European Journal of Neurology 2009, 16: 168173 doi:10.1111/j.1468-1331.2008.02379.

REVIEW ARTICLE

Classification and diagnosis of dementia: a mechanism-based approach

M. Emre
_
Professor of Neurology, Department of Neurology, Istanbul _
Faculty of Medicine, Capa Istanbul, Turkey

Keywords: Dementia is an acquired disorder of the brain, designating an impairment of estab-

classication, dementia,
diagnosis
Received 23 July 2008
Accepted 15 October 2008
lished mental functions due to various aetiologies, representing a decline from pre-
morbid level which is severe enough to impair normal daily functioning. Classication
of dementias is commonly based on individual aetiological categories, more recently
molecular-pathological classications have been proposed for degenerative dementias.
This article is an attempt to provide a comprehensive, yet simplied classication of
dementias following a mechanism-based approach. A systematic approach to diag-
nostic work-up is also proposed based on this classication.

Introduction Classification of dementias

Dementia is an acquired disorder of established mental
function, dened as deterioration in more than one
cognitive domain below the pre-morbid level, severe
enough to impair normal daily functioning (DSM IV)
[1]. As such, it is dierentiated from developmental dis-
orders of mental functions in which normal functioning
had never been attained. Accordingly, the dening fea-
ture for the diagnosis of dementia is that mental function
must decline below the pre-morbid level, irrespective of
the previous level of intellectual capacity and achieve-
ment. The stipulation that more than one cognitive do-
main must be aected dierentiates dementia from
single domain decits such as aphasia due to stroke, or
amnesia due to Korsako disease. Current DSM IV
criteria for dementia [which are more tailored for Alz-
heimers disease (AD)] demand that memory impairment
must be present in addition to a decit in any other
cognitive domain. The third component in the denition
mandates that the decits are severe enough to interfere
with normal daily functioning, a criterion dicult to
assess at times, but single most dening aspect of the
current construct of dementia, which dierentiates it
from milder forms of mental dysfunction.
Dementia is merely a syndrome which may be caused
by a number of dierent aetiologies aecting the brain.
The types and causes of dementia can be classied using
dierent approaches, the usual classications are based
on individual aetiological categories, topographical
involvement or symptom complexes [29] In this article
a practical classication for dementia is proposed by
adopting a mechanism-based approach which also
conceptualizes the diagnostic screening and work-up.
_
Correspondence: Prof. Dr Murat Emre, Istanbul Tp Fakultesi,
_
Noroloji Anabilim Dal, 34390 Capa Istanbul Turkey (tel/fax: 90-212-
5338575; e-mail: muratemre@superonline.com).
With regard to underlying aetiology and mechanism of
dysfunction, dementia can be divided into two main
categories: primary degenerative dementias and sec-
ondary (or symptomatic) forms of dementia (Table 1).
Primary degenerative dementias are characterized by
selective neuronal loss in vulnerable, functionally con-
nected brain areas, predilection sites varying across
various disorders. Within this category, a subgroup can
be discerned in which dementia is the sole clinical fea-
ture throughout the disease or until its late stages.
Typical examples in this category include AD, Picks
disease and other progressive focal atrophies. A second
group of dementias due to neurodegenerative disorders
can be labelled as dementia-plus. These are charac-
terized by the presence of additional features in addi-
tion to dementia, such as extrapyramidal, pyramidal or
autonomic symptoms either as preceding, concomitant
or early features accompanying mental dysfunction.
This group includes diseases in which degenerative
process involves basal ganglia and other cortical-
subcortical structures, such as DLB, Parkinsons dis-
ease (PD) dementia, progressive supranuclear palsy,
corticobasal ganglionic degeneration and Huntingtons
disease.
The secondary forms of dementia can be subdivided
into three main groups based on their pathophysiology
and the mechanism by which the aetiological factor
exerts its detrimental eects on mental functions. These
include (i) those disorders which directly damage the
brain tissue, (ii) those which cause increased intracra-
nial pressure and thus distort the brain mechanically
and (iii) those which cause malfunction of the otherwise
intact brain cells due to lack of necessary constituents
or inappropriately high/low level of normal ingredients
in the blood, such as endocrine, toxic and metabolic
conditions (Table 1).

