1997 Lopera et al Clinical features of early onset Alzheimer disease

Clinical

Features of

_Early-Onset

Alzheimer Disease

in

a

Large

Kindred

With

an

E280A

Presenilin-1 Mutation

Francisco

_Lopera,

MD; AlfredoArdilla,

PhD;

Alonso

Mart\l=i'\nez;

Lucia

_Madrigal;

Juan Carlos

_{Arango-Viana,}

MD;

Cynthia

A.

Lemere, PhD;

JuanCarlos

_{Arango-Lasprilla;}

Liliana

_{Hincapi\l=e'\;}

Mauricio

_{Arcos-Burgos,}

MD;

Jorge

E.

Ossa, DVM, PhD;

IsabellaM.

Behrens,

MD; Joanne Norton; Corrine Lendon,

PhD;

Alison M.

Goate, PhD;

Andres

Ruiz-Linares, MD;

Monica

Rosselli,

PhD;

Kenneth S.

Kosik,

MD

Objectives.\p=m-\To

characterize clinical features of a _very

_{large pedigree}

with

early-onset

Alzheimerdisease

_(AD)

inwhich allaffected

individuals

_{carry the}

iden-tical

_glutamic

acid-to-alanine mutation atcodon 280 in the

_presenilin-1

_gene.

Design.\p=m-\Clinical

historieswere obtained

_{by patient}

and

_family

interviewsand

through

medicalorcivil records.

Using

standard

_diagnostic

criteria,

a caseseries

of 128 individualswas

identified,

ofwhich 6 have definitive

(autopsy-proven) early\x=req-\

onset

_AD,

93 have

probable

early-onset

AD,

and 29 have

possible early-onset

AD.

Setting.\p=m-\Community

basedin

_Antioquia,

_Colombia.

Patients.\p=m-\A

_{population-based}

_sample

in which all members of 5 extended

families

_(nearly

3000

_individuals)

were

surveyed.

Criteriaforinclusion

required

ob-taining

sufficientinformationto

_categorize

the individual asaffected.

Main Outcome

_{Measures.\p=m-\Age}

at

onset,

neuropsychological profile,

neuro-logic history,

and examination.

Results.\p=m-\The

_patients

hada mean _age at onset_{of 46.8 years}

_(range,

34-62

years).

The average interval until deathwas8_{years. Headache}was noted in

af-fected individuals

_{significantly}

more

frequently

thaninthosenotaffected. Themost

frequent presentation

was _{memory loss followed}

_by

behavior and

personality

changes

and

_progressive

loss of

_{language ability.}

In the final

_stages,

_gait

disturbances, seizures,

and

_myoclonus

were

frequent.

Conclusions.\p=m-\Otherthan the

_early

onset,

this

clinical

_phenotype

is

indistin-guishable

from

_sporadic

AD

_except

that affected individuals

_frequently

complained

of headache

_preceding

and

_during

the disease.

_Despite

the uniform

genetic

basis for the

disease,

therewas

significant

variability

in_{the age}at

onset,

_suggesting

an

important

role forenvironmental factorsor

genetic

modifiersin

determining

the age at onset.

JAMA. 1997;277:793-799

THE GENETIC basis for_manycasesof

early-onset

familial Alzheimer disease

(AD)

hasnowbeen established. Remark¬

ably,

mutations in at least 3 different

genesleadtoadiseasesimilar both clini¬

cally

and

_{neuropathologically.}

Themu¬

tated_genes are the

amyloid

_precursor

protein

(APP)

geneonchromosome

21,'

presenilin-1

(PSl)

on chromosome

14,

and

_presenilin-2

(PS2)

on chromosome

l.2"6Most of the describedmutationsoc¬ curatvarious loci within the PSl

_gene.2,6·7

Oneaimin

_{genetically defining}

_{the many} mutated loci

_capable

of

_causing

ADis to

understandhowdifferent mutations

_give

risetothe disease

_phenotype.

A detailed

description

of the

_phenotype

is a _pre¬

requisite

to

tracing

the mechanism

_by

which

_specific

mutations leadtothe_pa¬

thology

and the clinical

_picture

ofthe disease.Insome_cases,small differences

in the

_specific

mutated codon ofa

single

genecan leadto

_{significant phenotypic}

differences. For

_example,

mutations within APP lie on either side of the

sequence that

corresponds

to the ex¬

cised

_ß-amyloid

(or

Aß)

peptide,

the

ma-j

or

protein

foundinsenile

plaques.

These

mutations lead to a

phenotype

that is

typical

of

_AD,

_except

for the

_early

on¬

set.

_However,

amutation within the

Aß

sequence

gives

risetoadistinct

pheno¬

type—designated hereditary

cerebral

hemorrhage

with

_{amyloidosis-Dutch}

type.8

This

_single-base

_mutation,

which

causesa

glutamic

acid-to-glutamine

sub¬

stitution in codon

_693,

shifts the most

prominent

site of

_{amyloid deposition}

from the

_neuropil

to the cerebral

vascula-tureand shifts the clinical

_presentation

from dementiatocerebral

_hemorrhage.

