Sorbi et al 2012 European Journal of Neurology.pdf

European Journal of Neurology 2012, 19: 1159–1179
doi:10.1111/j.1468-1331.2012.03784.x
E F N S - E N S G U I D E L I N E S / C M E A R T I C L E
EFNS-ENS Guidelines on the diagnosis and management of
disorders associated with dementia
S. Sorbia, J. Hortb, T. Erkinjunttic,d, T. Fladbye,f, G. Gainottig, H. Gurvith, B. Nacmiasa,
F. Pasquieri, B. O. Popescuj, I. Rektorovak, D. Religal,m, R. Rusinan, M. Rossoro, R. Schmidtp,
E. Stefanovaq, J. D. Warreno, P. Scheltensr on behalf of the EFNS Scientist Panel on Dementia
and Cognitive Neurology
aDepartment of Neurological and Psychiatric Sciences, University of Florence, Florence, Italy; bMemory Disorders Clinic, Department of
Neurology, Charles University in Prague, 2nd Faculty of Medicine and University Hospital Motol, Prague, Czech Republic; cDepartment of
Neurology, Helsinki University Central Hospital, Helsinki, Finland; dDepartment of Neurological Sciences, University of Helsinki, Helsinki,
Finland; eDepartment of Neurology, Akershus University Hospital, Lørenskog, Norway; fFaculty Division Akershus University Hospital,
University of Oslo, Oslo, Norway; gNeuropsychology Service, Policlinico Gemelli/Catholic University, Rome, Italy; hIstanbul Faculty of Medi-
cine, Department of Neurology, Behavioral Neurology and Movement Disorders Unit, Istanbul University, Istanbul, Turkey; iUniversite´ Lille
Nord de France, UDSL, Lille, France; jDepartment of Neurology, University Hospital, School of Medicine, ‘Carol Davila’ University of Medi-
cine and Pharmacy, Bucharest, Romania; kFirst Department of Neurology, Faculty of Medicine, St. Anne’s Hospital and Applied Neuroscienc-
es Research Group, CEITEC, Masaryk University, Brno, Czech Republic; lDepartment of Neurodegenerative Disorders, Medical Research
Center, Polish Academy of Sciences, Warsaw, Poland; mDepartment of Neurobiology, Care Sciences and Society, Karolinska Institutet,
Stockholm, Sweden; nDepartment of Neurology, Thomayer Teaching Hospital and Institute for Postgraduate Education in Medicine, Prague,
Czech Republic; oDementia Research Centre, Department of Neurodegeneration, UCL Institute of Neurology, University College London,
London, UK; pDepartment of Neurology, Medical University Graz, Graz, Austria; qInstitute of Neurology, School of Medicine, University of
Belgrade, Belgrade, Serbia; and rDepartment of Neurology and Alzheimer Center, VU University Medical Center, Amsterdam, The Netherlands
Keywords:
Background and objectives: The last version of the EFNS dementia guidelines is
dementia, diagnosis,
from 2007. In 2010, the revised guidelines for Alzheimer’s disease (AD) were pub-
guideline, management,
lished. The current guidelines involve the revision of the dementia syndromes out-
recommendation, review,
side
of
AD,
notably
vascular
cognitive
impairment,
frontotemporal
lobar
treatment
degeneration, dementia with Lewy bodies, corticobasal syndrome, progressive supra-
nuclear palsy, Parkinson’s disease dementia, Huntington’s disease, prion diseases,
Received 24 April 2012
normal-pressure hydrocephalus, limbic encephalitis and other toxic and metabolic
Accepted 9 May 2012
disorders. The aim is to present a peer-reviewed evidence-based statement for the
guidance of practice for clinical neurologists, geriatricians, psychiatrists and other
specialist physicians responsible for the care of patients with dementing disorders. It
represents a statement of minimum desirable standards for practice guidance.
Methods: The task force working group reviewed evidence from original research
articles, meta-analyses and systematic reviews, published by June 2011. The evidence
was classiﬁed (I, II, III, IV) and consensus recommendations graded (A, B, or C)
according to the EFNS guidance. Where there was a lack of evidence, but clear con-
sensus, good practice points were provided.
Results and conclusions: New recommendations and good practice points are made
for clinical diagnosis, blood tests, neuropsychology, neuroimaging, electroencepha-
lography, cerebrospinal ﬂuid (CSF) analysis, genetic testing, disclosure of diagnosis,
treatment of behavioural and psychological symptoms in dementia, legal issues,
counselling and support for caregivers. All recommendations were revised compared
with the previous EFNS guidelines. The specialist neurologist together with primary
care physicians play an important role in the assessment, interpretation and treat-
ment of symptoms, disability and needs of dementia patients.
Correspondence: Sandro Sorbi, Department of Neurological and Psychiatric Sciences, University of Florence, Largo Brambilla 3, 50134
Florence, Italy (tel.: + 39 055 4298474; fax: + 39 055 4271 380; e-mail: sorbi@uniﬁ.it).
This is a Continuing Medical Education article, and can be found with corresponding questions on the Internet at http://www.efns.org/EFNS
Continuing-Medical-Education-online.301.0.html. Certiﬁcates for correctly answering the questions will be issued by the EFNS.
© 2012 The Author(s)
European Journal of Neurology © 2012 EFNS
1159

1160
S. Sorbi et al.
Background
the fact that there is signiﬁcant evidence for the beneﬁts
of early diagnostic evaluation, treatment and social sup-
The change in global age demographics and the pre-
port, the rate of diagnosis and treatment in people with
dicted rise in the incidence of age-related diseases,
dementia still varies considerably in Europe.
including dementia, are of major public health con-
cern. Dementia aﬀects 5.4% of people over 65 years,
Search strategy
and its prevalence further increases with age [1]. The
number of people aﬀected will double every 20 years
The evidence for these guidelines was collected from
to 115 million by 2040, according to the Alzheimer
Cochrane Library reviews, other published meta-anal-
Disease International (ADI) World Alzheimer Report
yses and systematic reviews, evidence-based manage-
2010. In the EU, more than 160 million people are
ment guidelines in dementia and original scientiﬁc
aged over 60 years, the crude estimate prevalence of
papers published in peer-reviewed journals before
dementia is 6.2% and almost 9.95 million have a form
June 2011. The search strategy sought only studies
of
dementia.
Almost
14
million
Europeans
are
published in English. The principal search term was
expected to have dementia in 2030.
dementia.
Other
terms
entered
into
the
search
Despite the fact that there is signiﬁcant evidence for
included diagnosis, guideline, management, recom-
the beneﬁts of early diagnostic evaluation, treatment
mendation, review, treatment. For each topic, the
and social support, the rate of diagnosis and treat-
evidence was sought in MEDLINE according to pre-
ment in people with dementia varies considerably in
deﬁned search protocols*. The scientiﬁc evidence for
Europe [1]. Primary care physicians play a major role
diagnostic investigations and treatments was evaluated
in the identiﬁcation, diagnosis and management of
according to pre-speciﬁed levels of certainty (class I,
patients with dementia, but advanced diagnostic tech-
II, III and IV), and the recommendations were graded
niques necessitate the involvement of specialists, espe-
according to the strength of evidence (grade A, B or
cially neurologists, preferably in multidisciplinary
C), using the deﬁnitions given in the EFNS guidance
teams established to facilitate the management of the
[3]. In addressing the important clinical questions, for
complex needs of patients and caregivers during the
which no evidence was available, the task force group
course of the dementia disease.
recommended ‘good practice points’ based on the
experience and consensus of the task force group.
Final inclusion of articles in this practice parameter
Objective
was based on consensus of the committee.
The present revised guidelines consider dementias
other than Alzheimer’s disease (AD), which was cov-
Reaching consensus
ered in a recent guideline [2]. The other types of
dementia reviewed include mixed dementia, dementia
A proposed guideline with speciﬁc recommendation
with Lewy bodies (DLB), vascular dementia (VaD),
was drafted for circulation to task force members and
frontotemporal lobar degeneration (FTLD), cortico-
displayed on EFNS web pages for comments from all
basal syndrome (CBS), progressive supranuclear palsy
panel members. Consensus was reached at three task
(PSP), Parkinson’s disease dementia (PDD), Hunting-
force meetings during 2010 and 2011 and through ﬁve
ton’s disease (HD), prion diseases, normal-pressure
revisions via the web.
hydrocephalus (NPH) and limbic encephalitis (LE).
The main goal of the task force was to determine
Dementia, dementia types and clinical
whether further evidence had become available relat-
criteria
ing to biomarkers such as magnetic resonance imaging
(MRI), positron emission tomography (PET) and
Dementia
cerebrospinal ﬂuid (CSF) and to determine the evi-
dence for use in practice. Special attention was given
The term dementia refers to an acquired deﬁcit of
to the results of recent clinical trials, both for cogni-
cognitive function(s), which may include complex
tive and behavioural aspects of the disease.
These guidelines represent desirable standards, but
*Searching terms used in the search strategy: vascular cognitive
may not be appropriate in all circumstances as clinical
impairment, frontotemporal lobar degeneration, dementia with Lewy
presentation of the individual patient and available
bodies, corticobasal syndrome, progressive supranuclear palsy, Par-
kinson’s disease dementia, Huntington disease, prion diseases, nor-
resources should be taken into account. Cost-eﬀective-
mal pressure hydrocephalus, limbic encephalitis, dementia, CSF,
ness is not discussed, as heterogeneity across Europe will
MR, SPECT, FDG-PET, amyloid-PET, genetics, biopsy, DNA,
result in diﬀerent, country-speciﬁc conclusions. Despite
EEG, dementia and ethics.
© 2012 The Author(s)
European Journal of Neurology © 2012 EFNS European Journal of Neurology

