NEUROPATHOLOGICAL INVESTIGATION OF DEMENTIA: AGUIDEFORNEUROLOGISTS

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1 v8 Correspondene to: Professor Seth Love, Department of Neuropathology, University of Bristol Institute of Clinial Neurosienes, Clinial Siene at North Bristol, Frenhay Hospital, Bristol BS16 1LE, UK; bris.a.uk NEUROPATHOLOGICAL INVESTIGATION OF DEMENTIA: AGUIDEFORNEUROLOGISTS WHY D SLove J Neurol Neurosurg Psyhiatry 2005; 76(Suppl V):v8 v14. doi: /jnnp ementia is among the most ommon and disabling of diseases and plaes a huge burden on arers and families as well as on soial and medial servies. Its prevalene rises from about 1.4% of adults aged between years to 23.6% of those over 85. The number of patients with dementia is predited to inrease steeply as the proportion of people surviving well in to old age ontinues to rise. The annual eonomi ost is estimated at 7 billion per annum in the UK and over $100 billion in the USA. Aurate diagnosis of most diseases that ause dementia depends on post-mortem neuropathologial examination. In this review, I shall over some of the pratial issues involved in the post-mortem investigation of dementia and desribe the prinipal abnormalities in the more ommon diseases that are responsible. This is not an exhaustive review of the neuropathology of dementia, whih is well overed in many large referene books and is beyond the sope of the present text. BOTHER EXAMINING THE BRAIN POST MORTEM? In most published series, the auray of linial diagnosis of the different diseases that ause dementia is of the order of 70 80%. Establishing a preise diagnosis by post-mortem neuropathologial examination will not, of ourse, benefit the individual patient but matters nonetheless, for several reasons: With rare exeptions, brain tissue from patients with dementia annot be obtained for diagnosis exept post mortem. The post-mortem examination yields aurate epidemiologial data and is an important means of auditing and assuring the quality of linial are. The findings help to eduate liniians, and the post-mortem diagnosti proess to train pathologists. Many neurodegenerative diseases are inherited or are assoiated with speifi geneti risk fators (table 1). Aurate diagnosis is important for assessing the risk to other members of the family. This is a field in whih improvements in understanding of disease aetiology and pathogenesis are rapidly being translated into new approahes to diagnosis and treatment. However, reliane on linial diagnosis without neropsy onfirmation risks misinforming the studies on whih these advanes rely. Prion disease an mimi other dementias but, unlike these, may have publi health impliations, partiularly if the patient has had a surgial proedure or donated tissue that arries a risk of transmission of disease. With rare exeptions, brain tissue from patients with dementia annot be obtained for researh exept post mortem. CONSENT Sine the Bristol Heart Inquiry and the Royal Liverpool Children s Inquiry into the retention of tissue at Alder Hey Hospital (the reports of both inquiries were published in 2001) it has, in the UK, beome muh more diffiult to obtain onsent from relatives for post-mortem examination. This is partiularly so if the examination entails the retention of an entire organ (the brain) for several weeks. As will be evident from the advie below, the proess of obtaining onsent is now quite ompliated and time onsuming. On the plus side, the inquiries into organ retention have led to the formulation of learer guidane as to how onsent should be obtained, the provision of model onsent forms (these an be downloaded from the Department of Health website: TissueGeneralArtile/fs/en?CONTENT_ID = &hk = pjrv4o) and, perhaps, improved publi awareness of both the omplexity and benefits of properly examining the brain post mortem. Written, informed onsent from the next-of-kin is a prerequisite for post-mortem neuropathologial examination of the brain to asertain the ause of dementia; with few exeptions this is requirement applies even if the neropsy is performed on behalf of the oroner or prourator fisal. Several points merit emphasis during disussions with the next-of-kin before the neropsy:

2 Table 1 Neurodegenerative and vasular diseases that present with or often ause dementia: patterns of inheritane and key neuropathologial abnormalities Disease Types of inheritane in familial forms/geneti assoiations Distintive neuropathologial abnormalities Alzheimer s disease (AD) Dementia with Lewy bodies and Parkinson s disease dementia Frontotemporal lobar degenerations (FTLDs): a pathologially and pathogenetially heterogeneous group of diseases haraterised by the restrition of erebral ortial degeneration to frontal and/or temporal regions Cortiobasal degeneration (CBD), progressive supranulear palsy (PSP), and argyrophili grain disease (AGD) Huntington s disease Prion disease Cerebral amyloid angiopathy (CAA) Cerebral autosomal dominant arteriopathy with subortial infarts and leuoenephalopathy (CADASIL) and rarer inherited arteriopathies Autosomal dominant in a minority of ases, due to mutations of: APP (amyloid-b preursor protein gene) PSEN1 (presenilin-1 gene) PSEN2 (presenilin-2 gene) Also has strong assoiation with e4 allele of APOE gene, and partiularly in late onset ases, there is an assoiation between AD and an inrease in the number of mtdna polymorphisms or the presene of mutations in omplex I mtdna. Several other geneti assoiations have been reported (see om/gen/alzgene/) but not onfirmed Very rarely autosomal dominant, due to mutation (Park1) or tripliation (Park4) of SNCA (a-synulein gene) Also has assoiations with e4 allele of APOE and B allele of CYP2D6 gene (for debrisoquine 4-hydroxylase) Several forms of autosomal dominant FTLD (FTDP-17 and some ases of Pik s disease) are aused by mutations in MAPT, enoding the mirotubule assoiated protein tau. Rarely FTLD-U or FTLD-MND/ALS is familial CBD and PSP are assoiated with H1 haplotype of MAPT Autosomal dominant inheritane with antiipation; risk related to extent of CAG expansion in huntingtin gene Autosomal dominant forms of disease due to mutations in PRNP (prion protein gene) aount for a minority of ases CAA is usually sporadi and often ours in assoiation with AD (either sporadi or familial see above), but may be the predominant abnormality in several unommon familial diseases inluding: hereditary erebral haemorrhage with amyloidosis of Duth type (HCHWA-D) due to mutation in APP; hereditary erebral haemorrhage with amyloidosis of Ielandi type (HCHWA-I) due to mutation in ystatin C gene, CYST C; familial British and Danish dementias due to mutations in BRI2 gene CADASIL is aused by mutations in NOTCH3. Another autosomal dominant disease, hereditary endotheliopathy with retinopathy, nephropathy, and stroke (HERNS), is linked to 3p21.3-p21.1. Linkage has not yet been established for erebral autosomal reessive arteriopathy with subortial infarts and leuoenephalopathy (CARASIL) in whih patients also develop spinal dis disease and alopeia Ab plaques diffuse and neuriti Neurofibrillary tangles and neuropil threads Ab amyloid angiopathy in.90% of patients Lewy bodies, of both ortial and brain stem type Lewy neurites,75% of patients also have AD-type neuropathologial abnormalities Pik s disease: Pik bodies, swollen/ahromasi neurons ( Pik ells ), predominane of 3-repeat tau Frontotemporal lobar degeneration and parkinsonism linked to hromosome 17 (FTDP-17): tau immunopositive ytoplasmi inlusions (usually numerous) in neurons, astroytes, and oligodendroglia; relative proportions of 3- and 4- repeat tau depend on mutation FTLD-U: superfiial ortial mirovauolation, ubiquitylated ytoplasmi and nulear inlusions in small neurons in dentate gyrus and superfiial ortex FTLD-MND/ALS: hanges of FTLD-U ombined with those of motor neuron disease/amyotrophi lateral slerosis FTLD-NF: neurofilament immunopositive neuronal ytoplasmi inlusions FTD: FTLD laking demonstrable tau, ubiquitylated or neurofilament inlusions All are assoiated with abnormal neuronal and glial aumulation of 4-repeat tau CBD: nigral degeneration and superfiial ortial mirovauolation, tau-immunopositive neuronal and glial inlusions in basal nulei (espeially nigra ortiobasal inlusions ) and ortex and inluding ortial astroyti plaques; swollen/ahromasi ortial neurons PSP: usually predominantly nigral and other subortial degeneration with tau-immunopositive neuronal and glial inlusions but an involve ortex AGD: grain-like tau immunopositive argyrophili bodies in hippoampus, entorhinal ortex, and some subortial nulei; granular tau immunopositivity of neurons in these regions Striatal degeneration (partiularly of putamen); mild erebral ortial atrophy; nulear inlusions (predominantly neuronal) that label for ubiquitin, polyglutamine, and huntingtin Neuronal loss, mirovauolation of affeted grey matter (spongiform degeneration), severe astroytosis, aumulation of protease resistant prion protein PrP S / PrP Res /PrP P HCHWA-D: Ab amyloid angiopathy mainly affeting ortial and overlying leptomeningeal blood vessels; diffuse Ab plaques HCHWA-I: ystatin C amyloid angiopathy mainly affeting ortial and overlying leptomeningeal blood vessels Familial British and Danish dementias: severe, widespread CAA due to deposition of ABri or ADan, respetively; parenhymal ABri or ADan plaques, some assoiated with dystrophi neurites; tau-immunopositive neurofibrillary tangles and neuropil threads CADASIL: predominantly subortial infarts and ishaemi damage; pronouned thikening of leptomeningeal and parenhymal arteries and arterioles with aumulation of deeply eosinophili, highly eletron dense granular material adjaent to smooth musle ells in the tunial media v9

