SECTION XIII.

DEMENTIAS
CHAPTER 106. ALZHEIMER DISEASE AND
RELATED DEMENTIAS
SCOTT A. SMALL AND RICHARD MAYEUX
Degenerative Diseases
Vas!"ar Diseases
In#eti$!s Diseases
In%erite& Meta'$"i Diseases
S!ggeste& Rea&ings
The defining features of deentia ha!e e!o"!ed sin#e the ter $as first
introdu#ed o!er %&& 'ears ago. In this era of standardi(ed #riteria) those of
the Diagnostic and
Statistical Manual of Mental Disorders) *th edition +DSM,I-. are ost
#oon"' used. A##ording to DSM,I-) the diagnosis of deentia re/uires 0the
de!e"o1ent of
u"ti1"e #ogniti!e defi#its that are suffi#ient"' se!ere to #ause i1airent in
o##u1ationa" or so#ia" fun#tioning.2 The #ogniti!e defi#its ust in!o"!e
eor' and other
#ogniti!e doains) ust re1resent a de#"ine fro 1reor3id fun#tion) and
#annot 3e attri3uted to de"iriu +see Cha1ter 4..
The #e""u"ar and o"e#u"ar e#haniss under"'ing the 1athogenesis of
!arious fors of deentia ha!e 3een e"a3orated in the "ast de#ade. A"though
there are an'
sii"arities) there are a"so i1ortant differen#es. Thus) the need for a
#"assifi#ation s'ste reains. Deentia #an 3e grou1ed into four a5or
#ategories6
degenerati!e)!as#u"ar) infe#tious) and eta3o"i# diseases.
DE(ENERATIVE DISEASES
A")%ei*er Disease
The ost fre/uent"' en#ountered deentia $as naed after A"ois A"(heier
3' 7rae1"in. A"(heier des#ri3ed the #"ini#a" features and the 1atho"ogi#
anifestations
of deentia in a 84,'ear,o"d $oan at the turn of the #entur'. 9or an' 'ears
A"(heier disease $as #onsidered a 1reseni"e for of deentia) "iited to
indi!idua"s
$ith s'1tos 3eginning 3efore the age of :8. Ho$e!er) su3se/uent #"ini#a")
1atho"ogi#) u"trastru#tura") and 3io#hei#a" ana"'ses indi#ated that A"(heier
disease is
identi#a" to the ore #oon seni"e deentia 3eginning after age :8.
Clinical Syndrome
The anifestations of A"(heier disease e!o"!e unifor"' fro the ear"iest
signs of i1aired eor' to se!ere #ogniti!e "oss. The #"ini#a" #ourse is
1rogressi!e)
terinating ine!ita3"' in #o1"ete in#a1a#it' and death. ;"ateaus soeties
o##ur< #ogniti!e i1airent does not #hange for a 'ear or t$o) 3ut
1rogression then
resues.
Meor' i1airent for ne$"' a#/uired inforation is the usua" initia"
1resenting #o1"aint) $hereas eor' for reote e!ents is re"ati!e"'
uni1aired at the
3eginning of the i""ness. As the disease 1rogresses) defi#its in "anguage)
a3stra#t reasoning) and e=e#uti!e fun#tion #an 3e e"i#ited on s1e#ifi# 1ro3ing.
Ma5or
de1ression $ith insonia or anore=ia o##urs in 8> to ?> of 1atients $ith
A"(heier disease unre"ated to se!erit'. De"usions and 1s'#hoti# 3eha!ior
in#rease $ith
1rogression of A"(heier disease and reain 1ersistent in @&>. Agitation a'
#oe=ist in u1 to @&>) in#reasing $ith ad!an#ed disease. Ha""u#inations o##ur
$ith
sii"ar fre/uen#' and a' 3e either !isua" or auditor'.
E=#e1t for the enta" state) the neuro"ogi# e=aination is usua""' nora") 3ut
e=tra1'raida" features) in#"uding rigidit') 3rad'Ainesia) shuff"ing gait) and
1ostura"
#hange) are re"ati!e"' #oon in "ater stages of the disease. ;riar' otor
and sensor' fun#tions are other$ise s1ared. O#u"ootor) #ere3e""ar) or
1eri1hera" ner!e
a3nora"ities on 1h'si#a" e=aination strong"' raise the 1ossi3i"it' of soe
other for of deentia.
Diagnosis
Criteria for the #"ini#a" diagnosis of A"(heier disease $ere esta3"ished 3' a
5oint effort of the Nationa" Institute of Neuro"ogi#a" and Couni#ati!e
Disorders and
StroAe and the A"(heier Disease and Re"ated Disorders Asso#iation in 4B?*
and are referred to as the NINCDS,ADRDA #riteria. These in#"ude a histor' of
1rogressi!e deterioration in #ogniti!e a3i"it' in the a3sen#e of other Ano$n
neuro"ogi# or edi#a" 1ro3"es. ;s'#ho"ogi# testing) 3rain iaging) and other
#riteria
esta3"ish three "e!e"s of diagnosti# #ertaint'. The designation of 0definite2
A"(heier disease is reser!ed for auto1s',#onfired disease. If there is no
asso#iated
i""ness) the #ondition is #a""ed 01ro3a3"e2 A"(heier disease< 01ossi3"e2 refers
to these $ho eet #riteria for deentia 3ut ha!e another i""ness that a'
#ontri3ute)
su#h as h'1oth'roidis or #ere3ro!as#u"ar disease. Co1aring the #"ini#a"
$ith the 1atho"ogi# diagnosis) the NINCDS,ADRDA #riteria 1ro!ide B&>
sensiti!it' for the
diagnosis of 1ro3a3"e or 1ossi3"e A"(heier disease and :&> s1e#ifi#it'. The
designation of definite A"(heier disease has 3een reser!ed on"' for auto1s',
#onfired
disease.