Dementia guidelines
1161
attention, executive ability, learning and memory, lan-
atrophy of the frontal and/or temporal lobes. Our
guage, visuospatial-perceptual ability praxis and social
understanding of these diseases has been transformed
cognition. The cognitive deﬁcits may or may not be
by recent genetic and histopathological advances [7–12]
accompanied by behavioural disorders and must be
summarized in Table 2. FTLD is over-represented as
suﬃcient to interfere with functional independence.
a cause of young onset dementia. Onset is typically in
The clinical diagnosis of the dementia syndrome
the sixth decade of life but may be as early as the
should rely on the DSM-IV or ICD-10 criteria [4,5].
third or as late as the ninth decade. Estimates of pop-
In the development of DSM-5, scheduled for 2013,
ulation prevalence range from 4 to 15/100 000 below
the term ‘dementia’ is replaced by major or minor
age 65 in European and US epidemiological studies
neurocognitive disorder [6]. Clinical criteria for the
[8]. The prevalence of FTLD in older age groups has
diﬀerent types of dementia have been published
almost certainly been underestimated, although few
(Table 1).
data are available. FTLD has a substantial genetic
component with an autosomal-dominant inheritance
pattern and/or identiﬁable disease-causing mutations
Frontotemporal lobar degeneration
in around 10–20% of cases in large series [13] and
‘Frontotemporal lobar degeneration’ (FTLD) is a
some family history in a higher proportion. Most
macro-anatomical descriptive term for a clinically and
familial cases are attributed to mutations in the micro-
pathologically heterogeneous group of disorders char-
tubule-associated protein tau or progranulin genes or
acterized collectively by relatively selective progressive
the recently identiﬁed hexanucleotide repeat expansion
in the C9ORF72 gene [14,15]. Most patients with
Table 1 Criteria for clinical diagnosis
FTLD present with features conforming predomi-
Condition
Criteria
References
nantly
to
one
of
the
three
canonical
clinical
syndromes (see Table 2): ‘behavioural variant fronto-
Dementia
ICD 10
[5,173]
temporal dementia’ (bvFTD), semantic dementia (SD)
DSM IV
[4,173]
Dubois criteria
[174]
or progressive non-ﬂuent aphasia (PNFA). The clini-
Alzheimer disease
NIA and Alzheimer
[175]
cal spectrum of FTLD overlaps partly with corticoba-
Association Working
sal syndrome, progressive supranuclear palsy and
Group
motor neurone disease. Alzheimer variant syndromes
Frontotemporal lobe degeneration (FTLD)
also overlap with FTLD, especially PNFA [16–19];
bvFTD
International bvFTD
[19]
Criteria Consortium
thus, the ‘logopenic’ subtype of progressive aphasia
PNFA
International PPA
[12]
appears to be chieﬂy associated with Alzheimer
Consortium
pathology [12,18]. FTLD continues to present many
SD
International PPA
[12]
unresolved nosological and diagnostic diﬃculties.
Consortium
Recently re-formulated consensus diagnostic criteria
Parkinson’s disease
Clinical Diagnostic Criteria
[27,28]
dementia (PDD)
for dementia associated
for behavioural [11,19] and aphasic [12] subtypes of
with PD
FTLD are based on class IV evidence.
PSP
NINDS/SPSP Criteria
[32,33]
NINDS/SPSP Criteria
Behavioural variant frontotemporal dementia (bvFTD)
Lewy bodies dementia
Consensus criteria
[25,176]
Behavioural
variant
frontotemporal
dementia
(LBD)
Diagnostic criteria
Corticobasal syndrome
MDS (non-validated
[177]
accounts for around half of all cases of FTLD and is
(CBS)
formally)
characterized by a progressive decline in inter-personal
Huntington disease (HD)
(Genetic criteria)
[178]
and/or executive skills, with loss of emotional respon-
Prion diseases
sivity, impaired autonomy and emergence of a variety
Sporadic CJD (s-CJD)
Updated WHO Criteria for
[42]
of abnormal behaviours including disinhibition, ady-
s-CJD
Updated MRI-CJD
[41]
namia, obsessions, rituals, stereotypies and alterations
Consortium Criteria for
in feeding and other appetitive functions. More ﬂorid
s-CJD
psychiatric manifestations including delusions and hal-
Variant CJD (v-CJD)
Diagnostic criteria
[42]
lucinations are not uncommon, particularly in associa-
Normal-pressure
NPH diagnostic criteria
[49,179]
tion with non-tau pathologies [20]. Within the broad
hydrocephalus (NPH)
Limbic encephalitis (LE)
Diagnostic criteria
[180]
bvFTD phenotype, clinical phenomenology in individ-
Vascular dementia
Diagnostic criteria
[45]
ual patients is variable, and the bvFTD syndrome is
Subcortical ischaemic
Research criteria
[46]
also the most anatomically and pathologically hetero-
vascular disease and
geneous and the most heritable of the FTLD syn-
dementia (SIVD)
dromes (see Table 2). Recent work has shown that
© 2012 The Author(s)
European Journal of Neurology © 2012 EFNS European Journal of Neurology

1162
S. Sorbi et al.
Table 2 Summary of clinical, neuroimaging and molecular features of the FTLD spectrum
Cognitive
associations
Neurological associations
Clinical
AAO
Dur
syndrome
(yrs)
(yrs)
MRI atrophy
Molecular associationsa
Ofa
PL
mem
park
MND
other
bvFTD
+
+
50–60
5–15
asymm F
Tau: 3r-Pick’s
L, R TL
+
+
50–70
5–10
asymm FL-PL
Tau: 4r-CBS
+
gaze palsy
55–75
rel symm FL,
Tau: 4r-PSP
midbrain
+
+
40–60
10–15
rel symm aTL, FL
Tau: 4r/3rb
+
+
+
rare
40–80
5–10
asymm R >>L FL, PL, TL
TDP43: type Ac
+
50–70d
3–10
rel symm FL–TL
TDP43: type B/Ae
+
IBMf
40–60
10–>20
FL, TL*
TDP43: type Dg
h
h
20–70
5–10
FL, caudate
FUSi
+
+
+
+
45–65
3–20
Generalized*
Ubiquitin+TDP/FUS-j
PNFA
+
+
+
50–60
5–15
L > R
Tau: 3r-Pick’s
peri-Sylvian
+
+
50–70
5–10
asymm FL-PL
Tau: 4r-CBS
+
gaze palsy
55-75
asymm FL, midbrain
Tau: 4r-PSP
+
+
+
40–60
10–15
rel symm aTL, FL
Tau: 4r/3rb
+
+
50–70
3–10
L > R
TDP43: type B/Ae
peri-Sylvian
+
+
+
40–80
5–10
asymm L>>R FL, PL, TL
TDP43: type Ac,k
SD
?
55–70
10–15
asymm aTL, usu L > R
TDP43: type CL
+
rare
TDP43: type B
+
?
50–60
Tau: 3r-Pick’s
+
40–60
rel symm aTL, FL
Tau: 4r/3rb
AAO, age at onset (typical values shown, where suﬃcient data available); asymm, asymmetric; aTL, anterior temporal lobe; bvFTD, behavio-
ural variant frontotemporal dementia; CBS, corticobasal syndrome; Dur, clinical disease duration; FL, frontal lobe; FUS, fused-in-sarcoma
protein; IBM, inclusion body myopathy; L, left; mem, episodic memory impairment; MND, motor neurone disease; ofa, orofacial apraxia;
park, parkinsonism; PL, parietal lobe; PNFA, progressive non-ﬂuent aphasia; PSP, progressive supranuclear palsy; r, repeat number (tau iso-
form); R, right; rel, relatively; SD, semantic dementia; symm, symmetrical; TDP, transactive response DNA-binding protein; usu, usually;
*limited information.
apredominant histopathological inclusion type;
bparticularly mutations in tau (MAPT) gene;
cTDP43 subtyping here follows Mackenzie 2011 [181] harmonized classiﬁcation scheme, type A includes mutations in progranulin (GRN) gene;
dearlier onset in some genetic cases;
eincludes C9ORF72 mutations [14,15]; rarely mutations in TDP43 gene;
falso associated with Paget’s disease (variable clinical and cognitive features);
gmutations in valosin-containing (VCP) protein;
hin familial FTD-MND cases with FUS mutations and sporadic cases with neuronal intermediate ﬁlament inclusion disease (NIFID);
icases include atypical FTLD with ubiquitin inclusions (aFTLD-U) and NIFID, rare mutations in FUS gene;
jrare mutations in charged multivesicular body protein 2b (CHMP2b);
kphenotype of progranulin-associated aphasia continues to be deﬁned; L>75% of cases of SD.
structural and functional changes in a medial paralim-
aﬀecting knowledge of words [22]. Patients commonly
bic network (including anterior cingulate, orbital fron-
present with ﬂuent but empty speech with loss of
tal and frontoinsular cortices) occur early in bvFTD
vocabulary and surface dyslexia and dysgraphia. A
[8], but this insight is of limited diagnostic usefulness
more pervasive semantic impairment aﬀecting visual
in the individual patient. Phenocopies of bvFTD with
information (prosopagnosia, visual agnosia) and other
normal structural and functional brain imaging and
non-verbal domains generally supervenes later in the
lack of clear progression on serial neuropsychological
course. SD is associated with selective, asymmetric
assessment are increasingly recognized [21]: the nature
antero-inferior temporal lobe atrophy [23], which is
of the underlying disease in these cases (and whether
predominantly left-sided in the majority of cases but
it is neurodegenerative in nature) remains unclear.
may be predominantly right-sided in cases led by
non-verbal semantic deﬁcits. This anatomical proﬁle
Semantic dementia (SD)
of SD is the best deﬁned amongst the FTLD syn-
This is a fairly uniform syndrome led by progressive
dromes, and SD also shows the closest histopathologi-
breakdown of semantic memory, typically initially
cal association (>75% of cases have TDP43-positive
© 2012 The Author(s)
European Journal of Neurology © 2012 EFNS European Journal of Neurology

Dementia guidelines
1163
inclusions [7,22] and the least heritability of the FTLD
intense fear to indiﬀerence or even amusement, are
syndromes [13]). A small proportion of cases with SD
very typical observations in these patients. The pres-
have other pathologies, including tauopathies and
ence of visual hallucinations and delusional misidentif-
Alzheimer’s disease.
ication as early symptoms showed sensitivities and
speciﬁcities of >50% but <75% (class IV evidence)
Progressive non-ﬂuent aphasia (PNFA)
[24–26]. Cognitive impairment is usually the present-
Progressive non-ﬂuent aphasia is led by a progressive
ing feature with extreme ﬂuctuation within a single
breakdown in language output, initially aﬀecting
day over minutes or hours and is associated with
speech but subsequently also literacy skills in most
shifting levels of attention and alertness. The BrainNet
cases; patients commonly present with eﬀortful, non-
European Consortium recently published a protocol
ﬂuent speech containing articulatory errors (speech
for post-mortem assessment [26].
apraxia), agrammatism and variable involvement of
more posterior cortical functions. The broad category
Dementia in Parkinson’s disease
of non-ﬂuent language breakdown encompasses sev-
eral more or less distinct clinical syndromes [18]. Brain
The suggested clinical diagnostic criteria for PDD
atrophy in PNFA frequently involves anterior peri-
[27,28] involve four domains that are anchored in core
Sylvian cortices, more prominently in the left hemi-
features, associated clinical features, features that
sphere [23], but varies widely in extent and severity
make the diagnosis uncertain, and features that are
between patients. Non-ﬂuent speech breakdown and
not compatible with the diagnosis of PDD. When all
the development of parkinsonism are more frequently
four criteria are satisfactorily met, probable PDD is
associated with tau than non-tau pathologies; how-
designated; when the ﬁrst and last criteria are met,
ever, there are important exceptions to these broad
but clinical characteristics are atypical or uncertainty
generalizations. In particular, non-ﬂuent aphasia syn-
factors exist, possible PDD is designated (class IV evi-
dromes caused by TDP43 pathologies are associated
dence) [27,28].
with motor neurone disease and with GRN mutations
The point prevalence of dementia in PD is close to
[7,8]. ‘Progranulin-associated aphasia’ may constitute
30%, and the incidence rate is increased 4–6 times
a distinct language-led syndrome within the FTLD
compared to age-matched controls. The cumulative
spectrum [18]: this syndrome is often associated with
prevalence is at least 75% of PD patients who survive
early prominent parietal signs but lacks the prominent
for more than 10 years [29]. PDD and DLB are both
speech apraxia that is a hallmark of most PNFA
synucleinopathies that diﬀer clinically in the temporal
cases.
evolution of parkinsonism and dementia with a time-
period of 12 months being the arbitrary cut-oﬀ for
the development of dementia (class IV evidence). But
Dementia with Lewy bodies (DLB)
even in PDD alone, the time from onset of PD to
Dementia with Lewy bodies is the second most com-
dementia varies considerably and is related to the type
mon type of degenerative dementia accounting for 10–
and extent of brain pathology [30,31] (class IV evi-
15% of cases [24], and it represents one part of a
dence). The major neurotransmitter deﬁcit is choliner-
spectrum of neurodegenerative disorders that share
gic, related to the loss of cholinergic neurons in the
dysregulation and aggregation of alpha-synuclein. The
nucleus basalis of Meynert (NBM) and projecting cor-
clinical manifestations of Lewy body disease include
tical pathways (class IV evidence) [30].
DLB, Parkinson’s disease and autonomic failure. Clin-
ically, DLB is characterized by progressive cognitive
Progressive supranuclear palsy (PSP)
decline accompanied by core features: recurrent visual
hallucinations, ﬂuctuating attention and cognition,
Progressive supranuclear palsy is a tauopathy leading
and motor features of parkinsonism [25]. Suggestive
to a clinical syndrome featuring parkinsonian signs,
features include neuroleptic sensitivity, changes in
impairment of vertical gaze, postural instability and
dopamine transporter SPECT imaging and REM
dementia [32]. The National Institute of Neurological
sleep behaviour disturbance [25].
Disorders and Stroke (NINDS) have published PSP
Most previous studies observed a more severe
clinical diagnostic criteria [33]. Most patients become
impairment in visual-spatial abilities, attention and
dependent within 3–4 years of diagnosis. Recently,
executive functions in persons with DLB compared
two clinical phenotypes have been described in
with persons with AD [24] (class IV evidence). The
autopsy-proven cases: Richardson’s syndrome (RS)
complex
visual
hallucinations
with
emotional
and PSP-parkinsonism (PSP-P) [34]. Cases of RS were
responses to these experiences, which vary from
characterized by the early onset of postural instability
© 2012 The Author(s)
European Journal of Neurology © 2012 EFNS European Journal of Neurology