3 v10 An aurate diagnosis annot be made without the retention and histologial examination of tissue from the brain. The likelihood of establishing the diagnosis will depend on how muh tissue is retained. The likelihood of establishing the diagnosis will also depend on the time onstraints under whih the examination has to be performed. Optimum preservation of the brain for marosopi and mirosopi examination is ahieved by suspending and fixing it intat for 2 3 weeks in formalin. Aurate neuropathologial assessment requires omprehensive sampling, a relatively long proessing shedule for embedding the samples of brain tissue in bloks of paraffin wax, and the use of a range of tintorial and immunohistohemial stains on the setions that are ut from those bloks. Retention of frozen tissue is sometimes needed for western blotting or moleular geneti studies. While diagnoses an sometimes be made by examining limited samples of brain tissue after only relatively brief fixation, this approah inreases the risk of missed diagnosis or misdiagnosis. There is a ompromise to be struk between auray and speed of diagnosis. With these onsiderations in mind, it is important to establish and doument, before the neropsy, what level of assessment is wanted by the next-of-kin in a given ase, and to explain the assoiated advantages or limitations: The family may wish the brain to be retained in its entirety for omprehensive assessment, and not returned to the body before burial or remation. The family may allow the brain to be retained briefly and omprehensively sampled, provided that any remaining tissue is returned to the body within a few days. The family may onsent to only limited post-mortem sampling of brain tissue and indiate that the rest of the brain should be returned to the body at the time of the neropsy. The family may, of ourse, refuse to allow any retention of brain tissue, in whih ase there is little likelihood that an aurate diagnosis an be made. Exept in the event of refusal to allow any tissue retention, the family should be asked whether fresh brain tissue might be frozen and stored for possible protein or moleular geneti analysis. Protools have been proposed to optimise the diagnosti value of the tissue even if onsent is limited to the retention of only a few samples of brain for histology (fig 1). In addition to establishing what level of assessment is wanted, the liniian responsible for obtaining onsent should find out and doument (1) whether the next-of-kin wish the tissue to be used only for diagnosis, or also for audit, teahing, or researh that has the approval of a researh ethis ommittee, and (2) whether tissue remaining after a diagnosis has been made should be kept, disposed of respetfully by the hospital trust, or released for remation or burial. This information should be sought irrespetive of whether or not the patient is to have a hospital neropsy or one performed on behalf of the oroner or, in Sotland, the prourator fisal. In the ase of neropsies performed on behalf of the oroner (but not the prourator fisal), it has, sine the implementation of The Coroners (Amendment) Rules 2005 on 1 June 2005 ( gov.uk/si/si2005/ htm), beome neessary to obtain onsent from the next-of-kin for retention beyond the inquest not only of remaining wet or frozen tissue but also of any tissue in paraffin bloks or in setions on glass slides. Muh of the stress and unpleasantness of dealing with all of these issues an be avoided if the possibility of brain donation is onsidered and disussed before death. A great deal of support and advie is available from organisations suh as the Alzheimer s Soiety ( org.uk) and the Parkinson s Disease Soiety ( parkinsons.org.uk). The Alzheimer s Soiety website inludes a list of brain banks that aept donations from patients with dementia ( Helping_ with_ researh/ info_ braindonations. htm). Most brain banks are very experiened in dealing with families and providing information about the neropsy