Families with a mutation at the

_adja¬

cent

_codon,

692,

havea

phenotype

with

features of both

_presenile

dementia and cerebral

_hemorrhage

attributabletoce¬

rebral

_amyloid

_angiopathy.9

In thecaseof the

presenilins, patients

with mutationsatvarious loci

_develop

a

slowly progressive

dementia that be¬

gins

in the thirdtofifth decade. Several

pedigrees

with PSl or PS2 mutations

have been

_reported,

and some of the

reports

have described distinctive clini¬ cal features.Haltia and

_colleagues10

de-From theDepartmentsofNeurology (DrsLoperaand Hincapi\l=e'\,Ms_Madrigal,and Mr_{Arango-Lasprilla),} Pa-thology (Dr Arango-Viana), Microbiologyand

Parasi-tology (Dr Ossa),andBiochemistry (DrsRuiz-Linares andArcos-Burgosand MrMartinez), Antioquia Univer-sitySchool of_{Medicine, Medellin, Colombia;}Miami

In-stitute ofPsychology (Dr Ardilla),and Florida Atlantic

University (Dr Rosselli),Miami, Fla;Departmentof Psy-chiatry (DrsLendon,Goate,and Behrens and Ms Nor-ton), Washington UniversitySchool of Medicine, St

Louis, Mo;andDepartmentof_{Neurology (Drs}Lemere andKosik),Harvard MedicalSchool,Boston,Mass.

Reprints:Kenneth S.Kosik, MD,Center for

Neuro-logicDiseases,Brighamand Women's_Hospital,221

LongwoodAveBoston,MA02115.

at Florida International University on March 3, 2011

jama.ama-assn.org

scribeda

family

with anM146Vmuta¬

tion in PSl that hasan

unusually early

onset,

ranging

from_age35to39 years.

Although early myoclonus

was

noted,

only

1

_patient

is described in

_detail,

and the

_myoclonus

was

_present

atalate

_stage

of the disease when that

_patient

became bedridden.

_Lampe

and

_colleagues11

de¬ scribed the "L

_family"

in whom

_they

noted

_{early myoclonus,}

_seizures,

and_pro¬

gressive

aphasia.

Of the 16

_reported

cases,the mean±SD age at onsetwas

41.6±4.7 years,and the mean±SD_age

atdeathwas47.2±3.8 years. In

only

6

patients

was a mean±SD _age docu¬ mented for the onset of

_myoclonus

(44.7±2.8

years);

likewise themean±SD age for theonsetof seizures

(44.8

±2.9

years)

was documented in 6

patients.

From these_ages,itseems

_that,

relative

tothe

_rapid

courseof thedisease in this

pedigree,

the onset of

_myoclonus

and seizures occurredwell after theonsetof

cognitive

symptoms

when the disease

wasadvanced.

Kennedy

and

colleagues12

also noted

_myoclonus

in the affected members of the

_{pedigree they reported,}

but no detailsare

given

regarding

the

onset of the

_myoclonus

relative tothe disease course.

Among

50 individuals

from the

_Volga

German families who harboraPS2

_mutation,

myoclonus

was

noted in

_12%,

and seizureswerenoted

in24%.13

_Findings

didnotoccur

_early

in the diseasecoursefor_anyof thosecases.

Myoclonus

and seizureswerealsoalate but

_frequent

occurrenceina

large

fam¬

ily

aggregate

from

_Normandy

in whom the diseasewaslinkedtochromosome

14.14

The first

_suggestion

that an

early-onset

_dementing

disorderwas

present

ina

large

kindred from the Colombian

state of

_Antioquia

was

presented

by

Cornejo

etal15andwasfollowed

by

the

identification ofseveral additionalfami¬ lies from thesame

geographical region.16

Membersofthe 5 Colombian kindreds describedinthis article allhavea

point

mutation in codon 280that resultsina

glutamic

acid-to-alanine substitutionin

PSl .6A

_{haplotype analysis}

demonstrates

that the families are

likely

to have a

commonfounder.17The

_large

size ofthese kindreds allowsadetailed

_study

of the

rangeof disease

phenotypes

associated

withthismutation.

METHODS

Ascertainment of the

_Pedigrees

Five

_pedigrees

from

_Antioquia

with

an index case of

_early-onset

AD were

assembled fromextensive

community-based searches foraffected families.The indexcasesforeach

_family

wereselected

from the

_Neurology

_Department,

Uni¬

versity

Hospital

SanVincentede

_Paul,

Medellin,

Antioquia.

These cases were

evaluated

_{by neurologic}

_and

neuropsy-chological testing.

The clinical

_diagnos¬

tic criteria used were the National

Institute of

_Neurological

and Commu¬ nication Disorders and Stroke-Alzhei¬ mer's Disease and Related Disorders

Association18 and the

_Diagnostic

and Statistical Manual

_of

Mental

_Disorders,

Fourth

_Edition;

6caseshad

_autopsy

con¬

firmation of their

_diagnosis

andmetthe established criteria forAD.19'20At least

1 case in each

family

was

analyzed

for

the_presence ofamutation in the PSl

gene.The

diagnosis

of

probable

ADre¬

quired

that the

_patient

be examined

_by

1ofthe

_{participating neurologists.}

When itwasnot

_possible

toevaluate anindi¬

vidual

_directly,

thecase wasconsidered

as

probable

AD if histories obtained from

2

_family

members both fulfilled the di¬

agnostic

criteria. Thecase wasconsid¬

ered as

possible

AD if itwas notpos¬

sible to obtain more than 1 reliable

history,

and itwasconsidered definite

AD iftherewas

_postmortem

confirma¬

tion.

