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Neuroimaging Biomarkers ofNeurodegenerative Diseases and
DementiaShannon L. Risacher, PhD1 Andrew J. Saykin, PsyD1
1Center for Neuroimaging, Department of Radiology and
ImagingSciences, and Indiana Alzheimer Disease Center Indiana
UniversitySchool of Medicine, Indianapolis, Indiana
Semin Neurol 2013;33:386–416.
Address for correspondence Andrew J. Saykin, PsyD,
ABPP-CN,Department of Radiology and Imaging Sciences, Center
forNeuroimaging, Indiana University School of Medicine, IU
HealthNeuroscience Center, Suite 4100, 355 West 16th Street,
Indianapolis,IN 46202 (e-mail: [email protected]).
Neurodegenerative diseases and dementias feature progres-sive
and often irreversible degeneration of cells within thecentral
nervous system (CNS). Although primarily affecting
older adults, some forms of neurodegenerative disease (suchas
variant Creutzfeldt-Jakob disease [CJD], multiple sclerosis[MS],
and HIV-associated neurocognitive disorder [HAND])
Keywords
► neuroimaging► dementia► Alzheimer's disease
(AD)► mild cognitive
impairment (MCI)► frontotemporal
dementia (FTD)► amyotrophic lateral
sclerosis (ALS)► dementia with Lewy
bodies (DLB)► Parkinson's disease
(PD)► Huntington's disease
(HD)► multiple sclerosis
(MS)► HIV-associated
neurocognitivedisorder (HAND)
► Cruetzfeldt-Jakobdisease (CJD)
► Gerstmann-Straussler-Scheinker disease(GSS)
Abstract Neurodegenerative disorders leading to dementia are
common diseases that affectmany older and some young adults.
Neuroimaging methods are important tools forassessing and
monitoring pathological brain changes associated with
progressiveneurodegenerative conditions. In this review, the
authors describe key findings fromneuroimaging studies (magnetic
resonance imaging and radionucleotide imaging) inneurodegenerative
disorders, including Alzheimer’s disease (AD) and prodromal
stages,familial and atypical AD syndromes, frontotemporal dementia,
amyotrophic lateralsclerosis with and without dementia, Parkinson’s
disease with and without dementia,dementia with Lewy bodies,
Huntington’s disease, multiple sclerosis,
HIV-associatedneurocognitive disorder, and prion protein associated
diseases (i.e., Creutzfeldt-Jakobdisease). The authors focus on
neuroimaging findings of in vivo pathology in thesedisorders, as
well as the potential for neuroimaging to provide useful
information fordifferential diagnosis of neurodegenerative
disorders.
Issue Theme NeurodegenerativeDementias; Guest Editor, Brandy
R.Matthews, MD
Copyright © 2013 by Thieme MedicalPublishers, Inc., 333 Seventh
Avenue,New York, NY 10001, USA.Tel: +1(212) 584-4662.
DOI http://dx.doi.org/10.1055/s-0033-1359312.ISSN 0271-8235.
386
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mailto:[email protected]://dx.doi.org/10.1055/s-0033-1359312http://dx.doi.org/10.1055/s-0033-1359312
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can affect younger individuals.1,2 With disparate, but
some-times overlapping clinical presentations and
etiologies,neurodegenerative disorders and dementias can be
difficultto correctly diagnose. Neuroimaging techniques have
thepotential to assist with clinical diagnosis and monitoring
ofdisease progression in most, if not all, of the
neurodegenera-tive disorders. Our goal here is to provide an
overview ofneuroimaging findings in the most common
neurodegenera-tive conditions, as well as recent developments in
each area(►Table 1).
Degenerative Diseases and Dementias
Alzheimer’s disease (AD) is the most common
age-relatedneurodegenerative disease, affecting more than 5
millionindividuals in the United States, mostly age 65 or older,
andthat number is expected to more than triple by 2050.3
Theearliest clinical symptoms are memory impairments, particu-larly
in episodic and semantic domains, as well as deficits inlanguage
and executive functioning.4 Patients with AD alsoshow a significant
impairment in daily functioning withdisruption or cessation of the
ability to perform complexactivities and later more simple tasks.
Clinicians and research-ers have recently updated AD diagnostic
criteria for use inclinical practice and research.4 Currently, the
diagnosis of AD ismade clinically, based on cognition and the
relative impact ofimpairments on daily activities. Attempts to
diagnose AD at anearlier stage have led to the development of a
clinical syn-drome termed amnestic mild cognitive impairment
(MCI).5
Recently, new criteria for diagnosis of MCI in clinical
andresearch settings have been published.6 Patients with
MCItypically show deficits in episodic memory that fall morethan 1
standard deviation below age and education adjustedand culturally
appropriate normative levels.6 More recently,researchers have
proposed dividing MCI into an earlier stage(earlyMCI [E-MCI]) and a
later stage (lateMCI [L-MCI]), with E-MCI patients showing a 1 to
1.5 standard deviation memorydeficit and L-MCI showing a greater
than 1.5 standard devia-tion deficit. This classification has only
recently been intro-duced and future studies will help to elucidate
differencesbetween these MCI subgroups. The most common
presenta-tion of MCI features memory impairment (amnestic MCI),
butcan co-occur with other cognitive deficits such as
executivefunction or language deficits (multidomain MCI).6
AmnesticMCI is widely considered to be a prodromal form of AD,
asnearly 10 to 15% of amnestic L-MCI patients convert to proba-ble
AD each year, relative to only 1 to 2% of the general olderadult
population.5 Recently, researchers and clinicians havebeen
attempting to detect AD-related changes and predictprogression even
earlier than MCI (e.g., pre-MCI or preclinicalAD). A conceptual
framework for identifying preclinical ADpatients has been presented
in a recent article.7
Alzheimer’s disease is characterized by two neuropatho-logical
hallmarks: amyloid plaques and neurofibrillary tangles.Amyloid
plaques are extracellular aggregations of the amyloid-β (Aβ)
peptide that are found throughout the brain of ADpatients.
Neurofibrillary tangles result from the hyperphos-phorylation of
the microtubule-associated protein tau, which
forms insoluble filamentous structures that combine to
createpaired helical filaments, a key component of the
neurofibril-lary tangles seen in the brains of patients with AD.
Thetemporal relationship and direct link between amyloid pla-ques
and neurofibrillary tangles is not completely elucidated atthis
time. Current theories suggest that amyloid plaque forma-tion
precedes neurofibrillary tangles, with amyloid accumula-tion
occurring during a long preclinical period lasting years
todecades.8 The biochemical processes involved in
Alzheimer’sdisease development ultimately converge upon
widespreadcell death and neuronal loss, likely through apoptosis.
The firstregions of the brain to show neuronal loss associated with
ADare in themedial temporal lobe (MTL), including the
entorhinalcortex, hippocampus, amygdala, and parahippocampal
cortex,as well as cholinergic innervations to the neocortex from
thenucleus basalis of Meynert.9 By the time a patient has reacheda
diagnosis of AD, neurodegeneration is usually foundthroughout the
neocortex and subcortical regions, with signif-icant atrophyof the
temporal, parietal, and frontal cortices, butrelative sparing of
the primary occipital cortex and primarysensory–motor regions.9
Although the majority of AD cases represent late-onset
orsporadic AD, nearly 5% of AD cases are caused by
dominantlyinherited genetic mutations, usually in one of three
genes:amyloid precursor protein (APP), presenilin 1 (PS1), or
pre-senilin 2 (PS2). Often featuring an onset of symptoms that is
atan earlier age than sporadic AD patients (i.e., before age
65),these cases are referred to as familial AD or early-onset
AD.Although these diseases can show somewhat different
symp-tomology and pathology than late-onset AD, the major
ADhallmarks (i.e., amyloid plaques, neurofibrillary tangles)
arepresent. Therefore, these patients may represent a usefulsample
for studying early changes in biomarkers, particularlybecause the
age of symptom onset tends to be consistentacross generations.
Therefore, using an estimated age ofsymptom onset (EAO), changes in
neuropathology and cog-nition can be assessed using biomarkers
decades before onsetof disease.10 Other diseases associated with AD
neuropathol-ogy show atypical presentation, including posterior
corticalatrophy (PCA) and logopenic aphasia. Posterior cortical
atro-phy is a disorder of higher visual function that
causessignificant visual dysfunction in the absence of ocular
disease,as well as constructional apraxia, visual field deficits,
andenvironmental disorientation.11,12 This disorder is
primarilythought to be associated with changes in posterior
brainregions, including the parietal and occipital lobes.
Logopenicaphasia is a type of primary progressive aphasia (PPA)
associ-ated with AD (i.e., amyloid) rather than
frontotemporaldementia- (FTD-) like pathology and features
impairedword retrieval and sentence repetition in the absence
ofmotor speech or grammatical abnormalities.13 Cerebral amy-loid
angiopathy (CAA) is also associatedwith AD-like amyloidpathology.
However, amyloid deposits are largely observed inthe walls of small
cerebral arteries and capillaries in CAA.14
Patients with CAA often show cognitive decline,
seizures,headaches, and stroke-like symptoms.15
Vascular dementia and vascular-associated cognitive im-pairment
(VCI), a form of cognitive impairment with notable
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Neuroimaging Biomarkers of Neurodegenerative Diseases and
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Table 1 Brief Summary of Neuroimaging Findings in Selected
Neurodegenerative Diseases and Dementias
Disease Clinicalsymptoms
Atrophypattern
Functionalactivation/connectivitychanges
Molecularchanges
Otherimaging
SporadicAlzheimer’sdisease (AD)
Memory decline;Impairment in othercognitive
domains;Dementia/Functional decline
MCI/mild AD:Atrophy of MTL(Hipp, EC)More advanced AD:Atrophy of
frontal,temporal, & parietallobes
" or ↓ activation oftask-related regionsduring cognitivetasks↓
connectivity ofbrain networks(e.g., DMN)
[18F]FDG:↓ metabolism intemporoparietalregionsAmyloid PET
positive↓ ACh, GABA,5-HT, & DAneurotransmission"
activatedmicroglia?