and examination of the brain. Donation to a brain bank ensures that the diagnosti workup is performed to a onsistent, high standard and that good use will be made of the tissue one the diagnosis has been established. CLINICOPATHOLOGICAL CORRELATION The neuropathologial approah to diagnosis should be informed by the linial history. The approah to postmortem investigation of, for example, frontotemporal dementia or Alzheimer s disease is very different from that to the investigation of erebrovasular dementia or prion disease. It is important that the neuropathologist be provided with a full linial history that inludes information as to the sequene, tempo, and age at onset of linial abnormalities, the neuroradiologial and eletrophysiologial findings at different stages of the disease, the possible involvement of other organ systems (for example liver, bone marrow), and any relevant family history. MAIN TYPES OF DEMENTIA In the great majority of ases, neuropathologial examination reveals one of three types of neurodegenerative disease or ombinations of these: Alzheimer s disease Dementia with Lewy bodies or Parkinson s disease dementia Cerebrovasular disease. ALZHEIMER S DISEASE (AD) Gross examination usually shows erebral atrophy, whih may be pronouned (fig 2). In most ases the atrophy affets all lobes but the oipital lobe may be relatively spared and the medial part of the temporal lobe (partiularly the hippoampus) is generally more severely atrophi than are other parts of the brain. Oasionally the atrophy is predominantly frontal and temporal, and the appearane mimis that of the frontotemporal dementias. On mirosopi examination, AD is haraterised by a ombination of abnormalities: Plaques proteinaeous extraellular deposits that onsist largely of a peptide known as amyloid-b or Ab. Ab is leaved from a larger transmembrane protein amyloid-b preursor protein by the ation of b- and -seretases, and its formation is prevented by the ation of a-seretase (fig 3). These deposits measure up to several hundred mirometres in diameter and are widely distributed throughout the erebral ortex (fig 4). Plaques vary in appearane, and two main subtypes are reognised. Diffuse plaques onsist largely of non-fibrillar extraellular Ab. Neuriti plaques ontain Ab that is mostly in the form of amyloid fibrils, among whih are irregularly swollen dystrophi neurites. The neurites are well visualised with silver stains. Miroglia and astroyte proesses are present towards the periphery of neuriti plaques.

4 Figure 1 Diagram illustrating the minimum set of small bloks (red retangles) of brain needed to establish the diagnosis in most ases of dementia. 1 = middle frontal gyrus; 2 = ingulate gyrus; 3 = superior and middle temporal gyri; 4 = hippoampus and parahippoampal gyrus; 5 = inferior parietal lobule; 6 = putamen and globus pallidus; 7 = midbrain; 8 = pons; 9 = audate nuleus; 10 = erebellar vermis; 11 = hemisphere (inluding the dentate nuleus); 12 = medulla. The illustrated bloks should be supplemented by samples of any marosopially visible lesions that are noted when the brain is slied. Adapted with permission from: Love S. Post mortem sampling of the brain and other tissues in neurodegenerative disease. Histopathology 2004;44: v11 J Neurol Neurosurg Psyhiatry: first published as /jnnp on 16 November Downloaded from Figure 2 Brain atrophy in Alzheimer s disease. The narrowing of gyri and widening of suli involves all of the lobes of the erebrum. The erebellum is marosopially normal. Figure 3 Cleavage of amyloid-b preursor protein. This diagram illustrates that leavage of transmembrane amyloid-b preursor protein by b- and -seretases leads to the formation of Ab. This is prevented by the ation of a-seretase. on 18 August 2018 by guest. Proteted by

5 v12 Figure 4 Ab plaques in Alzheimer s disease. The plaques have been immunolabelled with antibody to Ab and appear as brown strutures. Many of the plaques have a dense entral ore. Neuriti plaques may ontain a dense entral ore of amyloid. The most widely used (CERAD) riteria for a diagnosis of AD require that neuriti plaques be present in densities exeeding ertain illustrated standards, after adjusting for the age of the patient (with age some plaques may our in people who are ognitively normal). Neurofibrillary tangles looped or twisted, skein-like aggregates of filamentous material, largely omposed of hyperphosphorylated tau proteins (fig 5). Most tangles are faintly basophili. They an be impregnated with silver or immunostained for tau to failitate their light mirosopi