Foreword
It is an immense pleasure for us to introduce this eleventh
volume of the third series of the Handbook of Clinical Neurology,
which is devoted to the dementias. Until a few years ago, it would
have been unthinkable to have such a volume. Many people dealing
with neuropsychology and behavior believed that such a global
deterioration did not warrant their interest. Most clinicians and
even neuropathologists considered Alzheimers disease to be a
rarity, so much so that the 1967 edition of a famous American
textbook of neurology did not even have an Alzheimers disease
entry. In previous series of the Handbook of Clinical Neurology,
there were very good chapters dealing with various aspects of
dementia, but not a dedicated volume. This new addition to the
Handbook series is justified by the enormous progress that has
occurred regarding various aspects of the dementias, including
their symptomatic treatment, and the development of new
perspectives for their prevention. Charles Duyckaerts and Irene
Litvan, editors of the present volume, are to be congratulated for
bringing together a wide range of internationally acknowledged
authorities to summarize these new developments in the area of
dementia, from the most basic aspects to their clinical
implications. This ensures that this new volume will be an
essential and invaluable resource for those interested in the
fundamental aspects of the diseases that cause dementia, as well as
for those involved in the care of patients with these disorders. We
wish to express our deep gratitude to the numerous authors who
contributed their time and expertise to summarize developments in
their field and helped put together this outstanding volume. We
believe that it reflects the highest standards of scholarship and
provides a critical appraisal and synthesis of current concepts
concerning the dementias. As series editors, we reviewed all the
chapters included in this volume and were greatly impressed by
their scope and implications. We are proud that this new volume
fully exemplifies our concept of the Handbook series, which is that
of providing greater insight to the basic mechanisms of disease in
order to further a better appreciation of these disorders by
clinicians. As always, we are also grateful to the team at Elsevier
in Edinburgh for their unfailing and expert assistance in the
development and production of this volume. Michael J. Aminoff
Francois Boller Dick F. Swaab
Preface
Not so long ago, cognitive deficits that frequently occur from
aging were thought normal or nearly so. Softening of the brain was
the common diagnosis; Alzheimers disease was considered rare and
Picks disease, exceptional. Although Picks disease has remained
rare, Alzheimers disease, merging with senile dementia, has become
one of the major foreseen health problems of the near future. Not
only has the prevalence of dementias been better perceived, but the
diversity of the disorders that cause them has also been better
understood. Today, we know that the complexity of the diseases that
affect the cortex mirrors the complexity of the cortex itself and
no one doubts that we are just starting to discover a continent in
which only a few spots have been identified. Our understanding of
the biology of the various dementias has recently advanced. In the
past few months, the progranulin mutationone of the most frequent
causes of frontotemporal dementiawas identified. TDP-43 was
recognized as an ubiquitinated molecule in several dementing
disorders. These two findings have considerably changed diagnostic
and research perspectives. We have been adding information to this
volume up to the last minute, thanks to the patience, kindness and
expertise of the multiple contributors. We had to stop updating
this volume, but it was difficult to do so at a time of constant
change, when electronic information crosses the oceans much more
easily than piles of printed papers. If electronic information is
so easy to share, what are books for? What do the readers of this
volume expect? What are our expectations? The experts cover a
specialized field and they know where to find the information they
are looking for but they may have difficulties in exploring areas
that they do not master, and especially in synthesizing information
that they could otherwise rapidly collect by Internet. We have
planned this book as a handbook, a book close to the hand, in which
the reader may readily glean information on a large array of
subjects in a synthetic form. The general view that the reader may
rapidly acquire simplifies the understanding of new findings and
gives a background that, for most of the topics, remains stable for
years. The ideal of completeness is clearly out of reach today; we
believe that, thanks to the many collaborators of this book, our
coverage has been extensive, with a minimal amount of overlap. The
volume deals with neuropathology, physiopathology, biology,
clinics, and imaging of all or most dementing disorders that are
currently known. It also includes chapters on the legal and ethical
issues to give the health care worker a general view on diseases
that are not only scientific riddles but also the cause of
affliction of many patients and families. We believe that people
dealing with dementia, at whatever level of expertise, may find in
this book useful and synthetic information. We are proud and
thankful to have been able to bring together chapters from so many
outstanding scholars in the various fields. We would also like to
acknowledge the work of Lynn Watt, from Elsevier, who accompanied
us on this long journey, and gave us the secure hand of the guide
in many difficult passes. The Series Editors gave us much
appreciated help by carefully reviewing all the chapters of this
book. Is it useful to end by stating that, even if the scientific
questions raised by the dementias may be fascinating from an
intellectual point of view, we must keep in mind that the
intellectual curiosity is but a means to reach the final goal of
curing these dreadful diseases. In this sense, this book is
obviously dedicated to the patients. Charles Duyckaerts Irene
Litvan
List of contributors
D. Aarsland Centre for Clinical Neuroscience Research, Stavanger
University Hospital, Stavanger, and Institute of Clinical Medicine
University of Bergen, Bergen, Norway S. Al-Sarraj Department of
Clinical Neuropathology, Kings College Hospital, Brain Bank,
Institute of Psychiatry, London, UK C. Amador-Ortiz Department of
Neuroscience, Mayo Clinic, Jacksonville, FL, USA M.J. Aminoff
Department of Neurology, University of California, San Francisco,
CA, USA K. Andrade Department of Neurology, and Dementia Research
Center, INSERM, La Salpetriere Hospital, Paris, France F. Assal
Department of Clinical Neurosciences, HUG, Geneva, Switzerland S.N.
Azher Parkinsons Disease Center and Movement Disorders Clinic,
Baylor College of Medicine, Houston, TX, and Hudson Valley
Neurology, Poughkeepsie, NY, USA T.H. Bak Medical Research
CouncilCognition and Brain Sciences Unit, Cambridge, and Human
Cognitive Neuroscience, University of Edinburgh, Edinburgh, UK F.
Barkhof Department of Diagnostic Radiology and Alzheimer Center,
Vrije Universiteit Medical Center, Amsterdam, The Netherlands
S. Baudic INSERM/UPVM, Faculte de Medecine, Creteil, France C.
Bazille Service Central dAnatomie et de Cytologie Pathologiques,
and Faculte de Medecine de lUniversite, Paris, France L.J.
Beglinger University of Iowa, The Roy J. and Lucille A. Carver
College of Medicine, Iowa City, IA, USA C. Bergeron Department of
Laboratory Medicine and Pathobiology and Centre for Research in
Neurodegenerative Diseases, University of Toronto, Toronto, ON,
Canada J.L. Bernat Neurology Section, Dartmouth Medical School,
Hanover, NH, USA L. Bertram Department of Neurology, MassGeneral
Institute for Neurodegenerative Diseases (MIND), Massachusetts
General Hospital, MA, USA K. Blennow Institute of Clinical
Neuroscience, Department of Experimental Neuroscience, Sahlgrenska
University Hospital, Goteborg University, Goteborg, Sweden J.A.
Bobholz Medical College of Wisconsin, Milwaukee, WI, USA B.F. Boeve
Department of Neurology, Mayo Clinic, Rochester, MN, USA J.