There are no s1e#ifi# #hanges in routine "a3orator' e=ainations.
Cere3ros1ina" f"uid +CS9. is nora") 3ut there a' 3e a s"ight in#rease in the
1rotein #ontent.
Cenera"i(ed s"o$ing is seen regu"ar"' on the e"e#troen#e1ha"ogra +EEC..
Neuro1s'#ho"ogi#a" testing #an dete#t inia" or su3t"e #ogniti!e i1airent
ear"' in the
disease) #an do#uent g"o3a" i1airent) or #an fo""o$ the #ourse of the
disease.
Di"atation of the "atera" !entri#"es and $idening of the #orti#a" su"#i) 1arti#u"ar"'
in the fronta" and te1ora" regions) #an 3e o3ser!ed using either #o1uted
toogra1h' or agneti# resonan#e iaging +MRI.) es1e#ia""' "ate in the
disease. Mi"d #orti#a" atro1h') ho$e!er) is seen in soe o"der indi!idua"s $ho
fun#tion
nora""' 3' #"ini#a" and 1s'#ho"ogi# testing. 9un#tiona" 3rain iaging studies)
in#"uding 1ositron eission toogra1h' +;ET.) sing"e,1hoton eission
#o1uted
toogra1h' +S;ECT.) or fun#tiona" MRI) sho$ h'1oeta3o"is in the
te1ora" and 1arieta" areas of 1atients $ith oderate to se!ere s'1tos.
Ceneti# tests a'
3e usefu" in the diagnosis of A"(heier disease in fai"ies $ith ear"',onset
autosoa" doinant fors of the disease. 9or s1oradi# or fai"ia" "ate,onset
A"(heier
disease) the e* 1o"'or1his of the a1o"i1o1rotein E gene has 3een
asso#iated $ith a higher risA of the disease 3ut does not 1ro!ide suffi#ient
sensiti!it' or
s1e#ifi#it' to 3e used for diagnosis and is not re#oended.
Epidemiology
Defore age :8) the 1re!a"en#e) or 1ro1ortion) of indi!idua"s $ith A"(heier
disease is "ess than 4>) 3ut this ra1id"' in#reases to 3et$een 8> and 4&> at
age :8 'ears
and to as high as %&> to *&> at age ?8 and o"der. The age,s1e#ifi#
in#iden#e) or the nu3er of ne$ #ases arising o!er a s1e#ifi# 1eriod of tie)
a"so rises stee1"'
fro "ess than 4> 1er 'ear 3efore age :8 'ears to :.&> 1er 'ear for
indi!idua"s aged ?8 and o"der. The a!erage duration of s'1tos unti" death
a' 3e 4& 'ears)
$ith a range of * to 4: 'ears. Disease duration tends to 3e "onger for $oen
than for en. Rates of A"(heier disease are s"ight"' higher aong $oen
than in en)
1art"' 3e#ause affe#ted $oen genera""' "i!e "onger than en do. Ho$e!er)
the in#iden#e rates for A"(heier disease are a"so s"ight"' higher in $oen)
es1e#ia""'
after age ?8 'ears. In fai"ies $ith at "east one affe#ted indi!idua") $oen
$ho are first,degree re"ati!es ha!e a higher "ifetie risA of de!e"o1ing
A"(heier disease
than en.
Genetic Basis of Alzheimer Disease
Man' fai"ies $ith autosoa" doinant A"(heier disease ha!e 3een
des#ri3ed. Si3"ings of 1atients ha!e t$i#e the e=1e#ted "ifetie risA of
de!e"o1ing the disease.
A"so) ono('goti# t$ins ha!e signifi#ant"' higher #on#ordan#e of A"(heier
disease than do di('goti# t$ins. Mutations in three genes) the a'"oid
1re#ursor 1rotein
+A;;. gene on #hroosoe @4) the 1reseni"in 4 +;S4. on #hroosoe 4*)
and the 1reseni"in @ +;S@. on #hroosoe 4) resu"t in an autosoa" doinant
for of the
disease 3eginning as ear"' as the third de#ade of "ife. The e=isten#e of o!er
8& different utations in ;S4 suggests that this a' 3e the ost #oon
for of fai"ia"
ear"',onset A"(heier disease. A;; utations #an "ead to enhan#ed
generation or aggregation of a'"oid,3eta) indi#ating a 1athogeni# ro"e. On
the other hand) ;S4
and ;S@ are distin#t fro the iediate regu"ator' and #oding regions of the
A;; gene) indi#ating that defe#ts in o"e#u"es other than A;; #an a"so "ead
to #ere3ra"genot'1e and 1henot'1e.
