structural and chemical neuroimaging in dementia: a … · 2016-10-05 · structural and chemical...

REVIEW ARTICLE

2 3 41Lakshminarasimhan Ranganathan , Anusha Doraiswamy , Balasubramanian Samivel , Amarnath Chellathurai , 5 6 7Srinivasaraman Govindarajan , Priti Nagwani , Kannan Vellaichamy

1,2,3,7 Institute of Neurology, Madras Medical College and Government General Hospital, Chennai, India.

4Professor, Department of Radiology, Stanley Medical College, Chennai

5 6Consultant Radiologist, Consultant Nuclear Physician, Anderson diagnostics and Labs, Chennai

Corresponding author: Dr Lakshminarasimhan Ranganathan

Corresponding email: [email protected]

STRUCTURAL AND CHEMICAL NEUROIMAGING IN DEMENTIA: A REVIEW

ABSTRACT

Dementia is a devastating neurological illness with a globally increasing prevalence. The common causes are Alzheimer's disease,

vascular dementia, diffuse Lewy body disease, and frontotemporal lobar degeneration. Clinical evaluation plays a major role in

defining and diagnosing these conditions, but lately, neuroimaging has begun to contribute significantly to the diagnostic and

therapeutic aspects of dementia management as well as in the understanding of pathophysiology of these diseases.

Conventionally, neuroimaging in dementia evaluation was aimed at an “exclusionary approach” by excluding structural and potentially

reversible causes, but recent trends have shown remarkable advances in neuroimaging techniques enabling proper categorization of

dementia subtypes and understanding its neurobiology using biomarkers, thus supplementing clinical diagnosis and ensuring

appropriate management. Imaging criteria is now an essential component of diagnostic criteria employed for vascular dementia,

diffuse Lewy body disease and fronto-temporal dementia.

Different patterns of cortical atrophy and white matter changes are detected by structural neuroimaging whereas functional neuro-

radiologic techniques evaluate metabolic and perfusion abnormalities in the brain parenchyma that aid in proper classification of

dementia subtypes. Latest amyloid imaging techniques which have revolutionized diagnosis and workup of dementias show promising

potential for distinguishing dementia subtypes and detecting healthy individuals at risk of future dementia and help in identifying

candidates for early preventive measures.

This review aims to explain the various neuroimaging tools available to the neurologists and thus ensure judicious and appropriate

application of these techniques to the diagnosis and management of patients with dementia.

Key words: Dementia, Neuroimaging, CT, MRI, PET, SPECT, MRS, fMRI, Amyloid.

INTRODUCTION

WHO estimates that 35.6 million people worldwide have

dementia and that there are 7.7 million new cases of dementia 1each year. Alzheimer's disease is the most common cause and

contributes to 60–70% of cases of dementia. Dementia is a major

cause of disability amongst the elderly and it is estimated that its

numbers will double by 2030 and triple by 2050.

Recent medical advances and prolonged lifespan have led to a

recent rise in dementia prevalence. Dementia refers to a state of

global regression in cognitive, functional and emotional

attributes from a prior status of normal functioning, in addition to

associated neuropsychiatric disturbances. The causes of

dementia can be acute or recurring brain insults due to vascular,

metabolic and infective factors or may be secondary to an

ongoing chronic degenerative process (Table 1).

Type Diseases

Cortical

Alzheimer’s disease (AD) F ronto temporal dementia Diffuse Lewy Body Dementia

V ascular Multi-infarct dement ia S trategic lacunar infarct dementia Binswanger’s disease Cerebral amyloid angiopathy Cerebral autosomal dominant arteriopathy with subcortical infarctions and leukoencephalopathy (CADASIL)

Parkinson spect rum

Parkinson’s disease (PD) P rogressive supranuclear palsy (PSP) Corticobasal degeneration Multiple system atrophy

Infectious HIV/A IDS dementia P rogressive multifocal leukoencephalopathy (PML) Viral encephalit is, Neurosyphili s Lyme disease, Whipple’s disease Creutzfeldt-Jakob disease (CJD)

Table 1: Etiologies of dementia

AJCN 2013; 1 (2): 7 www.ajcn.in

VOL 1(2):PAGE 7 - 19

The most common cause of dementias is neurodegenerative

diseases. Our expanding knowledge base in dementia has

enabled accurate diagnosis and proper management of the

patient as well as in the prognostication of the illness. Earlier, the

role of neuroimaging was primarily to exclude the reversible and

treatable causes of dementia like subdural hematoma, normal

pressure hydrocephalus, and brain tumors. However, recent

advances in neuroradiology have enabled us to understand the

nuances of disease etiopathogenesis, and allow characterization

of the various neurodegenerative dementias by neuroimaging

techniques. Despite the rapid strides made in the evolving

scenario of neuroimaging, diagnosis of dementias still depends

upon the conventional neuropsychological assessment and

clinical findings. Further research in dementia neuroimaging is

anticipated to define the potential for the detection of

neurodegeneration at an early stage and identification of patients

for early preventive or disease modifying therapy.