Bogousslavsky Neurology Service, Genolier Swiss Medical Network,
Glion, Switzerland
xii F. Boller Bethesda, Maryland, USA
LIST OF CONTRIBUTORS U. De Girolami Department of
Neuropathology, APHP, La Salpetriere Hospital, Pierre and Marie
Curie University, Paris, France, and Departments of Pathology
(Neuropathology) Brigham and Womens Hospital and Childrens
Hospital; Harvard Medical School, Boston, USA R. de Silva Institute
of Neurology and Reta Lila Weston Institute of Neurological
Studies, University College London, London, UK S.T. DeKosky
Departments of Neurology, Psychiatry, and Neurobiology and
Alzheimers Disease Research Center, University of Pittsburgh School
of Medicine, Pittsburgh PA, USA M. del Pilar Amaya New York Brain
Bank/Taub Institute, The Presbyterian Hospital and Columbia
University, and the Gertrude H. Sergievsky Center and School of
Public Health, New York, NY, USA A. Delacourte INSERM, Lille,
France J.-Y. Delattre Federation de Neurologie Mazarin, La
Salpetriere Hospital, Paris, France D.W. Dickson Department of
Neuroscience, Mayo Clinic, Jacksonville, FL, USA D.A. Drubach
Department of Neurology, Mayo Clinic, Rochester, MN, USA F. Dubas
UPRES EA3143 and Department of Neurology, CHU, Angers, France B.
Dubois Department of Neurology, and Dementia Research Center,
INSERM, La Salpetriere Hospital, Paris, France K. Duff University
of Iowa, The Roy J. and Lucille A. Carver College of Medicine, Iowa
City, IA, USA
C. Bountra Neurology and GI CEDD, GlaxoSmithKline R&D Ltd,
Harlow, UK M.G. Bousser ` Department of Neurology, Hopital
Lariboisiere, Universite Paris VII, Paris, France J.-P. Brion
Laboratory of Histology, Neuroanatomy and Neuropathology,
Universite Libre de Bruxelles, Brussels, Belgium N.J. Cairns
Department of Pathology and Immunology, Washington University
School of Medicine, Saint Louis, MO, USA H. Chabriat ` Department
of Neurology, Hopital Lariboisiere, Universite Paris VII, Paris,
France L. Crews Department of Neurosciences, University of
California, San Diego, La Jolla, CA, USA J.L. Cummings Department
of Neurology, Psychiatry and Biobehavioral Sciences, UCLA
Alzheimers Disease Center, and Deane F. Johnson Center for
Neurotherapeutics, David Geffen School of Medicine at the
University of California, Los Angeles, CA, USA G. Dalla Barba
INSERM, La Salpetriere Hospital, Paris, France J. Dalmau Department
of Neurology, University of Pennsylvania, Philadelphia, PA, USA
J.B. Davis Neurology and GI CEDD, GlaxoSmithKline R&D Ltd,
Harlow, UK A. De Calignon Massachusetts General Hospital,
Charlestown, MA, USA
LIST OF CONTRIBUTORS A. Durr INSERM, Pierre and Marie CurieParis
6 University, UMR, Federative Institute for Neuroscience (IFR70),
and La Salpetriere Hospital, Paris, France C. Duyckaerts Escourolle
Neuropathology Laboratory, La Salpetriere Hospital, Paris, France
J.L. Eriksen Mayo Clinic, Birdsall, Jacksonville, FL, USA M. Farrer
Mayo Clinic College of Medicine, Department of Neuroscience,
Jacksonville, FL, USA I. Ferrer Institute de Neuropatologia, Servei
Anatomia ` Patologica, IDIBELL-Hospital Universitari de Belvitge,
Facultad de Medicina, Universitat de Barcelona, Spain N.L. Foster
Department of Neurology, Center for Alzheimers Care, Imaging and
Research, University of Utah, Salt Lake City, UT, USA A.R. Frank
Memory Disorder Clinic, Ottawa, ON, Canada R.L. Frierson Department
of Neuropsychiatry and Behavioral Science, University of South
Carolina School of Medicine, Columbia, SC, USA D. Galasko
Department of Neurosciences, University of California, San Diego
and Veterans Affairs Medical Center, San Diego, CA, USA S. Gauthier
McGill Center for Studies in Aging, Montreal, QB, Canada A. Gleason
Medical College of Wisconsin, Milwaukee, WI, USA L.I. Golbe
Department of Neurology, University of Medicine and Dentistry of
New JerseyRobert Wood Johnson Medical School, New Brunswick, NJ,
USA T. Gomez-Isla Massachusetts General Hospital, Charlestown, MA,
USA
xiii
D.S. Goodin Department of Neurology, University of California,
San Francisco, CA, USA F. Gray Service Central dAnatomie et de
Cytologie Pathologiques, and Faculte de Medecine de lUniversite
Paris VII, Paris, France K. Gwinn-Hardy Department of
Neurogenetics, National Institute of Neurological Disorders and
Stroke, Bethesda, MD, USA J. Hardy Laboratory of Neurogenetics,
National Institute on Aging, Bethesda, MD, USA C. Harper Department
of Neuropathology, University of Sydney, Sydney, Australia J.-J.
Hauw Department of Neuropathology, La Salpetriere Hospital, Pierre
and Marie Curie University, Paris, France L.-N. Hazrati Department
of Laboratory Medicine and Pathobiology and Centre for Research in
Neurodegenerative Diseases, University of Toronto, Toronto, ON,
Canada M.W. Head National Creutzfeldt-Jakob Disease Surveillance
Unit, Western General Hospital, and School of Molecular and
Clinical Medicine, University of Edinburgh, Edinburgh, UK C.A.
Heath National CJD Surveillance Unit, Western General Hospital,
Edinburgh, UK J.R. Hodges Medical Research CouncilCognition and
Brain Sciences Unit, and University of Cambridge Neurology Unit,
Addenbrookes Hospital, Cambridge, UK S. Humbert Institut Curie,
Orsay, France M. Hutton Department of Neuroscience, Mayo Clinic,
Jacksonville, Jacksonville, FL, USA B.T. Hyman Massachusetts
General Hospital, Charlestown, MA, USA
xiv
LIST OF CONTRIBUTORS F. Letournel Cell Biology Laboratory, CHU,
and UPRES EA3143, Angers, France J.B. Leverenz University of
Washington, and Mental Illness and Parkinsons Disease Research,
Education and Clinical Centers, and VA-PSHCS, Seattle, WA, USA R.
Levy Department of Neurology, and Dementia Research Center, INSERM,
La Salpetriere Hospital, Paris, France J. Lewis Mayo Clinic,
Birdsall, Jacksonville, FL, USA A.M. Lipton Dallas, TX, USA I.
Litvan Movement Disorders Program, University of Louisville,
Louisville, KY, USA O.L. Lopez Departments of Neurology,
Psychiatry, Neurobiology and Psychology and Alzheimers Disease
Research Center, University of Pittsburgh School of Medicine,
Pittsburgh, PA, USA J. Lowe School of Molecular Medical Sciences,
Medical School, Queens Medical Centre, Nottingham, UK G.A. Marshall
Department of Neurology and Memory Disorders Unit, Brigham and
Womens Hospital, Harvard Medical School, Boston, MA, USA E. Masliah
Department of Neurosciences, University of California, San Diego,
La Jolla, CA, USA I. Matsumoto Department of Pathology, University
of Sydney, Sydney, Australia R. Mayeux The Taub Institute on
Alzheimers Disease and the Aging Brain, The Gertrude H. Sergievsky
Center and School of Public Health, New York, NY, USA I. McKeith
Institute for Ageing and Health, Newcastle General Hospital,
Newcastle upon Tyne, UK
K. Ikeda Zikei Hospital and Zikei Institute of Psychiatry,
Okayama, Japan J.W. Ironside National Creutzfeldt-Jakob Disease
Surveillance Unit, Western General Hospital and School of Molecular
and Clinical Medicine, University of Edinburgh, Edinburgh, UK K.A.
