Diagnostic and Interventional Imaging (2014) 95, 377—398

REVIEW / Neuroradiology

Early-onset dementias: Specific etiologiesand contribution of MRI

C. Quacha,∗, C. Hommetb, K. Mondonb, M.A. Lauvina,X. Cazalsa, J.P. Cottiera

a Department of general radiology/diagnostic and interventional neuroradiology, BretonneauHospital, Tours University Hospitals, boulevard Tonnellé, 37044 Tours cedex, Franceb Department of Internal Geriatric Medicine and CMRR (French Memory Research andResource Centre), Bretonneau Hospital, Tours University Hospitals, 37044 Tours cedex, France

KEYWORDSEarly-onsetdementia;MRI;Dementia

Abstract Early-onset dementias are defined by onset of first symptoms before the age of 65.They have specific diagnostic features which differ from those of elderly patients in terms oftheir many causes and atypical clinical presentations. MRI is an essential procedure for identi-fying the underlying cause of the dementia (degenerative, vascular, infectious, inflammatory,metabolic or toxic). Clinical clues and MRI signs are described, and their defining featuresare related to the young age of the patients concerned. Diagnostic algorithms are proposedfrom signs which can be seen on the different MRI sequences (T1-weighted volume acquisition,T2-weighted FLAIR sequences, T2-weighted gradient-echo, diffusion-weighted imaging). Onceobvious causes have been excluded, MRI can point towards the rarer causes of dementia which

are characteristic in young people (particularly metabolic and autoimmune) and which requirespecific management and genetic counseling.© 2013 Éditions françaises de radiologie. Published by Elsevier Masson SAS. All rights reserved.

Early-onset dementias are defined by the onset of initial symptoms before the age of 65years old. They are major clinical and social problems with devastating consequences onpatients and their families. The average prevalence of dementia under the age of 65 yearsold is 80 per 100,000 people and increases from the age of 55 onwards [1]. Patients whosedisease started before the age of 60 make up 8% of ‘‘memory’’ consultations and 26% ofthe French Memory Resource and Research Centre (CMRR) consultations [2]. Early-onset

dementia has specific diagnostic features compared to dementia in the elderly. It hasmore causes and can present atypically with a wide range of behavioral, cognitive, psychi-atric and neurological problems. After excluding the obvious causes (traumatic, vascular,progression of known neurological disease), the diagnostic approach involves combiningclinical findings, family history and imaging appearances in order to identify the cause ofthe dementia and, particularly, to identify some of the rare metabolic and autoimmune

∗ Corresponding author.E-mail address: celine.quach@etu.univ-tours.fr (C. Quach).

2211-5684/$ — see front matter © 2013 Éditions françaises de radiologie. Published by Elsevier Masson SAS. All rights reserved.http://dx.doi.org/10.1016/j.diii.2013.07.009

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78

auses, which require specific management and/or geneticounseling [3]. Magnetic resonance imaging (MRI) plays aundamental role in this etiological investigation. The aimf this investigation is to establish the etiological features ofarious early-onset dementias, to demonstrate their imagingeatures on MRI and to offer diagnostic algorithms based onhe signs which may be seen.

iagnostic approach

he causes of dementia developing before the age of 65an be divided into different groups: degenerative andascular diseases, and toxic, infectious, inflammatory oretabolic causes. The causes become more similar to those

f patients aged over 65 years old as patient age increases,he commonest causes being Alzheimer’s disease (AD), vas-ular dementias and frontotemporal lobar degenerationFTLD) (Fig. 1) [4]. Genetic and metabolic causes becomencreasingly common the earlier the dementia starts [5].he clinical presentation in adolescents and young adults

s usually as a ‘‘dementia plus syndrome’’ in which cog-itive disorders are combined with assorted neurologicalroblems [6]. The standard MRI investigation protocol forhe young is the same as for any dementia (French Nationalealth Authority guidelines, 2011 [7]) with T1-weightedolume acquisitions, axial T2-weighted FLAIR sequences,2-weighted gradient-echo, diffusion and coronal sectionserpendicular to the hippocampus by T2-weighted spin echoRI. Depending on the abnormalities which are found, addi-

ional MR sequences may be performed (gadolinium chelatenhancement, MR angiography or spectroscopy).

The ‘‘secondary’’ dementias (due to tumors, trauma orhronic adult hydrocephalus) and those which represent theate stage of neurological disorders, which do not raise fur-her diagnostic difficulties, have been excluded from thiseview.

egenerative diseases

hilst AD and FTLD are the most common degenerativeauses of early-onset dementia (except in people under5 years old) [8], the clinical and imaging features may

igure 1. Distribution of the main causes of early-onset dementia.

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iffer in comparison to the same diseases presenting in oldereople.

lzheimer’s disease

lzheimer’s disease is responsible for 30 to 40% of casesf dementia under the age of 65 years old [4,8]. Clinicaligns usually begin around the age of 40 although the prob-ems may develop from the age of 25 [6,9,10] in autosomalominant inherited forms of the disease [11]. These geneticorms account for less than 1% of AD, and are mostly dueo a mutation of the presenilin-1 gene (PSEN1) which isocated on chromosome 14. The mutation may also involvehe APP gene which codes for the amyloid � precursor pro-ein on chromosome 21 (this was initially studied because ofhe significantly increased incidence of young forms of ADn patients with Down Syndrome [12]). It often has atypi-al clinical features in young people. The diagnostic criteriaor the disease recognize amnesic and non-amnesic presen-ations amongst the cognitive disorders [13]. One third ofhe cases involve non-amnesic disease, compared to only% of cases in patients over 65 years old. The non-amnesicorms of the disease are characterized by visuo-spatial prob-ems in focal parieto-occipital disease (Benson’s syndrome)14] and by language difficulties (logopenic aphasia) [15,16].he new diagnostic criteria for AD [17] highlight the impor-ance of new biomarkers (cerebrospinal fluid [CSF] markers,orphological and functional imaging) in making an earlyiagnosis. Three types of biological marker found in CSFre currently used: �1-42 (A�42) amyloid protein, levels ofhich are reduced in AD and total (T-tau) and phosphory-

ated (P-tau) tau proteins, levels of which are increased inD [18]. According to Hansson et al., a combination of T-taund A�42 concentrations has a sensitivity of 95% and speci-city of 83% in the detection of pre-dementia AD [19]. Moreecently, Bateman et al. have shown that CSF A�42 levelsall 25 years before and that tau protein levels increase 15ears before the first clinical signs [20] in patients sufferingrom autosomal dominant forms of AD.