Beginning

with the index _cases, we

assembleda

pedigree

for each extended

family.

Toconstructthe

_family

treeand

to determine the status of individual

cases,several

strategies

wereused:

door-to-door search for all

_family

members and examination of

_baptismal

_records,

notary

registries,

and clinical records of the Mental

_Hospital

of

_Antioquia

and the

_University

_Hospital

San Vincente de Paul. Consentforevaluationwasob¬

tained from all

_{subjects according}

toa

protocol approved by

the human sub¬

jects

committee of the

_University

of

Antioquia.

Clinical and

Neuropsychological Analysis

In additiontoroutine

_neurologic

ex¬

amination,

a random subset of15indi¬

viduals

_mildly

to

_moderately

affected

by

AD and 34 normal controls under¬

went

neuropsychological testing.

Con¬

trolswererelatives taken from thesame

familiesasthe familial AD

_patients

and

werethereforeat

risk,

but

_they

matched the familial AD group in sociocultural

conditions,

including

educational level. At the time ofthe

_examination,

_they

were

active,

functionally

normal,

and

withno

significant complaints

or_memory

impairments.

The

_{neuropsychological}

test

_battery

in¬ cluded

_{Spanish-language}

versions ofin¬ strumentsused

_by

theConsortiumtoEs¬ tablisha

Registry

for Alzheimer's Disease

(CE

RAD)21

and several additionaltests

adapted

tothe cultural and

_linguistic

id¬

iosyncrasies

ofthe

_target

_population.

The

battery

included the

_following

sections: verbal

_{fluency, naming,}

Mini-Mental State

Examination

_(MMSE),22

_memory of

words,

constructional

_praxis,

recall of

words,

recognition

of

_words,

recall of line

drawings,

and

_trail-making

tests.23Some additional

_{neuropsychological}

testswere

also administered: the Raven

_Test,24

the Wechsler

_Memory

_Scale,25

the

_praxis

abil¬

ity

test,

the Boston

_Naming

_Test,

_Span¬

ish

_version,26

the Boston

_{Diagnostic Apha¬}

sia

_Examination,

_{Spanish version,27}

the

Rey-Osterrieth Complex Figure

with the

scoring

system

proposed by Taylor,28

and Serial Verbal

_Learning.29

The Wechsler

Memory

Scale,

Boston

_Diagnostic

_Apha¬

sia

_Examination,

_{Rey-Osterrieth}

Com¬

plex Figure,

and Serial Verbal

_Learning

testshave been

_previously

normalized in Colombia in different_ageand educational

groups.29"33

Analysis

of Postmortem Tissue

Autopsy

materialwasavailable from

6 individuals in2

_pedigrees.

The brain

was fixed with

formalin,

and sections were taken from the

frontal, parietal,

temporal,

and

_occipital

_cortices,

and the

hippocampus,

caudate, thalamus,

mid-brain,

pons,

medulla,

and cerebellum.

Sectionswerestained with

hematoxylin-eosin,

amodified

Bielschowsky

_method,

and antibodies tothe

_Aß

_{peptide, glial}

fibrillary

acidic

_protein,

and tau. The

neuropathological diagnosis

of ADwas

basedon

quantitative

criteria

suggested

by

CERAD34 and

_by

Khachaturian.19

Some

_specific

_aspects

of the

neuropa-thology

were

presented

as

_part

ofan

immunocytochemical

study.36

RESULTS

Pedigrees

and

_Sample

Characteristics

Fiveextended families with

_early-on¬

setADwereidentifiedin

_Antioquia.

The families livein townslocated in arela¬

tively

small

_altipiano

areawithin a ra¬

dius centeredat6°53.04'

_N,

75°20.13'W

ata meanaltitude of 1700mabovesea

level. These families trace their _gene¬

alogies

over5to 7

_{generations (Figure}

1).

Acommon

origin

of all 5 families is

likely

basedonthe_presenceof thesame

PSl mutation

_(E280A)

in all of the af¬ fected

_patients,

the _presence ofa rare

haplotype,17

the limited

_geographic

dis¬ tribution of the

_family

_members,

and the

_sharing

of4lastnames_amonga

high

proportion

of the

_family

members. The

mostcommonof these lastnames canbe

tracedto

_1783,

when thenamewas_reg¬

istered forthe first time in the townof

Yarumal,

Colombia

(founded

in

1780).

Thecombined

_sample

size_amongall of the

_{pedigrees, including healthy}

and at-risk

_individuals,

is

_{approximately}

3000

individuals. From this

_sample,

a

diag¬

nosis of

_probable

AD was made in 93

at Florida International University on March 3, 2011

jama.ama-assn.org

Generation

DjO

"C>Ö

IV

û-o &ò#oòòOè0

VI VII

ìèiEi

_{0 *}

[ ]

Generation

14 11 19 1

O O

26 15

<>o ODO

2916 34 7 38 17 1113 2 2

líiJrjrjMrjroiriiiiiH»

j-

i

_I

_iíí

á

4 jrjíújro

6o 0Ò666Ó6

12 40 5 8 25 253 6 2 6 I 18

í

iiímuffii

21 12

VI Vil

O-i-O

hLa

ù

La

DrO

oL Lo La La

_{2 6}

um

O 6_{16 10}

Figure1.—Five extended families(A through E)withearly-onsetAlzheimer disease Identified InAntioquia.These familiestracetheir_genealogiesover5to 7gen¬

erations. Roman numerals Indicate the_generationnumbers.Squares(male)and circles(female)indicatefamilymembers classifiedasaffected_(filledin)or

non-affected_(empty).Slashes indicate deceasedfamilymembers.OffspringInwhom thediagnosiswasIndeterminateorwhohavenotreached the age of risk have been collected Intoa_singlediamond(totalnumber ofoffspringshown under eachdiamond).

individuals,

possible

AD in 29 individu¬

als,

and definite AD

_{(autopsy-confirmed)}

in 6 individuals. The sex distribution

amongthecases was66men

(52%)

and

62 women

(48%).