1164
S. Sorbi et al.
and falls, supranuclear vertical gaze palsy and cogni-
ent pathological types: CBD (55%), PSP (20%), Pick’s
tive dysfunction, and cases of PSP-P were character-
disease (7%) and non-tau pathologies for the remainder
ized by asymmetric onset, tremor and a moderate
[36]. The clinical onset of CBD occurs usually during
initial therapeutic response to levodopa and were fre-
the sixth to eighth decades of life, and the mean survival
quently confused with Parkinson’s disease. Patients
is about 7 years [37].
with RS showed shorter time from disease onset to
diagnosis and more neuropsychological and neuro-
Limbic encephalitis (LE)
behavioural deﬁcits than patients with PSP-P. Cogni-
tive impairment in PSP suﬃcient to be labelled
The clinical features of LE are diverse, and early diag-
‘dementia’ varies with rates up to 70% reported [35].
nosis of the disorder is frequently diﬃcult [38,39]. The
The degree of cognitive slowing in PSP appears inde-
cardinal sign of LE is a severe impairment of short-term
pendent of motor slowing. Frontal executive impair-
memory or of episodic, anterograde memory (class IV
ments are early and pervasive. Non-verbal reasoning
evidence) [38,39]. Anterograde amnesia is often associ-
and tasks of verbal ﬂuency are greatly reduced with
ated with behavioural and psychological symptoms of
poorer performance on letter than semantic ﬂuency.
dementia (BPSD) such as anxiety, depression, irritabil-
Memory complaints in PSP are usually mild and con-
ity, personality change, acute confusional state, halluci-
sist of impaired free recall with preserved recognition
nations and complex partial and secondary generalized
memory. Personality and behaviour change can be
seizures. The symptoms typically develop over a few
quite ﬂorid; limb apraxia in PSP is typically ideomo-
weeks or months, but they may evolve over a few days.
tor, symmetrical and a common ﬁnding (40%) when
Examination of the CSF may show lymphocytic menin-
studied systematically (class IV evidence) [34,35]. As
gitis. The main diﬀerential diagnoses include infectious
in CBD, language and speech disorders, logopenia or
encephalitis,
corticosteroid-responsive
autoimmune
dynamic aphasia and apraxia of speech are a feature
encephalopathy, glioma or lymphomatous inﬁltration,
of PSP; in particular, progressive non-ﬂuent aphasia
and Wernicke–Korsakoﬀ encephalopathy. It often has
because of PSP pathology is well recognized [35] (class
a paraneoplastic origin mostly associated with lung or
IV evidence).
testicular cancer and in women with ovarian teratomas
(class III evidence) [39]. It is often associated with anti-
bodies against intracellular neuronal antigens or with
Corticobasal syndrome (CBS)
antibodies
to
voltage-gated
potassium
channels
Corticobasal syndrome is a rare syndrome with a pro-
(VGKC). Neuropathological studies show dominant
gressive course, in most cases unresponsive to levodopa
parenchymal inﬁltrates of T cells supporting the
or other medication (class IV evidence) [36]. At onset,
hypothesis that the disorder is mediated by a T cell dri-
CBS typically presents with asymmetrical rigidity,
ven immune response, presumably against the same
bradykinesia and apraxia of the aﬀected limbs, usually
antigens recognized by the antibodies.
of the limb-kinetic type. During the evolution of the
disease, postural and action tremor, limb dystonia,
Huntington’s disease (HD)
focal reﬂex myoclonus, postural instability and falls,
alien hand-like phenomenon, corticospinal signs, oculo-
Huntington’s disease is an autosomal-dominant neuro-
motor and eyelid motor deﬁcits and dysarthria develop
degenerative disease caused by the expansion of a cyto-
in more than half of cases. CBD, the commonest cause
sine–adenine–guanosine trinucleotide (CAG)n repeat
of CBS, is a 4-repeat tauopathy deﬁned by unique neu-
within the HD gene, encoding an abnormally long poly-
ropathological features including cortical atrophy, ni-
glutamine moiety within the huntingtin protein (class I
gral degeneration, achromasia (swollen neurons with
evidence) [40] that leads to marked atrophy of basal
eccentric nuclei and loss of cytoplasmic staining) in the
ganglia structures, the caudate and putamen, as well as
cortex and underlying white matter and tau immuno-
less marked atrophy of other brain nuclei. It is proba-
reactive astrocytic plaques. Dementia is not an early
bly the most common inherited adult neurodegenera-
feature in classical CBS, occurring in approximately
tive disease, aﬀecting 1 in 15 000. The average age of
one quarter of cases at a later stage. However, dementia
onset is 30–50 years of age; in some cases, symptoms
is more common in patients with CBD who do not
start before the age of 20 years with behaviour distur-
present with classical CBS (class IV evidence) [36].
bances and learning diﬃculties at school (Juvenile Hun-
CBD is currently considered to involve a spectrum of
tington’s disease; JHD) and onset in older adults also
diﬀerent clinical phenotypes, such as CBS, PSP, demen-
occurs. The hallmark of the illness is chorea, but some
tia, bvFTD, progressive non-ﬂuent aphasia, speech
patients have little or no chorea and instead appear
apraxia. Conversely, CBS can be associated with diﬀer-
with parkinsonian features [40].
© 2012 The Author(s)
European Journal of Neurology © 2012 EFNS European Journal of Neurology

Dementia guidelines
1165
Cognitive decline often accompanied by psychiatric
Increased awareness has raised concern about the risk
symptoms is the other main sign of HD and can be pres-
that human prion diseases (especially vCJD) are trans-
ent long before the ﬁrst motor symptoms appear, but
missible by blood transfusion. The very rare new vari-
can also remain mild in far-advanced stages of the dis-
ant CJD (vCJD) is related to BSE (bovine spongiform
ease. Changes are mostly in executive functions includ-
encephalopathy). More than 200 vCJD cases have
ing changes in goal-directed and planned abilities as
been reported since 1996, the majority in the UK.
well as the capacity to distinguish what is relevant and
vCJD is characterized by a younger age of onset
what can be ignored (class III evidence) [40]. The
(mid-teens to early 40s) and by longer illness duration
patients become rapidly unable to organize their life
(range, 4–25 months). Clinical features are often lim-
with frequent misjudgements. Usually language is rela-
ited to psychiatric disturbance or sensory symptoms,
tively spared. Episodic memory becomes impaired,
until ataxia, cognitive impairment and involuntary
although semantic memory is relatively spared. The ill-
movements develop later in the course [42].
ness leads to death, with an average duration of symp-
toms of about 20 years. How the mutation leads to the
Vascular cognitive impairment and vascular dementia
onset of a disorder of motor, emotional and cognitive
control in people who have matured normally until mid-
Recently, the term vascular cognitive impairment
dle age is still unknown. The discovery of mutations in
(VCI), which reﬂects an awareness of the importance
the HD gene has made genetic diagnosis common, both
of the vascular burden on cognition, has been pro-
in neurologically normal patients (pre-symptomatic test-
posed [44]. The previous concept of VaD caused by
ing) and in neurologically or psychiatrically impaired
small or large brain infarcts (strokes) was recently
patients (diagnostic testing) (class III evidence) [40].
extended
from
only
multi-infarct
(multi-stroke)
dementia (MID) to a whole spectrum of vascular
causes of cognitive impairment and dementia, sub-
Prion diseases
sumed within the term vascular cognitive impairment
Creutzfeldt–Jakob disease (CJD)
[44].
Sporadic CJD, the most common prion disease (85%
The main subtypes of VaD included in current clas-
of cases), has a prevalence estimated to be 0.5–1.5
siﬁcations are large vessel (LV) VCI, also referred to
cases per million; the mean age at onset is 65 years
as cortical VCI, multi-infarct VCI or post-stroke VCI,
(range, 14–92 years), and the median and mean dura-
small vessel (SV) VCI, subcortical ischaemic vascular
tion of illness are 4.5 and 8 months, respectively; only
disease and dementia (SIVD), strategic infarct demen-
4% of patients survive longer than 2 years. Diagnostic
tia and hypoperfusion VCI resulting from global cere-
criteria for sporadic CJD have been published based
brovascular insuﬃciency. Further subtypes include
on clinical signs, EEG, 14-3-3 protein in CSF and
haemorrhagic dementia, hereditary vascular causes
MRI ﬁndings (class IV evidence) [41,42]. The classical
(e.g. cerebral autosomal dominant arteriopathy with
diagnostic triad is a rapidly progressive dementia,
subcortical infarct and leucoencephalopathy (CADASIL)
myoclonus and a characteristic EEG pattern. Myoclo-
and AD with cerebrovascular disease (CVD). The
nus is an important manifestation, but seen often only
most widely used clinical diagnostic criteria for VaD
in late stages of the disease. Ataxia and visual abnor-
are the NINDS-AIREN criteria [45]. In addition,
malities are frequent, with visual ﬁeld defects, percep-
research criteria for SIVD have also been proposed
tual abnormalities and occasionally hallucinations [43].
[46].
The NINDS-AIREN criteria handle VaD as a syn-
Genetic prion diseases
drome with diﬀerent aetiologies and diﬀerent clinical
Genetic prion diseases occurring in 10–15% of cases
manifestations rather than a single entity and list pos-
are caused by prion protein gene (PRNP) mutations,
sible subtypes to be used in research studies. These
showing the patterns of autosomal-dominant inheri-
criteria incorporate diﬀerent levels of certainty of the
tance with incomplete penetrance. The disorders mani-
clinical diagnosis (probable, possible, deﬁnite). How-
fest as familial Creutzfeldt–Jakob disease (fCJD),
ever, in randomized clinical trials using the NINDS-
Gerstmann–Stra¨ussler–Scheinker disease (GSS) or
AIREN criteria, all potential subtypes have been
fatal familial insomnia (FFI).
lumped together as ‘general VaD’. The SIVD criteria
of Erkinjuntti et al. [46] represent an attempt to deﬁne
Accidentally transmitted (iatrogenic)
a more homogeneous subtype.
CJD has been related to corneal graft transplantation,
In a neuropathological series, the sensitivity of the
contaminated human pituitary-derived growth hor-
NINDS-AIREN criteria for probable and possible
mone
or
gonadotropin
and
dura
mater
grafts.
VaD was 58% and speciﬁcity was 80% [47]. The
© 2012 The Author(s)
European Journal of Neurology © 2012 EFNS European Journal of Neurology