MRS: ↓ NAA," mInsDTI: Widespreadatrophy of frontal,temporal,
& parietalwhite matter tractsASL/SPECT:↓ perfusion
oftemporoparietal regions
Familial AD Decline in memoryand other
cognitivedomains;Dementia/Functional decline
Atrophy in the MTL(Hipp, EC), lateraltemporal lobe, andparietal
cortex
" or ↓ activation oftask-related regionsduring cognitivetasks"
and ↓ connectivityof DMN network
[18F]FDG:↓ metabolism intemporoparietalregionsAmyloid PET
positive– sporadic AD-likepattern plus striatalbinding
DTI: Reduced integrityof fornix, CC, cingulum,and subcortical
whitematter tractsSPECT:↓ perfusion oftemporoparietal regions
Posteriorcortical atrophy
Visual andvisuospatial deficits
Atrophy of posteriorbrain regions (posteriortemporal,
parietal,occipital lobes)
n/a Amyloid PET positive DTI: ↓ white matterintegrity in ventral
visualprocessing streamASL/SPECT:↓ perfusion inoccipitoparietal
lobe, "in frontal lobe,anterior cingulate,mesiotemporal lobe
Logopenicaphasia
Impaired language(word retrieval,sentence repetition)
Atrophy of posteriortemporal lobe,temporoparietal lobe,medial
parietal lobe,MTL (left > right)
n/a [18F]FDG:↓ metabolism lefttemporoparietallobeAmyloid PET
positive
DTI: ↓ white matterintegrity in lefttemporoparietal
regionASL/SPECT:↓ perfusion in lefttemporoparietal lobe
Cerebralamyloidangiopathy
Cognitive/functional declinein any domain
Generalized cerebralatrophy with
cerebralmicrohemorrhages,microbleeds, and
otherischemic-relatedchanges
Altered vascularreactivity duringvisual stimulation
Amyloid PET positive SPECT: ↓ perfusion inparietal, temporal,
andfrontal lobes
Vasculardementia
Significantcognitive declinein any domaincoupled withvascular
event
Atrophy of the cerebralcortex and
MTL;ischemic-relatedchanges(i.e., white matterlesions)
↓ Activation andaltered blood flow-metabolic
couplingduringcognitive and motortasks↓ Connectivity in
theposterior cingulate
[18F]FDG:↓ metabolism infrontal and parietallobesAmyloid
PETnegative
DTI: ↓ white matterintegrity in widespreadcortical regions (even
innormal appearing whitematter)ASL/SPECT:↓ perfusion in frontaland
parietal lobes
Behavioralvariant FTD
Personality andbehavior changes(disinhibition,apathy, loss
ofempathy, etc.)
Atrophy in the frontallobe, anterior cingulate,anterior
insula,thalamus
↓ Activation infrontal and parietallobe during
workingmemory;altered activationduring emotionaltasks↓ Connectivity
inbasal ganglia, frontallobe(i.e., saliencenetwork)
[18F]FDG:↓ Metabolismfrontal lobeAmyloid PETnegative
DTI: ↓ white matterintegrity in frontal andtemporal
lobesASL/SPECT:↓ perfusion in frontaland parietal lobes
Semanticdementia
Impaired language/fluency (fluentaphasia, anomia,etc.)
Asymmetrical atrophyof the anterior, medial,& inferior
temporallobes(left > right)
Altered activationduring sound,memory, & languagetasks↓
connectivity infrontotemporal andfrontolimbicnetworks;"
connectivity in PFC
[18F]FDG:↓ Metabolism in theleft anteriortemporal lobeAmyloid
PETnegative
DTI: ↓ white matterintegrity in bilateral(left > right)
temporallobesASL/SPECT:↓ perfusion in the leftanterior temporal
lobe
Progressivenonfluentaphasia (PNFA)
Impaired language(difficulty in speechproduction,
Mild PNFA: Atrophy inleft inferior frontal,insula, premotor
cortex,temporal lobe
↓ Activation duringsentence readingand comprehension
[18F]FDG:↓ metabolism in thefrontal lobe, insula,motor areas
DTI: ↓ white matterintegrity in frontal lobe,insula, &
superior motorpathway
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Table 1 (Continued)
Disease Clinicalsymptoms
Atrophypattern
Functionalactivation/connectivitychanges
Molecularchanges
Otherimaging
agrammatism,apraxia of speech)
Advanced PNFA:Atrophy spreads toinclude temporal andparietal
lobes, caudate,and thalamus
Amyloid PETnegative (exceptthose with Pick’sdisease)Reduced
striatal DA
ASL/SPECT:↓ perfusion in the leftanterior temporal lobe
FTD with motorneuron disease(FTD-MND/FTD-ALS)
Behavioral/languageimpairments withmotor dysfunction
Atrophy of frontal andtemporal lobes, anteriorcingulate,
occipital lobe,precentral gyrus
↓ Activation infrontal lobe, anteriorcingulate,
temporallobe,occipitotemporallobe during verbalfluency andemotional
taskAltered connectivityin sensorimotor,motor,
&frontoparietalnetworks
[18F]FDG:↓ metabolism in thefrontal andtemporal lobes,basal
ganglia,thalamusReduced frontal lobe5-HT bindingReduced
GABA-Areceptors in cerebralcortex and insula
DTI: ↓ white matterintegrity in CC, CST,cingulum, frontal
lobewhite matter tractsASL/SPECT:↓ perfusion frontal andtemporal
lobes
Amyotrophiclateral sclerosis
Motor dysfunction Atrophy of motor andextramotor regions(i.e.,
precentral gyrus)
" or ↓ activation oftask-related regionsduring motor
&emotional tasksAltered connectivityin sensorimotor &motor
networks,DMN
[18F]FDG:↓ corticalmetabolismReduced DA andGABA cells in
thebasal ganglia &substantia nigra" activated microgliain CST
and extra-motor regions
MRS: ↓ NAA," mIns, choline, Glmn,GlmtDTI: ↓ white
matterintegrity in CC, CST,PLIC, cingulum, frontal& temporal
whitematter tractsASL/SPECT:↓ cortical perfusion
Parkinson’sdiseasedementia(PDD)/dementia withLewy
bodies(DLB)
Motor dysfunctionwith cognitiveimpairment(spontaneous
motorparkinsonism, visualhallucinations, etc.)
Widespread cortical andsubcortical atrophy
" or ↓ activationduring visual tasksAltered global
andlocalcortico-connectivity
[18F]FDG:↓ metabolism in thebasal ganglia,cerebellum,
andcerebral cortexSome amyloid PETpositive↓ striatal DA
&cortical AChneurotransmission
MRS: ↓ NAA/Cr↓ Glmn/GlmtDTI: ↓ white matterintegrity in
temporallobe, medial parietallobe, visual
associationareasASL/SPECT:↓ perfusion in posteriorcortex
Parkinson’sdisease(no dementia)
Motor dysfunction(spontaneous motorparkinsonism,
visualhallucinations, etc.)
Less atrophy than inPDD/DLB but with asimilar
anatomicdistribution
Similar but less se-vere functional andconnectivitychanges to
thoseseen in PDD/DLB
[18F]FDG:↓ metabolism in thebasal ganglia,thalamus, andcerebral
cortex↓ DA, 5-HT, ACh,GABA, opoidneurotransmission" activated
microgliain striatal andextrastriatal regions
Similar but less severechanges on MRS, DTI,and ASL/SPECT to
thoseseen in PDD/DLB
Huntington’sdisease
Motor dysfunctionwith
cognitiveimpairment(bradykinesia,incoordination, etc.);linked to
mutation inHTT gene
Atrophy of striatum,cerebral cortex,cingulate, thalamus,and
white matterregions
" or ↓ activationduring motor &cognitive tasksAltered
connectivityin cortical-striatalnetwork& DMN
[18F]FDG:↓ corticalmetabolism↓ DA receptors" activated
microgliain striatum,extra-striatalregions,hypothalamus
DTI: ↓ integrity infrontal lobe,sensorimotor cortex,CC, internal
capsule, andbasal ganglia
Multiplesclerosis (MS)
Heterogeneoussymptoms(autonomic, visual,motor, &/or
sensorydysfunction)
Focal hyperintenselesions in white matteron T2-weighted
scans;cerebral and cerebellaratrophy
" or ↓ activationduring memory,attention, andexecutive
tasksAltered connectivityin salience, workingmemory,sensorimotor,
visualnetworks, & DMN
[18F]FDG:↓ metabolism inthalamus, deep graymatter structures,
&frontal lobe" activated microgliain normal andlesioned gray
matterand white matter
DTI: ↓ integrity ofnormal and lesionedwhite matter and
graymatterASL/SPECT:↓ cerebral perfusion
HIV-Associatedneurocognitivedisorder
Impairment inexecutive function,motor
speed,attention/workingmemory andepisodic memory;
Gray matter atrophy inanterior cingulate,lateral temporal
lobe,and cerebral cortex;Cortical thinning inprimary motor and
" or ↓ activationduring memory,attention, executivefunction, and
motortasksAltered connectivity
[18F]FDG:↓ corticalmetabolism but "metabolism in thebasal
ganglia
MRS: ↓ NAA, " mIns,choline, choline/Cr,mIns/Cr in frontal
graymatter, white matter,and basal gangliaDTI: ↓ integrity in
(Continued)
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cerebrovascular pathology and/or risk factors, can be
identi-fied using self-reports of stroke and/or other vascular
eventsor diseases (myocardial infarction, atherosclerosis,
hyperten-sion, etc.), neurologic and psychometric evaluation,
and/orstructural and functional imaging techniques. The
majorrequirements for a diagnosis of vascular dementia or
vascu-lar-associated MCI include the presence of clinically
signifi-cant cognitive impairments, which can be in any
cognitivedomain, but are commonly observed in executive
functionand/or memory, and the presence of significant
cerebrovas-cular pathology and/or risk factors, assessed using
clinical orneuroimaging techniques. Beyond these requirements,
pa-tients are diagnosed by clinical severity and the impact
onactivities of daily living (ADLs), similar to the diagnosis of
AD.Specifically, patients diagnosed with vascular-associated
MCImust show a cognitive deficit, but no significant impairmentin
ADLs, whereas a diagnosis of vascular dementia requiressignificant
impairment in both clinically assessed cognitivestatus and
ADLs.