2008 The Author(s)

168 Journal compilation 2008 EFNS
 Classication of dementia 169

Table 1 Classication of dementias

I Primary degenerative dementias

A: Dementia pure: neurodegenerative disorders primarily involving cerebral cortex
Alzheimers disease
Focal degenerations
Frontotemporal lobar degenerations (FTD)
Behavioural subtype
Primary progressive aphasia
Semantic dementia
Posterior cortical atrophies
Primary progressive visual-spatial impairment
Primary progressive apraxia
B: Dementia plus: neurodegenerative disorders involving additional brain areas such as basal ganglia or other subcortical structures
Dementia with Lewy bodies
Parkinsons disease dementia
Multiple system atrophy
FTD-Parkinsonism-17
FTD with motor neuron disease
Corticobasal degeneration
Progressive supranuclear palsy
Familial multiple system tauopathy
Huntington disease
Progressive subcortical gliosis
Dementia lacking distinctive histopathological features
Some forms of spinocerebellar ataxias (such as SCA 1-3, DRPLA)
II Secondary forms of dementia
A: Disorders damaging the brain tissue directly
Vascular-ischaemic causes: multiple territorial infarcts, multi-infarct or lacunar state, strategic (critical) infarcts, subcortical vascular
encephalopathy, hypoxic encephalopathy, CADASIL, primary CNS vasculitis, amyloid angiopathy
Infections: Jacob-Creutzfeld and other prion diseases, syphilis, HIV, herpes encephalitis, Lymes disease, subacute sclerosing panencephalitis,
progressive multifocal leucoencephalopathy, Whipples disease; sequel of or chronic viral, fungal, parasitic, bacterial infections such as
tuberculose meningitis
Demyelinating disorders such as multiple sclerosis or acute demyelinating encephalomyelitis
Inborn metabolic disorders involving the brain, affecting neuronal or glial metabolism, such as disorders of:
Lysosomal metabolism: metachromatic leukodystrophy, Niemann-Pick type C, Gaucher, Krabbe and Fabry diseases, GM-1 and GM-2
gangliosidosis, mucoploysaccaridosis III
Peroxisomal metabolism: adrenoleukodystrophy
Carbohydrate metabolism: adult polyglusocan body disease, Lafora body disease
Lipid metabolism: cerebrotendinous xanthomatosis, membranous lipodystrophy, Kufs disease
Metal or ion metabolism: Wilsons disease, neuroferritinopathy, neurodegeneration with iron accumulation, Fahrs disease
Mitochondrial function: MELAS, MERFF
Others: neuroacanthocytosis, urea cycle defects
Traumatic brain injury, dementia pugilistica
Post-radiation dementia
Some brain tumours such as glioblastoma
Parasitic cysts or brain abscess
B: Disorders changing intracranial contents and distorting brain structures
Normal pressure or obstructive (e.g. aquaduct stenosis) hydrocephalus
Subdural or intraparenchymal haematoma
Primary or metastatic brain tumours
C: Systemic diseases or conditions affecting the brain
Metabolic-nutritional (Vitamin B-12, B-1 or folate deciency, cardiac, pulmonary, hepatic or renal insufciency, porphyria)
Endocrine (hypo- or hyperthyroidism or parathyroidism, Cushings syndrome, Addisons disease, insulinoma, prolonged hypoglycaemia)
Toxic (drugs, chronic alcoholism, heavy metals or organic substances, carbon monoxide, dialysis dementia)
Systemic immune-mediated or inammatory disorders (systemic lupus erythematosus, vasculitides associated with other collagen-tissue
disorders, Hashimotos encephalopathy, Behcets disease, sarcoidosis, paraneoplastic limbic encephalitis)

CADASIL, cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy; SCA, spino-cerebellar ataxias;
DRPLA, dentatorubralpallidoluysion atrophy; MELAS, mitochondrial encephalomyopathy, lactic acidosis, strokelike episodes; MERFF,
myoclonic epilepsy with red ragged bres.