The e* 1o"'or1his of the a1o"i1o1rotein E +A;OE. gene on #hroosoe
4B has 3een asso#iated $ith the ore t'1i#a" s1oradi# and fai"ia" fors of
A"(heier
disease) usua""' 3eginning after age :8. In #ontrast to the disease,#ausing
utations in the A;; and ;S4E@ genes) the e* 1o"'or1his of A;OE is a
nora""'
o##urring !ariant of the gene that a11ears to signifi#ant"' in#rease
sus#e1ti3i"it' to the disease. In soe fai"ies $ith "ate,onset A"(heier
disease) in a fe$ fai"ies
$ith utations in the A;; gene) and in 1atients $ith Do$n s'ndroe) ea#h
A;OE e* a""e"e #an "o$er the age at onset of deentia. The asso#iation
3et$een the
A;OE e* 1o"'or1his and A"(heier disease is $eaAer aong Afri#an,
Aeri#ans and Cari33ean His1ani#s. Consistent $ith other genes in!o"!ed in
A"(heier
disease) a1o"i1o1rotein E a' a"so a#t through a #o1"e= and 1oor"'
understood re"ationshi1 $ith a'"oid. The a1o"i1o1rotein E 1rotein is an
o3"igator' 1arti#i1ant in
a'"oid a##uu"ation) and different a1o"i1o1rotein E 1rotein isofors
#orres1onding to 1o"'or1hiss e=ert at "east soe of their effe#ts 3'
#ontro""ing a##uu"ation.
A geneti# "o#us on #hroosoe 4@ has 1ointed to the 1ossi3i"it' of 'et
another sus#e1ti3i"it' gene for A"(heier disease. At "east t$o 1o"'or1hiss
in the gene
en#oding the a@,a#rog"o3u"in 1rotein ha!e 3een asso#iated $ith A"(heier
disease in these fai"ies. This #andidate gene has a"so 3een i1"i#ated in
a'"oid
#"earan#e. Thus) utations in at "east three genes are asso#iated $ith fai"ia"
A"(heier disease 3eginning 3efore age :8) and 1o"'or1hiss in t$o genes
are
asso#iated $ith sus#e1ti3i"it' to A"(heier disease after age :8 + Ta3"e 4&:.4..
TA+LE 106.1. CENETIC LOCI IN ALFHEIMER DISEASE
Other Risk Factors
Though in#onsistent) A"(heier disease has a"so 3een asso#iated $ith
trauati# head in5ur') "o$er edu#ationa" a#hie!eent) 1arenta" age at the tie
of 3irth)
soAing) and Do$n s'ndroe in a first,degree re"ati!e. In se!era"
o3ser!ationa" studies) the use of estrogen re1"a#eent thera1' in
1osteno1ausa" $oen and the
regu"ar use of anti,inf"aator' agents in 3oth en and $oen ha!e 3een
asso#iated $ith "o$er risAs of A"(heier disease and are #urrent"' 3eing
in!estigated in
randoi(ed #"ini#a" tria"s + Ta3"e 4&:.@..
TA+LE 106.,. RIS7 9ACTORS MOST CONSISTENTLY ASSOCIATED GITH
ALFHEIMER DISEASE
Pathology
A"(heier disease is #hara#teri(ed 3' atro1h' of the #ere3ra" #orte=. At
auto1s') the 1ro#ess is usua""' diffuse) 3ut it a' 3e ore se!ere in the
fronta") 1arieta") and
te1ora" "o3es +9ig. 4&:.4.. On i#ros#o1i# e=aination) there is "oss of 3oth
neurons and neuro1i" in the #orte=< soeties) se#ondar' de'e"ination is
seen in
su3#orti#a" $hite atter. Huantitati!e or1hoetr' suggests that the ear"iest
#e"" "oss o##urs in the entorhina" region of the edia" te1ora" "o3e. The ost
#hara#teristi# histo1atho"ogi# arAers are the argento1hi"i# seni"e 1"a/ues
and neurofi3ri""ar' tang"es.
-I(. 106.1. A"(heier disease. Diffuse atro1h' of 3rain) es1e#ia""' se!ere in
fronta") te1ora") and 1arieta" "o3es $ith s1aring of 1re#entra" and 1ost#entra"
g'ri.
+Courtes' of Dr. Ro3ert Terr'..
The seni"e neuriti# 1"a/ues are s1heri#a" i#ros#o1i# "esions that are 3est
seen $ith Die"s#ho$sA' stain< a #ore of e=tra#e""u"ar a'"oid is surrounded 3'
en"arged
a=ona" endings +neurites.. The a5or 1rotein in a'"oid is 3eta,1e1tide) $hi#h
is deri!ed fro A;;Ia transe3rane 1rotein. This 1rotein undergoes
1roteo"'sis)
resu"ting in the a##uu"ation of 3eta,a'"oid 1e1tide in 3rain) a Ae' ste1 in
the 1athogenesis of the disease. A'"oid is a generi# des#ri1tion a11"ied to a
heterogeneous grou1 of 1rotein 1re#i1itates that a' 3e de1osited in a
genera" anner throughout the 3od' +s'stei# a'"oids. or #onfined to a
1arti#u"ar organ
+e.g.) #ere3ra" a'"oid) rena" a'"oid.. In A"(heier disease) a'"oid is
de1osited around eningea" and #ere3ra" !esse"s and in gra' atter. The
gra' atter
de1osits are u"tifo#a") #oa"es#ing into i"iar' stru#tures Ano$n as 1"a/ues +
9ig. 4&:.@.. ;aren#h'a" a'"oid 1"a/ues are distri3uted in 3rain in a
#hara#teristi#
fashion) differentia""' affe#ting the !arious #ere3ra" and #ere3e""ar "o3es and
#orti#a" "ainae. A region of the A;; o"e#u"e resides $ithin an
intrae3ranous
doain of the neuron) and it is 3e"ie!ed that 1roteases) tered g,se#retases)
are res1onsi3"e for #"ea!age of a site residing $ithin a e3ranous doain.
