Brain aging research at the close of the 20th century: from bench to bedside.

14 Pages·2001·0.28 MB·English

by  Cidis Meltzer, Carolyn

B a s i c r e s e a r c h
Brain aging research at the close of the 20th
century: from bench to bedside
Carolyn Cidis Meltzer,MD;Paul T.Francis,PhD
M
an (and woman) has long been fascinated with
the workings of the human mind.Yet it is only recently
that we have developed the tools to explore its biologi-
cal underpinnings in the living state.The 1990 to 2000
interval was hailed as the Decade of the Brain.Advances
in imaging,genetics,molecular biology,and pharmacol-
ogy continue to advance our horizons in neuroscience
research,but the scientific yield from these highly pro-
ductive past 10 years will surely both usher in the devel-
opments of the future and guide the research achieve-
Remarkable and continued growth in the field of brain ments to important clinical applications. The gap
aging research has been fueled by a confluence of fac- between bench and bedside is narrower than ever and,
tors. Developments in molecular biology, imaging, and importantly,there is increasing focus on not only length-
genetics coupled with the imperative caused by the ening the life span,but also improving the quality of
aging of the population has created fertile ground for mental and physical health in aging.
improved understanding of the interaction between
brain function and behavior. Aging changes in neuro- Anatomical and neurochemical systems
chemical systems may account for the spectrum of cog- affected by brain aging
nitive and behavioral states of successfully aged per-
sons, but may also contribute to enhanced vulnerability Imaging structural brain changes in aging
to depressive or dementing illness. In particular, the
refinement of in vivo imaging approaches to investi- Structural brain changes accompanying normal aging
gating the structure and function of the aging brain and neurodegenerative and psychiatric disorders may
has provided the opportunity to strengthen our knowl- parallel and provide insight into the etiology of changes
edge of the biological substrate of the aging brain and in cognition,mood,and motor function in the elderly.
neuropsychiatric disorders, and translate these into However,postmortem studies of brain morphology are
therapeutics. plagued by artifacts caused by changes in hydration
states just prior to death and tissue fixation.These stud-
ies are biased toward end-stage disease states and per-
mit only retrospective correlations with measures of
brain function and behavior.Magnetic resonance imag-
Keywords: Alzheimer’s disease; brain aging; depression; neurotransmitter; mag-
netic resonance imaging (MRI); positron emission tomography (PET) ing (MRI) offers a means of assessing structural brain
changes in vivo and provides the opportunity to evalu-
Author affiliations: Departments of Radiology and Psychiatry, University of Pitts-
ate the relationship of morphologic parameters to
burgh, Pittsburgh, Pa, USA (Carolyn Cidis Meltzer); Centre for Neuroscience
Research, GKT School of Biomedical Science, King’s College, London, UK (Paul T. mood,neuropsychological dysfunction,and treatment
Francis)
response.
Address for correspondence: Carolyn Cidis Meltzer, MD, University of Pitts- It is well known from both imaging and autopsy series
burgh Medical Center, PET Facility, B-938, 200 Lothrop Street, Pittsburgh, PA that cerebrospinal fluid (CSF) increases and cerebral
15213-2582, USA
volume reductions accompany normal human aging.1-8
(e-mail: [email protected])
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B a s i c r e s e a r c h
assessments.Preliminary findings support substantial
Selected abbreviations and acronyms
annual intrasubject whole-brain volume reductions esti-
AChE-I acetylcholinesterase inhibitor mated to average 5.5 mL,with 1.4 mL increases in total
AD Alzheimer’s disease CSF volume.11
APP amyloid precursor protein Nonspecific foci of increased white matter signal may be
CBF cerebral blood flow observed by MRI in normal individuals of all ages,but
CBV cerebral blood volume clearly increase in frequency with age,particularly after
ChAT choline acetyltransferase age 60.7,12,13Although of uncertain clinical significance,
CMR cerebral metabolic rate of glucose utilization these white matter hyperintensities have been found to
glc
CMR cerebral metabolic rate of oxygen be especially prevalent in persons with prominent risk
O2
CSF cerebrospinal fluid factors for cerebrovascular disease,particularly hyper-
GABA γ-aminobutyric acid tension.13-15 Pathologic correlates also point to an
HRT hormone replacement therapy ischemic basis for these lesions,16,17and blood flow reduc-
5-HT 5-hydroxytryptamine tions have been reported in association with white mat-
MRI magnetic resonance imaging ter hyperintensities.18-21Yet,whether white matter hyper-
NMDA N-methyl-D-aspartate intensities are associated with diminished cognitive
PET positron emission tomography function in aging is still unsettled.14,17,22
SPECT single-photon emission computed tomography Although substantial improvements in image processing
and quantitative methods have recently been made,there
are conflicting results among the numerous structural
Several studies have suggested that age-related volume MRI studies of the aging brain due to a number of fac-
loss tends to affect some brain regions more than others. tors.These include methodological differences in imaging
Jernigan et al1localized aging changes in brain volume data acquisition and analysis,small sample size,and selec-
to be most marked in the caudate nucleus,anterior dien- tion bias,such as failure to control for cerebrovascular
cephalic structures,association cortices,and mesial tem- risk factors.Still,morphologic changes in the brain that
poral structures,with no changes found in the thalamus accompany aging follow processes—often with substan-
and anterior cingulate cortex.Murphy et al6also found tial delay—that begin at the cellular level.For this reason,
significantly larger MRI-determined volume losses in investigative techniques that reflect functional or physio-
the caudate and lentiform nuclei than in the cerebral logic brain changes are typically more sensitive approach-
hemispheres in normal elderly men.These authors spec- es for identifying the earliest and potentially reversible
ulated that this finding was in accord with motor abnor- changes of healthy or pathologic aging.