ROLE OF NEUROIMAGING

Neuroimaging has lately been increasingly used to aid in the

evaluation of dementias. Except for few investigations like

serum vitamin B12 levels, thyroid function tests and syphilis

serology, other laboratory investigations have very minimal

yield in contributing to the evaluation and workup of dementia.

The emerging newer neuroimaging modalities have enabled

accurate diagnosis as well as appropriate treatment strategies

like the use of acetylcholinesterase inhibitors in Alzheimer's

disease and avoiding risk of neuroleptic malignant syndrome

precipitated by use of conventional antidopaminergic therapy in

diffuse Lewy body (DLB) disease and initiation of risk factor

modification in vascular dementia.

Thus the traditional “exclusionary approach” of dementia

neuroimaging which primarily aims to eliminate readily

detectable causes of dementia such as subdural hematomas and

brain tumors via structural neuroimaging, has paved way for an

inclusionary positive approach with the inclusion of

neuroimaging in the diagnostic criteria of several dementias 2(Figure 1).

The neuroimaging techniques are primarily categorized as

functional or structural, although they can be used for both

purposes. The commonly used structural techniques are

computerized tomography (CT) and magnetic resonance

imaging (MRI). Functional neuroimaging is done using single

photon emission computed tomography (SPECT) which

measures blood flow or positron emission tomography (PET)

that measures glucose metabolism using tracers. Emerging

neuroimaging like molecular imaging techniques using

magnetic resonance spectroscopy (MRS), establishing

functional connectivity using diffusion tensor imaging (DTI)

and functional magnetic resonance imaging (fMRI) are playing 3greater roles in the dementia evaluation (Figure 2).

Figure-1: The potential uses of neuroimaging in dementias

Figure-2: Various neuroimaging modalities in dementia

Structural imaging is commonly used to screen for evidence of

potentially treatable causes of dementia like normal pressure

hydrocephalus and chronic subdural hematoma or to aid in the

diagnosis by detecting vascular insults or cerebral atrophy. The

American Academy of Neurology recommends that at least one

structural neuroimaging study should be performed in the initial 4evaluation of patients with dementia. While neuroimaging

changes like hippocampal atrophy and entorhinal cortical

Toxic/ metabolic

Wernicke-Korsakoff syndrome (a lcohol/Vitamin B1 deficiency) Vitamin B12 deficiency Hashimoto’s encephalopathy Wi lson’s disease Heavy metals and organic poison exposure

S tructural/ space occupying

Normal-pressure hydrocephalus (NPH) Chronic subdural hematoma Neoplas ia

A utoimmune Mul tipl e scleros is Paraneoplastic limbic encephalopathy Anti–voltage-gated potass ium channel (V GKC) antibody mediated encephalopathy Lupus cerebritis

Traumat ic Traumatic brain injury

O thers Huntington’s disease Mitochondrial disease Adult onset leukodys trophie s


atrophy serve as an early and sensitive marker for Alzheimer's

disease (AD); cortical and subcortical infarcts with white matter

lesions are characteristic of vascular dementia (VaD).

Magnetic resonance spectroscopy has also shown promise in

developing into an early biomarker by providing evidence of

elevated myoinositol and decreased N-acetylaspartate (NAA)

levels in neurodegenerative dementias.

Diffusion tensor imaging (DTI) is a novel noninvasive

neuroimaging technique for mapping of the microstructural

integrity of the brain tracts which shows abnormalities in white

matter anisotropy in the frontal, parietal, and especially temporal

cortex in Alzheimer's disease. It has the potential to detect subtle

and early white matter changes not visible in conventional MRI

technique and may be used as an early screening tool for

dementias.

Functional and molecular imaging is based on the hypothesis

that functional loss precedes structural changes in dementias.

The two commonly used modalities which also require use of 18radioactive tracers are 2-deoxy-2-[ F] -fluorodeoxyglucose–

positron emission tomography (FDG-PET) that measures the

local cerebral metabolism of glucose uptake and the single 99photon emission CT (SPECT) using [ mTc] technetium-labelled

99D,L-hexamethylpropylene amine oxime ([ mTc] technetium-

HMPAO) tracer which measures changes in blood flow and

perfusion. FDG- PET is extremely useful to differentiate

Alzheimer's disease from other dementias based on specific

pattern of hypometabolism noted in the posterior cingulate,

precuneus, temporoparietal regions, and frontal cortices as well 5as in the medial temporal lobe. Earlier changes of

hypometabolism can also predict progression of minimal

cognitive impairment (MCI) to Alzheimer's dementia. In

contrast to Alzheimer's dementia, patients with fronto temporal

dementia show marked changes in metabolism and perfusion in

the frontal and anterior temporal regions, with different

syndromic variants of frontotemporal dementia showing

differing patterns of hypometabolism and hypoperfusion.

Occipital lobe, especially the primary visual cortex is markedly

involved in diffuse Lewy body disease which otherwise 6resembles the features of Alzheimer's disease radiologically.

fMRI studies using blood oxygen level dependent (BOLD)

signals can be used to demonstrate reduced activation in affected

cortical regions during performance of specific tasks.