ffects the pre-entorhinal cortex, the entorhinal cortex, theippocampi and then the temporal cortices (anterior, infe-ior and then middle) [21], the primary associative, visual

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Early-onset dementias: Specific etiologies and contribution

and/or the motor cortical regions (Fig. 2) [22]. Routine clin-ical investigation for hippocampal atrophy is still based onvisual analysis alone (Scheltens classification) [23]. A studyof people at risk of familial AD has shown that loss of volumeof hippocampal structures precedes the onset of symptomsby several years [24]. Whilst, typically, the hippocampalregions are initially affected in the elderly, these may appearnormal at the onset of the disease in young people [6].Disease is found predominantly in the posterior corticalregions in parieto-occipital forms of the disease with bilat-eral parietal or bilateral parietal and occipital atrophy [25].First-pass gadolinium enhancement techniques and ArterialSpin Labeling (ASL) can demonstrate a reduction in cerebralblood flow in the posterior parietal cingulate regions at anearly stage (Fig. 3) [26—28].

In classic amnesic forms of AD, positron emissiontomography (18-FDG PET-CT) and Monophoton EmissionComputed Tomography (MECT) show hypometabolism andhypoperfusion respectively, successively affecting thetemporal regions, the posterior cingulate cortex, the tem-poroparietal cortex and then the frontal regions [29].Molecular imaging techniques which directly reflect thedisease process are developing at an astonishing rate,although access to these techniques is still limited. Pitts-burgh compound B [11C]-PIB and [18F]-AV45 markers show upamyloid plaques, and [18F]-FDDNP highlights neurofibrillarydegeneration and amyloid plaques [30]. Increased [11C]-PIBuptake is reported to be visible 15 years before the onset ofsymptoms in autosomal dominant AD [20].

Fronto-temporal lobar degeneration

FTLD is a group of diseases characterized by frontal atro-phy of the frontal and temporal lobes. It is the third leadingcause of dementia in the young [4], with a usual age of onset

of symptoms between 45 and 60 years old [31]. A familyhistory of dementia is reported in 40% of cases [32] halfof which are transmitted as an autosomal recessive disease[33,34] and the clinical presentation within families is often

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Figure 2. A 40-year-old man suffering from Alzheimer’s disease. Famlarge increase in size of the subarachnoid spaces predominantly affectingrade 2 bilaterally (hippocampal atrophy).

I 379

ery variable. The leading genetic cause is due to a muta-ion of the tau gene, which is located on chromosome 1735]. Signs develop insidiously, and may be dominated byehavioral disorders, altered personality, and loss of empa-hy and motivation. Loss of planning and judgment mayead affected individuals to give up work early and is oftenttributed by their families to relationship difficulties orepression, which can delay the diagnosis. Three clinicalorms of FTLD are described [31] depending on the predomi-ant signs: frontotemporal dementia (behavioral disorders),rimary progressive nonfluent aphasia and semantic demen-ia (language difficulties). Unlike AD, FTLD is associated withn early onset of behavioral [5] or language difficulties (inhis case, primary progressive aphasia or semantic demen-ia) whereas memory and spatial orientation difficulties areot the main features.

The presentation in frontotemporal dementia predomi-antly involves a gradual deterioration in behavior (apathy,isinhibition and lapses of concentration) and character. OnRI, atrophy is seen in the frontal lobes, particularly the

rontal orbital cortex and the anterior part of the temporalobes (Fig. 4) [36]. ASL shows hypoperfusion in the frontalortical regions [37].

Primary progressive nonfluent aphasia is characterized byn insidious gradual reduction in spontaneous verbal expres-ion with anomia and agrammatism, but preserved memory38]. Other cognitive functions are also preserved in thearly stages of the disease. On MRI, atrophy is seen in thenferior frontal and left antero-superior temporal regions,nd predominantly in perisylvian regions (Fig. 5) [39].

Severe difficulties in understanding words and namingre seen in semantic dementia. Grammatical aspects ofanguage, visuospatial praxias and episodic memory are pre-erved. MRI shows abnormalities mostly affecting the leftnterior temporal region, although bilateral changes may be

een (Fig. 6). This asymmetry and the presence of an antero-osterior gradient distinguish semantic dementia from AD40]. Selective right anterior temporal atrophy has occa-ionally been described, characterized clinically by gradual

ily history (mother and three brothers): a: axial T1-weighted MR:g the parietal region; b: coronal T1-weighted MR: Scheltens scale:

380 C. Quach et al.

Figure 3. A 64-year-old woman with Alzheimer’s disease (amnesic form): a: coronal T1-weighted MRI: assessment of hippocampal struc-t left;s ood fl

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ures by the Scheltens scale: grade 0 on the right and grade 1 on thepaces; c: arterial spin labeling perfusion MRI. Reduced cerebral bl

ifficulty interpreting facial expressions and emotions, lossf empathy and behavioral disorders [41].