malities encountered in the elderly.Similarly,preferen-
tial reductions in the size of the hippocampal formation Cell loss in normal aging
in normal aging have been shown to correlate with
delayed memory performance.9It is important to bear It was widely accepted that substantial neuronal loss
in mind that age-related cerebral volume loss is highly occurred during normal aging with values as high as 50%
variable among individuals and further accelerated by in some hippocampal subregions,and that this was like-
coincident medical illness.Conversely,DeCarli et al10 ly to be responsible for age-related decline in memory.
showed that temporal lobe volumes did notchange over Most early neuropathological studies used measures of
a range of 19 to 92 years of age,when only successfully neuronal density rather than cell number as the basis for
aged men were included. measurement of cell loss.However,with the more recent
Due to considerable intersubject variability of age-relat- application of stereological techniques to this field,it has
ed structural brain changes,cross-sectional study designs become clear that normal aging is not accompanied by
provide limited information about the rates and influ- significant global decline in neuronal number.23,24Within
ences on such alterations.In a unique effort to determine the hippocampus and associated cortical regions,there is
the annual rate of brain volume changes in the healthy no significant cell loss in entorhinal cortex,CA1,or tem-
elderly,the Baltimore Longitudinal Study of Normal poral cortex of the undemented elderly.25 Some age-
Aging has followed 94 elders with five annual MRI related cell loss does occur in the dentate gyrus and
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Brain aging research - Meltzer and Francis Dialogues in Clinical Neuroscience - Vol 3 .No.3 .2001
subiculum.It is,therefore,not possible to account for brovascular system to respond to vasodilatory chal-
memory deficits in the elderly in terms of cell loss alone. lenge,40thus diminishing the brain’s ability to compen-
The substrate for such change is more likely to be relat- sate for changes in systemic perfusion pressure and per-
ed to disruption of important hippocampal circuits short haps enhancing its susceptibility to ischemic damage.
of cell loss.Such changes include the presence of neuro- PET studies of brain glucose utilization have similarly
fibrillary tangles within the entorhinal cortex,25synapse demonstrated disagreement among reports as to
loss in the terminal zone of the perforant pathway of the whether brain function declines with age.In 1982,Kuhl
dentate gyrus,26changes to dendrites,disruption of long- et al41reported a gradual aging decline in the mean cere-
term potentiation,27and decreases in the expression of bral metabolic rate of glucose utilization (CMR ).
glc
the N-methyl-D-aspartate (NMDA) receptor in the mol- Later studies supported a regional preference for age-
ecular layer of the dentate gyrus.24 related reductions in brain glucose metabolism in the
frontal lobes,which were most marked after age 60.42,43
Age-related alterations in brain metabolism Duara et al,44however,found no relationship between
and perfusion age and regional CMR in healthy men.Large inter-
glc
subject variability in the neurobiologic effects of aging
Functional imaging tools, such as positron emission has been noted by several investigators.44,45 These
tomography (PET),single-photon emission tomography reports,individually limited by small sample sizes,sug-
(SPECT),133Xe- or xenon-enhanced computed tomogra- gest that aging effects on brain function are likely high-
phy (CT),and optical imaging have permitted in vivo ly variable,affected by structural brain changes and sys-
evaluation of brain perfusion and metabolic measure- temic factors,and may differ between “successful aging”
ments.Yet,whether generalized physiologic measures and individuals with substantial medical burden.
such as resting cerebral blood flow (CBF) are altered in
normal aging remains a point of controversy.Using the Alterations in neurotransmitter systems
133Xe inhalation method,which suffers from particularly
poor spatial resolution relative to other methods,sever- The functional integrity of several neurotransmitter sys-
al investigators have demonstrated a significant reduc- tems is altered by the aging process.Characterizing the
tion in mean CBF throughout the adult life span.28-31With profile of normal aging changes in neurotransmitter-
PET,Leenders et al32similarly demonstrated a decline of mediated synaptic processes is the foundation upon
0.5%/year in CBF,cerebral blood volume (CBV),and which we will come to decipher the biological basis of
cerebral metabolic rate of oxygen (CMRO ) in cortical behavioral and mood alterations accompanying aging.