Extracellular deposition of insoluble protein aggregates of â-

amyloid (Aâ) are implicated in the pathogenesis of Alzheimer’s

disease and demonstrated by Congo red staining. Amyloid

imaging is the most recent and promising technology which may

be used as a biomarker to predict development of AD before the

onset and to assess the effect of therapy. A recently marketed,

novel diagnostic modality utilizing cerebral PET detection of

florbetaben, a beta-amyloid tracer that binds to beta-amyloid

plaques, which helps in the in-vivo assessment of

neuropathological amyloid burden in AD, is expected to increase

the overall confidence in diagnosing AD and possibly influence

the clinical decision making in patient management.

IMAGING TECHNIQUES

The various neuroimaging techniques available in the current

scenario are computerized tomography (CT), magnetic

resonance imaging (MRI), magnetic resonance spectroscopy

(MRS), diffusion tensor imaging (DTI), functional MRI (fMRI),

positron emission tomography (PET), single photon emission

computerized tomography (SPECT), amyloid imaging and DaT

scans.

As the utility of functional neuroimaging techniques in

dementias is beyond the scope of this review, we shall confine

this discussion to the uses of structural and chemical

neuroimaging in evaluation and management of common

dementias.

CT imaging

In spite of rapidly emerging neuroimaging technologies,

conventional CT still plays a major role in initial evaluation of

dementias and helps to characterize the gross structure of the

brain parenchyma and the cranium. Its use is especially noted in

patients with low affordability or poor accessibility to health

care and in elderly patients with comorbid medical conditions or

implants like cardiac pacemaker that is a contraindication to the

use of MRI. Volumetric studies using CT were done previously

to delineate atrophy of hippocampus in dementias but were

noted to be less reliable due to the poor gray-white–matter

discrimination and scan angle and better visualisation in coronal 7cuts. The evidence of vascular dementia can be made out in

plain CT films as areas of prior cortical infarction involving

typical vascular distributions with hypodensities involving

watershed areas, lacunar infarctions in the basal ganglia,

thalami, brainstem, or deep white matter or the presence of

periventricular leukoariosis. Normal pressure hydrocephalus is a

radiologic diagnosis easily made on CT with evidence of dilation

of the ventricular system, especially the temporal horns of the

lateral ventricles which are out of proportion to the appearance

of the cortical atrophy. Specific patterns of brain parenchymal

loss like frontotemporal atrophy in FTD, putaminal atrophy in

DLBD, caudate atrophy in Huntington's disease, atrophy of

midbrain and superior cerebellar peduncle in PSP help to

reasonably determine the type of dementia using CT. Contrast

enhancement can be seen in cases of hemorrhage, neoplasms,

infection and inflammation. Poor resolution, radiation exposure,

lack of multiplanar assessment and limited visualization of brain

stem and posterior fossa structures pose as disadvantages to CT

use.

Structural MR Imaging

Not only does MRI use nonionizing radiation, but it is also

capable of providing greater details with better 3-D resolution of

brain structures including the grey-white differentiation.

Alzheimer's disease

Patients with AD routinely demonstrate a cerebral atrophy

pattern involving the medial temporal lobe, especially the

hippocampus and entorhinal cortex, the posterior cingulate

cortex and the precuneus, insula and temporo-parietal

association neocortex with sparing of the sensorimotor cortex,

visual cortex, and cerebellum correlating to the clinical features

of amnesia, apraxia, aphasia and visuospatial disturbances.


Methods like voxel based morphometry can be used to quantify

magnitude of brain atrophy in patients with Alzheimer's disease.

Volumetric studies have shown that medial temporal or

hippocampal atrophy can help to distinguish patients with a 8clinical diagnosis of AD from controls. Corpus callosal

9involvement in AD has also been reported. Hippocampal

atrophy is strongly correlated to neuronal loss and severity of 10AD. Medial temporal lobe atrophy in Alzheimer's disease can

also be assessed using the validated 5 - point visual rating scale 11described by Scheltons et al. Studies have also shown that the

rate of change in the hippocampal volumes on serial MRI is a

more specific volumetric indicator for early identification of 12AD.

Cortical thickness assessment tools are also popular in research

studies especially in Alzheimer's disease and can be used

clinically for dementia assessment and can predict whether an 13individual is at risk for dementia. Dickerson et al demonstrated

the difference in cortical thickness between patients with AD and

healthy controls and showed that thinner cortices of specific

regions, also attributed the term of 'the Alzheimer cortical 14signature', was predictive of diagnosis of AD.

Frontotemporal lobar degeneration

In patients with FTLD, a relatively more atrophic frontal lobe

and the anterior temporal poles with a minimally involved

temporoparietal association neocortex is noted compared to

patients with AD. Patients who have FTLD show asymmetric

involvement with an anterior-posterior gradient of atrophy in

contrast to AD patients who show a more posterior and 15symmetric involvement. FTLD has further three syndromic

variants: the common behavioral variant (bvFTLD), semantic

dementia, and progressive nonfluent aphasia, each of which

shows different cortical involvement. bvFTLD shows

predominant atrophy of frontal and temporal lobes, while the

semantic variant shows asymmetric anterior temporal lobar

atrophy and the progressive aphasia variant predominantly

affects the perisylvian cortex, both of the latter showing marked

involvement on the left side. Advanced cases of FTLD show the

characteristic radiologic sign of “knife blade atrophy” in the

frontal and temporal regions (Figure 3).

