. Neuropsychological Test Scores of the Patients of the ABCD-2 Family*
Table Graphic Jump LocationTable 2. Alzheimer Disease−Associated Mutations in Human Presenilin 1 in Nucleotides Coding for an Amino Acid That Is Not Conserved Between Human Presenilin 1 and Other Presenilins*

References

Sherrington  RRogaev  EILiang  Y  et al.  Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease. Nature. 1995;375754- 760
Link to Article
Hardy  J Amyloid, the presenilins and Alzheimer's disease. Trends Neurosci. 1997;20154- 159
Link to Article
Rohan de Silva  HAPatel  AJ Presenilins and early-onset familial Alzheimer's disease. Neuroreport. 1997;8i- xii
Levy-Lahad  EWasco  WPoorkaj  P  et al.  Candidate gene for the chromosome 1 familial Alzheimer's disease locus. Science. 1995;269973- 977
Link to Article
Rogaev  EISherrington  RRogaeva  EA  et al.  Familial Alzheimer's disease in kindreds with missense mutations in a gene on chromosome 1 related to the Alzheimer's disease type 3 gene. Nature. 1995;376775- 778
Link to Article
Levitan  DGreenwald  I Facilitation of lin-12-mediated signaling by sel-12, a Caenorhabditis elegans S182 Alzheimer's disease gene. Nature. 1995;377351- 354
Link to Article
Levitan  DDoyle  TGBrousseau  D  et al.  Assessment of normal and mutant human presenilin function in Caenorhabditis elegansProc Natl Acad Sci U S A. 1996;9314940- 14944
Link to Article
Doan  AThinakaran  GBorchelt  DR  et al.  Protein topology of presenilin 1. Neuron. 1996;171023- 1030
Link to Article
Lehmann  SChiesa  RHarris  DA Evidence for a six-transmembrane domain structure of presenilin 1. J Biol Chem. 1997;27212047- 12051
Link to Article
Wechsler  D WAIS-R Manual.  New York, NY Psychological Corp1981;
Kertesz  A The Western Aphasia Battery.  New York, NY Grune & Stratton Inc1982;
Wechsler  D Wechsler Memory Scale–Revised Manual.  San Antonio, Tex Psychological Corp1987;
Mohs  RCRosen  WGDavis  KL The Alzheimer's Disease Assessment Scale: an instrument for assessing treatment efficacy. Psychopharmacol Bull. 1983;19448- 450
Folstein  MFFolstein  SEMcHugh  PR "Mini-Mental State": a practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res. 1975;12189- 198
Link to Article
Yasuda  MMaeda  KIkejiri  YKawamata  TKuroda  STanaka  C A novel missense mutation in the presenilin-1 gene in a familial Alzheimer's disease pedigree with abundant amyloid angiopathy. Neurosci Lett. 1997;23229- 32
Link to Article
Hutton  MBusfield  FWragg  M  et al.  Complete analysis of the presenilin 1 gene in early onset Alzheimer's disease. Neuroreport. 1996;7801- 805
Link to Article
McKhann  GDrachman  DFolstein  MKatzman  RPrice  DStadlan  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;34939- 944
Link to Article
Crook  REllis  RShanks  M  et al.  Early-onset Alzheimer's disease with a presenilin-1 mutation at the site corresponding to the Volga German presenilin-2 mutation. Ann Neurol. 1997;42124- 128
Link to Article
Tsuda  TChi  HLiang  Y  et al.  Failure to detect missense mutations in the S182 gene in a series of late-onset Alzheimer's disease cases. Neurosci Lett. 1995;201188- 190
Link to Article
Taniguchi  THashimoto  TTaniguchi  R  et al.  Cloning of the cDNA encoding rat presenilin-1. Gene. 1997;18673- 75
Link to Article
Sandbrink  RZhang  DSchaeffer  S  et al.  Missense mutations of the PS-1/S182 gene in German early-onset Alzheimer's disease patients. Ann Neurol. 1996;40265- 266
Link to Article
Reznik-Wolf  HTreves  TADavidson  M  et al.  A novel mutation of presenilin 1 in familial Alzheimer's disease in Israel detected by denaturing gradient gel electrophoresis. Hum Genet. 1996;98700- 702
Link to Article
Rossor  MNFox  NCBeck  JCampbell  TCCollinge  J Incomplete penetrance of familial Alzheimer's disease in a pedigree with a novel presenilin-1 gene mutation. Lancet. 1996;3471560
Link to Article
Cruts  MBackhovens  HWang  SY  et al.  Molecular genetic analysis of familial early-onset Alzheimer's disease linked to chromosome 14q24.3. Hum Mol Genet. 1995;42363- 2371
Link to Article
Kamino  KSato  SSakaki  Y  et al.  Three different mutations of presenilin 1 gene in early-onset Alzheimer's disease families. Neurosci Lett. 1996;208195- 198
Link to Article
Wasco  WPettingell  WPJondro  PD  et al.  Familial Alzheimer's chromosome 14 mutations [letter]. Nat Med. 1995;1848
Link to Article
Van Broeckhoven  CCruts  MBackhovens  H  et al.  Estimation of the presenilin-1 mutation frequency in a population-based sample of early-onset Alzheimer's disease [abstract]. Am J Hum Genet. 1996;59A291

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