At "east
one of these g,se#retases a' 3e under the #ontro" of ;S4E@. The generation
of high"' aggregata3"e 1e1tides is 3e"ie!ed to initiate the a##uu"ation of
a'"oid in a""fors of the disease.
-I(. 106.,. A"(heier disease. Le#t. ;roinent senia" 1"a/ues. Rig%t.
Se!era" neurons $ith neurofi3ri""ar' tang"es. Note a"so disru1tion of #orti#a"
organi(ation.
+Courtes' of Dr. Ro3ert Terr'..
Neurofi3ri""ar' tang"es are fi3ri""ar' intra#'to1"asi# stru#tures $ithin the
neurons and are) "iAe the 1"a/ues) a"so seen $ith the Die"s#ho$sA' stain.
E"e#tron
i#ros#o1' sho$s 1aired he"i#a" fi"aents. Aong the 1roteins $ithin affe#ted
neurons are 3eta,a'"oid and the tau 1rotein) a i#rotu3u"e 1rotein. A"though
neurofi3ri""ar' tang"es are not s1e#ifi# to A"(heier disease) the' o##ur first in
the hi11o#a1a" foration< "ater) neurofi3ri""ar' tang"es a' 3e seen
throughout the
#ere3ra" #orte= +Ta3"e 4&:.%..
TA+LE 106./. ;ATHOLOCIC CHANCES IN ALFHEIMER DISEASE
Other features of A"(heier disease in#"ude granu"o!a#uo"ar degeneration of
1'raida" #e""s of the hi11o#a1us and a'"oid angio1ath'. The Hirano 3od')
a rod"iAe
3od' #ontaining a#tin in a 1ara#r'sta""ine arra') $as first des#ri3ed in the
CuaJ1arAinsonisJdeentia #o1"e=< these neurona" in#"usions are a"so
found in
A"(heier disease. Soe in!estigators 3e"ie!e that #ogniti!e de#"ine
#orre"ates) not $ith in#reased nu3er of 1"a/ues 3ut $ith a de#rease in the
densit' of
1res'na1ti# 3outons fro the 1'raida" neurons in "aina III and I-)
es1e#ia""' in the idfronta" neo#orte=. Arterios#"eroti# #hanges are a3sent or
in#ons1i#uous in
ost #ases.
Dio#hei#a""') the ost #onsistent #hange is a 8&> to B&> redu#tion of the
a#ti!it' of #ho"ine a#et'"transferase) the 3ios'ntheti# en('e for a#et'"#ho"ine)
in the
#ere3ra" #orte= and hi11o#a1us. This en('e is found in #ho"inergi#
neurons) and there is a se"e#ti!e "oss of #ho"inergi# neurons) 1arti#u"ar"' of
the #ho"inergi#
1ro5e#tion 1ath$a') fro dee1 nu#"ei in the se1tu near the diagona" 3and of
Dro#a to the hi11o#a1us and fro the near3' 3asa" nu#"eus of Me'nert to
the #ere3ra"
#orte=. Aong the #ho"inergi# re#e1tor su3t'1es) M@Ia 1res'na1ti#
us#arini# re#e1torIdis1"a's de#reased 3inding in the 3rains of A"(heier
1atients. The
se!erit' of #ogniti!e "oss is rough"' 1ro1ortiona" to the "oss of #ho"ine
a#et'"transferase. There is de#reased #ontent of #orti#otro1in,re"easing fa#tor
and soatostatin)
3oth of $hi#h are found $ithin degenerating neurites of the neuriti# 1"a/ue.
C"utainergi# neurons a##ount for an' "arge neurons "ost in the #ere3ra"
#orte= and
hi11o#a1us) and there is !aria3"e "oss of as#ending and des#ending
serotoninergi# and adrenergi# s'stes.
reatment
Anti#ho"inesterases are #urrent"' the on"' U.S. 9ood and Drug AdinistrationJ
a11ro!ed treatents for A"(heier disease and) at 1resent) are #onsidered
1a""iati!e
treatents. Anti#ho"inesterases de#rease the h'dro"'sis of a#et'"#ho"ine
re"eased fro the 1res'na1ti# neuron into the s'na1ti# #"eft 3' inhi3iting
a#et'"#ho"inesterase) resu"ting in stiu"ation of the #ho"inergi# re#e1tor. At the
a=iu dosages of the t$o a11ro!ed drugs) ta#rine i1ro!es #ogniti!e test
1erforan#e s"ight"' ore than done1e(i". Done1e(i" s#ored s"ight"' 3etter in
the #"ini#iansK rating s#a"es) had fe$er side effe#ts) did not a"ter "i!er
transainases) and
#ou"d 3e gi!en on#e a da'. Though #urrent"' una!ai"a3"e in the United States)
ri!astigine and etrifonate #o1are $ith done1e(i" on #ogniti!e
1erforan#e) 3ut
ad!erse effe#ts ha!e 3een s"ight"' ore fre/uent.
Other drugs are a"so used. Doth a"1ha to#o1hero" and se"egi"ine are said to
de"a' the "ater stages of A"(heier disease. Un"iAe se"egi"ine) a"1ha
to#o1hero" does not
intera#t $ith other edi#ations) a""o$ing it to 3e used in ost 1atients $ithout
#on#ern. ;s'#hotro1i# drugs are fre/uent"' used to treat agitation) de"usions)
and
1s'#hosis in A"(heier disease. 9or de1ression) near"' a"" drugs are sii"ar in
effi#a#') 3ut there are on"' a handfu" of randoi(ed #ontro""ed studies u1on
$hi#h to
aAe thera1euti# de#isions.