Frontotemporal dementia (FTD) is an overarching diagno-sis that
encompasses multiple disorders with varying symp-toms. Behavioral
variant FTD (bvFTD) is characterized by achange in personality and
behavior, disinhibition, apathy, lossof empathy,
obsessive–compulsive behaviors, and changes inappetite.13,16,17
Behavioral variant FTD is most commonlyassociated with pathological
tau accumulation, such as seenin Pick’s disease, but can also
feature accumulation of a TAR-DNA-binding protein called
TDP-43.13,17 Primary progressiveaphasia (PPA) is another form of
FTD, which is divided intotwo forms: semantic dementia (SD) and
progressive non-fluent aphasia (PNFA). Semantic dementia features
fluentaphasia, anomia, and single-word comprehension deficitsand
later in the disease course behavioral symptoms similarto those
seen bvFTD. Pathologically, TDP-43 accumulation
usually underlies SD, but rare cases featuring tau
pathologyassociated with Pick’s disease have been observed.13,17
Pro-gressive nonfluent aphasia features speech production
diffi-culties with agrammatism and apraxia of speech, as well
asphonemic errors, anomia, and impairments in
sentencecomprehension.13 Progressive nonfluent aphasia
typicallyfeatures changes due to tau pathology, although
mutationsin the progranulin gene (GRN) resulting in TDP-43
pathology,can cause PNFA symptoms, but without apraxia
ofspeech.13,17 Frontotemporal dementia can also feature
motordysfunction and motor neuron disease (MND).13,17,18
Thesedisorders have been linked to Parkinson’s-like symptoms,such
as those seen in corticobasal degeneration (CBD) andprogressive
supranuclear palsy (PSP), which feature tau pa-thology, or changes
due to TDP-43 pathology, which presentsas FTD-MND with Lewy
body-like pathology or FTD associat-ed with amyotrophic lateral
sclerosis (FTD-ALS).13,17,18 Clini-cally, the Parkinson’s-like FTD
dementias (CBD and PSP) canshow either behavioral-type symptoms
(i.e., those seen inbvFTD) or language-type symptoms (most commonly
PFNA-like symptoms), along with executive dysfunction, in
thepresence of cortical and extrapyramidal motor dysfunction.13
Patients with FTD associated with TDP-43 (FTD-ALS, others)most
commonly present with behavioral symptoms (bvFTD-like) in the
presence of motor dysfunction.18 Amyotrophiclateral sclerosis can
also occur without behavioral symptoms,although non-FTD ALS
patients commonly still have sub-threshold cognitive changes.19
Parkinson’s disease (PD) is caused by deposition of inclu-sions
of α-synuclein called Lewy bodies and feature sponta-neous motor
parkinsonism, visual hallucinations, andpotentially changes in
cognition20; 70 to 80% of patientswith PD develop cognitive
impairment and/or dementiaover the course of the disease.20,21 Two
types of Parkinson’s
Table 1 (Continued)
Disease Clinicalsymptoms
Atrophypattern
Functionalactivation/connectivitychanges
Molecularchanges
Otherimaging
some motordysfunction
sensory cortices; whitematter atrophy inmidbrain and
frontallobe
in frontostriatalnetwork, DMN,salience network,and control
network;loss of internetworkconnectivitybetween DMN anda dorsal
attentionnetwork
↓ DA transporter inbasal ganglia
cortical white matter,CC, and corona radiataASL/SPECT:↓
perfusion in lateralfrontal and inferiormedial parietal regions;"
perfusion in parietalwhite matter and deepgray matter
structures
Sporadic/variant CJD;genetic CJD/GSS/FFI
Motor dysfunction,cognitiveimpairment, andpsychiatricsymptoms;
FFI alsofeatures insomnia
Abnormalities of thebasal ganglia, thalamuscerebellum,
corticalgray matter & whitematter
n/a [18F]FDG:↓ corticalmetabolism
MRS: ↓ NAA," mIns
Abbreviations: 5-HT, serotonin; ACh, acetylcholine; ASL,
arterial spin labeling; CC, corpus callosum; CJD, Creutzfeldt-Jakob
disease; Cr, creatinine; CST,corticospinal tract; DA, dopamine;
DMN, default-mode network; DTI, diffusion tensor imaging; EC,
entorhinal cortex; FDG, [18F]fluorodeoxyglucose;FFI, fatal familial
insomnia; FTD, frontotemporal dementia; Glmn, glutamine; Glmt,
glutamate; GSS, Gerstmann-Straussler-Scheinker disease;
Hipp,Hippocampus; MCI, mild cognitive impairment; mIns,
myo-inositol; MRS, magnetic resonance spectroscopy; MTL, medial
temporal lobe; NAA, N-acetylaspartate; PET, positron emission
tomography; PLIC, posterior limb of the internal capsule; SPECT,
single-photon emission computerizedtomography.
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dementias have been defined, including Parkinson’s
diseasedementia (PDD), in which patients develop cognitive
symp-toms more than 1 year after motor symptoms, and dementiawith
Lewy bodies (DLB), in which patients develop cognitivesymptoms
concurrent with or within a year of motor symp-toms.20 Cognitive
symptoms in PDD and DLB are variable, butoften feature impairments
in visual spatial functioning, exec-utive function, language,
and/or memory.20,21 However,whether PDD and DLB actually represent
separate disordersis under debate.20 Thus, in the present article,
PDD and DLBwill be discussed together.
Huntington’s disease (HD) is an autosomal dominantinherited
neurodegenerative condition caused by trinucleo-tide repeates (CAG)
in the gene coding for the proteinhuntingtin (HTT). Pathological
features include progressivedegeneration of striatal GABAergic
interneurons.2,22 Clinicalsymptoms of HD include motor symptoms,
such as chorea,bradykinesia, dystonia, and incoordination, and
cognitivesymptoms, including changes in visuomotor function,
execu-tive function, and memory.22 Because HD is an
autosomaldominant disorder, prodromal phases of this disease can
bestudied (i.e., prior to clinical onset in mutation carriers)
toassess disease development and progression.
Multiple sclerosis (MS) is a neurodegenerative
conditionfeaturing degeneration of the myelin sheaths that
surroundneuronal axons, which results in significant impairment
inneuronal transmission.23,24 Although the exact cause of MS
isunknown, it is thought to be the result of either an autoim-mune
syndrome in which inflammatory cells attack themyelin or a
dysfunction of the myelin-producing cells.25
Multiple sclerosis typically presents either as discrete
attacks(relapsing-remitting) or progressive over time
(progressiveMS).26 Symptoms of MS can vary dramatically, as MS
lesionscan occur throughout the cortical white matter, but the
mostcommon are autonomic, visual, motor, and sensory prob-lems.24
Cognitive symptoms usually include behavioral andemotional changes
(i.e., depression), as well as impairmentsin executive functioning,
attention, and memory.24
HIV-associated neurocognitive disorders (HAND) can beclassified
into three types based on severity: (1) asymptom-atic
neurocognitive impairment (ANI), which features cogni-tive
impairment 1 SD below age and education adjustednorms in two
cognitive domains but no functional im-pairment; (2) HIV-associated
mild neurocognitive disorder(HMD; also referred to as mild
cognitive motor dysfunction[MCMD]), which features cognitive
impairment 1 SD belowadjusted norms in two cognitive domains and
mild im-pairment in daily functioning; (3) HIV-associated
dementia(HAD; also known as AIDS dementia complex [ADC]), which
ischaracterized by cognitive impairment 2 SD or more belowage- and
education-adjusted norms in at least two cognitivedomains and
significant impairment in daily functioning.27 Inthe present
review, we will combine these three severitycategories into one
group (HAND). Although these classifica-tions may represent stages
of disease, further study is neededfor this determination.
Approximately 22 to 55% of patientswith acquired immunodeficiency
syndrome (AIDS) showcognitive dysfunction. Symptoms include
disorientation,
mood disturbances, and impairment in executive function,speed of
information processing, attention and workingmemory, motor speed,
and new learning and retrieval.28–31
However, long-term and semantic memory, language,
andvisuospatial function remain relatively intact.31 Some pa-tients
also show motor symptoms.29 However, symptomscan vary significantly
across individuals.31
Prion-associated diseases are rare neurodegenerative dis-orders
caused by abnormal processing of the prion protein,which leads to
lethal transmissible spongiform encephalopa-thies (TSEs).1
Prion-associated diseases can either be sporadic(sporadic
Creutzfeldt-Jakob disease [sCJD]; sporadic fatalinsomnia [SFI]),
genetic (genetic CJD; Gerstmann-Strauss-ler-Scheinker diseases
[GSS]; fatal familial insomnia [FFI]),or acquired through
infectious transmission of tissue carryingthe misfolded prion
protein (Kuru; iatrogenic CJD [iCJD];variant CJD [vCJD]).1 The
different variants of prion-associat-ed dementia show somewhat
different symptoms, includingvarying rates of progression and ages
of onset, but themajority feature significant motor and sensory
dysfunction,cognitive impairment, and personality changes or
psychiatricdisorders.1
Neuroimaging Biomarkers
The two types of neuroimaging most commonly used asbiomarkers of
neurodegeneration and dementia includemagnetic resonance imaging
(MRI) and radionucleotide im-aging (i.e., single-photon emission
computerized tomography[SPECT], positron emission tomography
[PET]). The mostwidely used neuroimaging technique to investigate
anatomi-cal changes and neurodegeneration in vivo is structural
MRI,which can assess global and local atrophic brain changes.More
advanced structural MRI techniques, including diffu-sion weighted
and diffusion tensor imaging [DWI/DTI], mag-netic resonance
spectroscopy [MRS], and perfusion imagingare also used for
investigation of dementia often in a researchcontext. DWI/DTI
techniques measure the integrity of tissueusing primarily two types
of measures, fractional anisotropy(FA) and mean diffusivity (MD) or
apparent diffusion coeffi-cient (ADC). Reduced FA and increased
MD/ADC are consid-ered to be markers of neuronal fiber loss and
reduced graymatter and white matter integrity. MRS is a
noninvasiveneurochemical technique allowing the measurement of
bio-logical metabolites in target tissue that has been used
instudies of brain aging, neurodegeneration, and dementia. Twomajor
metabolites that often show alterations in patientswith dementia
include: (1) N-acetylaspartate (NAA), amarkerof neuronal integrity;
and (2) myo-inositol (mIns), a measureof glial cell proliferation
and neuronal damage. However,other MRS analyte signals can also
provide informationrelated to membrane integrity and metabolism.