Those disorders which damage the brain tissue or critical sites involved in cognitive functions. Typical
directly cause mental dysfunction either by aecting examples include vascular-ischaemic dementias, such as
extensive areas of the brain so that a critical mass is lost, subcortical vascular dementia, multiple territorial in-

2008 The Author(s)

Journal compilation 2008 EFNS European Journal of Neurology 16, 168173
170 M. Emre
farcts, strategic infarct dementia, various forms of
vasculitis, destruction of brain tissue through external
agents, such as infections, auto-immune mechanisms or
through inborn metabolic defects, and traumatic brain
injury. Most of such pathologies would be visible in an
appropriate structural brain imaging or their presence
can be excluded.
The brain is located in the skull, a rigid frame which
does not leave brain mass much leverage to escape when
it is pressured. Any increase in intracranial contents, in
terms of pressure or mass, would distort the brain tissue
and cause malfunction simply through a mechanical
pressure eect. Typical examples include haematomas,
some tumours, normal pressure or obstructive hydro-
cephalus. Structural brain imaging serves also the pur-
pose of exploring such disorders which may be
complemented through dynamic measures as indicated.
Finally, the brain is an organ like all the others, and
as such it requires sucient quantity and good quality
blood containing appropriate amounts and right pro-
portions of main nutrients and other constituents.
When the normal constitution of blood with regard to
hormones, vitamins, electrolytes and end-products of
metabolism is altered, neurons which otherwise are
healthy may malfunction. These include endocrine,
metabolic and toxic disorders. Such disorders can be
detected by laboratory screening; the array of labora-
tory measures can be limited or expanded depending on
the clinical presentation and suspicions.
Diagnostic process
The diagnosis of dementia can be subsumed into two
main steps. The rst step is dierentiating dementia
syndrome from other conditions which can mimic
dementia, the second step involves dierential diagnosis
within dementia syndrome with an attempt to identify
underlying aetiology (Table 2). It should be noted,
however, that further diagnostic work-up with regard
to underlying aetiology may still be required in patients
with evidence of mental dysfunction, even if their de-
cits fall short of justifying the diagnosis of dementia.
Table 2 Conditions which can mimic dementia
Worried well
Mild cognitive impairment
Affective disorders such as depression, manic-depressive disease
Other psychiatric conditions, such as obsessive compulsive disorder,
old age psychosis and paranoid (delusional) disorder
Acute or prolonged confusion (delirium)
Single domain cognitive decits such as Korsakoff disease
Unrecognized complex partial seizures
Unrecognized drug or alcohol abuse
Adverse effects of medication
Journal compilation 2008 EFNS European Journal of Neurology 16, 168173
The most commonly encountered conditions which
need to be dierentiated from dementia include worried
wells (those individuals who are concerned about their
mental functions, but found to be normal in testing),
mild cognitive impairment (MCI) of various types,
acute confusion (delirium), depression and other pri-
mary psychiatric diseases, such as obsessive-compulsive
disorder, late-onset psychosis and single domain cog-
nitive decits, such as aphasia due to stroke or amnesia
due to Korsako disease.
The diagnosis of dementia syndrome is a purely
clinical undertaking, the main diagnostic tools at clini-
cians disposal are a good history including detailed
information from a caregiver and an adequate clinical-
neuropsychological examination. Most current
diagnostic guidelines for dierent types of dementing
disorders are based mainly on clinical characteristics
[1,1013], the recent research criteria for the diagnosis
of AD stipulate, however, that at least one or more
abnormal biomarkers should also be present for the
diagnosis [14]. Especially relevant are the mode of
onset, the rate of progression, the chronology of initial
and subsequent symptoms, the prole of cognitive
decits and the presence of behavioural, somatic-
neurological as well as systemic ndings. The gradual
onset of an amnestic syndrome with slow progression is
typical for AD. Neurodegenerative disorders involving
basal ganglia or other subcortical structures are char-
acterized by a dysexecutive syndrome associated with
impaired attention, memory and visuospatial functions
as well as prominent behavioural symptoms such as
apathy and psychosis. Personality and behavioural
changes, sole or disproportionate involvement of lan-
guage, visual-spatial or praxis functions are typical for
fronto-temporal dementias (FTD) or other focal corti-
cal atrophies [2,11]. Auxiliary methods are seldom
required to dierentiate dementia syndrome from other
causes of mental dysfunction. Once a dementia syn-
drome is diagnosed one would endeavour to uncover
the underlying cause. Here again the history and the
clinical examination are of paramount importance,
most guidelines recommend a structural brain imaging
and routine laboratory screening (including thyroid
hormones, vitamin B-12 levels; syphilis and HIV tests as
appropriate) to diagnose or exclude secondary forms of
dementia [15,16]. These auxiliary investigations will be
sucient to identify the underlying cause or exclude
alternative aetiologies in most patients, their diagnostic
yield is variable and not high in unsuspected cases. The
contribution of various imaging and laboratory inves-
tigations to diagnosis have been summarized in the
American Academy of Neurology (AAN) diagnostic
guidelines [16]. Structural imaging (preferentially MRI,
if not available CT scan) which should be performed
2008 The Author(s)