ewy body dementia

ewy body dementia (LBD) is associated with abnormaleurofilament protein aggregation (ubiquitin and alpha-ynuclein) in neurons [42]. It is rare before the age of 65,nd presents clinically in young people with a combinationf fluctuating cognitive difficulties, visual hallucinations andarkinsonism [43]. The full clinical presentation is rarelyeen in the initial stage of the disease. It should be diag-osed early as patients are hypersensitive to neuroleptics,

hich therefore need to be avoided. MRI shows cortical and

ubcortical atrophy without any specific features (Fig. 7).he differential diagnosis between LBD and AD or Parkinson’sisease (PD) with dementia is not always straightforward as

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b: axial T1-weighted MRI: diffuse enlargement of the subarachnoidow in the parietal regions (arrows).

he imaging findings may be similar in LBD and PD. The diag-osis of LBD is suggested if dementia occurs within a yearfter extrapyramidal signs develop [44]. The distinction withD is more difficult as memory problems and medial tempo-al atrophy may only develop secondarily in the early stagesf AD in this age group [45]. Perfusion cerebral scintigraphyn LBD shows diffuse cortical hypoperfusion of the tracernd DaTSCAN® (Ioflupane [123I]) shows reduced uptake in theentral gray nuclei due to dopaminergic denervation (Fig. 8)46].

untington’s disease

untington’s disease is an inherited neurodegenerative cen-ral nervous system disorder which predominantly affectshe central gray nuclei (with loss of GABAergic neurons andstrogliosis). It is transmitted as an autosomal dominant

Early-onset dementias: Specific etiologies and contribution of MRI 381

Figure 4. Fronto-temporal dementia in a 62-year-old woman.Axial T1-weighted MRI: enlargement of the subarachnoid spaces in

Figure 6. Semantic dementia in a 65-year-old woman. AxialT2-weighted FLAIR images. Bilateral anterior temporal atrophy(pronounced enlargement of the subarachnoid spaces combinedw

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mof the caudate nuclei and enlargment of the frontal horns

the frontal regions. Dilatation of the ventricular system, predomi-nantly affecting the frontal horns.

disease with complete penetrance. The mutated gene,which codes for the huntingtin protein, is located on theshort arm of chromosome 4 [47]. De novo mutations,although rare, may occur. It has a prevalence of five to sevenpeople per 100,000 in the Caucasian population [48] and has

two forms: the juvenile form beginning before the age of20 and the late form starting at around 40 years old. Theonset is often insidious and characterized by cognitive or

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Figure 5. Primary progressive aphasia in a 63-year-old woman: a: coaffecting the left side. Frontal white matter hypointensities due to assoperisylvian atrophy (enlargement of the frontal cortical and anterior tem

ith dilatation of the temporal horns).

sychiatric problems (depression) [49] preceding the chor-iform movements.

MRI shows atrophy of the caudate nucleus and puta-ens, with a loss of the usually clearly convex appearance

Fig. 9) [50]. The central gray nucleus may be hyperintensen T2-weighted MRI in juvenile forms of the disease. Atro-hy then extends to the globi pallidi, thalami, cortex and

ronal T1-weighted MR: bilateral temporal atrophy, predominantlyciated leukoaraiosis; b: sagittal T1-weighted left lateral MR: leftporal sulci and the sylvian fissure).

382 C. Quach et al.

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Figure 9. Huntington’s disease in a 56-year-old woman. CoronalT1-weighted MRI. Pronounced loss of volume of the head of thecaudate nuclei (arrows) with an enlargement of the frontal horns.Eh

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igure 7. Lewy body dementia. Axial T1-weighted MRI. Diffuseoderate enlargement of the subarachnoid spaces.

rain stem, causing appearances of predominantly frontal,iffuse cerebral atrophy. The disease progresses gradually to

oss of independence and death over an average of fifteeno twenty years. It progresses faster in earlier onset disease.

igure 8. DaTSCAN®. Tracer-uptake defects in the posterioregion of the central gray nuclei (arrows).

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nlargement of the subarachnoid spaces, frontal convexity, inter-emispheric scissure, sylvian regions and choroid fissures.

he definitive diagnosis is made by molecular biology (tripletxpansion in the IT15 gene).

orticobasal degeneration

orticobasal degeneration is a neurodegenerative diseaseery occasionally seen in the dementia stage before thege of 65. It involves neurofibrillary degeneration, pre-ominantly in the cortical and subcortical frontal regionsssociated with accumulation of tau proteins. The sug-estive clinical signs include asymmetrical motor disordersredominantly in the upper limbs, sensory abnormalitiesnd apraxia. MRI shows frontoparietal cortical atrophy,redominantly in the paracentral region (Fig. 10). Hyper-ntensities on T2-weighted MR may be seen in the motoregion (cortex and subcortical white matter). Hyperintensi-ies on T2-weighted imaging have also been reported in theosterior part of the putamens and substantia nigra [51].

rion dementia

rion diseases are transmissible neurodegenerative dis-ases characterized by diffuse cerebral spongiosis secondaryo abnormal fibrillar glycoprotein (PrP) deposition. Thiss coded by the PNRP gene located on chromosome 2052]. Human prion diseases, the most common of which isreutzfeldt-Jakob (CJD), may be sporadic (90% of cases),cquired (iatrogenic) or genetic [53]. The familial formsannot be distinguished clinically from sporadic disease.DJ is suggested by rapidly progressive dementia (over

few weeks) and development of suggestive neurologi-al signs (myoclonia, ataxia, pyramidal and extrapyramidaligns). The new variant form of the disease (vCJD), iden-

ified for the first time in the United Kingdom in 1996,as transmitted by eating beef from herds infected withovine spongiform encephalopathy. This affects younger

Early-onset dementias: Specific etiologies and contribution of MR

Figure 10. Basal cortical degeneration in a 62-year-old woman.Axial T2-weighted FLAIR MR. Asymmetrical enlargement of the sub-

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arachnoid spaces predominantly in the right parietal region andparacentral regions.

people between 30 and 40 years old and characteristi-cally causes dementia in the early stages of the disease[54]. Electroencephalography in advanced sporadic forms of

the disease (sCJD) (unlike vCJD) often shows characteristictriphasic periodic complexes. CSF analysis shows markers ofrapid neuronal destruction, such as high levels of protein

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Figure 11. Creutzfeldt-Jakob disease, sporadic form. Axial diffusion-wnuclei and lenticular nuclei (b) (arrows).