2
brain regions. Several other investigators have also Further,the potential interaction between age effects
observed aging declines in CMRO,with a milder influ- and neurochemical disturbances associated with neuro-
2
ence of age on CBF and oxygen extraction.33-36 One psychiatric disease states may influence the susceptibili-
important potential confound in many of these studies is ty of the elderly to certain neurobehavioral disorders.
the diluting influence of age-related cerebral volume loss Our knowledge of the effect of age on neuroreceptor
on these measurements.Due to the limited spatial reso- function is primarily inferred by postmortem studies,with
lution of many functional imaging techniques,partial vol- limited and variable regional sampling of the brain,and
ume averaging of cortical signal with enlarged sulcal CSF by animal models,which may not appropriately represent
spaces can result in underestimation of metabolic para- human brain aging.In contrast to studies of pathological
meters in older subjects.37Applying MRI-based partial changes in aging,there are many problems associated
volume correction to [15O]water PET data,Meltzer et al38 with the biochemical study of neurotransmission in
recently demonstrated no reduction in cortical CBF in humans.These include the effects of postmortem delay,
healthy aging.This work challenges the interpretation of hypoxia,and drug treatment,as well as the fundamental
older studies,which did not account for this source of point that the material is removed most often removed
artifact that may dilute metabolic measures in the elder- following a terminal illness,which may itself influence
ly.39Although resting CBF may be normal in the suc- neurotransmission regardless of the age at which the
cessfully aged individual,age effects on small arterioles patient died.The reader is referred to a comprehensive
may reduce the autoregulatory capacity of the cere- review of the subject by DeKosky and Palmer.46
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With the development of highly selective radioligands cortex and striatum (as reviewed Palmer and
for neuroreceptors,transporters,and other markers of DeKosky52) and in acetylcholine synthesis in temporal
neuronal function,it is possible to study the effects of cortex.53Furthermore,there are decreases with age in
aging and disease on brain neurotransmitter systems in both muscarinic and nicotinic cholinergic receptors.54
vivo with PET.This approach permits whole-brain Using proton magnetic spectroscopy, Cohen et al55
quantitative imaging in well-characterized subjects, demonstrated reductions in the uptake of circulating
with the potential for obtaining longitudinal measures. choline with advancing age.Selective imaging ligands
Such work has demonstrated specific aging reductions for the cholinergic system have proved elusive.Howev-
in dopamine and serotonin (5-hydroxytryptamine er,PET studies with the relatively nonselective cholin-
[5-HT]) receptor subtypes (Figure 1).47-50Interestingly, ergic receptor ligands [11C]benztropine,[11C]tropanyl
there is evidence that some neuroreceptors actually benzilate, and [11C]-N-methylpiperidyl benzilate
increase in density with age,a finding of note in the (NMPB) have supported in vivo losses in muscarinic
opiate system.51PET techniques are desirable relative receptor density withage,although they disagree on the
to neuroendocrine challenge studies,which lack spatial magnitude of the reductions.56-58Also,modest reductions
localizing information and physiologic specificity. in cholinergic terminal density with aging have been
However,the combination of PET with neuropharma- demonstrated by SPECT imaging of the vesicular
cologic probes is a powerful technique for localizing acetylcholine transporter [123I]iodobenzovesamicol.59
and quantifying neurotransmitter-mediated function in
aging and disease. Monoaminergic systems
Cholinergic system There is wide variation in the response of monoaminer-
gic systems to aging.While postmortem studies show
There is considerable evidence for a presynaptic cholin- considerable loss of markers of the 5-HT system (5-HT,
ergic deficit during aging in many brain regions based 5-HT ,and 5-HT receptors),particularly in the neo-
1A 2A
on reductions in the enzyme responsible for the synthe- cortex,and of dopaminergic markers (dopamine,major
sis of acetylcholine,choline acetyltransferase (ChAT),in metabolites,transporter,and receptors) in the striatum,
Young normal Elderly normal
2.0
High r=0.93
n
o
ositi tial 1.5
p n
e te
al slic Mid ng po 1.0
xi di
a n
ns Bi 0.5
a
r
T
Low 0.0
Age (years)
Figure 1.[18F]Altanserin positron emission tomography (PET) imaging of the 5-hydroxytryptamine (serotonin) type-2A receptor (5-HT ). Left.
2A
[18F]Altanserin PET images (summed over 20 to 90 min postinjection and displayed with scale normalized to cerebellum) at three brain levels
in healthy subjects, aged 20 (left) and 66 (right). Right. Scatter plot demonstrates a linear decline in the binding of [18F]altanserin to 5-HT
2A
receptors in the lateral orbitofrontal cortex over the adult life span.