Cerebralperfusion is also commonly measured in studies of
neuro-degeneration and dementia, including with MRI using
eitherdynamic susceptibility contrast enhancedMRI or arterial
spinlabeling (ASL),32,33 or using SPECT or PET techniques
(dis-cussed below). MRI can also be used to measure brainfunction.
Functional MRI (fMRI) measures brain activity
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during a cognitive, sensory, or motor task or at rest
bymeasuring blood flow and blood oxygen levels. The
primaryoutcomemeasured inmost fMRI studies is blood
oxygenationlevel dependent (BOLD) contrast signal in which
regionalbrain activity is measured via changes in local blood flow
andoxygenation.34 Under normal conditions activity-relatedbrain
metabolism is tightly coupled to regional blood oxy-genation and
flow (i.e., blood flow increases to keep theregional blood oxygen
level high during brain activationand associated increases
metabolic demand). Therefore, theBOLD signal is a useful measure
for brain activation.35 How-ever, altered coupling of
neuronalmetabolism and blood flowdue to brain atrophy and/or
hypoperfusion may cause alter-ations in the BOLD signal. Therefore,
fMRI studies in older anddemented patient populations with brain
atrophy should becarefully evaluated and interpretedwith these
considerationsin mind. fMRI studies often evaluate brain activity
duringcognitive or functional motor tests. In addition to estimates
ofregional task-related brain activity, quantification of
brainnetworks can provide a unique measure of brain
activity.Techniques for quantifying brain connectivity from fMRI
datahave recently been developed and applied in studies of
brainaging during functional activation (i.e., during performance
oftasks), as well as during a “resting” or “task free” state.36
SPECT and PETuse radiolabeled ligands to measure
perfu-sion,metabolic, and neurochemical processes in vivo. SPECT
isprimarily used to evaluate brain perfusion in studies
ofneurodegeneration and dementia. Multiple types of PETligands have
been utilized in studies of dementia, including:(1)
[18F]fluorodeoxyglucose (FDG), which measures brainglucose
metabolism; (2) tracers that assess brain proteindeposits, most
commonly to measure amyloid deposition(e.g., [11C]Pittsburgh
Compound B (PiB), [18F]florbetapir,others); (3) tracers that assess
neurotransmitter systems(i.e., dopamine, serotonin, acetylcholine
[ACh], etc.) by bind-ing to neurotransmitter receptors,
neurotransmitter trans-porters, or other associated proteins (e.g.,
catabolic ormetabolic enzymes); and (4) tracers that measure the
levelof activated microglia (e.g., [11C]PK11195,
[11C]DAA1106,[11C]PBR28, others). PET studies allow for an
assessment offunctional changes in brain metabolism and
neurotransmit-ter and other protein levels, which can provide
importantinformation about degenerative changes occurring in
thebrains of patients.
Neuroimaging Biomarkers of DegenerativeDiseases and
Dementias
Alzheimer’s Disease and Prodromal StagesThe most widely used
neuroimaging technique to investigatestructural changes and
neurodegeneration in AD is structuralMRI. MRI estimates of regional
volumes, extracted usingeither manual or automated techniques, as
well as globaland regional tissue morphometry, show the presence
ofsignificant brain atrophy in AD patients, following an
ana-tomical distribution similar to the stage-specific
neuropath-ological pattern reported by Braak and Braak.9
Severalstructural MRI studies have investigated atrophy in AD
and
found a pattern of widespread atrophy, including in the MTLand
lateral temporal lobe (LTL), medial and lateral parietallobe, and
the frontal lobe,with relative sparing of the occipitallobe and
sensory-motor cortex (►Fig. 1A,►Fig. 2A).37–39MCIpatients have been
shown to have intermediate atrophybetween AD patients and healthy
older controls (HC), sup-porting this as an intermediate clinical
stage between healthyaging and AD.40 MCI patients tend to have more
focal reduc-tions in volume and gray matter density than AD
patients,particularly in the more clinically mild patients, in
theentorhinal cortex and hippocampus, as well as focal
corticalatrophy particularly in the temporal, parietal, and
frontallobes (►Fig. 1A).41–43 MRI measures of volume, morphome-try,
and rates of brain atrophy have also shown promise inpredicting MCI
to AD progression, with significantly reducedhippocampal and
entorhinal cortex volumes, as well asreduced cortical thickness in
the medial and lateral temporalcortex, parietal lobes, and frontal
lobes, in patients destinedto convert from MCI to probable AD
(MCI-converters), up to2 years prior to clinical conversion,
relative to MCI patientsthat remain at a diagnosis of MCI
(MCI-stable).39,44–46 Longi-tudinal studies have shown higher rates
of cortical atrophy inpatients with AD and MCI, particularly in the
temporal lobe.Patients with AD have an approximate annual
hippocampaldecline of -4.5%, while MCI patients have an annual rate
ofhippocampal decline of -3%, relative to only an approximate-1%
annual change in HC (for a meta-analysis, see Barneset al47).
Cognitively normal older adults at risk for progressionto dementia,
due to the presence of cerebral amyloid, geneticbackground, or the
presence of subjective cognitive decline,also show notable brain
atrophy and increased atrophy rates,particularly in regions of the
MTL.48–57
AdvancedMRI techniques have also been used in studies ofpatients
with AD, MCI, and older adults at risk for AD. DWI/DTI studies have
indicated that AD patients have reduced FAand increased diffusion
relative to HCs in many white matterstructures throughout the
brain, with MCI patients showingintermediate changes58–61.
Furthermore, DTI measuresshowed significant white matter changes in
older adults atrisk for dementia due to subjective cognitive
decline relativeto those without significant complaints.62 MRS
techniquesdemonstrated that AD patients have decreased NAA
levelsand increasedmIns relative to HCs throughout the brain,
withthe most significant changes in the temporal lobe and
hippo-campus.63,64 MCI patients have also been shown to
havereductions in NAA relative to HC,63,65 although NAA valuestend
to be intermediate between those seen in AD and HCparticipants.
Studies of brain perfusion with MRI have con-sistently demonstrated
decreased perfusion or “hypoperfu-sion” in patients with AD,
particularly in temporoparietalregions, as well as frontal,
parietal, and temporal cortices,66
whereas MCI patients showed decreased brain perfusion inthe
medial and inferior parietal lobes.32
Results from fMRI studies in AD and MCI patients haveshown
conflicting results. Most studieswith AD patients haveshown
decreased or even absent activation relative to HCs inthe MTL,
posterior cingulate, parietal lobe, and frontal lobeduring episodic
memory encoding and recall tasks.67,68
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Furthermore, some studies in MCI patients have showndecreased
activation relative to HC during episodic memoryencoding67,69,70
and recall tasks.67,69,70However, other stud-ies in both AD and MCI
showed increased activation duringcognitive tasks.67,68,70–72
Interestingly, the level of diseaseseverity of patient populations
may explain some of theseconflicting findings. Increased activation
may represent acompensatory mechanism engaged to assist with
successfulcompletion of the task in less impaired patients
(particularlythose with MCI), while more impaired patients,
especiallythose with advanced atrophy, show decreased
activation
during tasks.67,68,73 Patients at risk for progression to ADdue
to genetic background also show altered hippocampalactivation
during episodic encoding and recall, as well asaltered activation
during working memory tasks.74–77
Functional connectivity studies have also
demonstratedalterations in patients with AD and MCI, including
decreasedconnectivity in task-related and resting-state
net-works.67,78,79 In particular, a network of brain regions
thatare deactivated upon task initiation that includes the
medialparietal lobe, MTL, and medial frontal lobe, which is
referredto as the default mode network (DMN),36,80 shows
decreased
Fig. 1 Differences in atrophy, glucose metabolism, and amyloid
deposition between patients with Alzheimer’s disease (AD), patients
with mildcognitive impairment (MCI), and healthy older adults (HC).
The pattern of differences between AD, MCI, and HC is demonstrated
in (A) brainatrophy (measured using T1-weighted structural magnetic
resonance imaging [(MRI]), (B) glucose metabolism (measured using
[18F]fluorodeoxyglucose positron emission tomography [FDG PET]),
and (C) amyloid accumulation (measured using [11C]Pittsburgh
compound Bpositron emission tomography [PiB PET]). Relative to HC,
patients with AD show significantly reduced brain gray matter
density throughoutcortical and subcortical regions (A; AD versus
HC), reduced glucose metabolism in regions of the medial and
lateral parietal lobe, medial andlateral temporal lobes, and medial
and lateral frontal lobes (B; AD vs. HC), and greater amyloid
accumulation throughout the cerebral cortex(C; AD vs. HC). Patients
with MCI also show focal changes relative to HC, including reduced
gray matter density in the medial and lateral temporallobes (A; MCI
vs. HC), reduced glucose metabolism in the medial and lateral
temporal lobes, medial and lateral parietal lobes, and frontal
lobe(B; MCI vs. HC), and greater amyloid deposition in the frontal,
parietal, and temporal cortices (C; MCI vs. HC). The comparisons of
these measuresbetween patients with AD to patients with MCI also
show interesting patterns of relating to disease severity. Patients
with AD show significantlymore gray matter atrophy in regions of
the medial and lateral temporal lobes and parietal lobes (A; AD vs.
MCI) and reduced glucose metabolism inthe medial and lateral
temporal lobes, medial and lateral parietal lobes, and frontal lobe
(B; AD vs. MCI) relative to MCI patients. However, onlyminor
differences in amyloid are observed between AD and MCI patients (C;
AD vs. MCI), suggesting the majority of amyloid accumulation
occursbefore a participant has reached a clinical diagnosis of MCI.