Jacoby Department of Neuropsychiatry and Behavioral Science,
University of South Carolina School of Medicine, Columbia, SC, USA
J. Jankovic Parkinsons Disease Center and Movement Disorders
Clinic, Baylor College of Medicine, Houston, TX, USA C. Janvin
Psychiatric Clinic, Stavanger University Hospital, Stavanger,
Norway K.A. Josephs Department of Neurology, Divisions of
Behavioral Neurology and Movement Disorders, Mayo Clinic and Mayo
Foundation, Rochester, MN, USA G. Karas Department of Diagnostic
Radiology and Alzheimer Center, Vrije Universiteit Medical Center,
Amsterdam, The Netherlands C. Keller New York Brain Bank/Taub
Institute, The Presbyterian Hospital and Columbia University, and
the Gertrude H. Sergievsky Centre and School of Public Health, New
York, NY, USA J.K. Krauss Department of Neurosurgery, Medical
University Hannover, Hannover, Germany A. Kutzelnigg Division of
Neuroimmunology, Center for Brain Research, Medical University of
Vienna, Austria H. Lassmann Division of Neuroimmunology, Center for
Brain Research, Medical University of Vienna, Austria A.J. Lees
Institute of Neurology and Reta Lila Weston Institute of
Neurological Studies, University College London, London, UK
LIST OF CONTRIBUTORS M. Mesulam Cognitive Neurology and
Alzheimers Disease Center, Northwestern University Feinberg School
of Medicine, Chicago, IL, USA J. Miklossy University of British
Columbia, Kinsmen Laboratory of Neurological Research, Vancouver,
BC, Canada B.L. Miller Memory and Aging Center, University of
California, San Francisco, CA, USA S. Miller Medical College of
Wisconsin, Milwaukee, WI, USA L. Morrow Department of Psychiatry,
University of Pittsburgh, PA, USA D.G. Munoz St Michaels Hospital,
University of Toronto, Toronto, ON, Canada D. Neary Clinical
Neuroscience Group, Salford Royal Hospital, Salford, UK R. Nitrini
University of Sao Paulo School of Medicine, Sao Paulo, Brazil
A.M.P. Omuro Federation de Neurologie Mazarin, La Salpetriere
Hospital, Paris, France J.S. Paulsen University of Iowa, The Roy J.
and Lucille A. Carver College of Medicine, Iowa City, IA, USA M.-T.
Pelle Service Central dAnatomie et de Cytologie Pathologiques, and
Faculte de Medecine de lUniversite Paris VII, Paris, France R.C.
Petersen Memory Disorder Clinic, Ottawa, ON, Canada S.
Pickering-Brown Clinical Neurosciences, University of Manchester,
Manchester, UK
xv
A. Pittman Institute of Neurology and Reta Lila Weston Institute
of Neurological Studies, University College London, London, UK A.
Probst Department of Neuropathology, University Hospital Basel,
Basel, Switzerland G.D. Rabinovici Memory and Aging Center,
University of California, San Francisco, CA, USA K. Rascovsky
Memory and Aging Center, University of California, San Francisco,
CA, USA A. Richardson Clinical Neuroscience Group, Salford Royal
Hospital, Salford, UK J.C. Richardson Neurology and GI CEDD,
GlaxoSmithKline R&D Ltd, Harlow, UK K. Ritchie ` INSERM,
Hopital La Colombiere, Montpellier, France E. Rockenstein
Department of Neurosciences, University of California, San Diego,
La Jolla, CA, USA G.C. Roman University of Texas Health Science
Center at San Antonio and Veteran Administration, Audie L. Morphy
Hospital, San Antonio, TX, USA S.M. Rosso Department of Neurology,
Erasmus Medical Centre, Rotterdam, The Netherlands N. Sacktor
Department of Neurology, Johns Hopkins University School of
Medicine, Baltimore, MD, USA S.A. Sami University Memory and Aging
Center, University Hospitals of Cleveland, Cleveland, OH, USA F.
Saudou Institut Curie, Orsay, France
xvi
LIST OF CONTRIBUTORS S.F. von Stuckrad-Barre Department of
Neurology, Goethe-Universitat Frankfurt, Frankfurt, Germany S.
Weintraub Cognitive Neurology and Alzheimers Disease Center,
Northwestern University Feinberg School of Medicine, Chicago, IL,
USA P.J. Whitehouse University Memory and Aging Center, University
Hospitals of Cleveland, Cleveland, OH, USA R.G. Will National CJD
Surveillance Unit, Western General Hospital, Edinburgh, UK A. Wimo
Neurotec, Karolinska Institutet, Stockholm, Sweden B. Winblad
Neurotec, Karolinska Institutet, Stockholm, Sweden N.W. Wood
Department of Molecular Neuroscience, Institute of Neurology,
University College London, London, UK S.H. Zarit Department of
Human Development and Family Studies, Pennsylvania State
University, PA, USA C. Zehr Mayo Clinic, Birdsall, Jacksonville,
FL, USA D. Zekry Department of Neuropathology, La Salpetriere
Hospital, Pierre and Marie Curie University, Paris, France, and
Department of Rehabilitation and Geriatrics, Thonex, Switzerland I.
Zerr Dementia Research Center, National Reference Center for TSE,
Department of Neurology, Georg-August University, Gottingen,
Germany H. Zetterberg Institute of Clinical Neuroscience,
Department of Experimental Neuroscience, Sahlgrenska University
Hospital, Goteborg University, Goteborg, Sweden
J. Saxton Department of Neurology, University of Pittsburgh, PA,
USA P. Scheltens Department of Diagnostic Radiology and Alzheimer
Center, Vrije Universiteit Medical Center, Amsterdam, The
Netherlands D.J. Selkoe Department of Neurology, Center for
Neurologic Diseases, Brigham and Womens Hospital and Harvard
Medical School, Boston, MA, USA T. Spires Massachusetts General
Hospital, Charlestown, MA, USA M. Tolnay Department of
Neuropathology, University Hospital Basel, Basel, Switzerland L.
Traykov University Hospital Alexandrovska, Department of Neurology,
Medical University, Sofia, Bulgaria, and CHU, Henri Mondor
Department of Neurology, University Paris XII, Creteil, France K.
Tsuchiya Department of Laboratory Medicine and Pathology, Tokyo
Metropolitan, Matsuzaura Hospital, Tokyo, Japan T. Uchihara
Department of Neurology, Tokyo Metropolitan Institute for
Neuroscience, Fuchu, Tokyo, Japan I. van Balken Movement Disorders
Program, University of Louisville, Louisville, KY, USA J.C. van
Swieten Department of Neurology, Erasmus Medical Centre, Rotterdam,
The Netherlands A. Venkataramana Department of Neurology, Johns
Hopkins University School of Medicine, Baltimore, MD, USA D.
Villebrun ` INSERM, Hopital La Colombiere, Montpellier, France
J.P.G. Vonsattel New York Brain Bank/Taub Institute, The
Presbyterian Hospital and Columbia University, New York, and the
Gertrude H. Sergievsky Centre and School of Public Health, NY,
USA
Handbook of Clinical Neurology, Vol. 89 (3rd series) Dementias
C. Duyckaerts, I. Litvan, Editors # 2008 Elsevier B.V. All rights
reserved
Chapter 1
History of dementiaFRANCOIS BOLLER * Bethesda, Maryland, USA
1.1. IntroductionThe history of dementia obviously did not start
with the contributions of Alzheimer and his colleagues. However,
the years around the beginning of the 20th century saw a series of
neurological and neuropathological breakthroughs in the field of
dementia which certainly did not happen by chance. This chapter
will mention some of the early central characters in the field as
well as the evolution of the concept of dementia before Alzheimer.