-r$nt$te*0$ra" De*entias
;i#A disease is a 1rogressi!e for of deentia #hara#teri(ed 3' 1ersona"it'
#hange) s1ee#h distur3an#e) inattenti!eness) and soeties e=tra1'raida"
signs. In
#ontrast to A"(heier disease) ;i#A disease is rare. The disease #an 3e
fai"ia". Atro1h' of the fronta" and te1ora" 1o"es and arg'ro1hi"i# round
intraneurona"
in#"usions +;i#A 3odies. are the #hara#teristi# or1ho"ogi# #hanges. C"ia"
rea#tion is often 1ronoun#ed in affe#ted #ere3ra" gra' and $hite atter.
Tau,iunorea#ti!e g"ia" in#"usions and neuriti# #hanges are re#ogni(ed.
Dio#hei#a" and iuno#'to#hei#a" studies deonstrate that a3nora" tau
1roteins are
the a5or stru#tura" #o1onents of ;i#A 3odies and differ fro those seen in
A"(heier disease. As $ith other frontote1ora" deentias) ;i#A disease
sho$s
fi"aentous tau 1atho"og' that has 3een asso#iated $ith utations in tau
1rotein. Tau is a i#rotu3u"e,asso#iated 1rotein found ain"' in a=ons< it is
in!o"!ed in
i#rotu3u"e asse3"' and sta3i"i(ation.
9rontote1ora" deentias other than ;i#A disease are a"so rare and ha!e
3een asso#iated $ith utations on #hroosoe 4L in the tau gene. Se!era"
different
utations a##ount for a di!erse arra' of #"ini#a" anifestations in addition to
#ontri3uting to a #hara#teristi# 1atho"ogi# #hange o3ser!ed in A"(heier
disease6 the
neurofi3ri""ar' tang"e. Ta3"e 4&:.* "ists the diseases asso#iated $ith utation
in tau. 9rontote1ora" deentias are a"so #hara#teri(ed 3' 1ersona"it'
#hange)
deterioration of eor' and e=e#uti!e fun#tions) and stereot'1i#a" 3eha!ior.
E=tra1'raida" signs are usua""' 1roinent. Standard neuro1s'#ho"ogi# tests
and
#on!entiona" 3rain iaging su#h as MRI and S;ECT a' not 3e sensiti!e to
the ear"' #hanges in the !entroedia" fronta" #orte=. This suggests diffi#u"t' in
distinguishing this for of deentia fro other deentias ear"' in the i""ness.
O!er tie) ho$e!er) there are a3nora"ities on S;ECT) fronta" atro1h' on
MRI) or a
neuro1s'#ho"ogi# 1rofi"e ore t'1i#a" of frontote1ora" deentia.
18
Sleep and Quality of Life in
Alzheimers Disease
and the Dementias
Doug Neef and David Larson
Summary Sleep changes are inherent to dementia but dicult to de!ne or
measure" As the sleep changes in dementia are
probably related to neuronal changes in the brain# the location and severity of
these changes# manifested as di$erent clinical
dementias# a$ects the presentation of sleep pathology" %n the case of most
dementias# including Alzheimers dementia# the
sleep problems a$ect both the patient and the caregiver" &reatment involves a
multifaceted approach# including identi!cation
of treatable medical problems# correction of sleep hygiene# and identi!cation and
treatment of the particular form of dementia"
'holinesterase inhibitors seem to be emerging as the drug of choice for sleep
problems in dementia"
Keywords Dementia ( Alzheimers disease ( dementia )ith Le)y bodies (
cholinesterase inhibitors ( suprachiasmatic
nucleus *S'N+ ( normal aging
Learning objectives:
, Sleep changes are fre-uently seen in dementia but
are dicult to de!ne and measure in this population"
, Sleep changes in dementia are probably related to
speci!c neuronal changes in the brain" &he location
and severity of these changes# manifested as di$erent
clinical dementias# a$ect the presentation of sleep
pathology"
, &reatment of sleep disturbance in dementia involves
a multifaceted approach.identifying treatable
medical problems and correction of sleep hygiene#
as )ell as the identi!cation and treatment of the
speci!c form of dementia"
%ntroduction
Sleep problems are sometimes hard to de!ne even in healthy
patients# but )hen you add dementia and aging# these problems
become even harder to de!ne and harder to measure" /or
e0ample#
1" 1o) does one de!ne a sleep problem in a demented
patient2
3" 1o) does the clinician measure a sleep problem in a
demented patient2
4" Does the sleep problem bother the patient or the
caregiver2
5" %s it a sleep problem if it bothers the caregiver but not the
patient2
6" 7ho does the reporting# the patient or the caregiver2
8" Are caregiver reports ade-uate substitutes for patient
reports in patients )ith dementia2
9" 'an dementia patients accurately report a sleep problem2
8" 7hat type of dementia is it2
:" 1o) severe is the dementia2
1;" 7hat role do other factors *besides the dementia+ play in
the sleep problem2
Numerous other -uestions could be as<ed# and all )ould illustrate
the problems associated )ith current research involved
)ith sleep in dementia" %nvestigational studies must not only
de!ne the type of dementia# but also -uantify it# as di$erent
dementias in di$erent stages a$ect sleep di$erently" Similarly#
methods must be developed to both identify and -uantify
sleep problems in the di$erent forms of dementia" A useful
!rst step is identifying the several causes of sleep disruption
in the elderly and the demented )hich include= *i+ physiological
changes associated )ith >normal? aging@ *ii+ sleep
problems associated )ith physical or mental health problems
*>disease?+ and their treatment@ *iii+ primary sleep disorders@
*iv+ poor >sleep hygiene#? that is# poor sleepArelated practices
and habits@ and *v+ some combination of the above *1+" Sleep
changes in dementia are li<ely related to the degenerative
/rom= B" '" Cerster et al" *eds"+= Sleep and Quality of Life in Clinical Medicine
Dc 3;;8 1umana Eress# &oto)a# NB
166
168 Neef and Larson
neuronal changes in the brain associated )ith the di$erent
clinical dementia syndromes" &he location and severity of
those changes# manifested as di$erent clinical dementias#