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Brain aging research - Meltzer and Francis Dialogues in Clinical Neuroscience - Vol 3 .No.3 .2001
there is little evidence of change outside those regions year-old humans.74Furthermore,spermine stimulation
or in markers of the noradrenergic system.52The devel- of [3H]MK801 binding via the polyamine site disappears
opment of selective imaging ligands for the 5-HT and by 80 years of age and zinc inhibition also declines with
dopamine binding sites has allowed these systems to be increased age.74Reduction in binding to one or more
further studied in humans in vivo. sites on the NMDA receptor complex with age may
PET studies confirm substantial aging reductions in spe- reflect losses of the entire receptor complex,a selective
cific binding to dopamine D and D receptors.47,48,60 loss of certain subunits,or both.There is some evidence
1 2
Further,alterations in cognition and coordination of from studies in mice that changes in receptor subunit
motor activity that frequently accompany aging have composition occur with age and may form the basis for
been shown to correlate with PET measures of changes in the affinity of certain binding sites.75
dopamine receptor function.61Aging losses of presynap-
tic dopamine transporter sites have also been demon- Influence of gender on brain aging
strated with PET and SPECT,suggesting that age affects
the integrity of dopaminergic neuronal pathways.62-65 The profound impact of sex steroids on brain structure
Recently developed PET ligands for several 5-HT and function is evidenced by sexual dimorphisms in
receptor subtypes and the 5-HT transporter have facili- brain organization and development,76which have been
tated in vivo imaging of this important neurotransmitter associated with gender-based differences in behavior
system,which is central to mood and sleep regulation.66,67 and learning.77Recent evidence of male–female differ-
Marked widespread aging reductions in binding of the ences in brain aging supports an ongoing dynamic rela-
pharmacologically well-characterized 5-HT receptor tionship between sex steroids and neural structure and
2A
using [18F]altanserin and [18F]setoperone have been function.This includes work by Honeycutt et al,78which
shown by several investigators.49,50,68The magnitude of demonstrates differential aging patterns for the mor-
the inverse relationship between age and 5-HT recep- phology of mesial temporal structures,particularly the
2A
tor binding supports the hypothesis that loss of seroton- amygdala, in men and women. In vivo evidence of
ergic function in aging may contribute to the suscepti- male–female differences in neuroreceptor distribution
bility of the elderly to alterations in mood and has been shown for 5-HT receptors,and a specific
2A
5-HT–mediated behaviors.Intriguing preliminary evi- age–gender interaction on 5-HT receptors has recent-
1A
dence suggests gender differences in the effect of age on ly been reported.69Gender preferences for psychiatric
the 5-HT receptor.69 disorders,particularly depressive illness,also support a
1A
biological underpinning for functional brain differences
Amino acid systems in men and women.Women clearly exhibit higher rates
of depression in early and middle adulthood, with
Glutamic acid decarboxylase,responsible for the syn- enhanced risk associated with surgical menopause and
thesis of γ-vinyl γ-aminobutyric acid (GABA),declines antiestrogen treatment for breast cancer.79,80However,
with age in cortex,hippocampus,and striatum,while there is evidence for a narrowing of the gender gap in
there is limited evidence for decreases in markers of the mood disorders in older middle adulthood,for which a
glutamatergic system (transporter and NMDA recep- neuroendocrine basis is speculated.81,82
tor).46,70It is,however,difficult to assess the status of the Animal models demonstrating a positive effect of estro-
presynaptic glutamatergic system since the neurotrans- gen on memory task performance,particularly working
mitter is a ubiquitous component of all cells.71 memory,83,84and the observation that normal hormonal
While no changes have been reported in [3H]MK801 cycling affects cognitive performance in women85-88sug-
binding (to the ion channel) from middle age to old age, gest a role for ovarian steroids in mediating cognitive
age-related changes in the ability of glutamate and function.However,variable outcomes have resulted
glycine binding sites to influence binding within the from clinical investigations of hormone replacement
channel have been observed.72,73For example,the abili- therapy (HRT) and cognition in aging women.In a com-
ty of glutamate and glycine to enhance [3H]MK801 munity-based study of over 700 postmenopausal
binding in the frontal cortex is reduced from a 44% women,Jacobs and colleagues89noted higher cognitive
increase in young adults to a 35% increase in 80- to 100- measures in HRT users relative to nonusers.They also
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found slight improvements in verbal memory perfor- tension and/or atherosclerotic disease may parallel and
mance over the follow-up interval.However,these find- provide insight into the role of cerebral ischemia in the
ings were not independent of age and education level. etiology of late-life depression,since an increased preva-
Other investigators have reported no clear beneficial lence of both cerebrovascular risk factors103and white
effect of estrogen replacement therapy on cognitive matter hyperintensities has been observed in elderly
function,90,91and no relationship between endogenous depressed patients,106particularly those with a late onset
estrogen levels on cognitive test performance.92,93(Inter- of their disease.22,104,107,108 These observations have led
estingly, an association between higher endogenous some investigators to postulate an MRI-defined vascu-
testosterone levels and cognitive performance has been lar or atherosclerotic form of depression,107,109which sup-
noted in women.92) It has been further suggested that a ports a strong link between aging and biological factors
lack of epidemiological evidence of gender differences in depression occurring in the elderly.Also,evidence for
in cognitive decline with aging argues against a link serotonergic control of the regulation of CBF110,111and
between estrogen deficiency and cognitive dysfunction.94 the potential influence of age on this regulatory mecha-
Research to date on male aging has been limited and the nism112 suggest an interaction—although as yet ill-
clinical relevance of the aging decline of testosterone defined—between disturbances in serotonergic function
levels in men is debated.95Although androgens clearly and risk of cerebral ischemic injury.