I 383

4-3-3. T2 and diffusion-weighted MR in the sporadic formf the disease shows bilateral and symmetrical hyperinten-ities in the central gray nuclei, thalamus, cerebral corticalibbon (particularly in the frontal and temporal lobes) andn the cerebellum (Fig. 11) [55]. Diffusion-weighted MRIs the most sensitive method in terms of detecting singlebnormalities [56]. In familial disease, the cortical hyper-ntensity on a diffusion-weighted sequence may even beresent before clinical signs develop [57]. In vCJD, the char-cteristic finding is hyperintensity in the pulvinar nuclei andorso-median thalamic nuclei (‘‘hockey-stick’’ appearance)Fig. 12) whereas a cortical hyperintensity is rarely present58,59]. Ninety percent of affected people die within a yearf diagnosis. The definitive diagnosis is histological: in theew variant form of the disease, the diagnosis can be maderom tonsillar biopsy from immunological labeling of therion protein [60] although brain tissue examination is stilleeded for sporadic CJD.

ascular dementia

ascular dementia (VD) is the second leading cause of early-nset dementia [4], and includes all forms of dementiahich are secondary to cerebrovascular damage. Variouslinical and pathological presentations have been describedepending on the site and appearance of the cerebralesions: VD due to multiple cerebral infarctions is due totrategic infarctions, subcortical ischemic VD with Cere-ral Autosomal Dominant Arteriopathy with Subcorticalnfarcts and Leukoencephalopathy (CADASIL), VD secondaryo multiple hemorrhagic lesions and VD due to cerebral

ultiple infarctions was described initially by Hachinskit al. [61] and is based on the combination of cardiovascu-ar risk factors, sudden onset and/or stepwise progression

eighted MRI (a, b). Hyperintensity in the cortical band (a), caudate

384 C. Quach et al.

Figure 12. New variant form of Creutzfeldt-Jakob disease. Diffusion (a) and FLAIR images (b). Hyperintensity in the pulvinar and dorso-median thalamic nuclei (arrows) producing a ‘‘hockey-stick’’ appearance.

with focal signs on clinical examination. The infarctionsmay be due to occlusion of the large or medium cerebralarteries (extensive parenchymal infarction) and/or smallarteries (perforating arteries causing focal infarction withinthe white matter or central gray nuclear region) (Fig. 13).

VD due to strategic infarctions or single vascular lesionsoccurs in territories involved in cognition or memory. Thevarious territories involved are cortical (left angular gyrus,mesial part of the left temporal lobe [62], median part of the

Figure 13. Multiple infarctions in a 63-year-old man. Axial T2-weighted FLAIR MRI. Old infarctions in the left frontal region andright parietal region.

frontal lobes) and subcortical regions (thalamus, particularlythe left) (Fig. 14).

Ischemic subcortical VD refers to two former diagnoses,Binswanger’s encephalopathy [63] and lacunar dementia

Figure 14. Strategic infarction. Axial T1-weighted image. Oldbithalamic infarctions (arrows) (infarction in the territory of theartery of Percheron).

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Early-onset dementias: Specific etiologies and contribution

[64]. These are now defined by the revised NINDS-AIRENcriteria [65] and on MRI, show image abnormalities in thewhite matter (T2-weighted spin echo and FLAIR hyperin-tensities due to leukoaraiosis), lacunar infarctions (cavitiesunder 15 mm in size, with the same appearances as CSF onall sequences, located in the territory of the perforatingarteries) and by microbleeds (hypointensities under a cen-timeter in size on T2-weighted gradient-echo sequences).Sporadic (arteriolosclerosis, less commonly vasculitis) andgenetic causes (the leading cause of which is CADASIL) areseen. CADASIL is due to a mutation of the NOTCH 3 gene[66], which is located on chromosome 19 [67]. Sporadiccases of the disease have also been described [68]. Clinicalpresentations are extremely variable between affected indi-viduals and within the same family. The signs and symptomsmay include migraine with aura beginning between 20 and40 years old [69], mood disturbances, apathy [70], recurrentsubcortical ischemic events after 40 years old, and cognitivedisturbances [71]. The earliest and most common abnor-mal appearances are hyperintensities on T2-weighted FLAIRsequences in the white matter, which can be seen from theage of 20 to 30 years old. These are located in the periven-tricular regions, the semi-oval centers, the external capsuleand the anterior part of the temporal lobes (Fig. 15) [72,73].Temporal lobe involvement is seen in more than two-thirdof patients. The central gray nuclei and thalami may beaffected [74]. Lacunar infarctions are seen as fluid micro-cavities with restricted diffusion if they are recent [75].Microbleeds are present and appear as hypointensities onT2-weighted gradient-echo sequences [5,76]. The disease isconfirmed by testing for the NOTCH 3 gene mutation.