once at the time of diagnosis serves two purposes: to
assess the amount and the topography of any atrophic
changes and to assess the presence of space-occupying
lesions or tissue damage. Atrophy in hippocampus and
related structures has been given an important role in
the new research diagnostic criteria for AD [14].
Functional brain imaging such as cerebral blood ow
(CBF)-SPECT and PET scans can be helpful in early
cases of degenerative dementias where there is no dis-
cernable atrophy [17], imaging of specic receptor
binding sites such as dopamine transporter (DAT) scan
may be helpful in dierentiation of disorders such as
DLB [18,19]. Scintigraphy with [I-123] metaiodobenzyl
guanidine, which quanties post-ganglionic sympa-
thetic cardiac innervation, is reduced in DLB and has
been suggested to have high sensitivity and specicity to
dierentiate it from AD [20]. Other functional imaging
techniques such as MR spectroscopy or functional MRI
are not established techniques for routine diagnosis;
visualization of brain amyloid load may become a
useful diagnostic aid in the future [21], more work needs
to be carried out, however, to dene cut-o values
which are specic and sensitive enough to dierentiate
patients from normals [22]. Electrophysiological inves-
tigations such as EEG or evoked/event-related poten-
tials, special laboratory tests including cerebrospinal
uid (CSF) examination are not routinely required but
can be employed under specic conditions. EEG may
remain unchanged until advanced stages of FTD; re-
cently, EEG was reported to dierentiate between early
stage patients with AD versus DLB; in posterior leads,
dominant frequencies were slower and dominant fre-
quency variability was higher in patients with DLB [23].
Some CSF markers such as amyloid beta142 (Abeta-
42), total tau, phospho-tau and in particular Abeta-42/
tau ratios have been shown to have high sensitivity and
specicity to identify patients with AD and to dier-
entiate them from normal controls and possibly from
those with MCI [24,25]. Accordingly, CSF beta-amy-
loid/tau ratios have been proposed to support the
diagnosis of AD in the recent research criteria as well as
in the European Federation of Neurological Societies
(EFNS) guidelines for the diagnosis of dementia [14,15].
Quantication of certain plasma signalling proteins has
also been suggested to predict the diagnosis of Alzhei-
mer disease [26], it remains to be conrmed, however, if
this method possess enough discriminative power to
nd routine use. Genetic testing and brain biopsy re-
main to be reserved for special cases.
Special constellations
Certain constellations of symptoms and clinical features
imply certain aetiologies or disease categories (Table 3).
2008 The Author(s)
Journal compilation 2008 EFNS European Journal of Neurology 16, 168173
Classication of dementia 171
Table 3 Special constellations: frequent causes
Dementia plus extrapyramidal symptoms: PD-D, DLB, CBD, HD,
PSP, vascular dementia
The triad of dementia, gait disorder and incontinence: NPH, small
vessel disease, neurodenegerative diseases such as DLB, PD-D, MSA
Sudden onset and/or stepwise progression: vascular causes such as
multiple territorial, strategic or lacunar infarcts
Rapid course: Prion diseases such as Jacob Creutzfeld, infections such
as herpes encephalitis; endocrine, metabolic, immune-mediated or
inammatory diseases, such as CNS vasculitis, paraneoplastic
limbic encephalitis; subdural haematoma, primary or metastatic
brain tumours
Abnormal systemic ndings: endocrine, metabolic, toxic,
inammatory diseases
PD-D, Parkinsons disease dementia; CBD, cortico-basal ganglionic
degeneration; HD, Huntington disease; PSP, progressive supranuclear
palsy; NPH, normal pressure hydrocephalus; MSA, multiple system
atrophy.
Presence of extrapyramidal symptoms early in the
course of the disease could signal one of the dementia-
plus neurodegenerative diseases such as DLB, cortico-
basal ganglionic degeneration (CBD) and progressive
supranuclear palsy (PSP). Presence of focal decits,
pyramidal or extrapyramidal signs is typical of vascular
dementia, which may also be characterized by sudden
onset and stepwise progression, except for subcortical
vascular encephalopathy. The classical triad of demen-