play a role in brain development and sexual brain Depression has been widely attributed to deficient 5-
dimorphisms, central mechanisms for modulating HT neurotransmission.In the unique setting of geriatric
human behavior are less well characterized (for a depression,age-related alterations in the 5-HT system
review,see reference 96).Androgen receptors are found may perturb its functional integrity and thus potential-
in many brain regions with particular localization to the ly contribute to the high prevalence and distinct char-
hippocampus,97where,similar to estrogen,they modu- acter of depression in late life.Postmortem studies have
late hyperpolarization of pyramidal cells in the CA1 reported conflicting findings of 5-HT receptor status in
region.98In healthy young men,testosterone levels have suicide victims.113-119In a small group of elderly nonsui-
been shown to correlate positively with spatial cognitive cide depressed patients, reductions in binding to 5-
function and negatively with verbal performance.99Ben- HT ,but not to 5-HT ,sites in temporal,frontal,and
2A 1A
eficial effects on spatial cognitive function in men have parietal cortex were reported using membranes.120
been associated with an optimal level of testosterone, Using autoradiographic techniques,the density (B )
max
with deterioration of performance observed at both for the 5-HT receptor was reduced by approximate-
1A
high and low levels.100Although the concept of testos- ly 40% in the superficial layers of frontal cortex (Brod-
terone supplementation remains controversial,random- mann area 9) from patients undergoing surgery for
ized,controlled trials of androgen replacement therapy intractable depression.71 It is also worth noting that
in healthy older men have demonstrated enhanced spa- there was a 30% to 40% reduction in the concentration
tial cognitive ability.101Overall,the potential benefits of of the 5-HT metabolite,5-hydroxyindoleacetic acid (5-
androgen replacement in elderly men appear to weigh HIAA), in the ventricular CSF of these depressed
favorably against minor potential added risks to cardio- patients,underlining the possible relationship between
vascular and prostate health.102 disturbances of serotonergic neurotransmission and
depressive symptoms.
Late-life neuropsychiatric disorders Evaluation of serotonergic function through imaging tech-
niques has offered a unique approach to evaluating the
Depression heterogeneity of depression in the elderly.In an attempt
to assign neurochemical specificity to the blood flow and
The association of evidence of disruption of structural metabolic disturbances reported in depression,121-123fluo-
brain integrity (eg,white matter lesions) and late-life, rodeoxyglucose (FDG) PET coupled with the 5-HT–
particularly late-onset,depression further underscores releasing agent dl-fenfluramine provided indirect yet in
the potential multiplicity of biological factors relevant to vivo evidence of serotonergic dysfunction in the prefrontal
depressive illness occurring in the elderly.103-105The corre- cortex in depressed patients,who exhibited a blunted
lation between white matter hyperintensities and hyper- response relative to healthy controls.124,125With the subse-
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Brain aging research - Meltzer and Francis Dialogues in Clinical Neuroscience - Vol 3 .No.3 .2001
nificance. A disease of aging, the financial and
social burdens of AD are compounded by recent and
continued increases in the average life span.129,130
It has been estimated that the prevalence of AD will
continue to climb at a rapid rate,with an expected qua-
drupling of cases in the United States over the next 50
years.130 Thus,the need for developing early diagnostic
markers to complement new therapeutic approaches is
more acute than ever before.Indeed,a modest goal of
instituting treatment that could delay disease onset by
Figure 2.Combined structural and functional imaging. The sagittal brain just 2 years would profoundly impact these projections,
image (left) illustrates the distribution of 5-HT transporter bind- resulting in 2 million fewer cases by 2050.
ing sites imaged with positron emission tomography (PET) and
[11C](+)-McN5652 (summed over 40 to 90 min postinjection).
