Editorial
Arguably, no eponymous disorder exposes the vulnerability of what it is to be human more effectively than Alzheimer's disease. Whereas any vertebrate nervous system may suffer apoplexy, epilepsy or paralysis, the price paid for having a uniquely developed cerebrum is that it can go badly wrong. The threat of Alzheimer's disease casts its shadow over the worried well in an increasingly aging population. In recognition of the centenary—to the week—of the first description, this issue of Brain contains papers that relate exclusively to clinical and experimental aspects of Alzheimer's and related diseases, and to a few unrelated conditions that also affect cognitive function.Alois Alzheimer (1864–1915) realized the expectations of Emil Kraepelin (1856–1926) who planned institutes of psychiatry in the belief that abnormalities of brain structure might explain mental diseases. With his appointment as resident at the Municipal Asylum for the Insane and Epileptic at Frankfurt-am-Main in December 1888, Alzheimer was well placed to correlate the dementia that afflicted Auguste Deter with the changes he observed in her brain at autopsy. The clinical case notes were rediscovered in 1995. They tell a story of agitated suspicion relating to her husband's presumed infidelity; loss of memory; failure of former interests and the ability to interact socially; abnormal and disruptive behaviour sliding into a state of inanition and incontinence; and cachexia prior to her death on April 8th 1906, five years after presentation. Convinced from the time they first met, that Auguste D had an unusual illness, Alzheimer described the neurofibrillary tangles and amyloid plaques; these might be seen normally with aging but not in a woman of 51. His lecture ‘on a peculiar, severe disease process of the cerebral cortex’ was given to the 37th assembly of the Southwest German Psychiatrists in Tübingen on November 3rd 1906: ‘taken as a whole, I believe I have just presented a clearly defined and hitherto unrecognised disorder’ (A. Alzheimer, Über eine eigenartige Erkrankung der Hirnrinde. Algemeine Zeitschrift für Psychiatrie und Psychisch-Gerichtliche Medizin 1907: 64; 146–148). The reception was muted and Alzheimer remained modest about his contribution, ignoring the fact that the disorder was dubbed ‘Alzheimer's disease’ by Kraepelin in 1910. But contemporary neuropathology confirms the accuracy and originality of Alzheimer's description (M. B. Graeber et al. Histopathology and APOE genotype of the first Alzheimer's disease patient Auguste D. Neurogenetics 1998: 1; 223–228).
Arnold Pick (1851–1924) brought to medicine personal modesty, calm serenity and deep cultural interests in literature and the arts. His approach was classical: listen to the patient; carry out a detailed clinical examination and wait for pathological verification. At Dob
an, and subsequently in the German University of Prague, he faced the administrative and linguistic ambiguities of state ownership of the psychiatric hospital by the Kingdom of Bohemia, academic direction from the Austro-Hungarian Empire, professional dialogue in German, and psychiatric consultations in Czech. It was the study of aphasia that led Pick to describe lobar atrophy in five patients with fluent aphasia progressing to complete dissolution of the semantic components of language (A. Pick. Über die Beziehungen der senilen Hirnatrophie zur Aphasie. Prager Medizinische Wochenschrift 1892: 17; 165–167). Despite diffidence about his own eponym, Alzheimer generously coined the term ‘Pick's disease’ for those cases showing silver stained inclusions and swollen neurones, and he designated the lesions as ‘Pick bodies’. Now, the tables are turned. The term ‘Alzheimer's disease’ is retained and seen as a coherent entity, whereas Pick's disease has largely disappeared into the mists of the frontotemporal dementias.
It is axiomatic that the first description of a new disease is rarely the first description of a new disease. In ‘Language and memory disorder in the case of Jonathan Swift’, Marjorie Lorch makes no special claims for the Dean; but his description of the Struldbruggs, modelled on Uncle Godwin, in Gulliver's Travels (1726) is rather suggestive of Alzheimer's disease (page 3127). As for Swift, he was far from well himself. But from what did he suffer? A generous number of entries for coprolalia listed in Geoffrey Hughes recently published Encyclopedia of Swearing (and authorship of The Swearer's Bank, 1720) might suggest Tourette's disorder (to risk a medical anachronism) but there was evidently no tic-ing. Perhaps, therefore, it came as something of a relief to his contemporaries that Swift said very little during the last few years of his life when he suffered progressive memory loss, aphasia, altered personality and facial palsy. Neurologists can join Dr Lorch in attempting to badge Swift's disease; and, as she describes, there is no shortage of suggestions. We prefer this as the first case of the primary progressive aphasia—aka, Pick's disease.