It will discuss important technical advances that led to the early
20th-century contributions. Finally it will conclude with a brief
presentation of the work of more recent protagonists in the field
of Alzheimers disease. The history of other degenerative dementias
can be found in the appropriate chapters of this volume.
1.2. Ancient notions and contributions before AlzheimerThe
diseases that can produce dementia are as old as mankind. The major
risk factor for degenerative dementias was and remains age. Around
the year 2000 BC, ancient Egyptians, even though they held that the
heart and diaphragm were the seats of mental life, were aware that
age could be accompanied by a major memory disorder (Signoret and
Hauw, 1991). Greco-Roman authors also frequently pointed it out and
many, including Plato and later Horatius, seem to have thought that
old age per se was often synonymous with dementia. Solon (active in
the 6th century BC), whom some consider the father of modern legal
thinking, wrote that judgment can be impaired by physical pain,
violence, drugs, old age or the persuasion of a woman (Freeman,
1926). This may have led Cicero (Fig. 1.1) to point out in De
Senectute (Cicero,
44BC) that, on the contrary, aging is not necessarily
accompanied by significant mental changes. Aretaeus of Cappadocia
(end of the second century AD) wrote about organic mental disorders
and was probably the first to distinguish between acute and chronic
neurological and psychiatric disorders. Acute disorders, which he
described as reversible, were called delirium, whereas chronic
disorders (dementia) were characterized by irreversible impairment
of higher cognitive functions. Galen and before him Hippocrates
thought that these disorders were due to a cerebral impairment
which could be either primary or secondary to a disease process
located in other organs of the body. Galen, Aretaeus and
Hippocrates wrote in Greek and unfortunately their writings were
not translated into Latin and therefore not easily available to
Western scholars until much later. Actually Galen was active in
Rome for more than twenty years in his capacity as personal
physician to several emperors, including Marcus Aurelius.
Nevertheless his most important writings were translated into
Arabic before Latin. Meanwhile, because these contributions were
not recognized, and on the basis of Aristotles theories, the brain
continued to be seen as an organ not necessarily related to the
control of motor or cognitive functions. In medical thinking, the
center of the mind wandered from the liver to the lungs and other
organs. In the Middle Ages, dementia does not seem to have inspired
much interest or concern, perhaps in part because of the prominence
of deadlier epidemics such as the plague. The Zeitgeist also
undoubtedly played a role. At a time when society explained the
mysterious forces of nature through mysticism, the philosopher
Roger Bacon (12141294) could reasonably express the view that
senility is a consequence of the original sin (Albert and Mildworf,
1989). Not many more advances occurred at the time of the
Renaissance,
*Correspondence to: Francois Boller MD, PhD, 4301 Military Road,
NW. Washington DC 20015. E-mail: bollermeister@gmail. com.
4
F. BOLLER
Fig. 1.2. Statue of Philippe Pinel. Fig. 1.1. Portrait of
Cicero.
except perhaps for the perception that dementia implied not only
memory loss, but also a tendency to act in a childish fashion. For
instance Andre du Laurens (15581609) wrote about these patients
that their mind becomes feeble and the memory lost and the judgment
failing so that they become as they were in their infancy
(Dannenfeldt, 1987; Finger, 1994). One of the founders of modern
psychiatry, Philippe Pinel (17451826) (Fig. 1.2), did not invent
the term dementia (use of the term in France has been traced back
as far as 1381, see Boller and Forbes, 1998), but he was certainly
one of the first to provide good descriptions of dementia. A very
important leap forward was due to his pupil Jean Etienne Esquirol
(17721840) (Fig. 1.3), probably one of the most underrated medical
authors in the field of dementia. As an observer and a writer,
Esquirol was superb. He divided the dementias into three types:
acute, chronic, and senile. He provided an especially good
description of the senile variety, which he defined as une
affection cerebrale . . . caracterisee par laffaiblissement de la
sensibilite, de lintelligence et de la volonte (a cerebral disease
characterized by an impairment of sensibility, intelligence and
will). He added mence est prive des biens dont il lhomme en de
jouissait autrefois; cest un riche devenu pauvre. te Lidiot, lui, a
toujours e dans linfortune et la `re mise (a demented man has lost
the goods he
Fig. 1.3. Jean-Etienne Esquirol (17721840).
used to enjoy; he is a wealthy person turned poor. An idiot, by
contrast, has always been unfortunate and poor). (Esquirol, 1838)
These definitions remain quite apt today. As for the
pathophysiology of dementia, only vague theories were proposed,
such as inappropriate cooling of the brain (Boneti) or
inappropriate drinking, hemorrhoids or masturbation (Esquirol).
HISTORY OF DEMENTIA On the whole and despite some exceptionally
good premonitions (Finger, 1994, p. 29), it was not until Franz
Gall and especially Paul Broca that the role of the brain and the
concept of cerebral localization became accepted. The crucial
factor explaining why so much happened during those few years is
the fact that Alzheimer and other well known protagonists had their
minds oriented and prepared by their teachers, by the spirit of
curiosity for scientific research, and the prevailing interest in
neurological investigations throughout Europe at that time. The
evolution of concepts leading to our current views has been
reviewed in details (Finger, 1994; Boller and Forbes, 1998). The
next section will present another reason why so much progress
occurred in those years. It would not have been possible without
some technical advances that became available just around that
time.
5
1.3. Benefiting from improved methodologiesIn reviewing the work
of the great anatomists of the classical age such as Vesalius
(15141564), one is impressed by the extraordinary precision of the
drawings representing the human body, its muscles, its bones, and
so forth (Fig. 1.4). When it comes to the brain, however, even
though he had the best knowledge available at the time, Vesaliuss
pictures of the
brains anatomy show a striking lack of precision (Fig. 1.5).
Nevertheless, his work stimulated others to take a closer look at
the brain and to start thinking in terms of anatomical
correlations. A few of the main cerebral landmarks were identified
before the nineteenth century. The main fissure on the lateral
surface of the brain was described in 1641 by Franz de LeBoe or
Francois Dubois, a name which literally means of the forest, hence
Sylvius (silva means forest in Latin); it is therefore known as the
Sylvian fissure. Luigi Rolando (17731831) included a clear
representation of the central vertical fissure in his writing and
in his engravings. Even though Vicq dAzyr may have represented it
before him, Francois Leuret (17971851) was probably right in giving
it Rolandos name (Schiller, 1970). However, observation of the
brain in its fresh state is quite unrewarding. Of the many steps
necessary for scientific advances on brain morphology, this section
discusses in some detail fixation, staining and magnification.
1.4. FixationIn his monumental textbook Textura del sistema
nervioso del hombre y de los vertebrados (Histology of the nervous
system of man and vertebrates), Ramon y Cajal summarize the history
of the research methods in neurosciences showing the intricate
relationship
Fig. 1.4. Vesaliuss representation of bones and muscles.
6
F. BOLLER
Fig. 1.5. Vesaliuss representation of the brain.
between ideas and techniques (Cajal y Ramon, 1928). As Cajal
points out, the earliest techniques for fixing brain tissue relied
on alcohol, a method introduced by Felix Vicq-dAzyr (17461794), and
on freezing. A quantum leap took place with the introduction of
formaldehyde, commercialized under the name formalin. The first
person to propose formaldehyde (methyl aldehyde, formula HCHO)
solution as a fixative for tissues was Ferdinand Blum (Fox et al.,
1985). Since Blums proposal of formalin as a useful general
biological fixative in 1893, it has become an unsurpassed standard.