Nearly

all of the pa¬

tients live inarural

setting,

_except

for afew who live in the

city

of

Medellin,

Colombia. The mean educational level

attainedwasthe second

grade.

Thema¬

jority

of the male

_patients

werecoffee

farmers,

and the

_majority

of the female

patients

werehousewives. Themean±SD age at onset _among 88individuals for whom this informationwasavailable and

considered reliable

₍₄₁

women and 47

men)

was46.8±6.4_years

_(range,

34-62

years).

Therewas no

significant

differ¬

encein the _{age at onset}between men

and women.

Among

the

patients

for

whom there was an

adequate history,

27%were

_smokers,

12% consumed al¬ cohol

_excessively,

and7%hada

history

of headtrauma that resulted inuncon¬

sciousness. Atthe time of the

_analysis,

69 of the 93

_probable

AD

_patients

and

14 of the 29

_possible

AD

_patients

had died. Themean±SD_ageof

_death,

based

on54

observations,

was54.8±7.3_years

(range,

38-65

_years),

withno

significant

differences between men and women.

When

_possible

AD

_patients

were ex¬

cluded,

themean_{age at onset}was47.7

years

(range,

34-62

years),

and themean

ageatdeathwas60 years

(range,

48-65

years).

The_averageintervalbetweenon¬

setand deathwas8 years

(range,

3-18

years).

All of the

_patients

were taken

care of in their homes

throughout

the

duration of the

_disease,

and none re¬

ceived

_nursing

home care.

Clinical

Symptoms

and

Neurologic

Examination

Themost commoninitial

complaints

were

progressive

_memory loss and

changes

in

_personality

and behavior. Ev¬

ery

history

included the

complaint

of memorydisturbance.

Language

difficul¬

ties suchas

naming

were also

frequent

in the

_early

_stage

of the disease. Most of

the

_patients

did not have

_neurologic

problems

other than

_impairment

ofmen¬

talstatusuntil late in thediseasecourse.

Gait

_difficulty,

_seizures,

and

_myoclonus

were_amongthe latest

changes

observed.

A total of 73% of those affected com¬

plained

ofsevere

headache,

often as a

prodromal

feature,

up to severalyears

before the onset of dementia.

_Only

2

(17%)

of 12 nonaffected

_subjects

from the

_largest

families

_reported

headache. Table 1

_presents

the

_frequency

ofneu¬

rologic findings

among the

sample

of

affected

_patients

for whom

_complete

neu¬

rological

informationwasavailable

(118

patients).

Neuropsychological

Evaluation Patients with a

diagnosis

of

possible

AD and

_severely

demented

_patients

were

excluded from the

_compiled

mentalsta¬ tusdata. Two

_subjects

inthe control_group

(1

man, 1

woman),

and 3

subjects

in the

affected group

(1

man, 2

women)

were

completely

illiterate,

and theresthada

at Florida International University on March 3, 2011

jama.ama-assn.org

Table1.—FrequencyofNeurologic Findingsfor 118 Patients With Familial Alzheimer Disease

Symptom No._(%)

Memorydisturbance 118(100) Personalityand behavioralchanges 111

_¡94)

Languagedifficulty 96(81 )

Symptomsofdepression 93₍₇₉₎ Headache 86(73)

Gait_difficulty 77₍₆₅₎ Aggressiveness 77

_J65)

Wandering 74₍₆₃₎

Convulsions and_myoclonus 53(45) Suck reflex 49₍₄₂₎ Babinskl reflex 15₍₁₃₎

Graspreflex 4₍₃₎

Cerebellar_{signs 22(19)} Parkinsonism 22(19)

limited education. The

_highest

level of school attendance was _{13 years} in the

control_groupand_{11 years in}the familial AD_{group. In}the CERAD

_{neuropsycho¬}

logical

test

_{battery, statistically signifi¬}

cant differences between _{both groups}

were observed in the

following

tests

(Table

2):verbal

_fluency

_(except

the

46-to60-second

_interval),

_{naming (except}

for

high-frequency

words), MMSE,

memory

of words

_(except

_reading

and

_intrusions),

constructional

_praxis

_(except

for the circle and the

_rectangles),

recall of words

(but

not

_intrusions),

_recognition

ofwords

(cor¬

rect "no"

_response),

recall of

_drawings

(except

circle and

_cube),

and trail

_making

(part A,

errors).

Verbal

_fluency

andnam¬

ing

were both

impaired

in the affected

patients,

but verbal

_fluency

defectswere

moreevident than

naming

deficits. The

meanMMSEscoreintheaffected_group

was14.1 of

30,

and themeanMMSEscore

amongnonaffected

family

memberswas

27.1

_(range,

24-30).