This figure was generated using data from the Alzheimer’s Disease
NeuroimagingInitiative cohort and utilizing traditional methods
that have been previously described.39,424,425 Panel (A) is
displayed at a voxel-wise threshold ofp < 0.01 (family-wise
error correction for multiple comparisons) andminimum cluster size
(k) ¼ 50 voxels and includes 189 AD, 396 MCI, and 225HC
participants; panel (B) is displayed at a voxel-wise threshold of p
< 0.001 (uncorrected for multiple comparisons) and k ¼ 50 voxels
andincludes 97 AD, 203 MCI, and 102 HC participants; panel (C) is
displayed at a voxel-wise threshold of p < 0.01 (uncorrected for
multiplecomparisons) and k ¼ 50 voxels and includes 25 AD, 56 MCI,
and 22 HC participants. (Reproduced from Risacher et al426)
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activity at rest, decreased connectivity, and reduced
deacti-vation upon task initiation in AD and MCI
patients.67,78,80,81
However, similar to the task-related fMRI studies,
mildlyimpaired MCI patients actually show increased
functionalconnectivity between the memory network and the
DMN,suggesting compensatory changes,67,78,82 while more im-paired
MCI patients have decreased or absent connectivitybetween these
networks.67 In addition, older adults at risk forAD show changes in
task-related connectivity, as well asaltered resting-state
connectivity in the DMN.83–86
FDG PET studies of patients with AD have shown signifi-cant
reductions in cerebral glucosemetabolism relative to HC,with MCI
patients showing intermediate changes, in thetemporoparietal
cortex, posterior cingulate, parietal lobe,temporal lobe, and in
the MTL, including the hippocampus(►Fig. 1B).80,87,88 More impaired
AD patients also have morehypometabolism in the frontal lobe and
prefrontal cortexrelative to less impaired patients and HCs.88,89
Longitudinalstudies demonstrated a significantly greater rate of
annualdecline in metabolism in the temporal, parietal. and
frontallobes, as well as the posterior cingulate and precuneus in
ADandMCI relative toHC.90,91 Cognitively healthy older adults
atrisk for progression to AD due to genetic background and
thepresence of subjective cognitive decline also showalterationsin
glucose metabolism.91–93
PET imaging studies with tracers that bind to cerebralamyloid
(most commonly [11C]PiB) have shown increaseduptake in patients
with AD and MCI in brain regions knownto show amyloid deposition in
neuropathological studies,including the frontal, temporal, and
parietal lobes, posterior
cingulate, and precuneus (►Fig. 1C).54,94,95 Across
[11C]PiBstudies, 96% of AD patients showed significant amyloid
accu-mulation, measured as a “positive” [11C]PiB signal,96
whilenearly two-thirds of patients with MCI showed
significantamyloid accumulation.96 In addition, MCI patients with
signif-icant amyloid accumulation have a higher likelihood of
futureconversion toAD.97 Longitudinal assessments of amyloid
using[11C]PiB in AD and MCI patients have shown minimal in-creases
in [11C]PiB signal over 1 to 2 years in patients whoshowed
significant [11C]PiB signal at baseline.95,98However, inpatients
who do not show significant amyloid deposition atbaseline,
additional amyloid accumulation may be possible.Thus, researchers
have tentatively concluded that amyloiddeposition occurs early in
the disease and by the time suffi-cient cognitive decline for a
diagnosis of AD occurs, brainamyloid burden is relatively stable
and increased depositionisminimal. Finally, patients at risk for
progression to AD due togenetic background also show higher amyloid
accumula-tion.99–102 Given the results of amyloid PET studies to
date,it is noteworthy that in 2011 the United States Food and
DrugAdministration approved [18F]Florbetapir (Amyvid, Eli Lilly
&Co., Indianapolis, IN) for clinical assessmentof cerebral
amyloidin the context of cognitive decline.103
In addition to evaluating cerebral metabolism and thepresence of
amyloid, researchers have investigated specificalterations in
neurotransmitter systems and neuroinflamma-tion in AD and MCI
patients using PET. Using PET techniqueswith tracers specific for
acetylcholinesterase (AChE) as asurrogate measure for ACh synaptic
density, significant re-ductions in binding were found in AD
andMCI, particularly in
Fig. 2 Differences in atrophy between traditional Alzheimer’s
disease and atypical Alzheimer’s disease. (A) Significant but
generalized corticalatrophy, as well as dramatic volumetric
reductions in the medial temporal lobe (MTL) are observed in
traditional late-onset Alzheimer’s disease(AD) (arrows). However,
different patterns of atrophy are observed in (B) posterior
cortical atrophy (PCA) and (C) logopenic aphasia. (B) Patientswith
PCA show significantly more atrophy in posterior cortical regions
(parietal lobe, occipital lobe) than seen in other forms of AD
(arrows). (C)Patients with logopenic aphasia show relatively
localized atrophy in the posterior temporal lobe and
temporoparietal regions with greater atrophyobserved in the left
hemisphere than in the right (arrows). (Adapted from McGinnis et
al11)
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the temporal lobe.104–106 Studies in AD patients have alsoshown
decreases in GABA, serotonin, and dopamine synapticdensities,107
whereas MCI patients have been shown to havedeficits in
serotonergic neurotransmission only.108 Studies ofactivated
microglia have shown mixed results in patientswith MCI and AD. Some
studies demonstrated significantlyelevated global and regional
activated microglia in patientswith AD relative to HCs,109,110
while other studies haveshown minimal signal in AD and MCI relative
to HCs.111
These differences likely reflect small samples and
conflictingquantification methodologies. Future studies are needed
toelucidate the role of activatedmicroglia in AD andMCI, aswellas
utility of this class of PET tracers as a biomarker of immunestatus
in neurodegenerative disorders.
Overall, neuroimaging studies have been useful for quan-tifying
ongoing neuropathological changes in patients withAD, as well as in
the prodromal stages of disease. Measures ofbrain atrophy, brain
function and connectivity, brain perfu-sion and metabolism, and
levels of amyloid have shownprogressive changes associated with the
development andprogression of AD. Future studies utilizing newer
techniquesand in less-affected patient populations will be
important forfurther understanding AD pathology, early disease
detection,and the development of targeted therapies.
Familial and Atypical Alzheimer’s DiseaseNeuroimaging studies in
familial AD patients (i.e., those withmutations in APP, PS1, or
PS2) have shown greater brainatrophy, faster longitudinal atrophy
rates, white matterchanges measured using DTI, reduced brain
metabolism, andincreased brain amyloid, in affected patients and in
presymp-tomatic mutation carriers relative to
noncarriers.10,112–116
Overall, the use of biomarkers in the study of familial AD
hasshown similar neuropathological changes as seen in late-onsetAD,
in both presymptomatic and symptomatic familial ADpatients. Studies
in these patients may provide informationrelevant to the role of
biomarkers for late-onset AD, as well asto provide sensitive
measures for detecting disease relatedchanges and monitoring
disease progression in patients withfamilial AD. However, it is
also noteworthy that in some casesthe profile of biomarkers in
familial ADpatients can differ fromthat observed in late-onset AD.
For example, some familial ADpatients may show amyloid deposition
in the striatum, afinding which is not often observed in late-onset
AD.117 Futurestudies to explore the similarities and differences in
familialand sporadic AD pathology will provide important
informa-tion, such those associated with the Dominantly
InheritedAlzheimer Network (DIAN).10
Sporadic AD usually presents with changes in memory.However, a
few related disorders have been identified withatypical
presentations (atypical AD), including PCA and log-openic aphasia.
Both diseases show widespread amyloiddeposition and neurofibrillary
tangles, which supports thetheory that these disorders are AD
dementias despite theiratypical clinical presentation. Neuroimaging
studies of PCAhave demonstrated notable atrophy in posterior brain
re-gions, including in the posterior temporal, parietal,
andoccipital lobes (►Fig. 2B).11,118,119 A DTI study of white
matter integrity also showed notable atrophy of the
ventralvisual processing stream, with reduced FA in the
bilateralinferior longitudinal fasciculus and inferior
fronto-occipitalfasciculus.118 Patientswith PCA have also been
shown to havesevere hypoperfusion in occipitoparietal regions, but
in-creased perfusion in frontal, anterior cingulate, and
mesio-temporal regions.120,121 Finally, PCA patients show
positivebinding of [11C]PiB with a traditional AD-like pattern,
exceptfor more signal than AD patients in the occipital
lobe.122
Structural MRI studies in logopenic aphasia have
shownsignificant degeneration of the left posterior superior
tempo-ral lobe, temporoparietal junction, inferior parietal
lobe,posterior cingulate, precuneus, and MTL (►Fig. 2C). In
moresevere patients, atrophy was also observed in left
anteriortemporal lobe regions, along the sylvian fissure and into
thefrontal lobe, as well as in regions of the right temporal
andparietal lobes.13,16,123 DTI studies in logopenic aphasia
havealso shown atrophic changes, including
reducedwhitematterintegrity in the left temporoparietal junction
and bilateral(but left > right) inferior longitudinal
fasciculus, uncinatefasciculus, superior longitudinal fasciculus,
and other subcor-tical projections.124,125 SPECT and FDG PET
studies haveshown reduced perfusion and brain metabolism in the
lefttemporoparietal lobe, respectively.120,123,126 In addition,
arecent study demonstrated increased [11C]PiB uptake inpatients
with logopenic aphasia, suggesting the presence ofsignificant
cerebral amyloid.126
Cerebral amyloid angiopathy is primarily characterized
byvascular pathology on structural imaging. Patients with
CAAtypically show cerebral microhemorrhages, often at the cor-tical
gray matter/white matter interface and/or in cortico-subcortical
junctions of the frontomesial, fronto-orbital, andparietal lobes,
microbleeds found predominately in posteriorcortical regions, and
other ischemic related changes (i.e.,white matter lesions and
infarcts).14,120,127,128 A functionalMRI study of CAA patients also
demonstrated altered vascularfunction, including reduced vascular
reactivity to visualstimulation in the presence of normal blood
flow.129 Studieswith SPECT imaging showed hypoperfusion in
parietal, tem-poral, and frontal lobes in patients with CAA.130
Finally, a PETstudy with [11C]PiB in patients with CAA
demonstratedsignificant tracer uptake, supporting the presence of
exten-sive cerebral amyloid deposition.131
Vascular Cognitive Impairment and DementiaA few studies have
evaluated the extent of brain structuraland functional changes in
vascular dementia and VCI usingin vivo neuroimaging techniques.