For over 110 years, zoologists, botanists, histologists, and
pathologists have used formalin to preserve their materials for a
detailed anatomical, histological or cytological study. To
pathologists it represents up to now an admissible standard,
despite its relative toxicity. It must be pointed out that, while
formalin is suited to most histological techniques, it precludes
neurochemical studies such as isolation of proteins, Western blots
or assay of neuromediators. For these, the technique of choice is
freezing. Therefore the pendulum has come full circle.
1.5. StainingOnce fixed, the brain tissue needs to be
appropriately stained. The Germans had been pioneers in the
field
since the work of Ehrlich and, above all, of his cousin Carl
Weigert (18451904). In 1885, Weigert introduced hematoxylin to
stain myelin, based on his observation that when brain tissue is
mordanted in chromic salts, the myelin sheaths stain selectively
with hematoxylin or acid fuchsin (Neubuerger, 1970). Max
Bielschowsky (18691940), who was a pupil of Weigert and also of
Franz Nissl, introduced a new silver impregnation technique for
staining nerve fibers, initially described by Cajal (Weil, 1970).
It is with Bielschowskys technique that Alzheimer and his pupils
discovered and named the neurofibrillary tangles (NFT), thick
bundles of argyrophilic fibrillary material. Numerous developments
of the method were proposed, Gallyas techniques being the most
recent ones. Because they can be applied to large sections, they
helped H. Braak and his collaborators to describe the stages of
Alzheimer disease (Braak and Braak, 1992; Braak and Del Tredici,
2006). The work of Franz Nissl (18601919) (Fig. 1.6) is
particularly interesting. He joined Alzheimer as far back as 1889
when Alzheimer was still in Frankfurt. In 1894, Nissl discovered
that he could stain neurons with dahlia violet and with methylene
blue, thus introducing the Nissl stain, which first allowed
distinct visualization of the cell body of the neurons.
Incidentally, Nissl also did outstanding work in psychiatry
HISTORY OF DEMENTIA
7
Fig. 1.7. The first compound microscope.
Fig. 1.6. Portrait of Franz Nissl (18601919).
and neurology. He demonstrated the correlation of nervous and
mental diseases by relating them to changes in glial cells, blood
elements, blood vessels, and brain tissue in general. He also
worked with Alzheimer on general paresis (Rasmussen, 1970).
1.6. MagnificationThe invention of the microscope is often
attributed to Antony van Leeuwenhoek (16321723), a tradesman from
Delft, Holland, who had had no formal scientific or medical
training. He made some of the most important discoveries in
biology, including the description of nerve fibers in
cross-section. All of this was done with a very simple device that
could magnify up to 300. While it is therefore correct to consider
van Leeuwenhoek as the father of microscopy, most authors attribute
the invention of the compound microscope to Zacharias Janssen
around 1595 (Fig. 1.7). Janssens microscope consisted of three draw
tubes with lenses inserted into the ends of the flanking tubes. The
eyepiece lens was bi-convex and the objective lens was
plano-convex, a very advanced compound design for this period.
Focusing of this hand-held microscope was achieved by sliding the
draw tube in or out while observing the sample. The Janssen
microscope was capable of magnifying images approximately three
times when closed and up to ten times when extended to the maximum.
Technical developments occurred gradually in subsequent years (Fig.
1.8). Spectacular advances were
due to a new technique toward the end of the 19th century. In
1873, Ernst Abbe published his work on the theory of the
microscope. Up to this point, much of the design of microscopes had
been a matter of trial and error. He made clear the difference
between magnification and resolution and criticized the practice of
using eyepieces with too high a magnification as empty
magnification. His widely used formula to calculate resolution is
based on his wave light theory. At that time Abbe began a
collaboration with Carl Zeiss which lasted until his death. In
1873, Ernst Leitz introduced a microscope with a revolving mount
(turret) for five objectives. With this final advance, the
theoretical limit of resolution for light microscopes, depending on
the wavelength, had been reached (around 200 mm). With light
microscopy, lines separated by a distance smaller than 0.200 mm
cannot be distinguished. The introduction of the electron
microscope (EM) in the 1930s allowed visualization of much smaller
structures. The EM was co-invented by the Germans Max Knoll and
Ernst Ruska in 1931. The basic principle of EM is that electrons,
having a much shorter wavelength than light (only one
hundred-thousandth that of white light), will allow much better
resolution to be reached. Beams of electrons are focused on a cell
sample and are absorbed or scattered by the cells parts so as to
form an image on an electron-sensitive photographic plate. It is
thanks to the EM that Michael Kidd discovered the paired helical
filaments forming tangles. This was published in a seminal paper
that appeared in Nature in 1963 (Kidd, 1963). In an interview, Dr.
Kidd later said: I was sitting in the lab and, you remember lamp
cords used to be twisted? And I thought well, maybe they are
twisted (Katzman and Bick, 2000).
8
F. BOLLER
Fig. 1.8. Microscopes used in the 18th and 19th century.
1.7. The protagonists, well known and less well knownMuch has
been written about Alois Alzheimer and his time (Lewey, 1970;
Maurer et al., 2003; Dahm, 2006; Maurer, 2006) (Fig. 1.9). He would
probably be very surprised to know that his patronym has become a
household word for the disorder that carries his name, given that
he worked a great deal on other conditions such as cerebrovascular
diseases and neurosyphilis. In addition, the condition he described
was felt to be a very uncommon disease impossible to assign to any
of the known disorders (Alzheimer, 1907, p. 148). Alzheimer had
long been interested in dementia and published a paper on the
subject when he was in his thirties (Alzheimer, 1898) and also
discussed it in his Habilitation thesis (Alzheimer, 1904). On
November 3rd 1906, he reported the case of Auguste D at a local
meeting, the 88th meeting of South-West German psychiatrists held
in Tuebingen (Alzheimer, 1907; Bick
et al., 1987). The meeting was attended by only 88 people, but
they included such prominent characters as Otto Binswanger,
Friedrich Lewi, Heinrich Romberg, and Franz Nissl (Maurer, 2006).
At the end of his report there were no questions and the Chair of
the session, Alfred Hoche, did not make any comment. One can
speculate that this ice-cold reception may have had something to do
with the fact that Hoche was a notorious enemy of Emil Kraepelin,
Alzheimers Chairman. Furthermore, the organizers of the meeting
considered the talk unsuitable for publication (Dahm, 2006), but
fortunately changed their mind and the following year a short
report was published (Alzheimer, 1907). Kraepelin (Fig. 1.10) is in
great part responsible for saving Alzheimers communication and
preventing it from falling into oblivion. His Textbook of
Psychiatry was for many years the authority in the field for
medical students and for psychiatrists throughout the entire world.
The eighth edition of the Textbook distinguished various forms of
dementia and introduced
HISTORY OF DEMENTIA
9
Fig. 1.9. Alois Alzheimer (18641915).