VD secondary to multiple hematomas is usually dueto severe forms of amyloid angiopathy (AA). T2-weighted

gradient-echo MR shows multiple hypointensities (microb-leeds), typically located in the cortex and subcorticalregions, combined with lobar hematomas of various ages

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Figure 15. CADASIL in a 34-year-old woman. Axial T2-weighted FLAIRsubcortical periventricular white matter (a). Anterior subcortical tempo

I 385

Fig. 16). White matter demyelination is often also present.his is a rare diagnosis in young people and should suggestn autosomal dominant familial form of the disease (muta-ion of the APP gene located on chromosome 21 [77] or ofhe BRI gene located on chromosome 13 [78,79]). Vascularementia due to cerebral hypoperfusion is seen in situationsnvolving low blood flow velocity, causing ischemic damageo the junctional territories. As they are located in twoifferent vascular drainage areas, the external junctionalnfarctions (cortical) can be distinguished from the internalnfarctions (subcortical) [80]. The external infarctions at theunction of the territories of the Circle of Willis at the basef the brain are peripheral and have a triangular corticalorphology (Fig. 17) whereas the internal infarctions at the

unction of the cortical and perforating branches of the samertery have a linear morphology and are located in the whiteatter.Dural arteriovenous fistulae draining into cortical veins

re also a cause of dementia, which presents subacutely.hese are acquired arterio-venous communications withinhe dura mater, supplied by meningeal arteries arisingostly from the external carotid system [81]. They are

sually located in the transverse sinus and sigmoid regions82] and generally occur secondarily to a sinus thrombosis83]. Increased venous pressure due to turbulence and sinushrombosis is transmitted in a retrograde manner to the cor-ical veins with a risk of hemorrhage, congestion and venousschemia. The fistula presents via dementia in approximately0% of cases [83], in which case symptoms are due to chronicenous ischemic damage (low blood flow velocity becausef flow reversal in the veins draining the encephalon) [81].eadaches are associated with signs of cognitive deteriora-ion. MRI shows flow abnormalities within the venous sinuses

y thrombosis or stagnation and dilated cortical veins [84].he sinus may enhance in chronic thrombosis. White mat-er edema reflecting the raised venous pressure may also

image (a, b). Multiple nodular hyperintensities in the deep andral hyperintensities (b).

386 C. Quach et al.

Figure 16. Amyloid angiopathy in a 59-year-old woman. Axial T2-weighted gradient-echo MRI: multiple cortical micronodular hypointen-sities (micro-bleeds) (a, b). Left parietal hematoma: hyperintensity surrounded by hemosiderin (b). Note the opening of the hematomainto the adjacent subarachnoid space with superficial hemosiderosis seen(arrow).

develop [84]. Dynamic MR angiography performs better inthis situation than time of flight MR angiography and candiagnose by visualizing the fistula which is seen as contrastproduct passing from an arterial to a venous segment [85].The reference investigation to establish the architecture ofthe fistula is still conventional angiography. Cognitive func-tion can be restored by treatment, the first line of treatmentis an endovascular approach [86].

Figure 17. Old junctional infarctions. Axial T2-weighted MRI.Hyperintensities in the cortex and white matter at the junction ofdifferent arterial territories.

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lcohol-related dementia

radual intellectual deterioration is one of the psychiatricnd neurological complications of chronic alcoholism andnvolves defects in executive functions and autobiographicemory and confabulation. The concept of alcohol-relatedementia raises diagnostic difficulties as many patientsave clinical signs of the Wernicke-Korsakoff syndromethiamine deficiency), nutritional deficiencies and hepaticncephalopathy. Dementia occurring secondary to chroniclcohol use is multifactorial in origin, with a direct toxicffect of the alcohol which easily crosses the blood-rain barrier, alcohol-related deficiencies, repeated headnjuries, seizures with anoxia, ischemic vascular accidentsnd particularly hemorrhages.

In chronic alcoholism, MR shows diffuse cerebral atrophyith cortical atrophy predominantly in the fronto-parietal

egions (hippocampal atrophy proportional to the overalleduction in cerebral volume [87]), cerebellar atrophy, pre-ominantly in the superior vermis and paravermal area.ther more specific abnormalities may be present, includ-

ng atrophy of the central gray nuclei and mamillary bodiesKorsakoff syndrome), abnormal corpus callosum appear-nces (Marchiafava-Bignami disease) and abnormalities ofhe central part of the pons (as a result of central pontineyelinolysis) (Fig. 18).

nfectious diseases

he infectious diseases which usually cause subacute

ementia associated with focal neurological signs andequire a specific assessment, guided by the clinical picture.irst line investigations for early-onset dementia includeuman immunodeficiency virus (HIV) and syphilis serologies.

Early-onset dementias: Specific etiologies and contribution of MRI 387

Figure 18. Chronic alcohol abuse in a 50-year-old man: a: axial T2-weighted FLAIR image: diffuse enlargement of the cortical sulci; b:llar atrophy predominantly affecting the superior vermis. Hyperintensity

Inflammatory and autoimmune diseases

Amongst the causes of sporadic early-onset dementia,inflammatory and autoimmune diseases, including multiple

sagittal T2-weighted MRI: atrophy of the corpus callosum and cerebein the pons due to centro-pontine myelinolysis.

AIDS dementia complex

Brain disease secondary to direct nervous system attackby the HIV virus usually presents as subcortical dementiaassociated with walking difficulties and seizures. The cog-nitive decline, which is often a presenting feature of thedisease, occurs when the patient infected with the virusbecomes immunosuppressed when the CD4 count is low(< 200/mm3). MRI shows diffuse cerebral atrophy, initiallypredominantly in the subcortical region. The extent of ven-tricular enlargement, particularly in the caudate nucleusregion, is reported to correlate with poor performance inneurophsychological tests [88]. This is very often associatedwith periventricular white matter hyperintensities (particu-larly in the corpus callosum) [89] or diffuse hyperintensitiesin the white matter with preservation of the U-fibers(Fig. 19) [90—92].

Neurosyphilis

Neurosyphilis is a neurological disease which develops inthe late stage of syphilis (a third of patients have ter-tiary syphilis). It is characterized by behavioral problemsincluding agitation, abnormal social behavior and memoryand attention difficulties. The cortical dementia developsgradually. MRI of such presentations of dementia shows atro-

phy of the medial temporal regions similar to that which isfound in AD [93,94], abnormal intensities in the same regionwith T2-weighted hyperintensity similar to herpes or lim-bic encephalitis [95,96]. Vasculitic disorders and meningealenhancement may also be present. The diagnosis is con-firmed by blood and CSF tests (TPHA and VDRL).