The MMSE had been normalized in

_Antioquia,

and the normal

scorehasalower limitof23.

Among

the

literate

_subjects,

nodifferencesinread¬

ing

wordswere

found;

however,

_memory

ofwords differed

_{significantly.}

The fa¬ milial AD_grouphadmore

_difficulty

than the control _group with construction of

drawing complex

figures

(eg,

a

cube)

but

not

_{simple figures (eg,}

a

circle).

The

cube,

the

_only

3-dimensional

_figure

in the

test,

presented

the

_greatest

_difficulty

for the AD

_patients.

Inthe recall of

_figures,

the

mostdifficultwerethe

rectangle

and the

diamond,

and theeasiestwerethe circle

and the cube.

Statistically significant

differences

were observed in the

following

addi¬

tional

_{neuropsychological}

tests not in¬

cluded in CERAD: Wechsler

_Memory

Scale

_{(orientation,}

mental

_control,

_logi¬

cal memory, associative

_learning,

total

score, and memory

quotient), praxis

(right

hand and lefthand butnot

buc-cofacial),

Boston

_Naming

Test,

Rey-Osterrieth

_{Complex Figure (copy}

and

immediate

_recall),

and Serial Verbal

Learning

(first

trial and

_delayed

recall)

(Table 3).

Table 2.—CERADNeuropsychologicalTestBattery*

Test

Controls(n=34)

Mean SD

AD Patients(n=15)

-Mean —ISD Verbal_fluency 5.4 9.2

Naming 12.1 2.6 7.4 3.2

MMSE 27.1 2.8 14.1 4.4

Memoryof words

Correct 9.4 2.4 7.6 4.4 Intrusions 0.0 0.0 4.7

Constructional_praxis 10.0 1.5 3.9 3.3 Recall of words

Totalcorrect 1.2 Intrusions 0.4 0.6 1.4

Recognitionof words

Correct_{"yes"response} 9.6 1.1 5.4 2.9 Correct "no" response 9.6 1.3 5.4 2.6 Recall of_drawings 6.7 3.0 1.6

Trailmaking

PartA

Time 152 78.5 200 72.2

Errors 1.7 2.3 4.6 Part

Time 212 70.9 200 70.4 .72

.90

Errors 3.6 2.3 5.0 1.0

"CERAD indicates ConsortiumtoEstablisha_Registryfor Alzheimer'sDisease; AD, Alzheimerdisease;and MMSE,Mini-Mental StateExamination.Data,exceptfor verbalfluency, presentedasscores;verbalfluencyis expressedas_{words per 60-second interval.}

fTwo-tailed tests.

Results in the Wechsler

_Memory

Scale

were

particularly

notable.

Logical

memoryand associative

learning

(both

verbal memory

tests)

were

signifi¬

cantly impaired

in the AD

_patients,

whereas visual

_reproduction

_(nonver¬

bal

_memory)

scores were

remarkably

similarinboth_groups.The_{memory quo¬}

tient,

using

Colombian

_norms,29

was more

than 2 SDs lower in the familial AD group. In the

praxis ability

test,

diffi¬

cultiesin

_performing

movementsunder verbal commandwere

impaired

for both

hands. Buccofacialmovement_scores,al¬

though

decreased in the affected _pa¬

tients,

werebetter

preserved

than hand

movements. Inthe Boston

_{Naming Test,}

scores in the familial AD _group were

roughly

half of the scoresobserved in

the

_{controls; however,}

the control_group

performance

wasalso

_low,

as

expected

because of the limited education level of the

_{population. Naming}

difficulties

wereobservedinthe confrontationnam¬

ing subtest,

butnotin

_responsive

nam¬

ing

and

_{body-part naming.}

High-probability repetition

(but

not

low-probability repetition),

word

_reading

(but

notoral

_reading),

and

_writing

(mechan¬

ics butnot

_{primer-level writing)}

were

relatively

well

_preserved

in the demen¬

tia

_patients.

Those with dementia had

extremely

low scores in the

Rey-Osterrieth

_{Complex Figure-copy}

con¬

dition,

aconstructional

ability,

and the score for the

Rey-Osterrieth Complex

Figure

recall

_condition,

atest

_using

non¬

verbal memory,was

only

1

_point

of36.

The Serial Verbal

_Learning

testwas

es-pecially

difficult for the

_patients

with

_AD,

and

_{statistically significant}

differences

were observed in

delayed

recall.

Neuropathological

Features

In the6

_{autopsies performed,}

the brain

was

atrophie.

Three of the cases were

genotyped

and had the

_{expected glutamic}

acid-to-alanine substitutionat

_position

280

in the PSl _gene.

_{Histologically,}

all the

casesmetthe criteria for AD intermsof

plaque

and

_{tangle density.}

A

_description

ofthe

_pathologic

characteristics in 1case

is

_{representative.}

The brain

_weighed

700 g, and there was severe and extensive

cortical

_atrophy

and

_symmetrical

central

atrophy. Atrophy

of the frontal andtem¬

poral

lobes was _{most severe,} with the

gyri forming

thin

_projections

into the sub-arachnoid_space.The

_hippocampus

was

markedly

shrunken

_bilaterally,

and the

striatum,

particularly

the head ofthecau¬

date,

was

atrophie.