Fig. 1.10. Emile Kraepelin (18561926).
to the world the term Alzheimer presenile dementia (Kraepelin,
1910). Other individuals around Alzheimer also played an important
role. A famous picture (Fig. 1.11) shows him in the company of
Friedrich Lewy (Fig. 1.12), who first described the inclusion
bodies that are considered necessary for the diagnosis of
Parkinsons disease and are also present in the cortex in dementia
with Lewy bodies. There is also Franz Nissl (Fig. 1.6) and other
persons, several of whom are researchers who came from other
countries. One is a Spaniard, Nicolas Achucarro, a pupil of Ramon y
Cajal (Polak, 1953). There are several Italians, including Ugo
Cerletti (18771963), who was later to develop and introduce,
together with Luciano Bini, electroshock treatment. One also finds
Francesco Bonfiglio and Gaetano Perusini (Fig. 1.13), whose
contribution will be mentioned below. The group of visiting
students included an American, Dr. Solomon Carter Fuller (not shown
in the picture). Although there is little record of his work while
in Germany, a review of his life and work (Kaplan and Henderson,
2000) provides a fascinating glimpse of his background as an
African-American (born in Liberia) at the turn of the century and
his continuing research on Alzheimers disease (AD) after leaving
Germany and coming back to the USA in 1906. As mentioned, Alzheimer
himself thought he had described a rare condition, and indeed until
approximately 25 years ago references to AD in the clinical and
research literature were uncommon. According to Medline#, only 42
papers including AD as a keyword were published in 1975. Subsequent
years have seen an exponential increase of research in the field.
What has determined such a growth in interest among researchers
and, for that matter, in the general public? Clearly, demographic
changes are responsible and, in some cases, political decisions on
the part of some governments followed. For instance, in the USA,
the National Institute on Aging (NIA) created in 1974 played a
major role (Khachaturian, 2006). This is a clear case where
political rather than strictly scientific motives prevailed. As
Robert Butler, the first NIA Director, later said The National
Institutes of Health did not favor having a National Institute on
Aging, nor did the Department [this refers to the now defunct
Department of Health, Education and Welfare]. It was really thrust
on them by Congress (Katzman and Bick, 2000, p. 288). The next
crucial step took place when the mission of the new Institute had
to be decided. Many thought that the mission of the NIA was to
study normal aging and geriatric diseases in general, since it had
been established with an amorphous authorization to address the
problems and diseases of the aged. Once again it was the US
10
F. BOLLER
Fig. 1.11. Alois Alzheimer and his co-workers. Top row from
left: F. Lotmar; N.N.; S. Rosenthal; Allers?; N.N.; A. Alzheimer;
N. Achucarro; FH Lewy. Front row from left: Mrs Grombach; U.
Cerletti; N.N.; F. Bonfiglio; G. Perusini. This photograph was
taken in Alois Alzheimers laboratory on the 2nd floor of the
Nervenklinik Nussbaumstrasse in Munich during 1909 or 1910 and not,
as erroneously stated on the original legend (not shown), at the
Deutsche Forschungsanstalt fur Psychiatrie, which was founded only
years later. It is often stated that the person in the center
holding a cigar is Kraepelin. There is, however, no evidence that
this is the case. Courtesy of B. Lucci, MD, and F. Vinci, MD.
Congress which prevailed by appropriating funds targeted to
research on AD. Dr Zaven Khachaturian was hired to run the
Alzheimer program and he was enormously helpful (Katzman and Bick,
2000, p. 291). This was to lead to the creation of many Alzheimer
disease research centers starting in the early to mideighties.
Finally in 1979, the founding of the Alzheimer Disease and Related
Diseases Association (now Alzheimer Association) with Jerome Stone
as its first Chair contributed significantly to the dissemination
of knowledge about AD in the general public (Katzman and Bick,
2000, pp. 337351). This was followed by the creation of Alzheimer
Disease International (ADI) in 1984. Princess Yasmin Aga Khan,
daughter of Rita Hayworth, who is thought to have had Alzheimers
disease, was elected as the organizations president. The first
international meeting of ADI was organized by Dr Francoise Forette
and held in Paris in 1986. In 1977, the NIA, together with NINCDS
and NIMH, organized a Workshop Conference held in Bethesda. At the
conclusion of the proceedings, Robert Katzman, Robert Terry, and
Katherine Bick provided a set of Recommendations and stated there
is increasing
recognition that most patients with clinically defined senile
dementia (onset after age 65) manifest the same pathological
changes in their brains as do patients in their presenium (under
age 65) with Alzheimers disease (Katzman et al., 1978). It could be
argued that such conclusions opened the modern era of research
because AD was officially recognized as more than a rare condition
affecting only the presenium. Of course, in addition to Alzheimer
and his group, many others have contributed to our current concepts
concerning dementia and AD. The Scandinavian (and in particular
Swedish) contribution to the field of AD and related disorders is
now highly recognized, thanks mainly to the work of the groups in
Stockholm, Lund, and Uppsala. Earlier contributions include a
seminal study by Karl Gustaf Torsten Sjogren (18961974) concerning
the epidemiology of AD and Picks disease (Redlich, 1898; Sjogren et
al., 1952). This paper strongly influenced clinical diagnosis of AD
in Scan dinavia. Sjogren is also known for having brought to
international attention the syndrome known as Marinesco-Sjogren or
cataract-oligophrenia syndrome, abbreviated as MMS (Fischer, 1907;
Marinesco et al., 1931; Sjogren, 1950). Sjogren pointed out that,
in
HISTORY OF DEMENTIA
11
Fig. 1.12. Friedrich Lewy (18851950. Picture taken probably in
the late 1940s.).
Fig. 1.13. Gaetano Perusini (18791915).
addition to hereditary oligophrenia and to ocular problems,
these patients also show cerebellodental degeneration. Georges
Marinesco (or Marinescu, 18631938), the man who shares the eponym
in the MMS, is also worth mentioning. This Romanian neurologist,
trained in Paris, modified the staining techniques for glia
(previously developed by Cajal) and is credited for having
provided, together with Blocq, the first description of senile
plaques (SP) in the brain of two epileptic patients (Blocq and
Marinesco, 1892). Similarly Paul Divry (18891967), a Belgian
psychiatrist and neuropathologist, is best known for having
described the Van Bogaert-Divry syndrome, a condition involving the
skin, the meninges, and the cerebral white matter. It is less known
that he was the first to observe that senile plaques can be stained
by Congo red, a stain that has a high affinity for amyloid
substances, i.e., proteins that have a high proportion of -pleated
sheet structures (Divry, 1927; Bobon, 1967). The peptide that
precipitates in the senile plaque core was identified much later by
George Glenner (Glenner and Wong, 1984). The nature of the
neurofibrillary tangles also remained elusive for a long time. They
were initially thought to be composed of neurofilament proteins, or
of tubulins. Jean-Pierre Brion, also from Belgium, showed that they
were immunoreactive to a tau antibody (Brion et al., 1985). Tau
(which is the abbreviation of tubulin associated unit), a
microtubule-associated protein isolated in 1977, greatly
facilitates the polymerization of neurotubules (Cleveland et al.,
1977) and is the main constituent of NFTs (Grundke-Iqbal et al.,
1986). In the UK, one must cite particularly Bernard Tomlinson. Sir
Bernard is a distinguished neuropathologist, with a long
association with the Newcastle General Hospital and the University
of Newcastle upon Tyne. He must be recognized as another pioneer in
the neuropsychology and neuropathology of dementia. With his
colleagues Martin Roth and Garry Blessed, he showed that there is
correlation between severity of dementia and brain lesions in AD.
They also pioneered the concept that there could be dementia due to
loss of brain tissue following vascular events, rather than to
hardening of the arteries (Roth et al., 1966; Tomlinson et al.,
1970). Tomlinson was later to become a household name in UK
medicine because of the publication known as the Tomlinson report
dealing with the reorganization of hospitals in the UK. The
contribution of Michael Kidd is mentioned in the previous section.