1166
S. Sorbi et al.
inter-rater reliability of the NINDS-AIREN criteria is
evidence) [50]. Alterations may be suggestive of other
moderate to substantial (kappa 0.46–0.72) [44].
forms of dementia. For example, increased muscle
The research criteria for SIVD represent a more
tone and bradykinesia in the absence of tremor may
recent development. In SIVD, the biological markers
be suggestive of DLB; asymmetric reﬂexes, visual ﬁeld
of small vessel disease are conﬂuent white matter
deﬁcit, pyramidal or other lateralizing signs may be
lesions along with lacunes. Furthermore, changes in
indicative of VaD; myoclonus is suggestive for CJD;
the normal appearing white matter, frontal cortical
peripheral neuropathy may suggest toxic and meta-
atrophy, as well as microinfarcts may be important
bolic encephalopathies. It is of particular importance
surrogates. A similar approach to the small vessel dys-
to evaluate hearing and vision because impairment
executive phenotype criteria of SIVD is that of the
can inﬂuence mental status and neurological examina-
recent criteria for the amnestic phenotype of AD.
tion. Neurological examination should be accompa-
VCI cases that do not meet the criteria for dementia
nied by general medical examination to disclose
can also be labelled as VCI with no dementia or vascu-
systemic contribution to the cognitive impairment.
lar cognitive impairment, no dementia (CIND). These
There exists no evidence-based data to support the
patients have also been labelled as vascular mild cogni-
usefulness of speciﬁc routine blood tests for the evalu-
tive impairment (vMCI) in a similar way to amnestic
ation of those with dementia but these tests are useful
mild cognitive impairment (aMCI) for AD.
in excluding co-morbidities, revealing potential risk
factors, origin of confusional states and, rarely, in
identifying the primary cause of dementia. The value
Normal-pressure hydrocephalus (NPH)
of laboratory tests was assessed by the American
Data about the prevalence of normal-pressure hydro-
Academy of Neurology practice parameter publication
cephalus (NPH) syndrome vary between 0.12% and
[51]. Most expert opinion advises screening for vita-
2.9% with an estimated incidence of 5.5/100 000/year
min B12, folate, thyroid-stimulating hormone, cal-
[48]. Clinical diagnosis of NPH is diﬃcult as the criti-
cium, glucose, complete blood cell count, renal and
cal features of NPH represented by insidious onset of
liver function abnormalities. Abnormal vitamin B12
gait disturbance, incontinence and dementia are very
levels and thyroid function are commonly encountered
common in the elderly. Furthermore, a cognitive pro-
co-morbidities. They can inﬂuence cognitive function,
ﬁle may overlap with AD or subcortical VaD and gait
and it is useful to assess them even if the treatment of
disturbances may overlap with PD. The presence of
these disorders may not completely reverse dementia
typical clinical features accompanied by supplemental
(class IV evidence) [51]. Serological tests for syphilis,
investigations enable the classiﬁcation of NPH as pos-
Borrelia and HIV should be considered in individual
sible, probable or unlikely. International guidelines
cases at high risk or where there are suggestive clinical
suggest that probable clinical diagnosis has to be based
features (class IV evidence) [51].
on all three core features (class III of evidence) [49].
Recommendations: clinical diagnosis: medical history,
Diagnostic evaluation
laboratory, neurological and physical examination
• Clinical history should be supplemented by an
Clinical diagnosis: medical history, laboratory,
informant (Good Practice Point) [2,4–6]. A neuro-
neurological and physical examination
logical and general physical examination should be
The history, from the patient and a close informant,
performed in all patients with dementia (Good
should focus on the aﬀected cognitive domains, the
Practice Point) [2,4–6,50]. Routine blood tests are
course of the illness, and the impact on activity of
useful in excluding co-morbidities (Good Practice
daily living (ADL) and any associated non-cognitive
Point) [51].
symptoms. Past medical history, co-morbidities and
family and educational history are important. Infor-
Assessment of cognitive functions, screening tests
mation from the history can guide and target subse-
and assessment of specific cognitive domains
quent examinations. The neurological examination is
particularly
important
in
distinguishing
primary
Speciﬁc patterns of cognitive and behavioural dys-
degenerative and secondary dementias and co-morbid-
functions are detectable in early rather than in
ities [2,4–6] (class III evidence). It is largely normal in
advanced stages and reﬂect the disruption of speciﬁc
early AD with the exception of mental status evalua-
brain structures [51]. Thus, episodic memory impair-
tion. Additional abnormalities ‘dementia plus’ syn-
ment is often the ﬁrst symptom in AD with early
dromes can suggest speciﬁc diagnoses (class IV
involvement of entorhinal cortex and hippocampus
© 2012 The Author(s)
European Journal of Neurology © 2012 EFNS European Journal of Neurology

Dementia guidelines
1167
[52] (class II evidence). Disinhibition, apathy and
(CAMCOG) show that patients with DLB [60] and with
emotional disorders characterize the ﬁrst stages of
CBS [61] are particularly impaired on visual-spatial tasks;
bvFTD, with predominant atrophy in the antero-
patients with bvFTD and with CBS show pathological
mesial and orbito-frontal cortices (class II evidence)
scores on letter ﬂuency tasks [60] and on measures of
[19,20]. SD with atrophy of the left anterior temporal
social-behavioural disturbances, whereas those with SD
region is characterized by word ﬁnding and semantic
are selectively impaired on tests of visual naming and cat-
disorders, whereas a left anterior peri-Sylvian atrophy
egory ﬂuency [61].
is usually associated with a PNFA (class II evidence)
[22]. CBS features visual-spatial impairment, limb
Memory functions
apraxia and an alien hand syndrome reﬂecting parietal
Episodic
memory:
A comparison between scores
and frontal lobe atrophy (class II evidence) [36,37].
obtained on free recall and on cued recall is very useful
Parietal occipital atrophy is associated with the visual
in the diﬀerential diagnosis between AD and non-AD
hallucinations and the visual-spatial disorders of
dementia (class II evidence), because the provision of a
DLB. On the other hand, the subcortical forms of
cue (helping encoding and retrieval processes) signiﬁ-
dementia (PDD, NPH and VaD with multiple subcor-
cantly improves the memory scores of patients with
tical infarcts), in which the subcortical-frontal loops
lesions aﬀecting the frontal lobes and subcortical struc-
are usually disrupted, are characterized by psychomo-
tures. The provision of a cue is, on the contrary, of no
tor slowing and executive dysfunctions subsumed by
help in AD patients, where delayed recall is severely
the frontal lobes.
impaired as a consequence of mesial temporal lobe
The most widely used cognitive screening test is the
atrophy, which disables consolidation. Investigations
Mini-Mental State Examination (MMSE) [53] which
conducted with the Buschke’s Free and Cued Selective
does not investigate frontal functions. Other screening
Reminding Test (FCSRT) and the California Verbal
tests are available of good accuracy in the general diag-
Learning Test (CVLT) have shown that cues provided
nosis of dementia or have been proposed speciﬁcally for
more beneﬁt to patients with VaD [62] and with FTD
the diﬀerential diagnosis between the diﬀerent forms of
[63] than to AD patients.
dementia. These two groups of screening tests are given
Semantic memory: Selective impairment is typical of
in Table 3, together with some neuropsychological bat-
SD. Several authors [64] have shown that patients
teries oriented to the diﬀerential diagnosis of dementia.
with SD perform worse in categorical ﬂuency and
The patterns of impairment observed on the screen-
visual naming tests, compared with bvFTD and AD.
ing tests reported in Table 3 can guide the diﬀerential
diagnosis. Thus, in addition to the characteristic epi-
Executive functions
sodic memory impairment of AD:
A predominance of executive dysfunction over episodic
(a) visual-constructive disorders on copying the pen-
memory impairment is typical for bvFTD [58,65], CBS
tagons of the MMSE are associated with DLB
[65], VaD [66] and DLB [67]. Decreased ﬂuency on ver-
with a sensitivity of 88% and a speciﬁcity of
bal ﬂuency tests [68], perseverations on the Wisconsin
59% [54] (class II, Level B). Also associated
Card Sorting Test (WCST) [69], reduced speed of pro-
with DLB are reduced attention and working
cessing on the Trail-Making Test (TMT) [70], and
memory scores of the MMSE [55] and of the
defects in inhibiting the automatic responses on the
Addenbrooke’s Cognitive Examination Revised
Stroop test [71] may be caused by subcortical or frontal
(ACE-R) [56] (class II, Level B);
lesions [65,66,68,69,71]. However, it must be noted that
(b) reduced scores on the ‘letter ﬂuency’ subtest of
Reed et al. [72] have recently reported that executive
the ACE-R are associated with FTD, CBS and
impairment is not a useful diagnostic marker for VD,
PSP [56] (class II, Level B);
when assessed in a series of autopsy conﬁrmed AD and
(c) stimulus-bound responses of the clock-drawing
cerebrovascular cases.
test are associated with PDD and subcortical
forms of vascular dementia (class II, Level B) [57].
Visuospatial and visual recognition abilities
Similar results are obtained on the more complex
Results of individual studies [60,61] and of systematic
screening and neuropsychological batteries reported in
reviews (e.g. [67]) have shown that patients with DLB
Section 2 of Table 3. Thus, according to Slachevsky
[60,67] and with CBS [61] are particularly impaired on
et al. [58], but not to Lipton et al. [59], the results
visual-spatial tasks. On the other hand, several
obtained on the FAB correctly identify about 80% of
authors have shown that in patients with right tempo-
patients aﬀected by bvFTD. Furthermore, the results
ral variant of FTD, a defect of familiar people recog-
obtained on the Philadelphia Brief Assessment of Cogni-
nition, aﬀecting both faces and voices, is frequently
tion (PBAC) and the Cambridge Cognitive Examination
observed (see [73] for a systematic review).
© 2012 The Author(s)
European Journal of Neurology © 2012 EFNS European Journal of Neurology

1168
S. Sorbi et al.
Brief
disorders
disorders
Learning
Verbal
Philadelphia
behavioural
behavioural
PBAC,
California
Emotional
Emotional
+
task;
g
CVLT,
;
Test
Verbal
ﬂuency
+
Verbal
ﬂuency
+
+
clock-drawin
Reminding
CDT,
Scale;
Selective
Rating
Cued
Visual-spatial
functions
+
+
+
Visual-spatial
functions
+
+
References
[62]
[186]
[187]
[187]
[64]
[68]
[70]
[71]
[185]
[184]
and
Free
dementia
Dementia
of
Mattis
Language
+
+
++
FCSRT,
forms
Language
domains
MDRS,
diﬀerent
Examination;
memory
Revised;
social-emotional)
amongst
Cognitive
(and
Attention
working
++
Attention
working
memory
++
++
diagnosis
Orientation
test
Examination
tests
test
cognitive
Line
Cambridge
of
of
recall
ﬂuency
diﬀerential
naming
ﬂuency
test
Cognitive
the
dementia
Test.
Coverage
Verbal
memory
++
++
for
Verbal
memory
recall
FCSRT
CVLT
Category
Boston
Verbal
WCST
TMT
Stroop
Judgment
Clock-drawing
of
CAMCOG,
proposed
Addenbrooke’s
Battery;
diagnosis
–96
89
97
87
Trail-Making
AD)
56
dementia
for
(in
in
general
Speciﬁcity
97
batteries
Speciﬁcity
ACE-R,
TMT,
patients.
cue
Assessment
the
a
Test;
AD
in
accuracy
domains
by
functions
from
a
Frontal
Sorting
Examination;
accuracy
–92
94
98
67
78.9
93
FTD
cognitive
obtained
FAB,
Diagnostic
dementia
Sensitivity
71
Sensitivity
Card
cognitive
neuropsychological
State
of
good
of
and
speciﬁc
(beneﬁt
of
Cognition;
tests
tests
functions
Wisconsin
distinguishing
[185]
of
in
memory
functions
Assessment
memory
[53]
[182]
[183]
Mini-Mental
3
[61]
[184]
[58]
WCST,
Screening
Screening
Assessment
Table
(1)
Test
MMSE
ACE-R
MDRS
CDT
(2)
Test
PBAC
FAB
CAMCOG
(3)
Episodic
provision)
Semantic
Executive
Visual-spatial
MMSE,
Assessment
Test;
Accuracya
© 2012 The Author(s)
European Journal of Neurology © 2012 EFNS European Journal of Neurology