The susbtantia

nigra

was

depigmented.

Histologically

thecasesatisfiedthe cri¬

teria for AD. Inthe cerebral cortexthe neuritic

_plaque

_density

often exceeded

30/mm2.

By

digital image quantitation

of the inferior frontal gyrus, there was a

total

_{plaque density}

of 150/mm2on cross

section; however,

only

a

portion

of these

plaques

had

_adjacent

neurites or dense

amyloid

cores atthe center.Of interest wasthe_presenceof neuritic

plaques

and

densecore

_plaques

inthe cerebellumas

well as abundant diffuse

plaques

often

located within the

_depths

of the

_tertiary

cerebellar folia. Within the

_hippocampus

at Florida International University on March 3, 2011

jama.ama-assn.org

Table 3.—AdditionalNeuropsychologicalTests*

Controls(n=34) Test -Mean —ISD

AD Patients(n=15)

-Mean SD Pf WechslerMemoryScale

Information 5.1 1.1 1.6 1.1 .11 .004 .001 .001 Orientation 5.0 0.0 2.2 1.3

Mental control 2.1 1.0 1.9 Logmemory 6.9 2.7 1.5 1.6

Digits

Forward 4.9 3.4 1.5 .98 .92 .001 .97 .02 .01 Backward 2.4 1.6 1.2 1.5

Associative_learning 13 3.9 2.5 2.2 Visualreproduction 3.7 Totalscore 47.1 10.0 13.8 11.8

Memory quotient 99.1 14,8 65.8 17.0

Praxis

Righthand 90.9 5.5 71.6 11.1 .004

.001 .97

.001

Left hand 89.9 6.1 66.7 13.0 Buccofacial 94.0 4.6 85.0 8.6

Boston_NamingTest

BostonDiagnostic AphasiaExamination

Auditory Comprehension

Word order 68.4 4.7 47.8 16.5 .93

.92

Body-partidentification 3.0 14.8 2.4

Commands 14.3 0.9 8.9

Complexmaterial 3.8 2.9 Naming

Responsive 29.9 _0.5 27.7 3.6 _.91

.31 .99 Confrontation 90.5 6.8 70.7 20.2

Body-part naming 25.' 2.8 20.2 4.8 Reading

Word_reading 27.8 4.7 20.0 11.5 .98 .96

Oralreading 9.3 2.0 6.2 3.6 Repetition

High probability 0.6 5.5 2.0 .97

.11

Low_probability 7.4 1.2 4.0 2.0

Writing

Mechanics 5.0 0.0 3.5 .94 .26

Primer level 13.9 1.4 7.1 6.5

Rey-Osterrieth Complex Figure

Copy 23.4 4.3 .001 .001 Immediate recall 5.5

SerialVerbal_Learning

First trial 1.6 1.0 0.2 0.4 .24

6~

.02

Maximum 9.5

Delayedrecall

*ADindicates Alzheimer disease. Data_presentedas scores.

tTwo-tailed/tests.

and cerebral

_cortex,

there were

promi¬

nent

_{neurofibrillary}

_tangles

and

_"ghost

tangles."

The

_{neurofibrillary tangles}

stained withtau antibodies and the dif¬

fuse and

_compact

_plaques

stained with

Aß

antibodies

_{(Figure 2,}

_top

and

bottom).

The detailed characteristics of the

_Aß

staining

with antibodies

_against

various forms of

the

Aß

peptide

have been re¬

ported.35

Other

_stigmata

of AD such as

granulovacuolar degeneration

were ob¬

served inthe

_hippocampus,

but Hirano

bodieswerenotobserved. The entirece¬

rebralcortexshoweda

prominent

vacu-olation of the

_neuropil

in the

_superficial

layers, accompanied by

severe

gliosis

of¬

ten seen in Creutzfeldt-Jakob disease

(Figure

2, middle); however,

the tissue

tested

_negative

with antibodies

_against

prion protein.

Therewas

significant pal¬

lor within the central

_region

of thecen¬

trumsemiovale. Clinical Cases

Case1.—A

_47-year-old

man

_present¬

ed with the chief

_complaint

of

_gradual

progressive

memoryloss

beginning

lVfc years earlier. He had run a farm for

many years, but had gone

bankrupt

4 years earlier. From that time onward he worked

_irregularly.

When he was

seen in the

clinic,

his

family reported

that he often

_forgot

theirnames.He had

reduced verbal

_fluency,

didnotinitiate

conversation,

and had

_difficulty

follow¬

ing

the thread ofaconversation. Most

Figure2.—Brain sections froma_57-year-oldfamilial Alzheimer disease_patientwiththeE280A mutation.

Top,Numerous_{plaques(arrowheads)}infrontalcor¬

texstained with ß-amyloid (or Aß) antibody,C42.35

Middle,Glialflbrillaryacidicprotein stainingof

astro-cyticprocesses and cell bodies(arrowheads)inthe

same_regioninasection24mm_{away from that of the}

top. Bottom, Dystrophie neurites within a _plaque

(large arrowhead)and_{neurofibrillary tangles(small}

arrowheads)aredetected inasection_adjacenttothat of the middle. Scale bar=50mm.

recently

he had lost interestin hiswork andinhis

_{family responsibilities.}

Hebe¬

gan to wander and sometimes did not

seemto

_recognize

hisownhouse. How¬

ever,he remained

competent

tocarefor

himself in his

_{daily living}

activities. His MMSE score was4. Hecouldnotrecall

any

digits

orrecall asentence. Incat¬

egories,

henamed 8 animals in1

_minute,

2fruits in1

_minute,

and 1

_body

_part

in at Florida International University on March 3, 2011

jama.ama-assn.org

1 minute. He had _gone to

_elementary

school for

_only

2 years.