In view of the many people cited here (and many more who are not)
for having provided significant contributions to AD, it is
legitimate to raise the question
12
F. BOLLERK Beyreuther, C Haass, RM Nitsch, Y Christen (Eds.),
Alzheimer: 100 Years and Beyond. Springer, Berlin. Brion JP,
Passareiro H, Nunez J, et al. (1985). Mise en evi dence
immunologique de la proteine tau au niveau des lesions de
degenerescence neurofibrillaire de la maladie dAlzheimer. Arch Biol
(Brux) 95: 229235. Cajal S Ramon y (1928). Histology of the Nervous
System of Man and Vertebrates 1928. Oxford University Press,
London. Cicero MT (44 BC). De Senectute (On Old Age). English
translation (1923) WR Falconer. Loeb Classical Library. Harvard
University Press. Cleveland DW, Hwo SY, Kirschner MW (1977).
Purification of tau, a microtubule-associated protein that induces
assembly of microtubules from purified tubulin. J Mol Biol 116:
207225. Dahm R (2006). Alois Alzheimer and the beginnings of
research into Alzheimers disease. In: M Jucker, K Beyreuther, C
Haass, RM Nitsch, Y Christen (Eds.), Alzheimer: 100 Years and
Beyond. Springer, Berlin. Dannenfeldt KH (1987). Andre Du Laurens
(15581609): an early French writer on the aged. Gerontologist 27:
240243. Divry P (1927). Etude histochimique des plaques seniles.
Journal Belge de Neurologie et Psychiatrie 9: 649657. ` Esquirol JE
(1838). Des Maladies Mentales. Bailliere, Paris. Finger S (1994).
Origins of Neuroscience. Oxford University Press, New York. Fischer
O (1907). Miliare Nekrosen mit drusigen Wucherun gen der
Neurofibrillen, eine regelmassige Veranderung der Hirnrinde bei
seniler Demenz. Monatsschrift fur Psychiatrie und Neurologie 22:
361372. Fox Ch, Johnson FB, Whiting J, et al. (1985). Formaldehyde
fixation. J Histochem Cytochem 33: 845853. Freeman K (1926). The
Work and Life of Solon. London University Press, London. Glenner G,
Wong CW (1984). Alzheimers disease: Initial report of the
purification and characterization of a novel cerebrovascular
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Grundke-Iqbal I, Iqbal K, Quinlan M, et al. (1986).
Microtubule-associated protein tau. A component of Alzheimer paired
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AR (2000). Solomon Carter Fuller, M.D. (18721953): American pioneer
in Alzheimers disease research. J Hist Neurosci 9: 250261.
Khachaturian Z (2006). A chapter in the development on Alzheimers
disease research. A case study of public policies on the
development & funding of research programs. In: M Jucker, K
Beyreuther, C Haass, RM Nitsch, Y Christen (Eds.), Alzheimer: 100
Years and Beyond. Springer, Berlin. Katzman R, Bick K (2000).
Alzheimer Disease. The Changing View. Academic Press, San Diego.
Katzman R, Terry RD, Bick KL (Eds.) (1978). Alzheimers Disease:
Senile Dementia and Related Disorders. Aging Raven Press, New York.
Kidd M (1963). Paired helical filaments in electron microscopy of
Alzheimers disease. Nature 197: 192193.
of whether the eponym of Alzheimer is appropriate. Before
Alzheimer, we find good descriptions of the clinical picture of
dementia provided by Pinel and Esquirol among others. Senile
plaques had been described in Paris, in Germany (Redlich, 1898) and
by the Prague group led by Arnold Pick (Fischer, 1907). Of the many
people surrounding Alzheimer in Munich, the most noteworthy is
Gaetano Perusini (Fig. 1.13), who contributed so significantly to
our current understanding of AD that, in some countries, the
condition is still referred to as Alzheimer-Perusini disease
(Perusini, 1911; Pomponi and Marta, 1993; Macchi et al., 1997;
Lucci, 1998). However, Alzheimer crystallized years of observations
and understood that the neuropathological lesions which he
described could be used to individualize a disease: the eponym is
therefore considered justified by most observers.
AcknowledgementsThe author wishes to thank D. Stanley Finger and
Dr Charles Duyckaerts for their very valuable input. Dr Elisabeth
Koss and D. Neelakanta Ravindranath also provided help.
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Handbook of Clinical Neurology, Vol. 89 (3rd series) Dementias
C. Duyckaerts, I. Litvan, Editors # 2008 Elsevier B.V. All rights
reserved
Chapter 2
Neuropsychological examination in dementiaGIANFRANCO DALLA BARBA
1*, LATCHEZAR TRAYKOV 2 AND SOPHIE BAUDIC 31 2
triere Hospital, Paris, France INSERM Unit 610, La Salpe
University Hospital Alexandrovska, Medical University, Sofia,
Bulgaria, and CHU, Henri Mondor Department of Neurology, University
Paris XII, Creteil, France3
decine, Cre teil, France INSERM/UPVM Unit 421, Faculte de Me
2.1. IntroductionNeuropsychology is the only available tool for
the in vivo screening and diagnosis of dementia. Neuropsychological
tests, formal or informal, have always been fundamental for the
clinical diagnosis of Alzheimers disease (AD) and other dementias.
The recent development of pharmacological treatment for AD and
other dementias, and the introduction of new therapies in the near
future, make the assessment of dementia at its different stages a
scientific challenge of significant consequence for public health.
The need for a more solid, theoretical framework for the assessment
of dementia is becoming more apparent. In fact, tests most widely
used to evaluate dementia consist of arbitrary selected subtests
lacking a theoretical rationale. A direct consequence is that these
tests have poor sensitivity and specificity for both the screening
and the diagnosis of dementia, in particular at its early stage.
The proportion of patients who are actually classified as demented
by a test reflects its sensitivity. The sensitivity of a test
decreases as a function of the proportion of cases of dementia that
the test is unable to classify, i.e., false negatives. The risk of
increasing the sensitivity of a test is the parallel increase of
false positives, i.e., patients erroneously classified as demented.
Therefore, a second index is needed to exclude false positives:
specificity. Specificity reflects the proportion of non-demented
subjects who are correctly classified by the test. The majority of
tests used for screening and diagnosis of dementia show good
sensitivity and good specificity in the moderate stage of the
disease, but not in the early stage. For example, the Mini Mental
State
Examination (MMSE) (Folstein et al., 1975), which is probably
the most widely used test for the assessment of dementia, shows a
sensitivity of 87% and a specificity of 92% for scores of 2324 out
of 30 (Grut et al., 1993). The development of new screening and
diagnostic tests with high sensitivity and specificity in the early
stage of dementia would allow for early detection and treatment of
the disease and would delay the time of institutionalization. The
human and public health benefits of such tests are obvious. In this
chapter, we will review neuropsychological screening and diagnostic
tools applied to patients with AD and related disorders. We will
then analyze the tests to be applied to detect and assess deficits
in specific cognitive domains.
2.2. Screening testsBrief and simple neuropsychological tests
are particularly recommended for the screening of dementia because
they can be used in general practice. In fact, often people with
very early dementia may not mention their cognitive impairment to
their physician either because they are unaware of their cognitive
decline, or because they think that it is part of the normal aging
process. Sometimes, dementia goes undetected in primary care
settings even when the patients report their cognitive impairment
(Callahan et al., 1995). 2.2.1. Mini Mental State Examination The
MMSE continues to be the most widely used screening instrument for
dementia. It tests a limited number of
*Correspondence to: Gianfranco Dalla Barba, INSERM Unit 610, La
Salpetriere Hospital, Paris, France. E-mail:
[email protected].