Amongst seven papers on frontotemporal dementia, Anna-Lynne Adlam and colleagues from Cambridge (UK) and Madison, WI (USA) explore the relationship between fluent primary progressive aphasia and semantic dementia. Clearly the debate is constrained by the boundaries of definition but the authors make the case for ‘lumping’ based on the shared deficits of non-verbal memory, concept familiarity and typicality, and structural imaging. They propose a common degeneration of structures located in the rostral temporal lobes that subserve a functionally amodal system for cognitive processing (page 3066). Isabelle Le Ber, on behalf of the French Research Network on FTD/FTD-MND, provides details of the natural history and prognostic features in a cohort of 68 patients with the frontal variant of frontotemporal dementia studied at baseline for clinical, behavioural, familial and SPECT imaging features of the disease (page 3051); early brainstem hypoperfusion is correlated with a poor clinical prognosis. The pathology of frontotemporal dementia is characterized by inclusions having several distinct immunoreactive patterns, and varying brain distributions. Recently, the story has changed with the recognition that patients showing ubiquitin-immunoreactive inclusions may have mutations of the progranulin gene (PGRN), in contrast to cases with Tau mutations and filamentous inclusions of hyperphosphorylated tau. Both genes map to chromosome 17q21. In their scientific commentary, Michel Goedert and Maria Grazia Spillantini bring together what is now known, concerning the molecular biology of these disorders, and they clarify a number of ambiguous publications that have described genetic mutations involving tau (MAPT) and presenilin-1 (PSEN1) in ‘frontotemporal dementia with ubiquitin-positive but tau negative’ inclusions (page 2808). Now, these appear not after all to have been pathological given the revelations relating to progranulin. Our contribution to the flurry of interest in this subject is to gather five papers describing various aspects of the molecular neuropathology attributable to progranulin mutations: in frontotemporal dementia (page 3081); progressive non-fluent aphasia (page 3091); frontotemporal dementia with parkinsonism (page 3103); familial corticobasal degeneration (page 3115); and in a group of cases previously (but wrongly) attributed to rare PSEN1 and MAPT mutations (page 3124). Again, correlations between PRGN genotype and yet other mutations (encoded at 9p21-p12 and on chromosome 3) associated with ubiquitin-positive inclusions, and the variable pathological and clinical phenotypes seen in the context of specific mutations, support a lumping approach to classification of the frontotemporal dementias. These five papers join three others appearing since the original descriptions in August 2006 (Baker at al. Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17. Nature 2006: 442; 916–919; Cruts et al. Null mutations in progranulin cause ubuquitin-positive frontotemporal dementia linked to chromosome 17q21. Nature 2006: 442; 920–924), published in Human Molecular Genetics and Annals of Neurology that describe mutations of progranulin in hereditary dysphasic disinhibition dementia 2, and in cohorts of cases with frontotemporal dementia revealing a frequency of PRGN mutations at 
5%. Taken together, it has been a busy summer season for progranulin and, as Michel Goedert and Maria Grazia Spillantini point out, the identification of a growth factor implicated in neurodegenerative disease takes us back a step conceptually, but offers a potential new therapeutic opportunity.
The molecular neuropathology of Alzheimer's disease has a longer tradition. Colin Masters and Konrad Beyreuther review the accumulation of knowledge since they and others first elucidated the role of amyloid ß peptide (Aß) showing from its sequence that the Aß peptide is derived from proteolytic action on amyloid beta (A4) precursor protein (APP), and that inhibition of the biogenesis of Aß might be achieved through targeting these proteolytic events (page 2823). They highlight the therapeutic implications; and the options for treating Alzheimer's disease are also reviewed (page 2840) in a broader context by Hans-Wolfgang Klafki and colleagues from Erlangen (Germany) and Basel (Switzerland). It might be assumed that clinical progression results from yet more abnormal protein accumulation. But Henry Engler and investigators from Uppsala and Stockholm (Sweden) show surprising stability in the amount of Aß deposition in individuals with established Alzheimer's disease studied over time using N-methyl[11C]2-(4' methylaminophenyl)-6-hydroxy-benzothiazole (PIB) PET imaging, despite steady changes in cognitive profile and altered 18Fluoro-2-deoxy-d-glucose (FDG) uptake (page 2856), allowing William Klunk and colleagues to suggest in their commentary (page 2805) that the deposition of abnormal proteins is not linear but follows a changing dynamic that must be fully understood if strategies for limiting or reducing tissue damage based on the biology of Aß are to be timely and effective.