a$ects the presentation of both the disease and the sleep
pathology" &reatment involves a multifaceted approach= identifying
treatable medical problems# correcting sleep hygiene#
as )ell as treating the particular form of dementia" %n this
chapter# )e )ill concentrate on the sleep changes associated
)ith Alzheimers disease *AD+ but also brieFy loo< at
sleep problems in other types of dementia such as dementia
)ith Le)y bodies *DLG+ and frontotemporal dementia */&D+#
realizing that recognition of the sleep problem could even
provide a helpful <ey in the di$erential diagnosis of dementia"
Sleep disturbances associated )ith early or mild dementia
seem to be an e0acerbation of the changes in >normal? aging"
Hn IIJ# aged normal subKects had less stage 4 and stage 5
sleep# less rapid eye movement *LIM+ sleep# and more )a<efulness
than normally found in young adults" Eatients )ith
AD had even less stage 4 sleep# no stage 5 sleep# very little
LIM sleep# and e0perienced fragmentation of their sleep#
)ith fre-uent a)a<enings *3+" &his decrease in slo) )ave
sleep *S7S+ and LIM sleep is manifested as the duration and
fre-uency of a)a<enings and more daytime napping increases
*1# 3+# and although the sleep disturbance seems to )orsen
)ith increasing severity of the AD *a linear relationship+# there
is a possible inverted NAshaped pro!le in )hich patients )ith
moderate dementia have more sleep impairment than persons
in the early or advanced stages of disease *4+" &his highlights
again the diculty characterizing sleep problems in
dementia# as problems can vary )ith both the type and severity
of dementia"
&he clinical changes in sleep associated )ith dementia
are li<ely related to damage to the neuronal path)ays that
initiate and maintain sleep# starting )ith the S'N of the
hypothalamus" As outlined by Citiello and Gorson# the S'N
is believed to be the >internal? cloc< that generates circadian
rhythms" %t does this independently of environmental cues
but uses light and physical activity# and perhaps social interaction
and food# to synchronize these internal rhythms )ith
our 35Ah day *1+" &he S'N has input path)ays that lin< it
to the retina# limbic forebrain# other hypothalamic nuclei# the
raphe nuclei# and reticular formation# and it also responds to
various hormones" &he output path)ays through )hich the
S'N controls circadian rhythms are not as )ell understood but
seem to proKect to other areas of the brain controlling sleep#
)a<efulness# and arousal" &he S'N also regulates the production
of the >sleep hormone? melatonin# through connections
to the sympathetic superior cervical ganglion and# in turn#
to the pineal gland *1# 5+" &here are also subcortical path)ays
that regulate arousal and sleepO)a<e cycles# including
cholinergic path)ays *basal forebrain nuclei+# serotonergic
path)ays *raphe nuclei+# dopaminergic path)ays *nigrostriatal
and pallidostriatal+# and noradrenergic path)ays *locus
coeruleus+" Eart of the pathophysiology of dementia is felt to
be due to neurodegeneration of these di$erent path)ays# both
at a pathologic and biochemical level# )ith di$erent lesions
manifesting as di$erent forms of dementia" &hus# di$erent
aspects of sleep and )a<efulness can be a$ected depending
on the type and severity of dementia and the neurons and
biochemical transmitters involved" 1o)ever# there is also
overlap bet)een the structures and neurotransmitters a$ected"
Nltimately# dementia pathology a$ects not only the cognitive
functions of the corte0 but also deeper portions of the brain
that control such functions as memory and arousal" %t is the
damage to these deeper neuronal path)ays that initiate and
maintain sleep that is the probable cause of the acceleration of
the normal ageArelated sleep changes found in dementia *1+"
&hus# ho) and )hen sleep problems manifest themselves
can depend on the type of dementia involved as )ell as
the stage of the dementia although these di$erences in
sleep pattern presentation sho) more variation during the
initial stages of dementias than they do during the later
stages of those same diseases" A helpful categorization of
dementias is outlined by Goeve and Saper *6+# )ho have
divided the dementias into three groups based on the protein
lesion involved" AD is primarily an amyloidopathy# )ith
pathological changes caused by deposition of the DAamyloid
protein" Eic< disease# corticobasal degeneration# and progressive
supranuclear palsy *ESE+ are tauopathies# )ith changes
to the tau protein" /inally# in Ear<insons disease *ED+# ED
)ith dementia *EDD+# DLG# and multiple system atrophy
*MSA+# lesions are composed of intracellular DAsynuclein and
are thus termed synucleinopathies" Although there is often a
mi0ture of more than one pathology *i"e"# mi0ed dementia+
and there can be an overlap of symptoms# especially later in
the disease process# this distinction seems helpful in understanding
the dementias in regards to their typical presentation"
Although sleep problems di$er some)hat )ith the di$erent
dementias# they tend to be similar )ithin a pathologic class"
&herefore# it is important to clarify both the type and degree of
dementia as both can a$ect the sleep presentation" Lesearch
into the area of sleep and dementia is comple0 because it
re-uires di$erentiation of the di$erent dementia types as
)ell as assessment of di$erent sleep symptoms" Although
most studies have been performed on AD patients# studies on
patients )ith other dementias are starting to appear"
Sleep Disturbance in Alzheimers Disease