Laboratory

tests

included nonreactive

_VDRL,

_negative

human

_{immunodeficiency}

virus

_test,

and normallevels of

_{triiodothyronine,}

thy-roxine,

thyrotropin,

vitamin

_B12,

serum urea

nitrogen,

and creatinine. He car¬

ried the

_glutamic

acid-to-alanine sub¬ stitution at

_position

280 ofPSl. Over the_{next 2 years,}he

_{developed gait}

dif¬

ficulty,

total loss of

_{language ability,}

and

frequent

seizures. He died at age 50

years aftera

5-year

courseof dementia.

His

_autopsy

confirmed

AD,

Case 2.—A

_{47-year-old right-handed}

woman wasfirstseen8 yearsafter the

onset of

_progressive

_{memory loss. At} theonsetof the

_disease,

she oftenre¬

peated

the same

questions

or

stories,

and sheoften

_forgot

where she hadleft

objects.

She had no formal education

and worked as a housewife. _Over the

ensuing

years, she

developed

difficulty

in

_preparing

_meals,

_neglected

her fam¬

ily obligations,

and

_{appeared apathetic.}

She didnot

_complete

activities that she

began

andbecame isolated from others. Four_years after theonset of_memory

loss,

she

_{developed agitation,}

became

aggressive

at

_times,

and

_began

wander¬

ing.

She

_neglected

her

_personal

_hygiene,

and her

_language

functiondeteriorated.

By

6_yearsafter theonsetofher illness and_{2 years}before

_being

_examined,

she

developed urinary

and occasional fecal incontinence. She

_{developed myoclonic}

jerks

of the trunk. She hada

history

of

smoking

20

_cigarettes

_per

_day,

and she

rarely

drankalcohol. On examinationat

the time of

_{presentation,}

she had echo-lalia and

_hypophonia

and often mumbled the same words over andover

again.

Her MMSE score was 0. She had_gen¬

eralized

_{hyperreflexia, sucking,}

and

pal-momentalreflexes. She carried the

_glu¬

tamic acid-to-alanine substitution at

position

280 of PSl. She died_{at age}47

years

shortly

after

being

examined. Her

autopsy

confirmed AD. COMMENT

The first

_reported

kindred with

_patho¬

logically

documented familial AD was

published

in 1932.36 Since

_then,

more

than 100

_large

families with inherited AD have been

_reported.37

_Among

these

families,

the

_{multiplex family}

described in this articleis

undoubtedly

the

_largest

familial AD kindred in the literature.

By

virtue ofits size and the

_frequency

of

_{consanguinity,}

the extended

_family

could

_provide

an

important investiga¬

tive resource for _many current _ques¬

tions from ethical to

_genetic

issues.

Among

the

_latter,

asearch for

homozy¬

gotes

inthis

_population

_represents

an

important goal.

That all of thefamilies live within thesame

_{geographic region,}

have

_family

namesin_common,have the

same

_mutation,

and sharea rarealíele17

suggests

afoundereffect.

Anthropologi¬

cal,

genetic,

and historicalstudies of the

Antioquian

community

show that the

population originated

from the

_Basque

region

of

_Spain,

with a small

genetic

input

from the amerindian and black

populations.38·39 Genotypic

studiesaswell as asearchfor familial AD_amongfami¬

liesontheIberian

peninsula

_mayreveal afounderfor this PSl mutation.

Onecommon

complaint

_{among the af¬}

fected

_patients

was headache. This

symptom

has notbeen

_reported

in as¬

sociation with

_sporadic

_AD,

but it was

notedas a

possible prodromal

feature in

patients

with V717I mutations in the APP

_{gene.40 Many}

of the

_patients

inour

study

reported

chronic headache with

occipital predominance,

and this com¬

plaint

often

_preceded

the onset of AD

by

several _years.

The

_{neuropsychological}

characteris¬ ticswere

typical

of AD. The CERAD

and Wechslertests indicated a severe

progressive

alterationof verbal andnon¬

verbal memory, as well as

logical

_and

associative memory. Therewere

impair¬

ments of

_{language comprehension}

and

verbal

_fluency

and

_difficulty

in

_naming,

particularly

for

_{low-frequency}

words. There were

frequent

severe

impair¬

mentsin tests of constructional

_apraxia,

asdemonstrated

by

CERAD and

Rey-Osterrieth

_{Complex Figure}

results.Ex¬

ecutive functions

_dependent

onfrontal

lobes were

severely

affected,

as indi¬

cated

_by

the low

_phonologic

andseman¬

tic

_{categorical fluency.}

The

_testing

_para¬

digms

werenormalized for the

Hispanic

population

and for individuals with lim¬ ited formal education because_neuropsy¬

chological

tests are

highly

sensitiveto

educational

_variables,41

and

_illiteracy

correlates with an

extremely

low_per¬

formance in most

_{neuropsychological}

tests.42,43

Although

therewere afew_pa¬

tients whohad attained_up to 11 years

of

_schooling,

_{the size of this group}was

toosmalltodeterminetheeffect of edu¬ cationon _{age at}disease onset.