Three papers tackle the issue of whether over-production of APP increases the risk of Alzheimer's disease. Lucie Cabrejo and investigators from Rouen, Nantes, Pau, Saint-Etienne, Angers, Bordeaux and Valbonne (France) describe the phenotype, gross neuropathology and molecular neuropathology of the ‘newly described’ early onset Alzheimer's disease associated with cerebral amyloid angiopathy due to APP gene duplication (page 2966). Kristel Sleegers and a group from the University Hospital, Antwerp (Belgium), and with contributions from Rotterdam (The Netherlands), add to this description of early onset Alzheimer's disease correlating with cerebral amyloid angiopathy in the context of APP duplication but evidently this is not a common cause of early onset non-familial Alzheimer's disease (page 2977). Much the same team from institutions in Antwerp (Belgium) under the authorship of Nathalie Brouwers shows that mutations of the APP promoter occur more frequently than coding mutations in early onset Alzheimer's disease whereas APP transcriptional activity appears to make a greater contribution at a later stage in the disease (page 2984). Kazuki Tahara and colleagues from the Universities of Illinois and Birmingham (USA) investigate the role of inflammatory mechanisms in the pathology of Alzheimer's disease showing that manipulation of the innate immune system through mutations of Toll-like receptors reduces microglia-mediated clearance of Aß deposits (page 3006). Conversely, the serine protease inhibitor 
1 anti-chymotrypsin (ACT) increases Aß polymerization: Jaya Padmanabhan and a group from institutions in Florida (USA) show that over-expression of ACT increases tau phosphorylation in vitro and in vivo, and increases apoptotic death of neurones—effects that are mediated by glycogen synthase kinase 3 (GSK3) activity (page 3020). Hence, a case can be made both for enhancing and for suppressing different aspects of immunity in Alzheimer's disease. Whether the detection of phosphorylated tau is a marker for neurofibrillary pathology is considered by Katharina Buerger and investigators from Munich (Germany) and Kuopio (Finland): they find a strong correlation between the amount of phosphorylated tau in cerebrospinal fluid and the density of neurofibrillary tangles in the neocortex and neuritic plaques in the frontal regions (page 3035). Another potential biomarker is suggested by Abdul Hye and colleagues from King's College London and University College London (UK) who perform and validate a proteomics screen of plasma to show that complement factor H precursor and 2 macroglobulin are markers for the diagnosis and for severity in Alzheimer's disease (page 3042).
The assumption that moments of forgetfulness are the harbingers of dementia evokes particular concern; and the concept of mild cognitive impairment as a pre-Alzheimer's state understandably fuels these anxieties. Christian Mondadori and investigators from Zurich and Bern (Switzerland) trace detectable cognitive impairments in individuals from a family with a PSEN1 mutation over a 20 year period ahead of the usual age at onset (page 2908). Liana Apostolova and a team from the David Geffen School of Medicine, Los Angeles (USA) show that, following the known trajectory of neurofibrillary tangle deposition, loss of CA1 neurones bilaterally, and CA2 and CA3 tissue on the right, predict the maturation of amnestic mild cognitive impairment to Alzheimer's disease (page 2867). And in group studies, Vivek Singh and colleagues from Toronto and Montreal (Canada) correlate regional cortical thinning (medial temporal and parts of the frontal and parietal cortices) with progression from normality to mild cognitive impairment and Alzheimer's disease (page 2885). In a different context, the role of the hippocampus in spatial memory is explored by Eleanor Maguire, Rory Nannery and Hugo Spiers from University College London (UK) who follow up the senior author's study of hippocampal structures in normal London taxi drivers (awarded the 2003 Ig Nobel Prize for Medicine as a piece of research that ‘first makes people laugh and then makes them think.’) with a case study of one cabbie who suffered limbic encephalitis associated with voltage gated potassium channel antibodies, but managed a virtual journey along familiar London streets so long as he could access key roads—indicating that the hippocampus is required for negotiating large spaces but knowing one's way around also requires access to detailed spatial representations (page 2894). Problems with memory and spatial orientation, and the many other early clinical and cognitive aspects of Alzheimer's disease are reviewed by John Hodges (an Associate Editor of Brain) whose many contributions to behavioural neurology give him the perspective and scholarship needed to chart progress since Alois Alzheimer first described the cognitive and social decay of Auguste D. Professor Hodges reminds us that, prior to the appearance of this issue, Brain has previously published exactly 100 papers on Alzheimer's disease. Amongst the earliest are those suggesting the cholinergic hypothesis. In From the Archives, we review: (1) Neurotransmitter-related enzymes and indices of hypoxia in senile dementia and other abiotrophies. By David M. Bowen, Carolyn B. Smith, Pamela White and Alan N. Davison. Brain 1976: 99; 459–496. With (2) Chemical pathology of the organic dementias. 1. Validity of biochemical measurements on human post-mortem brain specimens. By D.M. Bowen, Carolyn B. Smith, Pamela White, Michele J. Goodhart, J.A. Spillane, R.H.A Flack and A.N. Davison Brain 1977: 100; 397–426. With (3) Chemical pathology of the organic dementias. 11. Quantitative estimation of cellular changes in post-mortem brains. By D.M. Bowen, C.B. Smith, P. White, R.H.A. Flack, L.H. Carrasco, J.L Gedye and A.N. Davison. Brain 1977: 100; 427–453.
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