Figure-3-a: Knife blade atrophy of frontal and anterior temporal

lobes in Fronto Temporal Lobar Degeneration (FTLD) seen in

T1- axial and coronal image.

Figure-3-b: PDG-PET showing frontal and anterior temporal

lobes hypomentabolism. in Fronto Temporal Lobar Degeneration

(FTLD).

Diffuse Lewy Body Dementia

Diffuse Lewy Body Dementia (DLBD) is a neurodegenerative

dementia syndrome with features characterized by cognitive

impairment, visuospatial impairment, visual hallucinations,

motor parkinsonian features, fluctuating cognition, REM sleep

behavior disorder and severe neuroleptic sensitivity. DLBD is

usually diagnosed clinically. Except for diffuse cortical atrophy,

no specific pattern of cortical loss has been found to be

classically associated with DLBD. Patients with DLB have less

atrophy of the medial temporal lobe and hippocampus and

greater atrophy of striatum especially putamen, midbrain and 16, 17hypothalamus compared to AD patients.

Vascular dementia

Vascular dementia is another common cause of dementia and

includes post-stroke dementia, multi-infarct dementia,

strategically located infarctions with dementia, and subcortical

ischemic vascular dementia (SIVD). The most commonly used

diagnostic criteria is by the National Institute of Neurologic

Disorders and Stroke - Association Internationale pour la

Recherche et l'Enseignement en Neurosciences rules (NINDS-

AIREN) which has poor sensitivity but high specificity.

White matter lesions and lacunes are classically seen in SIVD.

Progression of white matter lesions can be used as a surrogate 18marker for endpoint in trials in vascular dementia. Several

terms used for white matter ischemia in the recent past are

“leukoencephalopathy,” “unidentified bright objects,” “cerebral

small vessel disease,” “white matter lesions,” and white matter

hyper intensity (WMH ) which are described in MRI by using

visual rating scales or voxel-based methods. Fazeka et al

described the semi-quantitative grading of white matter vascular 19lesions in the brain. The advent of 3D T2 gradient-echo

imaging (GRE) has also helped in the recognition of cerebral

micro-hemorrhages or microbleeds in vascular dementia and

amyloid angiopathy (Figure 4).


Strategic infarcts are capable of mimicking dementia even in the

absence of multiple white matter lesions especially in locations

like the hippocampus, the medial thalamus, the caudate nucleus 20and the right parietal lobe. A recent criterion for vascular

dementia based on radiologic features with history of stroke and

clinical features has been proposed which estimates the

likelihood of vascular dementia in patients with cognitive 21decline. Vascular dementia typically shows white matter

hyperintensities affecting more than 25% of total white matter or 22white matter lesions with accompanying lacunars infarcts.

Cerebral autosomal dominant arteriopathy with subcortical

infarcts and leukoencephalopathy (CADASIL) is a genetically

inherited form of vascular disease manifesting with migraine,

strokes, mood changes and dementia in young adults. MRI

changes in CADASIL usually precede the onset of other

symptoms by 10–15 years and are invariably present after the

age of 35 years in all individuals with the characteristic NOTCH

3 (Neurogenic locus notch homolog protein 3) mutation. The

earliest abnormalities are T2 or fluid-attenuated inversion

recovery (FLAIR) punctiform or nodular hyperintensities in

periventricular areas and in the centrum semiovale, which later

coalesce to form diffuse symmetrical lesions with involvement

of the external capsule and the anterior part of the temporal lobes 23which is typical of CADASIL. A characteristic “etat crible”

24(status cribrosum) in the basal ganglia regions and microbleeds 25 detected on gradient echo (GRE) images can also be seen.

Involvement of 'U' fibres is typical in CADASIL with relative

preservation of the cortex. Cerebral microbleeds (CMB) are

another characteristic feature due to vasculopathy frequently

encountered in radiological assessment of vascular cognitive

impairment. Common causes are hypertensive vasculopathy and

cerebral amyloid angiopathy each of which has different patterns

of involvement. Hypertensive vasculopathy typically presents

with CMBs in the basal ganglia, thalamus, brainstem, and

cerebellum whereas cerebral amyloid angiopathy is associated 26with a lobar or peripheral distribution. A follow-up study over 6

years has shown that the presence of CMBs was consistently 27associated with progression to cognitive dysfunction. The

Rotterdam study showed that the presence of multiple

microbleeds in a predominantly lobar distribution is associated 28 with poor performance in measures of cognitive functioning.