Although the definitions ofvascular dementia and VCI vary
significantly across studies,samples of patients with subcortical
ischemic vascular de-mentia (SIVD) and leukoaraiosis, which is
extensive whitematter pathology identified using MRI, are most
commonlyevaluated. Several studies have investigated patients
withSIVD and other patients with vascular dementia using
struc-tural MRI techniques and shown that SIVD patients andpatients
with leukoaraiosis show greater number of whitematter lesion than
cognitively healthy older adults withoutsubcortical infarcts and
patients with AD.132–137 The
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presence of more white matter lesions is also
significantlyassociated with impaired cognition, particularly in
executivefunction and processing speed domains, as well as a
greaterdementia severity and the presence of cognitive
com-plaints.136,138–140 Patients with SIVD and leukoaraiosis
alsoshow significant gray matter, white matter, and
hippocampalatrophy relative to HCs,132,134,135,137,141–144 which
has alsobeen linked to the extent of white matter lesion
patholo-gy.133–136,145,146 Only a limited number of studies
haveinvestigated structural MRI changes in patients in
earlierstages of vascular dementia, such as
vascular-relatedMCI.133,134,136,143 Seo and colleagues reported
cortical thin-ning in patients with MCI linked to subcortical
ischemia,particularly in frontal, temporal, and occipital
regions.143
Patients with vascular-associatedMCI also showa significant-ly
greater extent of white matter lesions than HC, the pres-ence of
which is associated with progression to dementia.133
Studies utilizing DTI have demonstrated significant changesin
SIVD and leukoaraiosis patients, even in normal-appearingwhite
matter.147–154 In fact, DTI measures of decreased whitematter
integrity have shown significant association withdementia severity,
cognition, motor function, and cerebralatrophy.147,148,150–154 A
few studies have also evaluated fMRImeasures in patients with
vascular dementia, in particularSIVD. Two studies evaluated
task-related fMRI in SIVD pa-tients and demonstrated reduced
activation and altered brainblood flow-metabolic coupling during an
executive functionandmotor task, respectively.155,156 Finally, a
study by Sun andcolleagues showed altered posterior cingulate
cortex func-tional connectivity in SIVD patients using
resting-statefMRI.157 Schuff and colleagues assessed brain
perfusion inSIVD using ASL and demonstrated reduced cerebral
blood
flow, particularly in frontal and parietal lobes.158
Theseresults support previous studies utilizing PET and
SPECTtechniques, which showed reduced cerebral perfusion
andmetabolism in patients with vascular dementia.159,160 In
fact,FDG PET studies have shown hypometabolism in a
scatteredpattern in cortical and subcortical regions in vascular
demen-tia.161 Finally, amyloid PET tracers show minimal binding
inthe majority of patients with vascular dementia in theabsence of
CAA.162
Neuroimaging studies in vascular dementia have demon-strated
notable changes in brain atrophy, function, perfusionandmetabolism
secondary to vascular pathology. Prospectivestudies evaluating
patients in earlier stages of disease wouldbe useful to identify
the progressive changes associated withthe development of vascular
dementia, as well as the effect ofany interventional treatments. In
addition, studies of patientswith vascular pathology and other
types of comorbid pathol-ogy (AD, FTD, etc.) will provide the
opportunity to assess theoverlap of multiple diseases and the
relative contribution ofvarious pathologies to cognitive
decline.
Frontotemporal DementiaBehavioral variant FTD is characterized
primarily by changesin personality and behavior and is caused by
accumulation ofpathological tau protein or TDP-43 or in rare cases
by changesin the fused in sarcoma (FUS) protein.13,16,17 Genetic
forms ofbvFTD can be linked to mutations in the tau gene
(MAPT),which results in tau pathology, the progranulin gene
(GRN),which results in TDP-43 pathology, as well as several
othergenes.13,16,17 Generally, bvFTD patients show
widespreadatrophy in the frontal lobes, anterior cingulate,
anteriorinsula, and thalamus (►Fig. 3B).13,120,163,164
Longitudinally,
Fig. 3 Atrophy in frontotemporal dementia (FTD) subtypes. (A)
Significant left anterior temporal lobe atrophy is observed in the
semanticdementia variant of FTD (arrows), while bilateral frontal
and temporal lobe atrophy is seen in the (B) behavioral variant of
FTD (arrows). (C) Patientswith progressive nonfluent aphasia show
atrophy in the left inferior frontal, insula, and anterior temporal
lobe regions (left > right; arrows).(Adapted from McGinnis et
al11)
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faster atrophy rates are observed in the frontal
lobes.120,165
Some differences in atrophy are observed in bvFTD based
onunderlying pathology. bvFTD due to Pick’s disease showsatrophy in
the prefrontal cortex, temporal lobes, anteriorcingulate and
insula, which is typically bilateral but withslightly greater
atrophyon the left than right.17,166 The frontalatrophy in bvFTD
patients with Pick’s disease is usuallygreater than that seen in
other bvFTD forms, such as CBD,patients with MAPT mutations, and
those with underlyingTDP-43 pathology.17,167 Patients with MAPT
mutations tendto be a heterogeneous group with atrophy observed in
thefrontal and temporal lobes, insula, anterior cingulate,
parietallobe, basal ganglia, and brainstem.17,168 Furthermore,
pa-tients with MAPT mutations may show more temporal lobeatrophy
than other bvFTD forms.13,169 Patients with bvFTDwith TDP-43
pathology show widespread frontal, temporal,and parietal
atrophy,which tends to be asymmetric but eitherside can show
predominance.17,166,170,171 The parietal atro-phy tends to be more
severe in patients with TDP-43 bvFTDvariants than those caused by
tau pathology.17 Patients withmutations in the GRN gene show a
similar pattern of frontal,temporal, and parietal atrophy, but may
show a greaterasymmetry than bvFTD patients with TDP-43 who do
nothave a GRN mutation.172 Finally, bvFTD patients with under-lying
FUS pathology show a unique pattern of severe caudateatrophy, along
with similar frontal atrophy to that seen in theother bvFTD
forms.17,173DTI studies of whitematter integrityin bvFTD have
demonstrated reduced FA in frontal andtemporal white matter,
including in the uncinate fasciculus,anterior cingulum, superior
longitudinal fasciculus, and infe-rior longitudinal fasciculus
relative to HC.128,174,175 Patientswith bvFTD show greater frontal
lobe white matter changesthan AD patients, including in the
anterior cingulum, anteriorcorpus callosum, and uncinate
fasciculus.175,176DTI studies inbvFTD patients with MAPT and GRN
mutations have alsoshown reduced white matter integrity throughout
the fron-totemporal white matter.177
Studies of task-related fMRI activation in bvFTD haveshown
altered activation patterns during working memoryand emotional
processing tasks, including reduced frontaland parietal activation
during working memory178 and emo-tion-specific abnormalities in
frontal and limbic regions, aswell as altered activation in
posterior regions (i.e., fusiformgyrus, inferior parietal cortex)
during an implicit face-expres-sion task.179 Resting-state fMRI has
also demonstrated al-tered functional connectivity in patients with
bvFTD,particularly in the salience network, which is a network
ofregions involved in filtering sensory and emotional stimuliand
directed attention that includes the anterior cingulatecortex,
bilateral insula, dorsolateral prefrontal cortex, sup-plementary
motor area, and other temporal, frontal, andparietal cortical
regions.180 Patients with bvFTD show de-creased connectivity in the
dorsal and ventral salience net-work, including in the basal
ganglia and frontal lobe, butincreased connectivity in the
precuneus relative to HC.181–183
Relative to AD patients, bvFTD patients show an oppositepattern
of functional connectivity, with decreased connectiv-ity in the
salience network and increased connectivity in the
DMN.181,184 Alterations in connectivity of other regions hasalso
been reported, including in an attention/working mem-ory network,
which showed reduced connectivity with theDMN, and an executive
network, as well as in cingulate andfrontal white matter
regions.177,182 Patients with MAPT mu-tations also showalterations
in connectivity of the DMN,withincreased connectivity in the medial
parietal lobe and re-duced connectivity in the lateral temporal and
medial pre-frontal cortices.185 Patients with bvFTD showed
reducedcerebral perfusion, primarily in frontal and temporal
lobes,in studies utilizing both SPECT and ASL
techni-ques.120,128,163,164,174,186 FDG PET studies of brain
metabo-lism in bvFTD have also demonstrated notablehypometabolism
in frontal and temporal re-gions.120,128,163,164 Studies with
amyloid tracers (i.e., [11C]PiB) showed minimal binding in patients
with bvFTD.131
The semantic variant of primary progressive aphasia
(PPA),semantic dementia (SD), features language difficulties
withfluency, anomia, and single-word comprehension and is
mostcommonly associated with TDP-43 pathology. Patients withSD show
asymmetrical atrophy of the temporal lobes, mostcommonly left >
right, particularly in anterior and inferiortemporal lobe regions,
including the temporal pole, perirhinalcortex, anterior fusiform,
hippocampus, and amygdala(►Fig. 3A).13,16,187–189 More severe
patients may also showatrophy in parts of the superior and
posterior left temporallobe, regions of the left frontal lobe, left
insula, and leftanterior cingulate, as well as increasing atrophy
in the righttemporal lobe.13,190 Longitudinally, SD patients show
pro-gressive atrophy of the left temporal lobe, followed by
theright temporal lobe.13,191DTI techniques have shown reducedwhite
matter integrity in bilateral temporal lobes (left >right),
including in the inferior longitudinal fasciculus,
leftparahippocampal white matter, and in the uncinate fascicu-lus,
with the lowest FA values seen in the left anteriortemporal
lobe.125,174,175 fMRI studies of SD patients haveshown altered
activation patterns during a variety of tasks,including during
sound processing, autobiographical memo-ry, and surface
dyslexia.192–194 Resting-state functional con-nectivity studies
have also shown decreased connectivity offrontotemporal and
frontolimbic circuitry, but increasedconnectivity in local networks
of the prefrontal cortex inSD patients relative to HC.195 SPECT and
PET studies of SDpatients demonstrated reduced perfusion and
metabolismprimarily in the left anterior temporal lobe,13,120,126
while astudy with [11C]PiB showed minimal binding.126
The nonfluent variant of PPA, progressive nonfluent apha-sia
(PNFA), is more heterogeneous than SD featuring speechproduction
impairment with agrammatism, phonemic er-rors, anomia, sentence
comprehension impairment, and po-tentially apraxia of speech.
