Neuroimaging Biomarkers of Neurodegenerative Diseases and … · Alzheimer’s disease (AD) is the...

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.

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mailto:[email protected]://dx.doi.org/10.1055/s-0033-1359312http://dx.doi.org/10.1055/s-0033-1359312

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

Seminars in Neurology Vol. 33 No. 4/2013

Neuroimaging Biomarkers of Neurodegenerative Diseases and Dementia Risacher, Saykin 387

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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


Neuroimaging Biomarkers of Neurodegenerative Diseases and Dementia Risacher, Saykin388

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Table 1 (Continued)


Atrophypattern


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)


Atrophypattern


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,

Neuroimaging Biomarkers of Neurodegenerative Diseases and … · Alzheimer’s disease (AD) is the...

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