Sleep disturbances in patients )ith dementia have been
described for several decades in the medical literature *8# 9+"
&he reported incidence of sleep disturbance in AD has been
reported to range from 39 to 5;P depending on the level of
cognitive disturbance in the population being studied *8# :+"
Sleep disturbance in patients )ith AD is often multifactorial
in etiology" %ndividuals )ith AD may have disordered sleep
due to coAmorbid conditions such as obstructive sleep apnea#
arthritis# heart failure# JILD# and nocturia" Additional factors
including medication side e$ects# depression# an0iety# and
18" Sleep and Quality of Life in Alzheimers Disease and the Dementias 169
delirium can all contribute to sleep problems in AD *1+" &hose
)ho care for individuals )ith AD may also su$er from disordered
sleep" &his may have a detrimental e$ect on -uality of
life measures for these individuals as )ell"
Description of Sleep Disturbance in AD
&here is gro)ing evidence that the neuropathologies of AD
disrupt the circadian cloc<s output and result in sleep disturbance
for many individuals a$ected by this disease" A recent
study e0amining brain tissue from individuals )ith AD noted
di$erential e0pression of the genes involved )ith rhythmic
production of melatonin in the pineal glands of individuals
)ith only histologic evidence of AD as )ell as those )ith
clinical evidence of AD" %t is believed that these changes
are caused by uncoupling of the pineal gland from S'N
control" %ndividuals )ith a more advanced stage of AD had
more pronounced changes *5+" &hese changes at the molecular
level appear to manifest as characteristic alterations in the
sleep behavior of a$ected patients" %ndividuals )ith AD are
more li<ely than the nonAdemented elderly *NDI+ to report
sleep problems *8+" 7hen compared to the NDI# individuals
)ith AD are noted to spend an increased amount of
time in bed ta<ing naps during the day# spend more overall
time in bed at night# and have more fragmented nighttime
sleep *1;# 11+" Sundo)ning or nocturnal delirium is another
entity fre-uently referred to )ithin this population in association
)ith sleep disturbances" Although this concept has
no consensus de!nition in the literature# it has been conventionally
used to describe behavioral changes that occur in
patients )ith dementia around the daily onset of dar<ness or
that follo) a diurnal pattern *13+"
%n 3;;4# a group of e0perts in the study of sleep changes
and dementia proposed a set of criteria for diagnosing
disturbances in the sleepO)a<e cycles of AD patients" A
brief summary of their proposed criteria follo)s" /irst# a
complaint regarding insomnia or increased daytime sleepiness
is e0pressed by the patient or is observed by the caregiver"
Second# polysomnography# actigraphy# or sleep log observations
demonstrate t)o of the follo)ing four=
1" Ipisodes of )a<efulness after sleep onset long enough or
fre-uent enough to a$ect the daily functioning or )ellbeing
of either the patient or caregiver"
3" A decrease in total sleep time that is e-ual to oneAfourth of
the patients total premorbid nighttime sleep or a pattern of
sleeping less than 8 h bet)een :=;; p"m" and 8=;; a"m" if
the premorbid sleep pattern is un<no)n"
4" Eoor daytime )a<efulness as evidenced by daytime
napping increased in duration andQor fre-uency compared
to the individuals premorbid state"
5" Disrupted sleepO)a<e rhythm evidenced by an altered ratio
of dayOnight sleep"
&he above changes are noted in association )ith a diagnosis
of probable AD# are not present prior to the beginning of the
dementia and evolve over the course of the disease" /inally#
the sleep disturbance is not fully accounted for by comorbid
general medical conditions# other sleep disorders# or parasomnias"
&hese guidelines )ere put forth in an e$ort to facilitate
the study of sleep disorders in the population a$ected
by AD *14+"
%mplications of Sleep Disturbance for Eatient
and /amily Members
Sleep disorders can diminish the patients -uality of life
and become a speci!c challenge to caregivers" AD patients
)ho engaged in nighttime behaviors such as eating# drin<ing#
)andering# and )a<ing up to tal< )ere more li<ely to be institutionalized
at 1 year )hen compared to AD patients )ho had
no reported sleep disturbance at baseline" Sleep problems have
been noted to correlate )ith increased aggression that is often
a pro0imal cause for institutionalization in this patient population
*:# 15+" 'aregivers report that being a)a<ened at night
is the sleepArelated symptom they !nd most disturbing *16+"
Among individuals )ith AD# increased time spent in bed is
associated )ith )orsened miniAmental status e0am *MMSI+
scores" Disordered sleep appears to be a mar<er for more rapid
progression of cognitive and functional de!cits in individuals
)ith AD" As the neuronal >hard)are? responsible for cognition
and daily function is damaged by the progression of AD#
sleep seems to decay in parallel *8# 18O18+"
/amily caregivers of the disabled elderly have been noted
to have an increased ris< for psychiatric morbidity due
to the strain associated )ith caregiving" %n addition# caregivers
e0periencing emotional or mental strain in conKunction
)ith their caregiving role have been reported to have
an increased ris< of mortality )hen compared )ith noncaregiving
controls *1:+" Eoor sleep among caregivers of
AD patients is associated )ith increased serum levels of
interleu<inA8 and !brin DAdimer# )hich have proinFammatory
and procoagulant e$ects" %t seems plausible that disturbed