Progressive nonfluent aphasia canbe caused by either tau or TDP-43
pathology, the latter ofwhich does not show apraxia of speech.13
Patients with PNFAshow atrophy primarily in anterior perisylvian
regions, in-cluding in the left inferior frontal lobe, insula, and
premotorcortex,with further involvement of other frontal lobe
regions,the temporal and parietal lobes, as well as the caudate
andthalamus in later disease stages (►Fig.
3C).13,16,190,196,197
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Interestingly, PNFA patients with underlying Pick’s disease(tau)
pathology havemore severe temporal lobe atrophy thanother forms,
while those with a GRN mutation (TDP-43pathology) show notable
atrophy in the left lateral temporallobe.17,196 DTI studies in PNFA
patients demonstrated mod-erate decreases in white matter integrity
relative to HC in theleft arcuate fasciculus, most especially in
the frontoparietalcomponent, in the superior motor pathway, and in
leftperisylvian, inferior frontal, insular, and supplemental
motorarea regions.125,174,175A study utilizing fMRI in PNFA
patientsdemonstrated reduced activation in the left inferior
frontallobe during sentence reading and comprehension relative
toHC.198 FDG PET studies have demonstrated hypometabolismin left
inferior frontal gyrus, frontal operculum, insula, pre-motor
cortex, and supplementary motor area in PNFA pa-tients.11,199,200
Studies with [11C]PiB showed minimalbinding in patients with PNFA,
however, some signal wasobserved in those with underlying Pick’s
disease patholo-gy.126,199 Finally, PNFA patients show reduced
striatal dopa-minergic signal with a tracer targeting
pre-synapticdopaminergic transporters.201
Frontotemporal dementia with motor symptoms has multi-ple forms,
including CBD, PSP, FTD with motor neuron disease(FTD-MND), and FTD
with ALS (FTD-ALS). These diseases canpresent with behavioral or
language symptoms (typically PNFA),but usually they present with
behavioral symptoms. However,all of these disorders also feature
motor dysfunction. Cortico-basal degeneration and PSP are caused by
tau pathology, whileFTD-MND and FTD-ALS are associated with TDP-43
pathology.Structural imaging studies in CBD and PSP have shown
signifi-cant atrophy in the posterior frontal cortex in both
disorders,with more atrophy in the basal ganglia and faster
longitudinaldecline in whole brain volume in CBD than
PSP.17,166,202,203 Onthe other hand, PSP may show more atrophy in
the posteriorfrontal lobe white matter, brainstem, cerebellum, and
midbrainthan CBD.17,202 Atrophy in CBD is also typically
asymmetrical,while atrophy in PSP is usually symmetrical.17,204 DTI
studies inCBD demonstrated a loss of white matter integrity in the
motorthalamus, precentral and postcentral gyri, and bilateral
supple-mentary motor area, while PSP patients showed decreasedwhite
matter integrity in the anterior part of the thalamus,cingulum,
primary and supplementary motor areas, and fronto-orbital white
matter.205 ASL studies in CBD have also shownreduced cerebral
perfusion in the right hemisphere.206 SPECTstudies have
demonstrated reductions in neurotransmitters inboth CBD and PSP,
with reduced dopaminergic transporterbinding in the striatum and
reduced acetylcholine transporterbinding in the anterior cingulate
and thalamus relative toHC.207,208 FDG PET studies in CBD and PSP
also showed cerebralhypometabolism, with reduced metabolism in
cortical regionscontralateral to the physically affected side in
CBD and hypo-metabolism in the prefrontal cortex, caudate,
thalamus, andmesencephalon in PSP.209
FTD-MND and FTD-ALS are both primarily linked toTDP-43pathology
(although a few FTD-MND patients may show FUSpathology) and feature
behavioral or language deficits alongwith motor dysfunction.
Patients with FTD-MND or FTD-ALSshow frontal and temporal lobe
atrophy, in addition to atrophy
in the anterior cingulate, occipital lobe, and precentral gyrus
inFTD-ALS only.13,17,19,170,171,210 DTI studies have shown
de-creased white matter integrity relative to HC in frontal
andtemporal regions, including the corpus callosum,
corticospinaltract, cingulum, inferior longitudinal fasciculus,
inferiorfronto-occipital fasciculus, and uncinate fasciculus,
whichwas associated with poorer performance on
cognitivetasks.211–214 Task-related and resting-state fMRI and
functionalconnectivity studies have also shown alterations in brain
func-tion and connectivity in patients with FTD-ALS. Reduced
activa-tion in FTD-ALS patients measured using PET and fMRI
wasobserved in the frontal lobe, insula, and thalamus during
anexecutive task and in the frontal lobe, anterior cingulate,
supra-marginal gyrus, temporal lobe, and occipitotemporal
regionsduring averbalfluency task.19,215–217 Reduced frontal
activationduring an emotional task was also observed in
nondementedFTD-ALS patients.211,218 Reorganization of motor
networks anddecreased functional connectivity of a sensorimotor
network,theDMN, anda frontoparietal networkwere also seen in
resting-state studies of FTD-ALS patients.19,219 Patients with
FTD-MNDdemonstrated reduced perfusion in SPECT studies in the
frontallobe, including the premotor cortex andprecentral gyrus,
aswellas the temporal lobe, cingulate, insula, thalamus, and
stria-tum.220 Patients with FTD-ALS also show hypoperfusion
insimilar areas of the frontal and temporal lobes, which
correlateswith impaired cognition.19,211,221,222 FDG PET studies in
FTD-MND patients demonstrated reducedmetabolism in the
frontal,anterior and medial temporal lobe, basal ganglia, and
thalamus(►Fig. 4),223,224 whereas patients with FTD-ALS show
hypo-metabolism in the frontal lobe, superior occipital lobe,
andthalamus.19,211,225 Patients with FTD-ALS also show
reducedserotonin binding in the frontal lobe, as well as a
reducednumber of GABA-A receptors in the frontal lobe,
superiortemporal lobe, parietal lobe, occipital lobe, and
insula.19,211,226
Some forms of FTD-MND and FTD-ALS are caused by geneticmutations
in chromosome 9 (C9ORF72) or GRN.17,18
PatientswithFTD-MNDcarryingamutation in chromosome9havemorethalamic
atrophy than those with FTD-MND without the chro-mosome 9 mutation,
as well as greater frontal lobe, temporallobe, insular, and
posterior cortical atrophy than seen in FTDpatients with other
mutations.227,228
In sum, neuroimaging studies in FTD have been useful
foridentifying and quantifying structural and functional changesin
the brain during disease, including frontal and temporalatrophy,
altered brain function and connectivity, reducedcerebral perfusion
and metabolism, and changes in neuro-transmission. However,
additional studies in larger cohorts tobetter characterize and
differentiate the various FTD subtypes,as well as the overlap
between FTD and ALS, are needed.
Amyotrophic Lateral SclerosisAmyotrophic lateral sclerosis (ALS)
is a progressive degener-ative motor disease that includes
cognitive changes in up to63% of patients (FTD-ALS, see above
section).19 However,patients with ALS without cognitive symptoms
also showstructural and functional changes in the brain,
althoughusually these changes are less severe than those in
ALSpatients with cognitive decline.19 Patients with ALS show
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progressive atrophy in motor and extramotor regions,
mostespecially in the precentral gyrus.211,229–231 DTI
studiesdemonstrated widespread loss of white matter
integrity,including in the corticospinal tract, the posterior limb
ofthe internal capsule, cingulum, midposterior corpus cal-losum,
and in frontal and temporal white matter tracts,such as the
uncinate fasciculus, inferior longitudinal fascicu-lus, and
inferior fronto-occipital white matter.211–213,232–234
FunctionalMRI studies have shown altered brain activation inALS
patients during motor tasks, including increased activa-tion in
motor and premotor areas, the supplementary motorarea, inferior
parietal lobes, superior temporal lobes, andcerebellum during
movement and increased activation inbasal ganglia, cerebellum, and
brainstem duringmotor learn-ing.211,235–238 During a sensory task,
patients with ALS hadreduced activity in primary and secondary
sensory areas butincreased activation in associative sensory
areas.211,239 Al-tered activation during emotional processing in
nonde-mented ALS patients was also seen, with increasedactivation
in the left hemisphere but reduced activation inthe right frontal
lobe.218 Changes in functional connectivity inpatients with ALS
have also been observed. Studies havefound mixed findings, with
decreased connectivity of asensorimotor network, the DMN, and an
interhemisphericmotor network seen in some studies but increased
connec-tivity in sensorimotor, premotor, prefrontal cortex, and
tha-lamic networks seen in other studies.211,219,240,241 MRSstudies
have shown alterations in patients with ALS, includ-ing decreased
NAA and increased choline, glutamate, gluta-mine, andmIns in the
corticospinal tract, posterior limb of theinternal capsule, and
periventricular white matter, as well asa decreased NAA/choline
ratio in the thalamus, basal ganglia,middle cingulate, and frontal
and parietal lobes.211,242–245
SPECT and PET studies in ALS have observed reduced
corticalperfusion and metabolism, which was associated with
re-duced cognition even in nondemented ALS pa-
tients.211,246–248 Dopaminergic and GABAergic cell loss inthe
basal ganglia and substantia nigra has also been
re-ported.211,226,249 Finally, an increase in binding of a PET
tracerthat labels activated microglia, [11C]PK-11195, was
observedin ALS patients in the corticospinal tract and
extramotorregions with the greatest binding observed contralateral
tothe physically affected side.211,250,251
Neuroimaging studies in ALS,with andwithout concurrentcognitive
symptoms, have shown notable changes in brainstructure and function
likely due to ongoing neurodegenera-tion. Future studies designed
to investigate additionalchanges in ALS and FTD-ALS patients will
help to expandthe understanding of these diseases.