Dementia guidelines
1169
some non-AD dementias such as DLB, PDD or
Recommendations: assessment of cognitive functions,
FTLD [12,19,24,27] (class IV evidence). BPSD are
screening tests and assessment of specific cognitive
associated with declining cognitive and functional
domains
ability, decreased quality of life and increased institu-
• Cognitive assessment is central to diagnosis and man-
tionalization (class III evidence) [74,75]. Somatic co-
agement of dementias and should be performed in all
morbidity and environmental triggers should always
patients (Level A) [51]. Screening tests are available
be ruled out as a possible cause.
of good accuracy in the general diagnosis of dementia
Several global informant-based scales are used to
or have been proposed speciﬁcally for the diﬀerential
assess BPSD (class IV) [76] (see Table 4); however,
diagnosis between the diﬀerent forms of dementia
most of them have been speciﬁcally developed for
(Good Practice Point) [51]. Neuropsychological
AD, displaying low sensitivity for some characteristic
assessment should be performed in all patients in the
forms of BPSD occurring in non-AD dementias [77].
early stages of the disease (Level B) when the cogni-
The neuropsychiatric inventory (NPI) is a comprehen-
tive impairment reﬂects the disruption of speciﬁc
sive instrument used in most non-AD drug studies
brain structures [2,4–6,52]. The neuropsychological
although the change in the scale representing a clini-
assessment should include a global cognitive measure
cally meaningful improvement has not yet been estab-
and, in addition, more detailed testing of the main
lished [78]. Diﬀerent versions have been available
cognitive domains including memory, executive func-
including both an abbreviated version for routine clin-
tions and instrumental functions (Level C) [51].
ical practice and a more expanded version comprising,
for example, euphoria, disinhibition, compulsive and
repetitive behaviours [77]. The Middelheim frontality
Assessment of behavioural and psychological
score (MFS) is a validated scale that measures frontal
symptoms
features and reliably discriminates FTLD from AD
The term behavioural and psychological symptoms of
patients with a sensitivity and speciﬁcity of almost
dementia (BPSD) is used to describe the spectrum of
90% [77] (class II evidence).
non-cognitive symptoms of dementia (apathy, psycho-
A behavioural scale of frontal lobe dysfunction pro-
sis, aﬀective and hyperactive behaviours) [74]. Identiﬁ-
viding a behavioural cut-oﬀ to diagnose early FTD
cation of neuropsychiatric symptoms is essential for
and distinguish it from AD and VaD is available with
both the diagnosis and treatment, as some BPSD con-
a speciﬁcity of 95% and sensitivity of 91% [79] (class
stitute the core or supportive diagnostic features of
II evidence).
Table 4 Speciﬁc scales used to assess BPSD in dementing disorders
Behavioural domains
Scale/questionnaire
Purpose of use
assessed
Other characteristics
Reference
Middelheim frontality score
To discriminate FTLD and AD
Frontal features
Validated scale; sensitivity and
[77]
(MFS)
speciﬁcity close to 90%
Manchester Behavioural
To diﬀerentiate FTLD from
Frontal features
Semi-structured questionnaire;
[188]
Questionnaire
AD/CVD
overall accuracy of
classiﬁcation 95%
Frontotemporal behavioural
To diagnose early FTLD and
Frontal features
Validated scale; speciﬁcity of
[79]
scale
distinguish it from AD and VaD
95% and sensitivity of 91%
Cambridge behavioural
To diﬀerentiate FTLD from
Frontal features
Questionnaire; overall accuracy
[189]
questionnaire
AD; discriminate frontal
of classiﬁcation 71.4%
variant FTLD and semantic
dementia
Geriatric depression scale (GDS)
To assess depressive symptoms,
Aﬀective symptoms
15-item validated scale
[76]
diagnosis of depression
Cornell scale for depression in
To assess depressive symptoms,
Depression
Validated scale; developed
[76]
dementia
diagnosis of depression
speciﬁcally for use in dementia
Dementia mood assessment scale
To assess depressive symptoms,
Depression
Validated scale; developed
[76]
(DMAS)
diagnosis of depression
speciﬁcally for use in dementia
REM sleep behaviour
To screen for REM sleep
REM sleep behaviour
Validated questionnaire
[81]
disorder screening
behaviour disorder
disorder (RBD)
questionnaire
in PDD/DLB
Questionnaire for impulsive-
To screen for impulsive-
Impulsive-compulsive
Validated questionnaire
[82]
compulsive disorders in PD
compulsive disorders in PD
disorders
© 2012 The Author(s)
European Journal of Neurology © 2012 EFNS European Journal of Neurology

1170
S. Sorbi et al.
Other useful scales discriminating FTLD from AD
evaluation (Good Practice Point) [83–89]. A semi-
in particular are listed in Table 4. More focused scales
structured interview from the caregiver is the most
evaluating speciﬁc symptoms as well as possible treat-
practical way to obtain relevant information, and
ment complications [80] of some non-AD dementias
various validated scales translated into diﬀerent lan-
have been available, including the assessment of
guages are available (Good Practice Point) [83–89].
depression (particularly the 15-item geriatric depres-
sion scale, Cornell scale for depression in dementia)
Assessment of co-morbidity
[76], REM sleep behaviour disorder [81] or impulsive-
compulsive disorders [82] (class II evidence).
Studies of the prevalence of co-morbidity and the eﬀect
of treatment of co-morbidities in non-AD dementia are
limited. A large autopsy study in various dementia
Recommendations: assessment of behavioural and
cases identiﬁed a high number of co-morbidities, which
psychological symptoms
would have aﬀected the clinical management of the
• Assessment of BPSD is essential for both diagnosis
patient had they been known ante-mortem. Amongst
and management and should be performed in each
these, the most frequent were atherosclerotic cardiovas-
patient (Good Practice Point) [74]. Information is
cular disease, myocardial infarct, bronchopneumonia,
gathered from an informant using an appropriate
emphysema and pulmonary thromboembolism (class
rating scale (Good Practice Point) [76]. Although
IV evidence) [90]. However, in a large cohort followed
speciﬁc BPSD form the core or supportive features
for 2 years in nursing homes, patients with dementia
of some non-AD dementias, co-morbidity should
had signiﬁcantly lower overall rates of infection and
always be considered as a possible cause (Good
similar rates of fever, pressure ulcers, and fractures
Practice Point) [12,19,24,27].
compared to non-demented residents (class IV evi-
dence) [91]. Depression is frequent in the elderly popu-
lation in general and depressive symptoms are common
Assessment of activities of daily living
in dementia, particularly in vascular dementia [92],
Impairment of everyday function is a key feature of
FTD [93] and PDD [94] and neurologists should be
dementia. Assessment of function in daily life is part
trained to recognize depressive disorders [95]. In PDD,
of the diagnostic work-up. Diﬀerent scales are used to
falls, fractures, symptomatic postural hypotension, uri-
measure these abilities objectively. These are based
nary incontinence and hallucinations are frequent
mainly on the interview with the patient and his/her
events [96]. Co-morbidity is a signiﬁcant predictor of
caregiver. Most scales include measurement of two
the quality of clinical outcome for patients with idio-
ﬁelds: basic (self-maintenance skills, such as eating,
pathic
normal-pressure
hydrocephalus
undergoing
dressing, bathing) and instrumental activities (complex
shunt therapy (class III evidence) [97].
higher order skills such as the use of devices, manag-
ing ﬁnances, shopping). Frequently used scales include
Recommendations: assessment of co-morbidity
the AD Cooperative Study (ADCS) ADL Scale [83],
Functional Activities Questionnaire (FAQ) [84], the
• Assessment of co-morbidity is important in demented
Progressive Deterioration Scale (PDS) [85], Instrumen-
patients, both at the time of diagnosis and through-
tal Activity of Daily Living (IADL) [86] and the Dis-
out the course of the illness (Good Practice Point)
ability Assessment for Dementia (DAD) [87]. These
[90] and should always be considered as a possible
scales are validated for diﬀerent populations and
cause of BPSD (Good Practice Point) [97]. Blood lev-
translated into most European languages; however,
els of folate, vitamin B12, thyroid-stimulating hor-
they are not validated in low-income countries [88].
mone, calcium, glucose, complete blood cell count,
There are diﬀerences in functional impairment across
renal and liver function tests should be evaluated at
subtypes of dementia [89], and these scales may be
the time of diagnosis and serological tests for syphilis,
used to monitor rate of change of functional abilities
Borrelia and HIV might also be needed in cases with
in dementia [83–89] (class IV).
atypical presentation or clinical features suggestive of
these disorders (Good Practice Point) [51].
Recommendations: assessment of activities of daily
living
Neuroimaging
• ADL and IADL impairment because of cognitive
Structural imaging in non-Alzheimer dementias
decline is an essential part of the diagnostic criteria
In clinical practice, CT and standard MRI are used to
for dementia and should be assessed in the diagnostic
exclude secondary causes for dementia such as tumour
© 2012 The Author(s)
European Journal of Neurology © 2012 EFNS European Journal of Neurology