High-resolution T1-weighted magnetic resonance imaging (MRI) Biological basis of Alzheimer’s disease
(middle) provides detailed anatomic information. However, the
coregistration of the PET and MRI depicted in the overlay image
Cell death and histopathological changes affecting a
(right) offers a unique combination of structural and functional
data. The localization of the raphe nuclei, which are not visible number of neuronal systems are considered to result in
by MRI alone, are functionally and anatomically defined by the the development of the typical symptomatology of AD
coregistered images.
characterized by gross and progressive impairments of
quent development of selective imaging agents for sero- cognitive function.The histopathological features are
tonergic receptor sites,it became possible to quantify cen- intracellular neurofibrillary tangles formed from a
tral 5-HT binding in depressed patients.Of particular hyperphosphorylated form of the microtubule-associat-
interest are the 5-HT and 5-HT receptors and the ed protein,tau,and extracellular deposits of a 40/42
2A 1A
5-HT transporter,which are all heavily implicated in the amino acid peptide,Aβ(derived from amyloid precursor
antidepressant response (Figure 2).There are few pub- protein [APP]),often in the form of senile or neuritic
lished studies to date of serotonergic PET imaging in plaques.Plaques,tangles,and cell loss have a character-
mood disorders and fewer conducted in elderly patients. istic regional and temporal distribution in the AD brain,
Biver et al126demonstrated a significant reduction in the affecting entorhinal,hippocampal,and temporal cortical
binding of [18F]altanserin to right orbitofrontal 5-HT structures first and frontal and parietal cortices later in
2A
receptors in a group of mid-life depressed subjects.How- the disease process,while sparing primary sensory and
ever,this agent failed to show a change in 5-HT recep- primary motor areas.131Indeed,this pathology is reflect-
2A
tor binding in late-life depression.127 Drevets et al128 ed in the characteristic regional pattern of blood flow
recently reported reductions in 5-HT binding of and metabolic disturbances demonstrated by PET or
1A
[11C]WAY100635 to mesiotemporal and brainstem raphe SPECT imaging in early AD.Evidence from biochemi-
areas in familial mood disorders including bipolar depres- cal studies also indicates that certain subcortical stuc-
sives.Whether this finding is generalizable to nonfamilial tures,including the nucleus basalis of Meynert and the
forms of mood disorders and late-life depression is yet dorsal raphe are also affected early in the disease.132
uncertain.The capability to selectively evaluate neuro- Most cases of AD are considered to be sporadic and
transmitter binding sites in vivo will likely continue to be therefore of unknown cause;however,there are a num-
a valuable tool for determining the biological underpin- ber of autosomal dominant mutations (Table I) that
nings of late-life depression and sources of treatment
response variability among patients. Chromosome Gene Number of Age of Proportion
mutations onset (years) cases
Alzheimer’s disease:breaking 21 APP 9 50s <0.5%
the disease barrier 14 PSI >40 40s 2%-4%
1 PS2 2 50s <0.5%
Alzheimer’s disease (AD),the most common form of
dementia,has enormous and growing public health sig- Table I. Genes causing Alzheimer’s disease (AD).
173
B a s i c r e s e a r c h
cause AD and several genetic risk factors, the best related to Braak staging.131Braak stages I and II are con-
known of which is apolipoprotein E (apo E) ε4 poly- sidered to represent the earliest presentation of AD
morphism,the presence of which carries an approxi- with neurofibrillary tangles in entorhinal cortex,and a
mately sixfold greater risk of developing AD.133While 20% to 30% loss in ChAT activity was reported in
the disease-causing mechanism behind apo E remains brains from patients at these stages of AD.139However,
controversial,most studies indicate that mutations in the another study using the Clinical Dementia Rating
genes APP,presenilin 1 (PS1),and presenilin 2 (PS2) (CDR) scale suggests that the greatest reduction in
alter the metabolism of APP so as to favor production markers of the cholinergic system occurs between mod-
of a long form of Aβ(Aβ1-42) (see,for example,refer- erate (CDR 2.0) and severe (CDR 5.0) disease with lit-
ence 134). tle change between nondemented and the mild stage
(CDR 0-2).140
Neurotransmitter changes in Alzheimer’s disease There has been a recent shift of emphasis regarding the
clinical significance of cholinergic deficits.Noncognitive
The majority of biochemical studies of AD have relied or neuropsychiatric,in addition to cognitive,symptoms
on information derived from postmortem brain,which also appear to have a cholinergic component.141 For
typically represents the late stage of the disease (8-10 example, visual hallucinations relate to neocortical
years after onset of symptoms).In these studies,there is cholinergic deficits,142such deficits (eg,loss of ChAT)
considerable evidence for multiple neurotransmitter being greater in dementia with Lewy bodies (DLB),
abnormalities affecting many brain regions.However, where hallucinations are common,than in AD,where
investigations of biopsy tissue taken from AD patients they are less common.143Reductions in cortical ChAT
3 to 5 years (on average) after the onset of symptoms activity in patients with dementia,in addition to corre-