Figure 19. A 55-year-old man infected with the humanimmunodeficiency virus. Axial T2-weighted FLAIR MRI: diffusehyperintensities in the white matter with preservation of theU-fibers (arrows), pronounced enlargement of the subarachnoidspaces.

3 C. Quach et al.

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88

clerosis (MS), lupus, Behcet’s disease and sarcoidosis, areccasionally responsible for isolated cognitive problems andenerally do not raise diagnostic difficulties once cognitiveroblems have developed [2]. MS (one of the most commonauses of secondary dementia), Sjögren’s syndrome and pri-ary angiitis of the central nervous system (CNS) are alliseases which can present with cognitive problems.

ultiple sclerosis

ultiple sclerosis rarely presents with cognitive problems,lthough these are common in the late stages of the dis-ase [97—99] and progress slowly. They are more severen progressive rather than remittent disease and correlateith the topography of the lesions, total lesion burdennd axonal disease [100,101]. The cortical and subcorticalesions are reported to contribute most to cognitive declinen these patients [102,103]. Subcortical damage is due toeterioration of the U-fibers which are involved in thenterconnections between different cortical regions [100].he extent of corpus callosum atrophy correlates with theegree of axonal damage [99]. Extensive damage to thehite matter causes fronto-subcortical disconnection, with

decline in executive functions.

jögren’s syndrome

jögren’s syndrome is a chronic autoimmune disease, whichredominantly affects females (sex ratio 9:1) which mayresent initially with mild frontal subcortical cognitive dis-urbance. MR shows non-specific nodular lesions which areyperintense on T2-weighted MR in the white matter, ofariable topography (periventricular, deep or subcortical),nd associated with diffuse cortical-subcortical atrophy. Ast improves with corticosteroid therapy, anti-Ro/SSA andnti-La/SSB antibodies should be measured and an acces-ory salivary biopsy should be performed if any suspicion isresent [104].

rimary angiitis of the central nervous system

he diagnosis of cerebral vasculitis is relatively straightfor-ard if the disease involves multiple systems (hence the usef renal, liver and opthalmological assessments) although its more difficult when it is restricted to the central nervousystem as is seen in primary angiitis of the CNS, the cause ofhich is still unknown. Focal inflammatory changes (granu-

omatous, necrotizing and/or lymphocytitic) preferentiallyffect the small leptomeningeal and intraparenchymal ves-els. Clinical presentations vary greatly from acute ‘‘pseudoS’’ encephalopathy or very gradual subcortical demen-

ia. Headaches are commonly associated, although mayot be present. MRI shows secondary vascular lesionsue to arteritis, appearing as plaques of demyelination,nfarctions, bleeds (microbleeds and hematomas) (Fig. 20).arietal involvement may be seen as thickening or contrastnhancement of the vascular walls. MR angiography, andarticularly arteriography (Fig. 21), shows stenosis and/or

ctasia (pearl necklace appearance) in small diameter arter-es. Raised inflammatory markers and auto-antibodies, MRIbnormalities, pleiocytosis with oligoclonal bands in the CSF,nd a pearl necklace appearance on arteriography suggest

Fce

eighted FLAIR MRI: hyperintensities in the white matter in bothemi-oval centres, with right medial parietal infarction.

ngiitis, although none of these signs can replace histol-gy, and unconfirmed suspected cerebral vasculitis remainsne of the indications for cerebromeningeal biopsy, beforeonsidering immunosuppressant therapy.

imbic encephalitis

he limbic encephalitides are a group of different disordersith selective involvement of the limbic system. Although

igure 21. Primary central nervous system angiitis. Lateralarotid arteriography: multiple focal arterial stenoses and areas ofctasia (arrows).

of MR

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W

Wtameadmsscpl

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Early-onset dementias: Specific etiologies and contribution

dysimmune (paraneoplastic or idiopathic) or infectious (HSVand HHV6 encephalitis) conditions (Fig. 22).

Dysimmune limbic encephalitis is a rare condition, char-acterized clinically by cognitive and anterograde memoryproblems which may be combined with seizures and psy-chiatric problems. It develops subacutely and may progressto dementia. CSF analysis shows inflammation with mod-erate pleiocytosis, increased cerebrospinal fluid proteinand oligoclonal bands. MR image abnormalities are usu-ally seen the anteromedial temporal cortex, hippocampiand amygdali, and appear as hyperintense plaques on T2-weighted sequences with no space occupying effect orcontrast enhancement. The MRI may initially be normal. Itis essential to search for a dysimmune cause by measuringspecific serum autoantibodies against intracellular neuronalcomponents (anti-Hu, anti-Ma2, anti-CV2) or nervous systemcell surface antigens (Voltage Gated Potassium Channels,anti-N-methyl-D-aspartate receptor antibodies) if the clini-cal and radiological features are suggestive, after excludinginfectious disease [105]. Patients found to have autoimmunelimbic encephalitis should also be examined for a coexistenttumor (small cell lung cancer in 50% of cases, testes, breast,thymoma or lymphoma). The treatment of paraneoplasticlimbic encephalitis involves treatment of the underlyingcancer and initiation of immunotherapy. Immunotherapy hasalso been shown to be particularly effective in idiopathicdysimmune limbic encephalitis [106].