Dementia guidelines
1171
and inﬂammatory disease, including abscess or nor-
does not exclude the diagnosis. Asymmetric atrophy
mal-pressure hydrocephalus (class I evidence) [98].
is often seen in primary progressive aphasia and in
Yet, only 2.2% of demented patients have a condition
semantic dementia with more pronounced atrophic
requiring imaging for diagnosis [98]. Nonetheless,
changes
occurring
in
the
anterior
than
in
the
imaging is used to reﬁne ante-mortem diagnosis, and
posterior portions of the temporal lobe (class III
based on current diagnostic criteria it is MRI that is
evidence) [21]. Greater left temporal atrophy than in
becoming a prerequisite in the diagnostic work-up of
AD was described in semantic dementia, and areas
dementia.
such as the temporal pole, parahippocampal gyrus
and lateral temporal lobe are also more aﬀected in
Vascular dementia
FTLD (class III evidence) [102]. In semantic demen-
Diagnostic criteria for VaD require the demonstra-
tia, ‘knife-edge’-type atrophy is almost always pres-
tion of cerebrovascular disease and a link between
ent in the anterior temporal lobes [103] (class IV
that and the onset of dementia [45]. The NINDS/AI-
evidence).
REN (National Institute of Neurological Disorders
and Stroke and Association Internationale pour la
Huntington’s disease (HD)
Recherche´ et l’Enseignement en Neurosciences) crite-
Atrophic changes are seen in the striatum, cortex, sub-
ria propose detailed imaging criteria for the diagnosis
stantia nigra, ventrolateral thalamus, subthalamic
of VaD [45]. These criteria separate large vessel and
nucleus, cerebellum and brainstem. The pronounced
small vessel disease and consider both topography
atrophy of the caudate nucleus and putamen is char-
and severity. Low inter-rater reliability led to opera-
acteristic, and the so-called bicaudate ratio doubles
tionalization of these guidelines which resulted in
[104] (class II evidence). The putamen can be hyperin-
good agreement amongst experienced readers (class
tense.
III evidence) [99]. Despite these attempts to produce
agreement on the types, topography and severity of
Progressive supranuclear palsy (PSP)
vascular lesions relating to the diagnosis of vascular
MRI is used to distinguish PSP from Parkinson dis-
dementia, much uncertainty remains. Although imag-
ease and Parkinson-variant of MSA. Pathological
ing criteria appear to be speciﬁc for a diagnosis of
ﬁndings and MR imaging evidence indicate that the
VaD, sensitivity can be lower than 50% (class III
midbrain and the superior cerebellar peduncles are
evidence) [100]. At the current state of knowledge,
atrophic in PSP, whereas
the middle cerebellar
demonstration of cerebrovascular disease on imaging
peduncles and the pons are mainly involved in MSA
is used to support the diagnosis; subcortical vascular
(class IV evidence) [105]. An MR parkinsonism
dementia is the most common entity amongst VaD
index was introduced for the combined assessment
and MRI, and criteria for this entity have been pro-
at routine MR imaging of the four brain structures
posed and already used in several clinical studies
diﬀerently involved in atypical parkinsonian syn-
[46]; a formal neuropathological validation is still
dromes [105] (class IV evidence). Validation is still
pending.
pending.
Dementia with Lewy bodies (DLB) and Parkinson
Corticobasal syndrome (CBS)
disease with dementia (PDD)
MRI demonstrates characteristically asymmetric fron-
Relative preservation of the hippocampus and medial
tal and/or parietal atrophy with less frequent involve-
temporal lobe compared with AD has been described
ment of the temporal lobe. Visual assessment of the
in DLB and PDD in around half of the patients, and
asymmetry has been reported to diﬀerentiate cortico-
distinct patterns of grey matter loss have been found
basal syndrome from PSP with high speciﬁcity [106]
in DLB and PDD. These involve frontal areas extend-
(class III evidence).
ing to temporal, occipital and subcortical areas, with
occipital atrophy in DLB and PDD being the only
Multiple system atrophy (MSA)
diﬀerence from the pattern seen in AD [101] (class III
Besides atrophic changes, T2-weighted MRI may
evidence). There remains considerable overlap between
show a posterolateral putaminal hypointensity because
AD, DLB and PDD, and the utility of MRI for dif-
of iron deposition, with a hyperintense rim because of
ferential diagnosis is unclear.
gliosis. Using T2* gradient echo sequences to detect
this hypointensity and FLAIR to detect the hyperin-
Frontotemporal lobar degneration (FTLD)
tense has a sensitivity of 69%, and speciﬁcity of 97%
Frontal
and
temporal
atrophy
are
supportive
was achieved in diﬀerentiating MSA from PD [107]
diagnostic features for FTLD, but their absence
(class III evidence).
© 2012 The Author(s)
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1172
S. Sorbi et al.
Prion disease
Limbic encephalitis (LE)
Hyperintensity of the cortical gyri (cortical ribboning),
The MR imaging ﬁndings of limbic encephalitis have
striatum (caudate and putamen) and/or thalamus on
been well described in a number of case reports and
FLAIR and DWI scans has high sensitivity and speci-
during the acute phase of the illness. They include hy-
ﬁcity (up to 90% sensitivity and 90% speciﬁcity for
perintense signal abnormality on T2-weighted images
DWI) in sporadic CJD [108] (class II evidence). MRI
within medial temporal lobe structures such as the
imaging is of increasing importance in sCJD diagnosis
hippocampi and amygdalae and, on occasion, the
and has recently been added to updated WHO criteria
hypothalamus [117] (class IV evidence).
as a diagnostic marker of probable sCJD, besides 14-
3-3 and EEG (class II evidence) [41]. The so-called
Functional imaging modalities include diffusion-tensor
‘pulvinar sign’, that is, symmetrical hyperintensity of
imaging (DTI) MRI, SPECT and PET
the posterior thalamus, has high diagnostic utility for
variant CJD (seen in over 90% of patients with subse-
Diﬀusion-tensor imaging MRI is performed as part of
quently pathologically conﬁrmed vCJD) [109] (class
an MRI protocol that usually includes FLAIR, T1, T2
III evidence).
and the DTI uptakes are evaluated in this context.
Importantly, DTI sequences add unique information on
Other rapidly progressing dementias
the integrity of white and of grey matter structure. This
Other rapidly progressive dementias can have MRI
information is obtained from data on the mobility (dif-
ﬁndings similar to CJD. Bartonella hensalae encepha-
fusibility) of water molecules in the tissue, and several
lopathy, Wilson’s disease and Wernicke’s encephalop-
parameters can be extracted. MD (mean diﬀusivity), FA
athy can show DWI hyperintensity in the deep grey
(fractional anisotropy), DR (radial diﬀusivity, perpen-
nuclei, whilst antibody-mediated encephalopathies and
dicular to axonal tracts) have consistently been shown to
neuroﬁlament inclusion body dementia can have
be useful, experimental and clinical data, showing close
FLAIR hyperintensity in the cortex and deep nuclei.
relationships between clinical parameters, tissue and
In these conditions, unlike prion disease, the underly-
imaging changes (Level A evidence, see below).
ing white matter is also often involved [109–113] (class
Recently, it has been shown that DTI MRI (in
IV evidence).
combination
with
morphometric
analysis)
distin-
guishes network degeneration in patterns consistent
Normal-pressure hydrocephalus (NPH)
with cognitive impairment in AD and FTLD patients,
According to Relkin criteria [49], MRI or CT must
when diagnosis was conﬁrmed using CSF biomarkers
show an Evan’s index (maximal ventricular width
and autopsy [118] (class II evidence). Also, a small
divided by the largest biparietal distance between the
case–control study suggests that white and grey matter
inner tables of the skull) of at least 0.3, as well as
DTI uptakes may distinguish between FTLD variants
temporal horn enlargement, periventricular signal
[119] (class IV evidence).
changes or an aqueductal/fourth ventricular ﬂow void
Similarly, comparing AD and DLB, diﬀusivity pat-
(class III evidence) [49]. A callosal angle of greater
terns complement morphometric data in the diagnos-
than 40° was included in these guidelines [49]. Also, a
tic process
and
correlate with
symptoms, DLB
narrow CSF space at the high-convexity/midline areas
patients having a more pronounced increased diﬀusiv-
relative to Sylvian ﬁssure size was recently shown to
ity, for example in the amygdalae [120] (class IV evi-
correlate with a diagnosis of probable or deﬁnite
dence). Compared with PDD and corresponding to
NPH [114] (class III evidence). Volumetric MRI,
the cognitive proﬁles of the patients, DLB patients
including ventricular, brain and peri-cerebral CSF vol-
have higher diﬀusivity in the posterior temporal, pos-
ume ratios, has not shown value in predicting which
terior cingulate and visual association ﬁbres [121]
patients will respond to ventricular shunting (class IV
(class IV evidence). As for other parkinsonian disor-
evidence) [115]. There is no correlation between out-
ders, data from a small DTI MRI case–control study
come of a high-volume lumbar puncture or ventricular
showed distinct patterns of diﬀusivity changes, with
shunting and CSF stroke volume as measured by cine
increases in the anterior thalamus in PSP, in contrast
phase-contrast MRI, even at a median duration of
to asymmetric thalamic motor increases in CBS [122]
symptoms of 1 year [116]. At this time, there is insuﬃ-
(class IV evidence). Diﬀusion-weighted imaging is also
cient evidence to determine the value of this imaging
of value in the early diagnosis of CJD [123] (class IV
technique in predicting response to shunting in NPH,
evidence).
but an elevated CSF stroke volume is considered a
The brain distribution of the SPECT perfusion
supportive criterion for diagnosis (class IV evidence)
ligand 99mTc HM-PAO and PET metabolic ligand
[116].
[18F]2-ﬂuoro-2-deoxy-D-glucose (FDG) reﬂect regio-
© 2012 The Author(s)
European Journal of Neurology © 2012 EFNS European Journal of Neurology

Dementia guidelines
1173
nal metabolic activity and blood ﬂow, often revealing
DTI MRI distinguishes FTLD from AD and con-
highly relevant hypoperfusion and hypometabolism in
trols (and AD from controls) (Level B) [118,119].
cerebrovascular and neurodegenerative disease. Voxel-
Measuring ﬂow void on MRI can increase conﬁ-
based methods for analysis increase sensitivity and
dence in NPI diagnosis and in the decision about
speciﬁcity. Combined morphometric MRI and SPECT
shunt placement (Good Practice Point) [115]. Hy-
imaging have been reported to reach speciﬁcity/sensi-
perintense
signal
abnormality
on
T2-weighted
tivity levels of 89%/84% for the diﬀerentiation of
images within medial temporal lobe structures such
DLB from AD, taking into account both occipital
as the hippocampi and amygdalae and, on occasion,
hypoperfusion and striatal volume ratios [124] (class
the hypothalamus are commonly seen in limbic
IV evidence). In a follow-up study, pre-synaptic dopa-
encephalitis (Level C).
mine transporter imaging scans at baseline (using
123I-FP-CIT SPECT) were reported to have sensitivity/
Functional imaging modalities
speciﬁcity values of 63%/100% for distinguishing DLB
• DTI MRI distinguishes FTD from AD and controls
from non-DLB dementia [125] (class II evidence).
(and AD from controls) (Level B) [118,119]. DTI
SPECT and PET perfusion and metabolic techniques
MRI shows the distinct patterns of diﬀusivity
are also useful in FTLD diagnosis, showing typical
changes in parkinsonism disorders (PSDD, DLP,
regional alterations with sensitivity reaching 90% for
PSP, CBS) (Level C) [119]. SPECT perfusion and
an FTLD diagnosis [126] (class III evidence), comple-
MRI morphometric imaging are useful to distinguish
menting the high speciﬁcity of the clinical criteria.
DLB, CBS, CJD from AD (Good Practice Point)
These techniques may also distinguish between FTLD
[120,122,123]. SPECT pre-synaptic dopamine trans-
language variants [127,128] (class IV evidence).
porter imaging is useful to distinguish DLB from
non-DLB dementias (Level B) [124,125]. SPECT and
PET perfusion and metabolic techniques are highly
Recommendations: neuroimaging
useful in FTLD diagnosis [126–128] (Level C).
Structural imaging
• Structural imaging should be used in the evaluation
Electroencephalography (EEG)
of every patient aﬀected by dementia (Level A rec-
ommendation) [98]. CT and standard MRI are used
Electroencephalography can provide early evidence for
to exclude secondary causes for dementia such as
CJD or suggest the possibility of a toxic-metabolic dis-
tumour and inﬂammatory disease, including abscess
order, transient epileptic amnesia or other previously
or normal-pressure hydrocephalus (Level A recom-
unrecognized seizure disorder [129] (class III evidence).
mendation) [98]. It is particularly diﬃcult to attri-
EEG can also be supportive for the diﬀerential diagno-
bute
clinical
signiﬁcance
to
the
evidence
of
sis of the degenerative dementias: EEG with only dif-
cerebrovascular disease in patients with cognitive
fuse abnormalities suggests AD, and EEG with both
impairment. At the current state of knowledge,
diﬀuse and focal changes suggests DLB, VaD or AD
demonstration of cerebrovascular disease on imag-
[130] (class III evidence). DLB is characterized by slow-
ing is used to support the diagnosis (Good Practice
wave temporal lobe transients, frontal intermittent
Point) [99,100]. Atrophy distribution is useful in the
delta activity and by a more pronounced EEG slowing
diﬀerential diagnosis of FTLD compared with AD
during the early phase of the disease compared with
and
of
the
subtypes
of
FTLD
(Level
C)
AD. FTLD is associated with normal resting-state
[21,102,103]. No established structural MRI pattern
functional connectivity and preserved dominant poster-
is characteristic for DLB and PDD (Good Practice
ior alpha activity, more EEG abnormality being present
Point) [101]. MRI is used to distinguish PSP from
in temporal than in frontal variant. The typical EEG in
DLB, being midbrain and the superior cerebellar
CJD shows generalized symmetrical periodic 1-Hz tri-
peduncles atrophic in PSP (Good Practice Point)
phasic or biphasic sharp-wave complexes [131]. The
[101]. The pronounced atrophy of the caudate
presence of periodic sharp-wave complexes has a sensi-
nucleus and putamen is characteristic, and the so-
tivity of 67% and a speciﬁcity of 86% for sCJD (class
called bicaudate ratio doubles in HD (Level B)
III evidence) [131]. EEG recordings in vCJD usually
[104,105]. MRI showing DWI cortical rims, striatal
show only non-speciﬁc slow-wave abnormalities.
and/or thalamic hyperintensities is useful for the
diagnosis of sporadic CJD (Level A) [41,108]. The
Recommendations: electroencephalography
MRI pulvinar sign, that is, symmetrical FLAIR hy-
perintensity of the posterior thalamus, has high
• EEG is recommended in rapid dementia and diﬀer-
diagnostic utility for variant CJD (Level B) [109].
ential diagnosis when CJD or transient epileptic
© 2012 The Author(s)
European Journal of Neurology © 2012 EFNS European Journal of Neurology