tia, gait disorder and urge incontinence is typically
associated with three disorders; normal pressure
hydrocephalus, small vessel disease (subcortical vascu-
lar dementia) and neurodegenerative diseases involving
basal ganglia. Acute or subacute onset and rapid pro-
gression are always suspicious for infections, such as
herpes encephalitis, Jacob Creutzfeld disease or syphilis
as well as endocrine, metabolic and inammatory dis-
orders. Familial cases of young onset AD may demon-
strate a fairly rapid progression and aggressive course
and may be associated with somatic neurological signs
early in the course. Any signs of systemic involvement,
such as fever or weight loss, involvement of other organs
such as organomegaly, abnormal laboratory ndings or
abnormal vital signs such as pulse rate change should
trigger suspicion for endocrine, metabolic and inam-
matory diseases.
Red flags
Because of a large number of rare, inherited or meta-
bolic disorders which may be potentially associated
with dementia, and a large array of laboratory investi-
gations made available by modern technology, the
possibilities for diagnostic work-up have virtually no
limits [27]. For a more rationale use of resources and to
reduce the burden on patients, more extensive work-up
172 M. Emre
Table 4 Red ags
Young onset (<65, if not in the context of known familial disease, or
typical FTD or AD prole and course)
Rapid progression
Early incontinence or other autonomic signs
Focal neurological decits or signs
Systemic ndings, abnormal vital signs
Abnormal parenchymal neuroimaging
AD, Alzheimers disease; FTD, frontotemporal degenarations.
should be reserved to certain cases with particular
clinical vignettes. The clinician is advised to be more
alert and undertake a broader diagnostic work-up when
these red ags are present (Table 4). Young age of
onset (below the age of 65) should be considered as an
alarming sign, unless dementia occurs in the context of
a known familial disease such as familial AD, or the
course and symptoms are compatible with typical
fronto-temporal lobar degenerations. Likewise, rapid
progression especially in young patients justies a more
extensive diagnostic work-up. Pronounced uctuations
of symptoms, if not in the context of typical DLB, may
be a sign of symptomatic dementias. Urinary inconti-
nence is not an early sign in AD, although urge
incontinence may occur early in Lewy body-related
dementias or other alpha-synucleinopathies; early or
full incontinence may signify presence of another aeti-
ology or concomitant urinary tract disease. Focal de-
cits, pyramidal or extrapyramidal signs, unless they
occur in the context of known cerebrovascular disease
or follow a typical time course for certain neurode-
generative diseases such as PD or DLB, should prompt
a more extensive search for other causes such as CNS
vasculitis. Finally, presence of systemic ndings sig-
nalling involvement of other organ systems, such as li-
ver, kidney, gastrointestinal tract, or changes in blood
pressure and heart rate may signify more widespread
disease pathology.
Conclusions
Dementia is a syndrome which may be caused by a
large number of underlying aetiologies. Although the
list of disorders which may potentially cause dementia
is long, they impair mental functions through a limited
number of mechanisms. The end-product, i.e. clinical
characteristics are determined by the mechanism of
action and the aected territory. The proposed classi-
cation helps to conceptualize how dierent disorders
cause their detrimental eects on the brain and lead to
dementia. As these disorders are classied based on
their mechanism of action, the proposed classication
also provides a logical framework for diagnostic work-
up. This makes it easier, especially for the non-experts,
Journal compilation 2008 EFNS European Journal of Neurology 16, 168173
to understand the relationship between the clinical
syndrome and the mechanism, the limits of auxiliary
investigations in revealing or excluding alternative
diagnosis as well as expanding the battery for diag-
nostic work-up based on the results of routine screening
and clinical suspicion.
Conflicts of interest
The author has no conicts of interest relevant for this
article.
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