Arterial spin labeling is a recent non-invasive MR perfusion

imaging study with potential applications in the evaluation of

vascular dementia. It is based on the technique of magnetic

labeling of water protons in the blood utilizing them as an

endogenous tracer without the use of an exogenous contrast

agent. ASL reactivity measurements can show brain parenchyma

at risk of future infarcts and may help to establish the diagnosis

by demonstrating decrease in perfusion at rest or after a

vasodilatory challenge. Thus, ASL is a technique that shows

areas of hemodynamically compromised brain regions that

appear normal on the standard MR imaging by measuring the 29cerebral perfusion.

Parkinsonian syndromes

Progressive supranuclear palsy (Figure 5) (Figure 6), multi

system atrophy and Huntington's disease are other rare causes of

dementias.

Figure-5: Humming bird or penguin sign in Progressive

Supranuclear Palsy (PSP) in midsagittal T1- weighed MRI

image showing atrophy of the midbrain

Figure-4: 3D T2* Gradient-echo image (GRE) showing multiple

lobar cerebral microbleeds (CMB) seen as punctuate hypointense

foci in Cerebral Amyloid Angiopathy (CAA)


Figure-6: Morning glory sign in Progressive Supranuclear

Palsy (PSP) in axial T2-weighted MRI image showing the

concavity of the lateral margin of the tegmentum of midbrain

Prion diseases

Prion diseases like Creutzfeld Jacob disease is a rare cause of

rapidly progressing dementia characterized by myoclonus,

cognitive impairment and coma. Several types are present

including the common sporadic form, familial, iatrogenic, and

variant form caused due to ingestion of prion contaminated meat

products. A sensitive investigation to show the earliest changes

is the diffusion MRI which shows hyperintensities within the

Table 2: Characteristic neuroradiological signs in dementias

These have typical radiological features due to pattern specific

atrophic changes and are enlisted in Table 2.

The “hockey stick” or “pulvinar” sign is represented by the

confluent hyperintensity within the dorsomedial and posterior 31thalamus and is characteristic of variant CJD (Figure 8).

Figure-7: Cortical ribbon sign in Creutzfeld Jacob disease

(CJD) on diffusion weighed MRI, also showing hyperintense

signals in basal ganglia

Figure-8: Pulvinar or hockey stick sign in variant CJD

R adiologic sign Location Diagnosis K nife edge sign Anterior

temporal lobe Frontotemporal dementia

H umming bird sign or penguin sign

Midbrain (sagittal)

Progressive supranuclear palsy

A trophy of caudate

Caudate Huntington’s dementia

Mickey mouse sign

Midbrain (axial) Progressive supranuclear palsy

Morning glory sign

Midbrain (axial) Progressive supranuclear palsy

H ot cross bun sign Pons Multiple system atrophy

Box car ventricles Lateral ventricles (coronal)

Huntington’s dementia

Cortical ribbon sign

Cortex (diffusion weighed sequence)

Sporadic Creutzfeld Jacob disease

H ockey stick sign or pulvinar sign

Dorsomedial thalamus and pulvinar

Variant Creutzfeld Jacob disease

Evan’s index >0.30

Frontal horn of lateral ventricle

Norma l pressure hydroc ephalus

basal ganglia, the thalamus, and cortex (also known as “the 30 cortical ribbon sign”) (Figure 7).


Normal pressure hydrocephalus

Normal pressure hydrocephalus (NPH) is another potentially

treatable cause of dementia, usually manifesting with a triad of

gait apraxia, urinary incontinence and dementia, sometimes

progressing to an akinetic rigid state. MRI images

characteristically show enlarged ventricles disproportionate to

the cortical atrophy. Periventricular white matter abnormalities

may be seen due to trans-ependymal seepage of CSF but can be

absent. A narrowed CSF space at the convexity in the midline in

relation to the Sylvian fissure has also been shown to correlate 32with a diagnosis of NPH. MRI usually shows an Evan's index,

or the frontal horn ratio, better defined as the maximal frontal

horn ventricular width divided by the transverse inner diameter

of the skull, measuring at least 0.3, along with the presence of

temporal horn dilatation (Figure 9).

Figure-9: Evan's index or frontal horn ratio in normal pressure

hydrocephalus (NPH)

An increased callosal angle greater than 40' is characteristically

noted in patients with NPH. Quantification of CSF flow in cine

phase-contrast MRI using measures of stroke volume, i.e. the

mean CSF volume passing through the cerebral aqueduct both in

systole and in diastole can help in the diagnosis of NPH. Stroke

volume greater than 42 ìl was an excellent predictor for the 33likelihood of better response to ventriculoperitoneal shunting.

Infections and others

Encephalitis manifesting as rapidly progressing dementias can

be easily detected on the MRI by demonstration of pathologic

changes of herpes encephalitis as FLAIR and T2

hyperintensities in the temporal, insular, and inferior frontal

cortices. Japanese encephalitis can show abnormalities in

subcortical gray matter regions with patchy enhancement with

contrast administration. HIV or AIDS related dementia which

primarily manifests with cortical atrophy can be diagnosed only

after ruling out primary CNS lymphoma, progressive multifocal

leukoencephalopathy and other causes like toxoplasmosis.

Other rare causes of dementias manifest with non-specific

radiologic features of subcortical white matter changes, cortical

atrophy, or gyral hyperintensities.