1174
S. Sorbi et al.
amnesia is suspected (Level B) [129–131]. There is
Therefore, not ﬁnding a mutation does not exclude a
not enough evidence to consider resting EEG for
genetic cause. There are identical risks for male and
the initial assessment of all dementia patients.
female oﬀspring of an aﬀected parent in the familial
forms, which are estimated at 30–50% of total FTLD,
and currently, changes in ﬁve genes have been associ-
CSF analysis
ated with autosomal-dominant FTLD [10]. Mutations
Routine analysis of CSF yields no speciﬁc information,
in the microtubule-associated protein tau (MAPT)
but may be performed if there is a suspicion of inﬂam-
and progranulin (GRN) genes on chromosome 17
matory causes of dementia, as well as neurosyphilis,
were identiﬁed as important causes of FTLD, explain-
HIV/AIDS, neuroborreliosis and paraneoplastic causes
ing 10–25% of familial FTLD patients and 5–10% of
(class III evidence) [132]. Abeta 1–42 is speciﬁc for AD,
all FTLD (class III evidence) [10].
but other isoforms of amyloid-beta, such as amyloid-
Approximately 10–15% of people with prion dis-
beta n-40, n-38, n-17, show promise in improving the
ease have a genetic form. Genetic CJD is a single-gene
diﬀerential diagnosis [133] (class III evidence) especially
disorder because of mutations in the prion gene
for FTLD [134] (class III evidence). Increased concen-
(PRNP) on chromosome 20. Several other changes in
trations of tau and p-tau signify neuronal death and hy-
the PRNP gene (called polymorphisms) do not cause
perphosphorylation, respectively. They support the
prion diseases directly, but may aﬀect an individual
diagnosis of AD, but they do not preclude a diagnosis
person’s risk of developing prion diseases or alter the
of DLB, VaD or FTLD.
course of the disease. Male and female are equally
In CJD, extremely high CSF concentrations of tau
likely to inherit the mutation and to be aﬀected (class
(with relatively less-elevated concentrations of p-tau)
III evidence) [138–140]. Cerebral autosomal-dominant
are observed, yielding very high sensitivity and speci-
arteriopathy with subcortical infarct and leucoence-
ﬁcity [135]; the same applies to the 14-3-3 level in
phalopathy (CADASIL) is the most common autoso-
CSF [136] (class II evidence). In subtypes of CJD,
mal-dominant inherited cause of stroke and vascular
notably variant CJD, tau levels may be lower than in
dementia [141] caused by mutations in the NOTCH3
sporadic CJD, but are still diagnostic [136] (class III
gene, which encodes a single-pass transmembrane
evidence). In all other forms of dementia, tau and p-
receptor. Other clinical signs are migraine with aura,
tau values overlap with normal values in controls as
mood disturbances and apathy. Genetic testing is indi-
well as the increased values seen in AD. This limits
cated if the patient has a combination of characteristic
their clinical utility and illustrates that other biomar-
clinical and neuroimaging features or a positive family
kers are needed to improve the diﬀerential diagnosis
history, particularly if there is no history of hyperten-
of dementia [135].
sion (class IV evidence). Genetic testing is more debat-
Alpha-synuclein has been studied as a biomarker for
able if a patient without a family history has only
DLB, but results have not been convincing [135]. In
migraine with aura and a few hypersignals on T2-
NPH, lumbar CSF opening pressure should be within the
weighted imaging [142] (class IV evidence).
range 5–18 mmHg (60–240 mmH2O). Gait improvement
The role of genetics in Huntington’s disease is well
following the drainage of 40–50 ml is indicative of NPH,
established, and guidelines for the molecular genetics
but cannot serve as an exclusionary test because of its low
predictive test in Huntington’s disease are available
sensitivity of 26–61% [137] (class IV evidence).
[143,144] (class IV evidence).
Recommendations: CSF analysis
Recommendations: genetic testing
• Routine CSF analysis may help to rule out or rule
• No studies have addressed the value of genetic
in certain infectious causes (Good Practice Point)
counselling for patients with dementia or their fami-
[132]. CSF abeta 1-42/tau/p-tau assessment helps to
lies when autosomal-dominant disease is suspected.
diﬀerentiate AD (Level B) [133]. Assessment of CSF
Because the genetics of dementing illnesses is a very
total tau and 14-3-3 protein is recommended in rap-
young ﬁeld, expertise in genetic counselling for the
idly progressive dementia when sCJD is suspected
dementias of the elderly is likely to be found only in
(Good Practice Point) [135,136].
specialized dementia research centres (Good Prac-
tice Point) [10,138,144]. Screening for known patho-
genic mutations can be undertaken in patients with
Genetic testing
appropriate phenotype or a family history of an
The genetics of FTLD dementias is a very young ﬁeld,
autosomal-dominant dementia. This should only be
and it is likely that additional genes will be identiﬁed.
undertaken in specialist centres with appropriate
© 2012 The Author(s)
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Dementia guidelines
1175
counselling of the patient and family caregivers, and
obesity) appear to be at higher risk for dementia than
with consent (Good Practice Point). Pre-symptom-
those without in observational and clinical trials [147]
atic testing may be performed in adults where there
(class IV evidence). Controlled trials suggest that vas-
is a clear family history, and when there is a known
cular risk management via some pharmaceutical inter-
mutation in an aﬀected individual to ensure that a
ventions may beneﬁt cognition, although results are
negative result is clinically signiﬁcant. It is recom-
inconsistent (class IV evidence) [147,148]. Finally, peo-
mended that the Huntington’s disease protocol is
ple who adhere to a Mediterranean diet or who have
followed (Good Practice Point).
high intake of antioxidants and omega-3 fatty acids
have reduced likelihood of dementia in observational
studies (class IV evidence) [147,148]. However, supple-
Biopsy and other investigations
mentation in controlled trials has not generally proved
Retrospective studies performed in tertiary centres
successful at improving cognitive outcomes. Results of
between 1989 and 2009 show that the overall sensitiv-
randomized controlled trials (RCTs) have so far been
ity of brain biopsy procedures for diagnostic purposes
negative and conﬂicting with those of observational
ranges between 57% and 74% [145] (class IV evi-
studies, perhaps due to methodological issues. There-
dence) with the tendency to carry out fewer biopsies
fore, future trials must carefully consider the target
with increased diagnostic yield in more recent years.
population, outcomes and duration of follow-up to be
Although information obtained at biopsy determined
used and should assess the problem of attrition [148].
treatment in only 11% of patients [146] (class IV evi-
dence), it may still provide useful diagnostic informa-
Recommendations: primary and secondary prevention
tion in patients with particularly rapid progressive
dementia where a treatable disease cannot be excluded
• No treatments or lifestyle have demonstrated eﬃ-
by other means.
cacy for preventing or delaying the development of
Biopsies of speciﬁc tissues can also be of diagnostic
the diﬀerent types of dementias until now.
value, such as a liver biopsy in Wilson’s disease or
skin and muscle biopsies in cerebral autosomal-
Treatment of cognitive deficits in non-Alzheimer
dominant arteriopathy with subcortical infarcts and
dementias
leucoencephalopathy (CADASIL), Lafora body dis-
ease or mitochondrial diseases (class IV evidence) [50].
With few exceptions, there are no established pharma-
Tonsillar biopsy can demonstrate the deposition of
cological treatments approved by the regulatory agen-
the pathological form of prion protein in vCJD (class
cies for non-Alzheimer dementias. However, as the
IV evidence) [50].
underlying proteinopathies in the individual neurode-
generative entities are being elucidated, the targeting
of pathological protein misfolding has become an
Recommendations: biopsy and other investigations
attractive goal for future mechanism-based treat-
• Brain and other speciﬁc tissue biopsies can provide
ments.
a diagnosis in rare or rapidly progressing dementias,
but should only be carried out in specialist centres
Frontotemporal lobar degeneration
in carefully selected cases (Good Practice Point)
There is no approved treatment for any of the FTLD
[145,146].
subtypes. One study demonstrated that despite the
lack of evidence from randomized, placebo-controlled
clinical trials oﬀ-label use of established cholinesterase
Management of the dementias
inhibitors (ChEIs) and memantine is common in
bvFTD (class III evidence) [149]. There are three
Primary and secondary prevention
notable open-label studies with each of the ChEIs
A number of trials were identiﬁed that assessed
[150–152], and two open-label studies with memantine
dementia incidence or cognitive decline as a primary
in FTLD [153]: all failed to provide robust evidence
or secondary study outcome [147,148]. Stimulating
for eﬃcacy in FTLD. A recent systematic review sta-
activity (cognitive, physical and social), vascular risk
ted
that
antidepressant
treatment
signiﬁcantly
factors and diet may be important in preventative
improves behavioural symptoms in FTLD, but most
strategies (class IV evidence) [147,148]. Dementia risk
studies were small and uncontrolled; serotonergic
may be modiﬁed by participation in stimulating activi-
treatments with SSRIs appeared to provide inconsis-
ties (class IV evidence) [147,148]. People with vascular
tent improvement in the behavioural but not cognitive
risk factors (hypertension, diabetes, dyslipidaemia and
symptoms of FTLD [154,155]. In a small RCT with
© 2012 The Author(s)
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1176
S. Sorbi et al.
trazodone, the cognitive measure MMSE remained
patients received placebo. Signiﬁcant beneﬁts were
unchanged, whilst there was a signiﬁcant improvement
observed for memantine on the global measure for
in behavioural symptoms [156]. Dopaminergic replace-
DLB and PDD patients. No statistically signiﬁcant
ment in FTLD ameliorates only the motor symptoms
diﬀerences were observed for individual cognitive test
with no evident eﬀect on cognition [8]. An RCT with
(class II evidence) [165]. There are no Cochrane
bromocriptine in language variant FTLD patients was
Library reviews on memantine in DLB or PDD yet.
negative (class III evidence) [157]. There is no relevant
Cochrane review.
Prion diseases
There are no Cochrane Library reviews. A systematic
Corticobasal syndrome and progressive supranuclear
review [166] found 33 published studies describing the
palsy
use of 14 drugs, 10 of which had been reported in sin-
One open-label study [158] and one RCT [159] in PSP
gle studies of three or fewer patients. No speciﬁc
showed no conclusive evidence in favour of donepezil.
treatment for prion diseases can be recommended at
No evidence exists for CBS.
the present time. A recent observational study with
the antimalarial drug Quinacrine [167] showed that it
Huntington’s disease
was reasonably tolerated but did not signiﬁcantly
The Cochrane Library review included 22 randomized,
aﬀect the clinical course of prion disease. Further
double-blinded, placebo-controlled clinical trials with
studies are ongoing [168].
a total of 1254 participants conducted on any symp-
tomatic therapy used for HD and concluded that
Normal-pressure hydrocephalus
there were no data for the treatment of cognitive
NPH may represent a treatable form of dementia;
impairment [160]. The Cochrane Library has also
however, it is diﬃcult to decide whether a patient
reviewed eight studies on 1366 patients with agents
would beneﬁt from a shunting procedure (class III evi-
with possible disease-modifying properties (i.e. vitamin
dence) [169]. Surgery seems to be more helpful in the
E, idebenone, baclofen, lamotrigine, creatine, coen-
cases that did not start with dementia, have milder
zyme Q10+ remacemide, ethyl-eicosapentanoic acid)
cognitive impairment, no aphasia and short duration,
and found no eﬀect on outcome measures [160].
or where a drainage test is positive. Cortical atrophy
reduces but does not eliminate the chance of improve-
Dementia associated with Lewy bodies and Parkinson’s
ment with surgery. Surgical treatment carries consider-
disease dementia
able short- and long-term risks (class III evidence)
Whilst patients with DLB respond to cholinesterase
[137]. However, there are no class I studies comparing
inhibitors with improvement in cognitive and psychi-
operative versus conservative management of NPH,
atric symptoms, they show a propensity to have exag-
and therefore surgical treatment cannot be considered
gerated adverse reactions to neuroleptic drugs, with a
as a standard approach. The online 2008 assessment
signiﬁcantly increased morbidity and mortality (class
as up to date of the 2002 Cochrane intervention
IV evidence) [161]. The Cochrane Library review on
review [169] failed to ﬁnd randomized controlled trials
ChEI treatment in PDD included only the EXPRESS
of shunt placement versus no shunt, thus concluding
study and concluded that there was evidence that riv-
that there is no evidence to indicate whether place-
astigmine had had a moderate eﬀect on cognition.
ment of a shunt is eﬀective in the management of
However, concerns about rivastigmine tolerability
NPH.
were stated [161]. The IDEAL study [162] was a large-
scale RCT in patients with AD and showed that the
Recommendations: treatment of cognitive deficits in
new transdermal patch form of rivastigmine is as eﬃ-
non-Alzheimer dementias
cacious as its conventional capsule form, whilst having
a comparable tolerability proﬁle to placebo.
• Use of ChEIs, memantine or SSRIs in any of the
There are three RCTs with memantine. In a small
FTLD subtypes is possibly ineﬀective for cognitive
RCT, a signiﬁcantly smaller proportion of meman-
improvement (Level C) [149,156]. Dopaminergic
tine-treated participants deteriorated globally com-
replacement
with
bromocriptine
in
progressive
pared with those treated with placebo [163]. In
aphasias is probably ineﬀective (Good Practice
another medium-sized RCT, at the end of the study,
Point) [157]. Given the insuﬃcient classes II and III
the patients in the memantine group had signiﬁcantly
evidence and the evidence being largely based on
better global scores (class II evidence) [164]. The lar-
class IV, the use of ChEIs and memantine in FTLD
ger RCT randomized 34 DLB and 62 PDD patients
cannot be recommended. There is little class III evi-
to the memantine arm, and 41 DLB and 58 PDD
dence in support of rivastigmine and memantine
© 2012 The Author(s)
European Journal of Neurology © 2012 EFNS European Journal of Neurology