Metabolic diseases

Amongst the metabolic diseases, respiratory chain abnor-malities due to a mitochondrial DNA mutation is reported torepresent approximately half of the cases of adult dementiaoccurring in those under 45 years of age [8]. These are oftenassociated with other neurological and systemic signs seen inMELAS syndrome (Mitochondrial Encephalopathy with Lactic

Acidosis and Stroke-like episodes) with combined myopa-thy and pseudo-cerebrovascular accidents, MERFF syndrome(Myoclonic Epilepsy with Ragged-Red Fibers) with myoclonicepilepsy, and NARP syndrome (Neuropathy, Ataxia, Retinitis

ppio

Figure 22. Dementia secondary to infectious encephalitis (HHV6 herpT2-weighted FLAIR MRI: a: hyperintensity in both hippocampi (arrows);Severe atrophy predominantly affecting the left side with a normal MRI

I 389

igmentosa). In MELAS syndrome, the disease usually beginsn childhood or early adulthood, although the dementia gen-rally occurs late. Cases presenting in adulthood as subacuteementia with myoclonia have been reported [107]. MRIhows diffuse cerebral atrophy (temporo-occipito-temporalortex with preservation of the medial temporal regions)ombined with multiple T2 hyperintensities in the deephite matter and in the region of the central gray nuclei

Fig. 23). Image abnormalities mimicking ischemic accidentsre seen in acute episodes (T2 and diffusion-weighted hyper-ntensities affecting the cortex and white matter in plaquesith a variable apparent diffusion coefficient) and pre-ominantly in the parieto-occipital regions. Spectroscopyay help by showing a lactate doublet in 60 to 65% of

ases (Fig. 24). Other diagnoses to be considered if a cere-rovascular accident (CVA) or pseudo-CVA is present, includeetabolic homocysteine and urea cycle abnormalities.

ilson’s disease

ilson’s disease is a curable cause of early-onset demen-ia which the patient needs to be examined for. It is anutosomal recessive genetic disease which has an esti-ated prevalence of 1/50,000 [108]. It is caused by

xcessive accumulation of copper, particularly in the livernd central nervous system. Behavioral and personalityisorders, depression and cognitive difficulties are com-on. The cognitive difficulties and related neurological

igns (tremor, ataxia and dysarthria) develop around theecond and third decades of life. Patients are examinedlinically for the corneal Kayser-Fleischer ring which isathognomonic, although is occasionally only visible on slitamp examination.

MRI shows symmetrical T2 hyperintensity or hypointen-ity in the putamens, caudate nuclei, thalami and globiallidi. The analyses of axial sections passing through theesencephalon are examined for the ‘face of the giant

anda’ appearance (mesencephalic hyperintensity on theeriphery of the red nuclei) (Fig. 25). T2-weighted hyper-ntensities in the pons and pontocerebellar bundles mayccur. The diagnosis is confirmed by laboratory findings:

es group virus) in a 59-year-old immunosuppressed man. Coronal b: 5 months later. Reduction in size of both hippocampal bodies.signal. Abnormal signal on the right persists.

390 C. Quach et al.

Figure 23. MELAS in an 18-year-old woman. Axial T2-weighted FLAIR MRI (a, b) and diffusion-weighted MR (c), mapping of apparentdiffusion coefficient (d). Frontal hyperintensity on T2 and diffusion-weighted images (a, c) affecting the cortex and white matter (pseudo-C increo nd s

rtt

N

TaImcckcn

aamt

todmt

VA). The apparent diffusion coefficient of the lesions was slightly

f the central gray nuclei (putamens, caudate nuclei and thalami) a

educed levels of serum ceruloplasmin, increased levels ofotal serum and urinary copper are all present. This can bereated with a life-long course of copper chelators.

euronal ceroid lipofuscinosis

his is a group of neurodegenerative diseases secondary toccumulation of ceroid lipopigments in neuronal lysosomes.t is transmitted as an autosomal recessive disease. Fourain forms are seen based on clinical, electrophysiologi-

al and neuropathological criteria: the early childhood, late

hildhood, juvenile and adult forms of the disease (alsonown as Kufs disease). They are due to an enzyme defi-iency. The gene responsible for this enzyme deficiency hasot yet been located [109].

lwrt

ased (mean ratio: 1.2). T2-weighted hyperintensities in the regionubcortical matter in the parietal regions.

Symptoms of the disease begin in the adult form atround 30 years old with myoclonic epileptic seizuresnd progressive dementia, ataxia and abnormal move-ents reflecting damage to the extrapyramidal sys-

em.MRI shows hyperintensities, particularly in the periven-

ricular white matter on T2-weighted FLAIR MRI due to lossf neuronal integrity, reactive gliosis and increased axonalemyelination [109,110]. T2 gradient-echo hypointensityay be seen in the central gray nuclei, particularly in the

halamic and putamen nuclei due to iron, secondary to the

ipofuscin accumulation (Fig. 26) [111]. This is associatedith diffuse cortical atrophy, particularly in the parietal

egions, which may extend to the central gray nuclei inhe late stages. Treatment is mostly symptomatic. Patients

Early-onset dementias: Specific etiologies and contribution of MR

Figure 24. Spectroscopy (echo time: 35 ms, monovoxel pos-itioned in the left middle frontal region). Lactate doublet present(arrow).

pt

C

Ciapocpdwpidth

ss

Figure 25. Wilson’s disease: a: axial T2-weighted MR: bilateral, symmcapsulothalamic regions); b: axial T2-weighted FLAIR MRI: mesencephaliof the giant panda’ appearance; c: immediately lower axial T2-weighted

tegmentum and tectum.

I 391

rogress to become bed bound and die within ten years afterhe signs appear.

ACH/VWM syndrome

hildhood Ataxia with Central Nervous System Hypomyelin-sation/Vanishing White Matter (CACH/VWM) syndrome is

recently recognized autosomal recessive leukodystro-hy. Signs usually develop before the age of 5 yearsld. Later forms of the disease which begin in adoles-ence or adulthood have been described, with an insidiousresentation involving isolated behavioral and cognitiveisorders [112]. MRI shows diffuse bilateral symmetricalhite matter demyelination. Supratentorial involvementredominates with preservation of the U-fibers. In thenfratentorial regions, the corticospinal and cerebellar bun-les are affected. FLAIR MRI shows hypointense cavities inhe periventricular frontal and occipital regions within the

yperintensity (Fig. 27).