MR spectroscopy

A proton MR Spectroscopy method (MRS) is a noninvasive

method to measure in-vivo biochemical metabolites. The

metabolites routinely assessed in neurological disease are N-

acetylaspartate (NAA), creatine and phosphocreatine (Cr), and

choline (Cho), myoinositol (mI), glutamate and glutamine

resonances (Glx) and lactate (Lac). Relevant metabolites in

dementia imaging are NAA and myoinositol; NAA is a marker of

neuronal dysfunction and myoinositol is a marker of gliosis. The

neuronal marker N-acetyl aspartate has found to be reduced in

the hippocampus in patients with AD and MCI compared with 34 controls. MR spectroscopy has also shown its value in

35differentiating patients with MCI from those with AD.

Decrease in NAA is noted in the mesial temporal lobe, posterior

cingulate, occipital lobe, temporal lobe, parietal lobe, 36parietotemporal region, frontal lobe and hippocampus in AD.

Decreased NAA was found to correlate with the severity of

neuropathologic findings like amyloid plaques and

neurofibrillary tangles in patients with AD and in addition, 37-39elevated glutamate has also been noted in AD. Myoinositol is

found in areas with gliotic changes and elevated myoinositol in

AD is noted earliest in mesial temporal lobe and later also

involves areas of anterior and posterior cingulate cortex as well

as parietal lobes. MR spectroscopy has also been used for the

treatment monitoring and prediction of response to treatment in a 40trial involving donepezil use in dementia and has shown

changes in MRS metabolite profile following use of 41rivastigmine in patients with Alzheimer's disease. NAA/Cr

measurements have been shown to predict cognitive decline and

are useful for monitoring disease activity in patients with 42,43clinically established AD. A study on a cohort of cognitively

normal elderly aimed at determining 1H MRS predictors of

preclinical AD showed that Cho/Cr elevation in the white matter

was the only predictor for progression to dementia, indicating its 44potential as a preclinical marker for AD in elderly.

Oxidative stress has been implicated in the pathogenesis of

neurodegenerative disease and studies have shown the utility of

MR spectroscopy in the detection and mapping of anti-oxidants

in the brain of MCI and Alzheimer patients. Mandal et al studied

the amount of glutathione in various brain regions of healthy

individuals, patients with MCI and Alzhiemer patients using

MRS and found statistically significant depletion of glutathione 45levels in AD patients compared to healthy subjects. A novel

multi-voxel 31-P MRS imaging method has also been found to

be useful to determine the levels of membrane based

neurochemicals and pH from the hippocampi. A single Indian

study has shown a significantly increased phosphodiester and a

corresponding decreased phosphomonoester levels in the

hippocampi of patients with AD compared with healthy 46controls. The same study also noted an interesting trend of

inversal of pH levels, from acidic pH in MCI patients to alkaline

pH in AD patients in the left hippocampus.

Coultard et al studied patients with FTD and found that they had

reduced NAA/Cr in frontal and temporal, but not in the parietal

lobes. Two patients with the fvFTD in their study were noted to

have increased mI/Cr in their cingulate cortices and showed the

utility of MR spectroscopy in revealing regionally selective


47abnormalities in FTD patients. Thus MRS is a useful tool for

non-invasively measuring metabolic biochemical changes in

vivo in patients with AD although more studies and research

needs to determine its role in other dementias.

The various uses of MR spectroscopy in dementias has been

tabulated in Table 3.

Table 3: Uses of magnetic resonance spectroscopy

Diffusion Tensor imaging

Diffusion Tensor Imaging (DTI) is a new MRI technique that

quantifies the measured movement of water within the brain

tissue and measures the angular variability of diffusion in three 48dimensions. Two most widely used numeric descriptors in DTI

are fractional anisotropy (FA), a marker of white-matter fiber

disruption; and mean diffusivity, a marker for cell density.

Parameters like axial (DA) and radial (DR) diffusivity provide

more information regarding axonal damage and demyelination.

Visual interpretation by using color-encoded directional

anisotropy maps to depict the white matter tracts can be done

using reconstructed images which is also known as DTI

tractography. Cognitive impairment in ageing can be a

manifestation of the normal age related changes in the brain.

Studies have shown changes of white matter myelination in

ageing thus attributing a probable reduction in neural

connectivity to the cognitive decline in ageing. Dementias are

commonly associated with cognitive decline as well as white

matter changes, which can be either due to vascular causes or due 49to neurodegenerative mechanisms. Thus, diffusion tensor

imaging can serve as an effective imaging modality to

characterize the structural integrity of brain connectivity.