16
G. DALLA BARBA ET AL. aged individuals, 50 of whom had dementia
according to the DSM-III criteria (American Psychiatric
Association, 1994). This test showed good sensitivity and
specificity for the screening of dementia. As a screen for AD, the
MIS had higher sensitivity (0.86 vs 0.65), higher specificity (0.97
vs 0.85) and greater PPV (0.80 vs 0.37) than the conventional
three-word memory test, which is a delayed free recall task widely
recommended as a dementia-screening test in clinical practice
(Kuslansky et al., 2002). This brief and simple test provides
efficient, reliable, and valid screening for AD and other dementias
and it is likely to become the master test for the screening of
dementia in clinical practice and in large epidemiological studies.
2.2.3. Mattis Dementia Rating Scale This scale, first described in
1976 (Mattis, 1976) and modified in 1988, assesses five cognitive
domains: attention, initiation and perseveration, construction,
conceptual thinking, and memory. An interesting feature is that the
most difficult items are presented first, contrary to many other
tests in which items are presented in ascending order of
difficulty. The total score clearly discriminates AD patients from
normal control subjects. When a cutoff score of 129/144 points was
used the sensitivity was 98% and the specificity was 97%. When the
rating scale was applied to a community-based sample the test
correctly identified 91% of the patients with AD and 93% of the
normal elderly subjects (Monsch et al., 1995). It also
differentiates patients with dementia from patients whose cognitive
functioning is compromised by psychiatric illness and from healthy
community elderly subjects with limited education (Marcopulos et
al., 1999). The scale has been used with success in patients with
conditions other than AD, including schizophrenia (Eyler Zorrilla
et al., 2000), vascular dementia (Paul et al., 2001) and AIDS
(Suarez et al., 2000). The subscales of the battery vary in
sensitivity. Vitaliano et al. (1984) have shown that Attention and
Concept formation do not discriminate controls from mildly impaired
patients. 2.2.4. Other screening tests Other short assessment
instruments include the Blessed Dementia Scale, which consists of
an information, memory and orientation test (Blessed et al., 1968),
the short portable mental status questionnaire (SPMSQ) (Pfeiffer,
1975) and Riesbergs Brief Cognitive Rating Scale (Reisberg, 1988).
It must be stressed that even though these screening tests are
usefully employed in clinical practice for the detection and
diagnosis of dementia and AD, most of them have no
cognitive functions and can be administered quickly (in 1015
min). The modalities for its administration and scoring are easily
learned. Since it has been translated into many languages, it
represents an almost universal way of assessing the severity of
dementia in individuals as well as in population samples. The score
ranges from 0 (worst) to 30 and most authors consider that the
cutoff score below which dementia can be suspected is 24. The MMSE
score is influenced by such variables as age and education. Ethnic
status also plays a role, but is probably related to education
since, if education is taken into account, no difference is found
between Spanish and English ethnic (Mungas et al., 1996) or between
Finnish and Chinese (Salmon et al., 1989). A modified version of
the MMSE has been proposed for patients with Parkinsons disease
(Mahieux et al., 1995). However, the test has been criticized along
several lines, including poor sensitivity and specificity, and poor
negative predictive value (NPV) and positive predictive value
(PPV), especially in the early stage of disease. In one study, the
MMSE was evaluated in a registry setting in which 150 consecutive
patients with cognitive complaints were administered the
examination, and the results were compared with a 1-year follow-up
diagnosis (Kukull et al., 1994). The data indicated that the
standard cutoff score of 12 Hz). During senescence, an alteration
in the appearance of the alpha rhythm is the principal EEG change.
For example, in an early study of 161 young and 50 elderly normal
subjects (Mundy-Castle et al., 1954) it was reported that, with
increasing age, the frequency of the
5.2. ElectroencephalographyRoutine EEGs (i.e., those without
computerized methods of analysis or utilizing averaging
techniques
*Correspondence to: Michael J. Aminoff, MD, DSc, FRCP,
Department of Neurology, Rm. M794, University of California, San
Francisco, 505 Parnassus Ave., San Francisco, CA 94143-0114, USA.
E-mail: [email protected].
64
M.J. AMINOFF AND D.S. GOODIN state. Thus, the finding of
periodic complexes (at $1 Hz) in the EEG of a patient with rapidly
progressive cognitive decline (Fig. 5.1) points to a diagnosis of
Creutzfeldt-Jakob disease (Traub et al., 1977; Steinhoff et al.,
2004). The EEG findings, however, must always be considered in
their clinical context. Similar EEG and behavioral changes have
been described in patients with lithium or baclofen toxicity
(Hormes et al., 1988; Smith and Kocen, 1988). Again, the finding of
triphasic waves occurring on a diffusely slowed background in an
individual with suspected dementia (Fig. 5.2) suggests the presence
of an underlying toxic-metabolic abnormality (Kuroiwa and Celesia,
1980; Kaplan, 2004). A localized EEG abnormality, such as a
polymorphic slow-wave disturbance (Fig. 5.3), in a patient without
focal clinical signs may be the first indication of a treatable
mass lesion such as a frontal meningioma or subdural hematoma.
However, the EEG changes seen during the course of dementia are
generally non-specific and do not easily distinguish normal
senescence from dementia. Thus, with the possible exception of a
reduction in the amount of beta activity, the changes reported in
the EEG of demented individuals are remarkably similar to those
that occur during normal aging. In mild dementia, the EEG may be
entirely normal, whereas in more advanced cases, the theta and
delta activities are increased, the frequency of the alpha rhythm
is lowered, and the amount of time that the alpha rhythm is seen in
the record of an awake individual is reduced (Table 5.1).
Consequently, most, if not all, of the differences between normal
aging and dementia on the EEG are quantitative, not qualitative. As
a result, the magnitude of the reported changes has often differed
markedly between studies. For example, in one early study the
frequency of the alpha rhythm was found not to be significantly
different between demented subjects and age-matched controls (Table
5.1). By contrast, another early investigator (Harner, 1975) found
that the alpha frequency of 9.7 0.7 Hz in the group of non-demented
subjects (aged 6079 years) was significantly greater than the alpha
frequency of 8.8 1.3 Hz in a group of comparably aged demented
patients. Such apparent discrepancies abound in the literature and
almost certainly relate, at least in part, to differences in
severity of dementia between patients in different studies.
Nevertheless, the overlap between the normal aged and demented
populations, especially in the group of mildly affected individuals
(i.e., those with MCI), is such that it has been difficult to
distinguish individuals reliably on the basis of qualitative EEG
changes.
alpha rhythm is mildly slowed, its amplitude is reduced, and it
becomes a less persistent feature of the EEG during the awake state
(Table 5.1). Others have reported similar findings with respect to
the alpha rhythm although there has been some discrepancy between
reports on the effect of senescence upon beta activity. Thus, some
authors have suggested that beta activity continues to increase
during normal senescence (Obrist, 1954, 1976; Roubieck, 1977; Duffy
et al., 1984; Marciani et al., 1994), whereas others have suggested
that it is reduced (Coben et al., 1990; Hartikainen et al., 1992;
Besthorn et al., 1997). As discussed below, however, beta activity
is reduced in patients with cognitive impairment so that part of
the apparent discrepancy may be explained by the inadvertent
inclusion of patients with minimal cognitive impairment (MCI) in
some of the reported series. Moreover, whether any such increased
fast activity is due to an increase in the slow beta (1325 Hz) or
the fast beta (2535 Hz) frequency bands is also unclear (Obrist,
1954; Roubieck, 1977). Another EEG feature, which is found commonly
in an elderly population of normal individuals, is an increased
prevalence in the number of EEGs that contain slow waves in the
theta (47 Hz) and occasionally delta (