indicate that a selective neurotransmitter pathology lating with cognitive decline,are also related to overac-
occurs early in the course of the disease.132 tivity and aggressive behavior.144
Acetylcholine.Changes affecting many aspects of the Glutamate.Although neurochemical studies of gluta-
cholinergic system in patients with AD have been mate neurotransmission have failed to demonstrate
reported since the initial discovery of deficits in ChAT extensive alterations,this may be related to the difficul-
activity in postmortem brains.135-137In biopsy samples ty in distinguishing the transmitter pool of glutamate
from AD patients,presynaptic markers of the choliner- from the metabolic pool.Nevertheless,glutamate con-
gic system were also uniformly reduced.132Thus,ChAT centration was reduced by 14% in temporal lobe biopsy
activity,choline uptake,and acetylcholine synthesis are samples and by 86% in the terminal zone of the per-
all reduced to between 30% and 60% of control values. forant pathway at autopsy of AD patients.145Uptake of
The clinical correlate of this cholinergic deficit in AD D-aspartate,a putative marker of glutamatergic nerve
was until recently considered to be cognitive dysfunc- endings,is also reduced in many cortical areas in the AD
tion.Such a conclusion was supported by clinicopatho- brain.146In addition,loss of synapses and pyramidal cell
logical studies in AD and parallel experiments in non- perikarya (both considered to be markers of gluta-
human primates or rodents, which demonstrated matergic neurones) from the neocortex of AD patients
disruptive effects of basal forebrain cholinergic lesions correlate with measures of cognitive decline.71Thus,addi-
on cognitive functions.Furthermore,cholinergic deficits tional factors other than impaired cholinergic function
in AD occur to the greatest extent in cortical areas pri- are likely to contribute to cognitive impairment in AD.
marily concerned with memory and cognition:the hip- However,it is important to remember that glutamater-
pocampus,adjacent temporal lobe regions,and selected gic neurons of the neocortex and hippocampus are influ-
frontal areas. Such studies led to the “cholinergic enced by acetylcholine through nicotinic and muscarinic
hypothesis of geriatric memory dysfunction.”138 receptors.147,148Thus,treatment of patients with choli-
On the basis of the above evidence,neocortical cholin- nomimetics is likely to increase glutamatergic function.
ergic innervation appears to be lost at an early stage of
the disease and this is supported by a recent study where Other neurotransmitters.In biopsy samples from AD
the cholinergic deficit (reduced ChAT activity) has been patients, some noradrenergic markers are affected,
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Brain aging research - Meltzer and Francis Dialogues in Clinical Neuroscience - Vol 3 .No.3 .2001
whereas markers for dopamine,GABA or somatostatin subtype of the nicotinic receptor,suggesting that cholin-
are not altered.When postmortem studies of AD brain ergic function through this receptor may be compro-
are considered many neurotransmitter systems,includ- mised because of high levels of (soluble) peptide in AD
ing GABA and somatostatin,are involved or are affect- brains.165
ed to a greater extent.71Changes in serotonergic neuro-
transmission seen at biopsy,postmortem,and recently in Translation of discoveries into therapeutics
vivo68,149may be linked to the behavioral disturbances of
AD,such as depression,rather than cognitive dysfunc- Biochemical studies in AD have generated a large num-
tion. For example, patients with AD who were also ber of therapeutic strategies for AD,many of which have
depressed had lower numbers of serotonin reuptake been tested in same-scale,inconclusive studies.Only a
sites in the neocortex than AD patients without this few strategies have gone on to full-scale clinical trials.
symptom.150Furthermore,both reduced serotonergic151,152 The best known of these is related to the cholinergic
and increased noradrenergic activities and sensitivi- deficit.Moreover,while there are a number of rational
ty153,154have been linked to aggressive behavior. approaches,including precursor loading and the use of
muscarinic or nicotinic agonists, the use of acetyl-
Neurotransmitter receptors.The majority of neurotrans- cholinesterase inhibitors (AChE-Is) is the most well-
mitter receptors appear to be unaffected in AD;howev- developed approach to the treatment of AD to date (Fig-
er,studies have demonstrated a reduced numbers of ure 3).166Tacrine underwent large-scale clinical studies
nicotinic and muscarinic (M ) acetylcholine receptors, and clearly established the benefits of AChE-I treatment
2
some of which are considered to be located on presy- in patients with a diagnosis of probable AD.Statistically
naptic cholinergic terminals. The M subtype is significant,dose-related improvements on objective per-
1
unchanged,but the coupling of the receptor to its G- formance-based tests of cognition,clinician- and care-
protein may be impaired.155,156 giver-rated global evaluations of patient well-being,and
A highly consistent receptor abnormality in AD is the also quality of life measures have been reported.167
loss of the nicotinic receptor,157-159which appears to pri- Tacrine was subsequently approved for use in some,but
marily reflect loss of the α4-containing subtype (gener- not all,countries.Adverse side effects,including raised
ally associated with α2),as opposed to α3 or α7 sub- liver enzymes,have limited the use of this compound.