The neuropathological changes in AD consist of extracellular,

insoluble amyloid deposition and intracytoplasmic tau-

associated neurofibrillary tangles (NFTs). Postmortem studies

have shown that neuropathologic changes in AD precede the

development of cognitive symptoms by several years. Some

patients develop amyloid plaques and NFTs but do not manifest

the disease. Studies have also shown that white matter

involvement in AD is a well-known phenomenon and that it 50,51correlates with disease severity. Studies of DTI in patients

with AD have not only consistently revealed decreased fiber

density in the temporal white matter, probably secondary to

degeneration of medial temporal grey matter but also shown

abnormalities in white matter anisotropy in the frontal and 52-57parietal cortices. Reduced fractional anisotropy of the

cingulum white matter fibers have been noted in patients with 58,59MCI and AD. Decreased anisotropy is noted in the posterior

cingulum fibers (Figure 10) which connects the

parahippocampal gyrus and posterior cingulate gyrus and is

dependent on acetylcholine, thus explaining the efficacy of

cholinergic drugs in Alzheimer's dementia.

Consistently noted early changes in white matter detectable

using diffusion are in the hippocampus, the temporal stem, and

the posterior corpus callosum in subjects with AD. Studies on

minimal cognitive impairment (MCI), which serves as a

precursor to Alzheimer's dementia, have shown significant 60 increase in mean diffusivity in bilateral hippocampus,

61 entorhinal cortices, bilateral parietal cortices, frontal and 57temporal cortices and cingulate cortex, with correspondingly

increased FA values in the affected regions. High hippocampal

mean diffusivity in MCI has been associated with a greater risk

of progression to AD and thus DTI may help identify patients 62,63with MCI who will progress to AD.

Thus, DTI has a potential role in identifying patients at risk of

Alzheimer's dementia at the earliest stages of disease or in pre-

symptomatic stages.

Studies have shown that DTI can differentiate patients with AD 64from those with dementia with Lewy bodies. Watson et al found

that patients with DLB had reduced FA primarily in the parieto-

occipital white matter tracts, pons and left thalamus as opposed

to patients with AD in whom the changes were noted to be much 65more diffuse. It has also been reported that white-matter FA

values are decreased in presymptomatic carriers of familial AD

Figure-10: Diffusion Tensor Imaging of Alzheimer's disease

showing reduced FA values (fractional anisotropy) in the

posterior cingulum fibres (white arrows) and the splenium

of corpus callosum (green outline)

Metabolite Potential marker Abnormalities noted in various studies on dementias

N -acetylaspartate (NAA )

Neuronal dysfunct ion

Reduced in hippocampus in AD and MCI patients

Myoinositol (mI) Glial proliferation Elevated in AD; earliest in mesial temporal lobe

Creatine and phosphocreat ine (Cr)

Energy metabolism

(Used as internal reference)

Choline (Cho) Cell membrane turnover

Elevated in AD in DLB

G lutamate and glutamine resonances (G lx)

Excitatory neurotransmission

Elevated glutamate and glutamine in AD

N AA/Cr ratio - Lower in AD and FTD; normal NAA /Cr levels in the posterior cingulate gyri in DLB

mI/Cr ratio - Elevated in AD and FTD ; normal in vascular dementia


66 mutations. The white matter degradation is more prominent in

FTD when compared to that of patients with Alzheimer's disease

with greater reductions of FA in frontal brain regions, making

DTI an important diagnostic tool to differentiate the two 67diseases. A multimodal combination of DTI and volumetric

MRI modalities has shown to provide a quantitative method for 68 distinguishing FTLD and AD. A study describing the various

gray and white matter changes using in diffusion tensor imaging

and voxel based MRI morphometry among the frontal (fvFTD)

and temporal (tvFTD) variants of frontotemporal lobar dementia

has described the separate patterns of gray matter atrophy and

white matter reduction in the two variants with involvement of

the superior longitudinal fasciculus in patients with fvFTD and 69the inferior longitudinal fasciculus in patients with tvFTD.

Abnormal diffusivity in the anterior corpus callosum is useful in

differentiating patients with bvFTD from those with other FTD 70variants. DTI has also been considered advantageous over

volumetric imaging in differentiating patients with behavioral 71variant frontotemporal dementia from normal individuals.

The main radiological features noted in commonly encountered

dementias have been enumerated in Table 4. Table-5, 6 and 7

mention the commonly used qualitative radiological techniques

for rating.

Table 4: Principal neuroradiological findings in common

dementias

FUTURE TRENDS

Recent technological advances in high field MRI include

diffusion tensor imaging (DTI), cortical thickness assessment,

arterial spin labeling (ASL) perfusion and white matter

hyperintensity (WMH) lesion assessment. WMH lesion

assessment used for assessing lesion load in patients with

dementia is commonly seen in patients with MCI and associated

with memory loss and progression to dementia. Future role of

neuroimaging has great unexplored dimensions which still need

unraveling. The possible trends in the near future include the use

of reliable neuroimaging biomarkers, which can be used in early

detection, monitoring and aiding in management strategies for

patients with incipient and overt dementia.

Biomarkers:

A biomarker is defined as an indicator of disease activity,

whereas a surrogate marker can substitute for a clinically

meaningful endpoint in a clinical trial. Biomarkers ideally

should be useful in monitoring a disease pathophysiology and

aid in the treatment as well as identify potential candidates for 72alternative management. Several initiatives are underway to

identify the ideal neuroimaging biomarker for dementia but still

there is no clearcut biomarker available till date. Studies on

white matter hyperintensities in brain have demonstrated

accelerated white matter injury preceding actual manifestation

Table 5: Scheltens MTA scale for temporal

atrophy 11

Table 6: Koedam scale for posterior atrophy 78

S core In volvement 0 A closed posterio r cingulate- and parieto-

occip ital su lcus and closed sulc i o f the parietal lobes and precuneus .