caregiver sleep may place the caregiver at an increased ris<
for cardiovascular morbidity *3;+"
&reatment Strategies
&here are several approaches to the treatment of the sleep
disturbances characteristic of AD" &hese strategies consist
of therapy for any comorbid conditions that may be e0acerbating
sleep problems# nonApharmacologic therapy targeted
at sleep pathology# and pharmacologic interventions" As
an e0ample of the importance of treating comorbid conditions
that compromise sleep# recently published papers have
demonstrated that treating obstructive sleep apnea *HSA+ )ith
continuous positive air)ay pressure *'EAE+ is both feasible
and bene!cial for patients )ith dementia" &he presence of
dementia should not discourage clinicians from treating AD
patients )ho su$er from HSA )ith 'EAE *31# 33+" Despite
168 Neef and Larson
these promising !ndings# there is a paucity of patientAoriented
evidence regarding the value of many therapies currently used
for sleep problems in the population a$ected by AD *1+"
Non-Pharmacologic Strategies
I0perts in the !eld of sleep disturbance and dementia
have recommended multifaceted behavioral strategies for
improving sleep in patients )ith dementia" Many of these
strategies involve improvement of the sleepO)a<e cycle
through modulators of the circadian rhythm *34+" &he socalled
sleep hygiene practices to improve sleep include establishing
consistent daily times for going to bed and arising
from bed# establishing a bedtime routine# and limiting napping
to a brief time in the morning or early afternoon" %t may
also be helpful to add daytime activities such as e0ercise or
group interaction to the patients routine in lieu of daytime
naps" I$orts should be made to optimize the patients e0posure
to natural outdoor light as )ell as bright light in the
daytime living -uarters" &he use of alcohol and ca$eine
should be minimized" A light bedtime snac< may decrease
nocturnal a)a<enings related to hunger" /inally# the individuals
sleeping area should be as -uiet and dar< as possible
*35# 36+"
Light therapy has also attracted interest as a potential treatment
for sleep disturbance" &he goal of light therapy is to
e0pose the patient to increased amounts of natural or arti!cial
light" &his added light e0posure may provide input to the
S'N that )ill facilitate entrainment of the individuals circadian
cloc< to the 35Ah day" &his may be especially important
in institutionalized patients )ho receive suboptimal light
e0posure from their environment" Studies e0amining the ecacy
of light therapy have had mi0ed results" An intervention
that included caregiver education about sleep hygiene#
daily )al<ing# and light e0posure from an arti!cial light
source appeared to provide a bene!t in terms of decreased
number of nighttime a)a<enings# decreased total time a)a<e
at night# and decreased daytime sleepiness *38# 39+" %t seems
that behavioral interventions pose a minimal ris< of adverse
side e$ects to patients and should be considered the !rst line
of therapy for sleep disturbance in AD"
Pharmacologic Interventions
Data describing the safety and ecacy of medications for
sleep problems in the population a$ected by dementia are
scarce" Lecent# small trials have e0amined the e$ects of
cholinesterase inhibitors on sleep in patients )ith AD" &hese
studies used actigraphy and polysomnography to measure
patient response to treatment" %n both studies# there appeared
to be signi!cant trends to)ard improvement in sleepArelated
parameters as measured by IIJ and actigraphy *38# 3:+"
%t remains to be seen )hether or not treatment )ith this
class of medications )ill have a bene!t for these patients as
demonstrated by improvements in meaningful -uality of life
measures"
&ypical and atypical neuroleptic agents are often prescribed
for individuals )ith dementia to treat symptoms such as
aggression# agitation and psychosis" &he neuroleptics appear
to be useful for the shortAterm treatment of these symptoms"
Although it ma<es intuitive sense that the treatment of psychiatric
symptoms )ould improve sleep# the usefulness of this
class ofmedication for sleep in dementia is not <no)n *1+" &he
adverse e$ects of neuroleptics in the population of patients
)ith AD have been )ell described" &hese adverse e$ects
include e0trapyramidal symptoms# dro)siness# and possibly
e0cess mortality" Antipsychotic agents should be used Kudiciously#
if at all# in this population *4;O43+"
Genzodiazepines and the nonAbenzodiazepine hypnotics
such as zolpidem and zaleplon are fre-uently prescribed as
shortAterm sleep aids in the general population" &hey have not
been )ellAstudied in individuals )ith dementia# and it is dicult
to comment on their safety or ecacy in this population"
Sleep aids )ith anticholinergic activity such as the tricyclic
antidepressants and the sedating antihistamines may e0acerbate
the cholinergic abnormalities inherent to AD and should
be avoided *1+"
%n light of the disturbance in melatonin production that
has been described )ith AD# there has been considerable
interest in melatonin and melatonin receptor agonists as a
treatment for disordered sleep in AD" Studies of melatonin
replacement have had mi0ed results *44# 45+" Lamelteon#
a melatonin receptor agonist# has recently been brought to
mar<et" Although this represents a promising possibility for
the treatment of disturbed sleep in AD *46+# further research
is needed to determine the role this class of drugs )ill play in
the treatment of sleep disturbances related to AD"