types.160 Immunohistochemically, loss of α4 and α2 Further AChE-Is have been developed including
reactive fibers has been observed in temporal cortex, donepezil,rivastigmine,metrifonate,and galantamine.166
associated with reactive neuropil threads,tangles,and Such compounds demonstrate a clinical effect and mag-
plaques.161 nitude of benefit of at least that reported for tacrine,
but with a more favorable clinical profile including
Links between neurotransmission fewer and less serious side effects.Furthermore,evi-
and neuropathology dence is emerging from clinical trials of cholinomimet-
ics that such drugs may improve the abnormal noncog-
There is increasing evidence that various neurotrans- nitive,behavioral symptoms of AD.The cholinesterase
mitter systems are capable of influencing the metabo- inhibitors physostigmine,tacrine,rivastigmine,and met-
lism of APP,favoring nonamyloidogenic processing.162In rifonate have variously been reported in controlled tri-
particular, stimulation of muscarinic M receptors als to decrease psychoses (hallucinations and delu-
1
increases APP secretion,while decreasing β-amyloid sions),agitation,apathy,anxiety,disinhibition,pacing
production.163These results suggest that compounds and aberrant motor behavior,and lack of cooperation
developed for symptomatic treatment may have a in AD.141,168
serendipitous effect on the continuing emergence of
pathology by reducing the production of Aβ. Future directions: merging
Cholinergic neurotransmission may be a specific target technologies
for Aβ,since it has been shown to reduce both choline
uptake and acetylcholine release in vitro.164 Further- Investigational neuropharmacologic techniques com-
more,Aβis reported to bind with high affinity to the α7 prise a powerful and complementary collection of
175
B a s i c r e s e a r c h
A. Proposed neurochemical changes in AD B. Rectification of neurotransmission
with cholinesterase inhibitors
AChE inhibitors
1 1
AChE
AChE
ACh ACh
nAChR Cortical pyramidal neuron Cortical pyramidal neuron
3 sAPPα 3
mAChR sAPPα 5 tau tau- P
tau tau- P APP Aβ 6 2 APP Aβ 4
4 Glu 5
Glu 7
Glu
2
Glu
KEY KEY
1. Reduced cortical cholinergic innervation 1. AChE inhibitors reduce the breakdown of
2. Reduced corticortical glutamatergic neurotransmission due endogenously released ACh, resulting in greater
to neurone/synapse loss activation of postsynaptic ACh receptors
3. Reduced coupling of muscarinic M1 receptors Hypothesized consequences:
to second messenger system? 2. Reduced phosphorylation of tau
4. Shift of tau to the hyperphosphorylated state - precursor 3. Secretion of sAPPα returned towards normal
of neurofibrillary tangles 4. Reduced Aβ production
5. Reduce secretion of sAPPα 5. Glutamatergic neurotransmission returns towards normal,
6. Increased production of Aβ(cid:31) possibly due to activation of muscarinic and nicotinic receptors
7. Decreased glutamate production
* It is hypothesized that the above changes give rise to the clinical symptoms
of AD and contribute to the spread of pathology
Figure 3.Schematic diagram of a neuron representing (A) alterations in neurotransmission in Alzheimer's disease and (B) the hypothetical mode of
action of acetylcholinesterase inhibitors. ACh, acetylcholine; AChE, acetylcholinesterase; Glu, glutamate; mAChR, ACh muscarinic receptor;
nAChR; ACh nicotinic receptor; sAPPα, the alpha secretory product of amyloid precursor protein; Aβ, β-amyloid protein.
Reproduced from reference 166: Francis PT, Palmer AM, Snape M, Wilcock GK. The cholinergic hypothesis of Alzheimer's disease: a review of progress. J Neurol
Neurosurg Psychiatry.1999;66:137-147. Copyright © 1999,Journal of Neurology, Neurosurgery, and Psychiatry.
research tools for studying the effects of aging and dis- realize their potential combined power.For example,the
ease on regional and specific measures of brain function. recent availability of animal PET scanners presents the
These have allowed us to characterize both the normal opportunity for the in vivo study of genetic models of
neurochemical changes that accompany successful aging disease, such as AD. Further, neuropharmacologic
and the accelerated or aberrant alterations seen in neu- approaches to cognitive enhancement and slowing of
ropsychiatric and behavioral dysfunction.Future work dementia progression may be evaluated and monitored
will carry the findings of the past decade into the realm by imaging strategies.Indeed,the challenges posed by an
of intervention.Advancements in structural and func- increasingly aged population in industrialized nations
tional imaging naturally complement those in molecular are formidable,but may best be met by the combined
neurobiology and genetics,but we are just beginning to application of developing technologies.❑
176