1 A m ild widening of the pos terior cingulate- and parieto-occip ital su lcus, with mi ld atrophy of the pariet al lobes and precuneus.

2 Substan tial widening of the posterio r cingulate- and pari etooccip ital su lcus, with substan tial atrophy of the parietal lobes and precuneus .

3 End-st age atrophy wi th ev ident widening of both su lci and kn ife-b lade atrophy of the parietal lobes and precuneus

Table 7: Fazekas scale for white matter lesions 19

S core P eriv entricula r w hite m a tter

D eep w h ite m atter

0 A b sen ce A b sen ce 1 “Cap s ” o r “pen cil lin in g” Pu nct ate fo ci 2 Sm o oth “h alo”

Beg in ni ng co nflu ence o f fo ci

3 I rreg u lar p er iven tr icu lar h yp er-i nten si ty ex tend in g in to deep w h ite m atter

L arge co nflu ent areas

Type of dementia Major neuroradiological findings Alzheimer’s disease

Cortical atrophy esp. the hippocampus and entorhinal cortex, high hippocampal diffusivity is noted in DTI, notable decrease in N-acetylaspartate and an increase in myo-inositol and choline in MRS,

Diffuse Lewy body disease

Non-specific pattern of cortical atrophy with relative preservation of the medial temporal lobe, the preservation of the NAA-to-creatine ratios on MRS

Fronto-temporal lobar degeneration

A strong antero-posterior gradient of temporal lobar atrophy.

Vascular dementia

Multiple infarcts or extensive white matter changes

Huntington’s disease

Caudate atrophy with enlargement of the frontal horns of the lateral ventricles

HIV dementia Reductions in cortical, hippocampal, and subcortical volume, diffuse white matter changes

Normal pressure hydrocephalus

Dispropotionately enlarged ventricles, esp frontal horns of lateral ventricles; Evan’s index >0.3; increased callosal angle

Creutzfeld–Jakob disease

Diffusion restriction in basal ganglia, thalamus and cortices, later T2/FLAIR hyperintense signals in the putamen (in sporadic disease) and in the pulvinar and grey matter (in variant form).

Progressive supranuclear palsy

Atrophy within the brainstem with involvement of the midbrain, pons, thalamus, superior cerebellar peduncle, and striatum; sometimes, hypointensity of the putamen

Multisystem atrophy

Atrophy and T2- hypo intensities within the lower brain stem, middle cerebellar peduncles, cerebellum, and putamen

Score Width of Choroid fissure

Width of Temporal horn

Height of hippocampal formation

0 N N N

1 ? N N

2 ? ? ? ?

3 ? ? ? ? ? ? ?

4 ? ? ? ? ? ? ? ? ?


of the disease, in particularly AD, casting doubts as to the

potential role of white matter changes as neuroimaging 73-75biomarker in AD, but literature is insufficient till now.

Detection, monitoring and prevention:

Research is underway to identify strategies and newer

neuroimaging modalities for the earlier detection of dementia at

the asymptomatic stage to ensure appropriate initiation of drugs

to arrest or reverse the disease pathogenesis. Further newer

modalities aimed at monitoring the disease progression and

biomarkers to herald the disease activity are under research.

Preventing the disease by early identification of neuroimaging

markers in asymptomatic individuals or in individuals at risk is

anticipated as the upcoming advancement in the current

neuroimaging era.

At present, the available structural imaging techniques have

greatly improved diagnostic accuracy enabling early initiation

of anti-dementia symptomatic treatments but greater impact is

expected from the current ongoing research and those under

development which may aid in the presymptomatic detection of

disease and provision of preventive treatment for age-related

cognitive decline and neurodegeneration.

INDIAN SCENARIO

In India, the commonest type of dementia was noted to be

Alzheimer's subtype, followed by vascular dementia, in a 76hospital based data from South India, but of a lower prevalence

than that of our Western counterparts. Neuroimaging has its

limitations in a developing country like India, due to the cost

constraints and lack of accessibility in many parts of rural India.

Although the emerging neuroradiologic technologies are

quickly marketed in the urban areas, economic constraints prove

that the general neurologist largely has to depend on

conventional structural MRI techniques alone in the diagnosis

and management of dementias.

SUMMARY

This review has broadly aimed to describe the available

neuroimaging technologies available to a practicing neurologist

and elaborated the various diseases and imaging modalities of

particular relevance in specific diseases. Judicious use of

available technology adjusted to the monetary capacity of the

patients as well as the relevance of these neuroimaging tools to

the clinical situation can serve the purpose of providing relief to

the demented patient.

CONFLICTS OF INTEREST

All authors have none to declare.

PERMISSIONS

The five tables used have been quoted with reference. Two

authors have replied with their consent.

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