In atleast2

reports

describing

smaller familieswith mutations in

_PSl,mi

clini¬ cal features

_appeared

to

_distinguish

fa¬ milial ADfamilies from

_sporadic

AD. The "L

_family"11

was

_reported

tohave

_early

progressive

aphasia, early-appearing

my¬

oclonus,

generalized seizures,

and para-tonia. A

_family

ofFinnish descent10was

reported

tohave

_early

and

_prominent

_my¬ oclonus. The

_{large sample}

size available

withinthe collectedmembersof the An¬

tioquian

pedigree

allow us to conclude

thattheE280Amutationcauses aformof

AD that is

_clinically

identicaltothe_range of

_signs

and

_symptoms

seenin

sporadic

AD, except

for the

_early

_{age at} onset.

Findings

such as

myoclonus, gait

diffi¬

culty,

and seizuresoccurlate.

Although

seizures4"7and aberrantmotor

_activity48

are well established as late manifesta¬

tions of

_sporadic

_AD,

all of the

_published

families,

including

those described

_here,

suggest

that seizures and

_myoclonus

arise

more

frequently

with PSl

_mutations,

but

always

after the onsetof the

_cognitive

impairment.

More

_likely,

the

_frequent

ob¬ servation of

_myoclonus

and seizures_rep¬

resentsthe

_rapid

_progression

ofthe dis¬

ease.

_Indeed,

a _{younger age at onset}

predicts

a

significantly

fasterrateof dis¬

ease

progression.49

The clinical

phenotypic

featuresdescribed for otherPSl muta¬

tions,

including

early myoclonus

and sei¬

zures,mayreflect the effects ofamuta¬

tion atsites other than

_position

280. In this

_regard,

aclinical

description

of the

family

with the

_Glu280Gly

mutation7

wouldbe of

_particular

interest because

they

haveamutationinthe identical codon

asthe

Antioquian

families.

Alternatively,

asthe

sample

size_growsfor familieswith

otherPSl

_mutations,

the clinical

_pheno¬

type

may appear

increasingly

similarto

sporadic

AD.

The

_postmortem

_findings

were

diag¬

nostic ofAD—senile

_plaques

andneu¬

rofibrillary tangles

wereabundant. The

cerebellum was also

significantly

af¬

fected with diffuse

plaques

as well as

neuritic

_plaques

and densecore

plaques.

Although

cerebellar senile

_plaques

are

well

_recognized

tooccurin

sporadic AD,

their presence is

variable,

and

_{only rarely}

are

they

associated with neuritic

changes

ordo

they

formcores.50Neuritic

changes

around

_plaques

were

_positive

with

ubiq-uitin antibodies and

_negative

withtau

antibodies.35

Despite

the

_significant

cer¬

ebellar

_involvment,

_{gait difficulty}

wasa

lateoccurrence.

Within this _very

_{large pedigree,}

a

number of

_commonly

assessed clinical features show

_phenotypic

_variability.

For

_example,

the _{age at onset}

_ranged

from34to62_years.If the2

_patients

at

the extreme of _{each range} were dis¬

cardedas

_outliers,

theonsetwould still

span 21 years

(ages

39to 60

_years).

Al¬

though

both of the outliers were cat¬

egorized

as

probable

ADbecause

they

lack

_autopsy

_{confirmation, they}

both carry the E280A mutation

and,

there¬

fore, provide

strong

evidence forawide

age range atdiseaseonset.The_{age range} of diseaseonsets

_reported

with various mutations inPSl is from35 to 55

_years,7

a _range that falls within _{the ages} ob¬

served inour

pedigrees.

The wide age

rangeofdiseaseonsets among

patients

that_carryanidenticalmutation

_strongly

suggests

an effect of

genetic

or envi¬

ronmental modifiers. One

_genetic

de¬ terminantbelieved toaffect _{age at}on¬ set is the number of

_{apolipoprotein}

E

at Florida International University on March 3, 2011

jama.ama-assn.org

(APOE)

e4

_alíeles51;

_however,

the APOE

e4alíele distribution in this

_population

doesnot correlate with_{age at} onset.17

Besides APOE

_e4,

other

_possible

_ge¬ netic disease modifiers include the

CYP2D6B

alíele,52

and

_{polymorphisms}

in

_{NACP/a-synuclein,53}

_possibly

al-an-tichymotrypsin,5456

and the intron 3'to

exon8 of PSl.57 Environmental _expo¬

sures,whichmayaffect the incidence of

AD,58

arealsoa

possible explanation

for

the wide range of ageat

onset;

however,

at this

juncture,

there are no obvious

clues

_concerning

the

_identity

of sucha

factor.

_Clearly,

these families

_provide

anideal clinical

setting

in whichtosearch

for

_genetic

and environmental modifi¬

ers of disease

expression.

Thisstudywassupported byColcienciasgrant 1115-04-040-95_(DrsLoperaandOssa).

The authorsgratefully acknowledgethe collabo¬ ration of the families and civil authorities of the

municipalitiesthat_participatedin this_study,the

University HospitalSan Vincente de_Paul,and the MentalHospitalofAntioquia.

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