Dementia guidelines
1177
[149,156]. There is no independent evidence for
this area although there are several methodological
recommending any therapeutic intervention for CBS
diﬃculties in performing such studies.
[159,168]. Rivastigmine is the approved ChEI for
the treatment of PDD with class I evidence. PDD
Recommendations: treatments of BPSD
diagnosis warrants the use of rivastigmine (Good
Practice Point) [161]. Parallels with PDD in terms
• Antipsychotic medications, conventional and
of clinical picture and disease mechanisms suggest
atypical agents, may be utilized in clinical practice
that rivastigmine is possibly eﬀective in DLB (Good
for aggression, psychosis and agitation as well-
Practice Point). The evidence for the eﬃcacy of gal-
selective serotonin re-uptake inhibitors for mood
antamine is insuﬃcient for both PDD and DLB.
and behavioural disorders (Good Practice Point)
Memantine is probably eﬀective for both PDD and
[170]; however, there is little evidence to guide
DLB (Level B) as there were consistently signiﬁcant
practice.
improvements in global measures but not in cogni-
tive measures in two class II studies [164,165]. There
Counselling and support for caregivers
is insuﬃcient evidence for recommending any spe-
ciﬁc agent in the treatment of human prion diseases.
In patients with mild to moderate dementia, the assis-
Surgical treatment can be considered in NPH (Level
tance of a caregiver is necessary for many complex
C), and risk to beneﬁt ratio must be individualized
ADL, for instance travelling, ﬁnancial matters, dress-
for each patient [137,169]. There is insuﬃcient evi-
ing, planning, and communication with family and
dence for recommending any of the non-pharmaco-
friends. With the progression of the disease, increasing
logical treatments.
amounts of time must be spent on supervision. In
patients with moderate to severe dementia, caregivers
often provide full-time assistance with basic ADL,
Treatments of BPSD
dealing with incontinence, bathing, feeding, and trans-
Pharmacological
treatments
in
BPSD
should
be
fer or use of a wheelchair or walker (Good Practice
evidence-based and targeted to speciﬁc syndromes that
Point) [170].
are clinically signiﬁcant because of their frequency,
The caring family members of people suﬀering
pervasiveness or impact. Antipsychotic medications,
from dementia are exposed to a great number of
conventional and atypical agents, have been increas-
physical, mental and social burdens, and restrictions,
ingly utilized in clinical practice for aggression,
putting themselves at risk of falling ill (Good Prac-
psychosis and agitation (class IV evidence) [170], but
tice Point). Caring family members need adequate
only a small number of clinical studies have investi-
forms of relief to be able to care for the family
gated their relative cost–beneﬁt ratio. Moreover, these
member at home for as long as possible, and with
beneﬁts have to be considered in the context of signiﬁ-
the best possible physical and psychological status
cant adverse events, including extrapyramidal symp-
(Good Practice Point) [170]. A systematic literature
toms, accelerated cognitive decline, stroke and death
review shows that a number of diﬀerent intervention
[170] (class IV evidence).
programmes have been described in the literature for
For depression in dementia, although there is little
caregivers of people with dementia, but the nature of
placebo-controlled evidence to guide practice, clinical
intervention has varied widely. Psycho-educational,
experience indicates that selective serotonin re-uptake
relieving, supportive, psychotherapeutic and multi-
inhibitors are safe and eﬀective in treating mood dis-
modal oﬀers, as well as counselling and case/care
orders in dementia (class IV evidence) [161].
management amongst caring family members all have
Cholinesterase inhibitors improve the apathetic syn-
been shown to have positive eﬀects on burden and
drome in AD and also may decrease or prevent psy-
satisfaction for caregivers of people with dementia
chotic symptoms, particularly hallucinations, in AD
(Good Practice Point) [170]. Further investigations
and DLB.
are needed.
A
variety
of
non-pharmacological
treatments,
namely interventions relating to quality of life, motor
Recommendations: counselling and support for
activity, behaviour, speech and language therapy, cog-
caregivers
nitive stimulation, have been proposed and are
unevenly utilized in diﬀerent settings in Europe [170].
• A dementia diagnosis mandates an inquiry to the
Some speciﬁc behaviour interventions have been
community for available public health care support
found to improve certain troubling behavioural symp-
programmes (Good Practice Point) [170]. Counsel-
toms in dementia, but more evidence is required in
ling and case/care management amongst caring fam-
© 2012 The Author(s)
European Journal of Neurology © 2012 EFNS European Journal of Neurology

1178
S. Sorbi et al.
ily members have positive eﬀects on burden and sat-
tions for patients with dementia, the assessment of
isfaction for caregivers of people with dementia
driving capabilities and the conﬁdentiality of medical
(Good Practice Point).
data with regard to third parties, such as national
driving licence authorities.
Decision-making and participating in research
Recommendations: driving
People with dementia often lack mental capacity
and subsequently need assistance in their decision-
• Assessment of driving ability should be made after
making.
Research
involving
persons
aﬀected
by
diagnosis with particular attention paid to visuo-
dementia can be ethically challenging as the lack of
spatial,
visuo-perceptual
and
executive
abilities
capacity may limit their ability to give free and
(Good Practice Point). Advice either to allow driv-
informed consent. The need to adopt special cau-
ing but to review after an interval, to cease driving,
tions in research involving individuals with compro-
or to refer for retesting should be given (Good
mised capacity has been highlighted by the most
Practice Point) [172].
relevant declarations on research ethics, like the
Nuremberg Code and the Declaration of Helsinki.
Disclosure of conflicts of interest
There is consensus over the fact that adults who
lack capacity should be supported by proxy consent
For the conception and writing of this guideline, no
when involved in research (Good Practice Point)
honoraria or any other compensations were received
[171]. Recently, Gainotti et al. [171] have reviewed
by any of the authors.
how legal proxy diﬀers between countries and how
The authors report the following ﬁnancial supports:
they are appointed.
Hort Jakub has received speaker’s honoraria from
The diﬀerent ways of obtaining surrogate consent
Pﬁzer, Elan, Novartis and EFNS. Pasquier Florence
for a subject’s participation in research in the EU
has received speaker and consultancy honoraria from
countries may have an impact on a country’s ‘attrac-
Bayer, Lilly, Janssen, Servier; Bogdan Ovidiu Popescu
tiveness’ for dementia research.
has received speaker’s honoraria from Novartis,
Glaxo Simth Kline, Pﬁzer, Boehringer-Ingelheim,
Lundbeck and UCB. Rektorova Irena has received
Recommendations: decision-making and participating
speaker’s honoraria from Novartis, Glenmark and
in research
UCB. Rusina Robert has received speaker’s honoraria
• Research involving persons aﬀected by dementia
from Pﬁzer, Lundbeck and Novartis. Rossor Martin
needs to adopt special precautions, and there is
is a member of Servier and Johnson & Johnson Data
consensus over the fact that adults who lack
Monitoring Committees for which UCL receive reim-
capacity should be supported by proxy consent
bursement. Sorbi Sandro has received a consultancy
when involved in research (Good Practice Point)
honorarium from Bayer and Novartis. Stefanova Elka
[171].
received speaker’s honoraria from Lundbeck, Novar-
tis, Glaxo Simth Kline, Pﬁzer and Boehringer-Inge-
leim. All other authors have nothing to declare.
Driving
Driving is a complex activity that always becomes
Abbreviations
impaired at some point in older adults with degenera-
tive dementia [172]. Neuropsychological tests measure
ADL, activity
of
daily
living;
ACE-R, Adden-
several aspects of cognition and are useful to evaluate
brooke’s Cognitive Examination Revised; AD, Alz-
elderly drivers with cognitive impairment (class IV evi-
heimer’s disease; ADCS, AD Cooperative Study;
dence) [172]. However, there is no consensus on a
ADI, Alzheimer Disease International; aMCI, amnes-
standard battery of tests that could accurately predict
tic mild cognitive impairment; BPSD, behavioural and
safe driving. Tests highlighting visuospatial attention
psychological symptoms of dementia; BSE, bovine
demands and executive function may be useful to pre-
spongiform encephalopathy; bvFTD, behavioural var-
dict the driving competence of demented individuals.
iant frontotemporal dementia; CAG, adenine–guano-
However, all drivers with dementia must ultimately
sine
trinucleotide;
CADASIL, cerebral
autosomal
retire from driving when dementia becomes moder-
dominant arteriopathy with subcortical infarct and
ately severe, and often in earlier stages of the illness.
leucoencephalopathy; CAMCOG, Cambridge Cogni-
However, there is a considerable variability across
tive Examination; CDT, clock drawing task; CVLT,
Europe with respect to the national driving regula-
California Verbal Learning Test; CBS, corticobasal
© 2012 The Author(s)
European Journal of Neurology © 2012 EFNS European Journal of Neurology

Dementia guidelines
1179
syndrome; CBD, corticobasal degeneration; CSF,
State Examination; MRI, magnetic resonance imag-
cerebrospinal ﬂuid; CIND, vascular cognitive impair-
ing; MSA, multi-system atrophy; NBM, nucleus ba-
ment no dementia; CJD, Creutzfeldt–Jakob disease;
salis
of
Meynert;
NINDS, National
Institute
of
CVD, cerebrovascular
disease;
DAD, Disability
Neurological
Disorders
and
Stroke;
NINDS/AI-
Assessment for Dementia; DLB, dementia with Lewy
REN, National Institute of Neurological Disorders
bodies; DMAS, dementia mood assessment scale;
and Stroke and Association Internationale pour la
DR, radial diﬀusivity; DTI, diﬀusion-tensor imaging;
Recherche´
et
l’Enseignement
en
Neurosciences;
EEG, electroencephalography; FA, fractional anisot-
NPH, normal-pressure hydrocephalus; PBAC, Phila-
ropy; FAB, Frontal Assessment Battery; FAQ, Func-
delphia Brief Assessment of Cognition; PDD, Parkin-
tional
Activities
Questionnaire;
FDG, 2-ﬂuoro-2-
son’s
disease
dementia;
PDS, Progressive
deoxy-D-glucose; FLAIR, ﬂuid attenuated inversion
Deterioration Scale; PET, positron emission tomogra-
recovery; fCJD, familial Creutzfeldt–Jakob disease;
phy; PNFA, progressive nonﬂuent aphasia; PRNP,
FCSRT, Free and Cued Selective Reminding test;
prion protein gene; PSP, progressive supranuclear
FFI, fatal familial insomnia; FTLD, frontemporal
palsy;
PSP-P, PSP-parkinsonism;
RS, Richardson’s
lobar degeneration; GDS, geriatric depression scale;
syndrome; SD, semantic dementia; SV, small vessel;
GRN, progranulin;
GSS, Gerstmann–Stra¨ussler–
SIVD, subcortical ischaemic vascular disease and
Scheinker disease; HD, Huntington’s disease; JHD,
dementia; TMT, Trail-Making Test; VaD, vascular
juvenile Huntington’s disease; IADL, Instrumental
dementia;
VCI, vascular
cognitive
impairment;
Activity of Daily Living; LV, large vessel; LE, limbic
vMCI, vascular mild cognitive impairment; vCJD,
encephalitis; MAPT, protein tau; MD, mean diﬀusiv-
new variant CJD; WCST, Wisconsin Card Sorting
ity; MDRS, Mattis Dementia Rating Scale; MFS,
Test.
Middelheim frontality score; MMSE, Mini-Mental
© 2012 The Author(s)
European Journal of Neurology © 2012 EFNS European Journal of Neurology

Dementia guidelines
e85
19. Rascovsky K, Hodges JR, Knopman D, et al. Sensitiv-
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