Parkinson’s Disease/Dementia with Lewy BodiesParkinson’s disease
(PD) is a degenerative motor disease thatmay or may not feature
cognitive impairments. However, up to80% of PD patients will
eventually develop cognitive symp-toms.21 Pathological and clinical
differences between Parkin-son’s disease with dementia (PDD) and
dementia with Lewybodies (DLB) are minimal and subject to debate.
Thus, imagingfindings in thesedisorders (PDD/DLB)will bediscussed
together,followed by a discussion of imaging in PD without
dementia.Patientswith PDD/DLB showfluctuations in attention,
executivefunction, and higher order visual function, in addition to
motorsymptoms which are the result of widespread deposition of
α-synuclein. Structural imaging studies have shown
widespreadatrophy in cortical and subcortical regions in patients
with PDD/DLB, including in the temporal, parietal, and frontal
lobes, in theMTL (hippocampus, amygdala, entorhinal cortex), basal
ganglia,thalamus, hypothalamus, substantia nigra, insula, and
occipitallobe.11,20,21,181,252–257 Although atrophy patterns are
similar inPDD and DLB, some studies have suggested increased
fronto-temporal atrophy but less caudate atrophy in DLB
patientsrelative to PDD.20,258,259 In addition, amyloid positive
PDD/DLBpatients showmore cerebral atrophy thanPDD/DLBpatients
Fig. 4 Hypometabolism in patients with frontotemporal dementia
with motor neuron disease (FTD-MND) relative to FTD without motor
neurondisease and healthy older adults (HC). (A) Significant
bilateral frontal lobe hypometabolism, with relative sparing of the
temporal lobe, wasobserved in patients with FTD with motor neuron
disease (FTD-MND) relative to HC. (B) However, relative to FTD
patients without motor neurondisease, FTD-MND patients show reduced
bilateral temporal lobe metabolism. (Adapted from Jeong et
al224)
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whoare amyloid negative.20,258,260 Longitudinally,
patientswithPDD/DLB show faster rates of cerebral atrophy than PD
patientswithout dementia and HC, particularly in regions of the
medialand lateral temporal lobe, as well as
occipitotemporalareas.20,21,203,258,261,262 DTI studies in PDD/DLB
demonstratedreduced white matter integrity in the frontal,
temporal, andparietal lobes, pons, thalamus, precuneus, caudate,
corpus cal-losum, and inferior longitudinal
fasciculus.20,128,181,263–267
Some studies again showed greater pathology in DLB thanPDD, with
more reduced FA in the bilateral posterior temporallobe, posterior
cingulate, and bilateral visual association areas inDLB.176,263 MRS
studies in PDD patients have shown reducedNAA/creatinine and
glutamine/glutamate ratios in the posteriorcingulate and bilateral
hippocampus.20,268–270 Studies of pa-tients with PDD/DLB utilizing
fMRI techniques demonstratedreduced activation in the lateral
occipitotemporal lobe duringvisual motion and in the ventral
occipitotemporal lobe duringfacematching, but increased activation
in the superior temporalsulcus during the latter task.20,271
Reduced activation in visualareas was also seen during presentation
of a simple visualmotion stimuli.272 Alterations in brain
activation during execu-tive functionparadigms
inpatientswithPDD/DLBhavealsobeenobserved,
althoughmixedfindingshavebeen reported includingincreased
activation and decreased activation in the prefrontalcortex during
various tasks.252,273 Resting-state functional con-nectivity
studies have also shown changes in brain connectivity
in patients with PDD/DLB, including reduced global and
localcortico-cortical connectivity.181 Other studies have shown
al-tered connectivity of the precuneus,with increased
connectivityof the precuneus with regions of the dorsal attention
networkand putamen, but decreased connectivity of the
precuneuswiththe DMN and visual cortices.274 ASL and SPECT studies
haveshown reduced cortical perfusion in posterior cortical areas
inPDD/DLB patients, including in occipital and
temporoparietalregions.11,129,272,275–277 Hypometabolism has also
been re-ported in FDG PET studies of PDD/DLB patients, particularly
inthebasal ganglia, cerebellum, and frontal, temporal, parietal,
andoccipital lobes with relative sparing of metabolism in
theMTL.11,21,128,275,278–280 Furthermore, occipital lobe
hypometab-olism was associated with visual hallucinations in DLB
pa-tients.253 PET studies with amyloid tracers (i.e., [11C]PiB)
haveshown positive amyloid binding in �40% of PDD/DLB patients(50%
of DLB, 30% of PDD), with a similar anatomical distributionto the
pattern seen in AD patients.131,260 Reduced dopaminergictransporter
binding in the basal ganglia has also been observedin PDD/DLB
patients, with decreased binding in the caudate,which is associated
with cognitive symptoms, and decreasedbinding in the putamen, which
is associated with motor symp-toms (►Fig. 5).21,131,253,258,281,282
Decreased cholinergic neu-rotransmission has also been seen in
patients with PDD/DLBthroughout the cortex, particularly in medial
occipital andposterior cortical regions, which is more severe than
changes
Fig. 5 Dopaminergic deficits in Parkinson’s disease (PD)
relative to healthy adults. Reduced dopaminergic neurotransmission
is observed inpatients with PD relative to healthy adults
(“healthy”), particularly in the posterior putamen (arrows).
123I-β-CIT labels the dopamine transporter(DAT), which is located
presynaptically on dopamine-releasing terminals. 11C-DTBZ labels
the vesicular monoamine transporter (VMAT) and 18F-dopa labels
amino acid decarboxylase (AADC). Both of these molecules are found
in neuron terminals releasing dopamine. Overall, these
threepositron emission tomography (PET) tracers provide sensitive
measures of the density of neuron terminals releasing dopamine in
the striatum.(Adapted from Brooks et al283)
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seen in PD patients without dementia and
ADpatients.21,128,131,258,283–287
Patients with PD without dementia also show atrophic
andfunctional brain changes, although they tend to bemilder
thanthose seen in PDD/DLB patients. Somestudies have
showngraymatter atrophy in the left anterior cingulate, left gyrus
rectus,left parahippocampal gyrus, and right frontal lobe in
PDpatients, while other studies show minimal or no atrophy.252
Mild hippocampal atrophy has also been observed,
althoughsignificantly less atrophy than seen in PDD/DLB
andAD.21,288–290 Further, patients with PD show a slightly
fastercortical atrophy rate than HC, particularly in regions of
thecingulate, occipitotemporal lobe, insula, hypothalamus, nucle-us
accumbens, and hippocampus.21,291 Studies utilizing PETtechniques
have most commonly been reported in PD. UsingFDG PET, patients with
PD showed reduced metabolism infrontal, temporal, parietal, and
occipital lobes, as well as in thebasal ganglia and
thalamus.21,278,292 Parietal and frontal me-tabolism also shows
longitudinal decreases over time.21,293
However, PET studies with [11C]PiB have shown no
significantbinding in PD patients without dementia.131 PET
studiesevaluating different neurotransmitter systems have alsobeen
widely used in PD patients, including assessments ofdopaminergic,
serotonergic, cholinergic, GABAergic, and opi-oid
neurotransmission. Reduced dopaminergic neurotrans-mission in the
striatum has been observed in patients withPD, with the most
significant changes in the putamen contra-lateral to thephysically
affected side (►Fig. 5).2,283,294,295 Earlyin the disease,
increased dopaminergic receptor binding hasbeen observed in the
putamen, frontal lobe, anterior cingulate,and globus
pallidus.283,296,297 However, later in the diseasecourse reduced
dopaminergic receptor binding is also seen inthe thalamus, anterior
cingulate, and frontal and temporallobes.283,298,299 Reduced
serotonergic neurotransmission inthe orbitofrontal cortex, caudate,
putamen, and midbrainhas alsobeen reported inpatientswith
PD.283,300 Furthermore,ACh neurotransmission is reduced in cortical
regions in PD,even early in disease, while increased ACh receptors
have beenreported in the frontal and temporal lobes.283,284,287,301
De-creased GABAergic neurotransmission has also been
reported,primarily in the pons and putamen,302while striatal,
thalamic,cingulate, and frontal areas show reduced opioid
neurotrans-mission.283,303 Finally, increased microglial activation
hasbeen observed in patients with PD in both striatal and
extra-striatal regions.283,304,305
Overall, studies in patients with PD with or withoutdementia, as
well as DLB patients, have shown significantatrophic, functional,
and molecular brain changes. Additionalstudies in early stage
PD-related disorders before cognitivechanges will help further the
understanding of disease devel-opment in relation to phenomenology,
aswell as the potentialfor neuroimaging biomarkers to be used in
clinical assess-ment and monitoring of treatments.
Huntington’s DiseaseHuntington’s disease (HD) is an autosomal
dominantly in-herited progressive degenerative disease causing
motor andcognitive abnormalities. Progressive reductions in
striatal
volume can be seen in both presymptomatic (pre-HD)
andsymptomatic (“manifest”) HD patients, even up to 15 to20 years
before the clinical symptoms appear(►Fig. 6).306–310 Atrophy of the
putamen is greater thanthat in the caudate early in the disease and
later atrophyexpands to the globus pallidus and nucleus
accum-bens.306,308,309,311 This striatal atrophy is associated
withimpairedmotor and cognitive function.308,311 Atrophy is
alsoseen in other gray matter and white matter regions in
bothpre-HD and manifest HD, including cerebral thinningthroughout
the cortex, atrophy in the cingulate and thala-mus, and atrophy of
the white matter tracts near the stria-tum, as well as the corpus
callosum, posterior white mattertract, and frontal lobe white
matter.306,312–314 Subcorticaland cortical atrophy, specifically in
the left superior frontalgyrus, left inferior parietal lobule, and
bilateral caudate, hasalso been shown to be associated with
impaired saccade eyemovement.315 Longitudinally, faster rates of
atrophy in thestriatum are observed in both pre-HD and manifest
HDpatients, whereas greater whole brain atrophy rates areobserved
in manifest HD patients only.306,310,312 DTI studieshave shown
reduced white matter integrity in the frontallobe, precentral
gyrus, postcentral gyrus, corpus callosum,anterior and posterior
limbs of the internal capsule, puta-men,