Other metabolic causes may be responsible for progres-ive dementia. These are rare and their MRI features arehown in Table 1.

etrical hyperintensities in the central gray nuclei (putamens andc hyperintensity on the periphery of the red nuclei producing ‘faceFLAIR section with pronounced hyperintensity in the mesencephalic

392 C. Quach et al.

Figure 26. Kufs disease in a 59-year-old man: a: axial T2-weighted FLAIR MRI: diffuse cortical and subcortical atrophy. Hyperintensities inthe periventricular white matter close to the posterior part of the lateral ventricles; b: axial T2-weighted gradient-echo MRI: pronouncedhypointensity in the head of the caudate nuclei and lenticular nuclei.

Figure 27. CACH/VWM syndrome in a 33-year-old woman. Axial T2-weighted FLAIR MR FLAIR image: a: diffuse hyperintensity in the whitematter with preservation of the U-fibers; b: hypointense cavity areas in the frontal periventricular regions (arrows).

Early-onset dementias: Specific etiologies and contribution of MRI 393

Table 1 MRI features of different metabolic causes.

Metabolic diseases MRI abnormalities

2-hydroxyglutaric Hyperintensity in the subcortical white matter affecting the U-fibersGlutaric aciduria, type 1 Fronto-temporal atrophy, diffuse leukoencephalopathyCerebral adrenoleukodystrophy Leukoencephalopathy involving the splenium of the corpus callosum and

then parieto-occipital regionMitochondrial cytopathies (MELAS) Pseudo-CVA, T2-weighted hyperintensities in the WM and CGN,

spectroscopy: lactatesBritish dementia Periventricular leukoencephalopathyGM2 gangliosidosis (adult form) Cerebellar atrophyHomocystinuria CVAMetachromatic leukodystrophy (adult form) Diffuse butterfly-shaped leukoencephalopathyFabry’s disease T1-weighted hyperintensities in the lateral pulvinarsKufs disease (type-4 ceroid lipofuscinosis) Parietal atrophy, leukoencephalopathy, T2 GE hypointensities in the CGNWilson’s disease Mesencephalic T2-weighted hyperintensity on the periphery of the red

nuclei (‘‘face of the giant panda’’ appearance)Pantothenate kinase-associated

neurodegeneration(PKAN)T2-weighted hypointensity in the pallidus with central hyperintensity(‘‘tiger eye’’ appearance)

Neuroferritinopathy T2-weighted hypointensity affecting the globi pallidiType C Niemann-Pick’s disease Parenchymal atrophy, T2-weighted hyperintensities in the white matterPhenylketonuria Leukoencephalopathy predominantly affecting the parieto-occipital

regionCACH/VWM syndrome Diffuse leukoencephalopathy, periventricular area cavitiesCerebrotendinous xanthomatosis Leukoencephalopathy, T2-weighted hyperintensities in the dentate nuclei

MELAS: Mitochondrial Encephalopathy with Lactic Acidosis and Stroke-like episodes; CVA: cerebrovascular accident; WM: white matter;CGM: central gray nuclei; GE: gradient echo; CACH/VWM: Childhood Ataxia with Central nervous system Hypomyelinisation/Vanishing

a

White Matter.

Conclusion: diagnostic algorithms

MRI is a key stage in investigating the cause of early-onset dementia. These need to be acquired following

wfc

TOPOGRAPHY

LOBAR

BASAL GAN GLIA

Bilateral fAnterior t

Anterior lBilateraly

Bilateral a

Global atCaudate n

Frontotem Circum sc

Pred omin (no n amn

Post erior Asymmet

Figure 28. Diagnostic algorithm for parenchymal atrophy.

strict protocol and always examined thoroughly. T1-

eighted volume acquisitions can be used to investigate

or and locate cerebral atrophy (Fig. 28) and enableoronal reconstructions to be made perpendicular to the

rontal empo ral lo bes

e� tempo ral (po ssible)

trop hy of hipp ocam pi

rophy ucleus and putamen

Fro ntotemporal demen�a

Hun�ngton’s disease

poral (asymm etric ) ribed le� pe risylvian

Prima ry progres sive

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Seman�c demen�a

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ippocampus in order to allow better medial tempo-al examination, sagittal and axial sequences to assesshe topography, to study the anteroposterior gradientnd to investigate whether or not aysmmetrical atro-hy, which is characteristic of degenerative disease, isresent. The topography of the hyperintensity on T2-

eighted FLAIR sequences (Fig. 29) can suggest a diagnosisf vascular leucopathy (subcortical, external capsule andontine hyperintensity), metabolic (bilateral symmetrical

spd

igure 29. Diagnostic algorithm for T2-weighted FLAIR image abnorm

igure 30. Diagnostic algorithm for T2-weighted gradient-echo abnorm

C. Quach et al.

yperintense plaques and/or affecting the corticospinalundles and cerebellum), inflammatory or infectiousasymmetrical periventricular, juxtacortical, nodular hyper-ntensity, possibly with enhancement). On T2-weightedradient-echo MRI (Fig. 30), micronodular hypointensitiesmicrobleeds) suggest a vascular cause. Hypointensities

pecifically affecting the central gray nuclei indicatearamagnetic deposition characteristic of a metabolicisease. A diffusion-weighted hyperintensity (Fig. 31)

alities.

alities.

Early-onset dementias: Specific etiologies and contribution of MRI 395

orm

Figure 31. Diagnostic algorithm for diffusion-weighted image abn

may be due to vascular disease, CJD or mitochondrialdisease.

MRI can therefore be used to determine the likely causeof the dementia (degenerative, vascular, infectious, inflam-matory, metabolic or toxic). Once the obvious causes havebeen excluded, it will guide investigation into the rarebut characteristic causes of early-onset dementia, someof which, notably the metabolic and autoimmune causes,require specific management and involve genetic counsel-ing.

Disclosure of interest

The authors declare that they have no conflicts of interestconcerning this article.

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