detetion. Tangles are formed within the neuronal ell body and most remain intraneuronal. However, when neurons degenerate, the tangles persist extraellularly, although they lose their basophilia and some of their affinity for silver salts. The swollen neurites that are present in neuriti plaques ontain tangle-like material, and this also aumulates in numerous fine nerve ell proesses (known as neuropil threads (fig 5)) in the viinity of the tangle bearing neurons. The involvement of different parts of the brain by tangles and neuropil threads follows a stereotyped progression that orrelates well with the evolution of linial disease. The earliest pattern of involvement is usually not assoiated with linial disease: tangles and neuropil threads are restrited to parts of the entorhinal ortex and the CA1 field of the hippoampus. As dementia develops, tangles and neuropil threads aumulate in inreasing density in other parts of the hippoampus and medial temporal neoortex, and then in other ortial regions and in subortial grey matter strutures suh as the hypothalamus and thalamus. A staging sheme devised by Braak and Braak (1995) is widely used to desribe the extent of tangle related abnormalities in AD and orrelates well with the severity of dementia. Cerebral amyloid angiopathy (CAA) the aumulation of Ab in the walls of blood vessels (partiularly arteries and arterioles) in the erebral ortex and overlying leptomeninges. This affets about 30% of normal elderly people but over 90% of patients with AD, in whom the angiopathy tends also to be muh more severe. CAA is an important ause of strokes in the elderly. Most of these are haemorrhagi, although CAA does also inrease the risk of ishaemi strokes and an, if very severe, ause diffuse ishaemi damage to the white matter. As CAA is onfined to superfiial erebral blood vessels, rupture of Figure 5 Neurofibrillary tangles and neuropil threads. The setion has been immunolabelled with antibody to hyperphosphorylated tau protein. The tangles appear as densely labelled flame shaped strutures within several of the nerve ells (arrows). The neuropil threads are present as a fine meshwork throughout the ortex in this figure but form denser aggregates within the neuriti plaques (arrowheads to some). the amyloid laden blood vessels usually auses relatively superfiial, lobar haemorrhages that may extend into the subarahnoid spae. Other abnormalities: redution in the density of synapti proteins in the erebral ortex neuronal loss astroyti gliosis miroglial ativation. DEMENTIA WITH LEWY BODIES (DLB) AND PARKINSON S DISEASE DEMENTIA (PDD) This term enompasses several disorders in whih dementia is assoiated with the presene of Lewy bodies in the erebral ortex. Clinial features in addition to dementia typially inlude parkinsonian extrapyramidal signs (although rarely tremor), flutuating ourse and reurrent visual halluinations. Figure 6 Lewy bodies in substantia nigra. In this ase of dementia with Lewy bodies, several remaining nigral neurons ontain Lewy bodies (arrows): homogeneously stained deeply eosinophili ytoplasmi inlusions that are surrounded by a paler halo. Note the lusters of pigment laden marophages (arrowheads), refleting previous neuronal degeneration.

6 DLB is differentiated linially from PDD on the basis that patients with DLB have had less than one year of parkinsonism preeding their dementia, but it is not possible to distinguish the findings in the two groups neuropathologially. There is also onsiderable overlap between the neuropathologial findings in DLB and those in patients whose Parkinson s disease is not ompliated by dementia. Gross examination of the brain may show little in the way of abnormalities apart from poor pigmentation of the substantia nigra in the midbrain and loi erulei in the pons. On mirosopi examination, DLB and PDD are haraterised by: Lewy bodies eosinophili neuronal ytoplasmi inlusions, the prinipal omponent of whih is a-synulein. Lewy bodies are almost invariably present in the substantia nigra and loi erulei, whih also show neuronal loss and gliosis, and may also be found in the dorsal motor nuleus of the vagus. In these brain stem nulei, Lewy bodies are usually roughly spherial, with an eosinophili ore surrounded by a paler halo (fig 6). Within the erebrum, Lewy bodies are usually present in the amygdaloid nulei, parahippoampal and ingulate gyri, and insula, but may also be found in other parts of the neoortex. The holinergi nuleus basalis of Meynert is generally affeted. Cortial Lewy bodies appear as regions of homogeneous eosinophili staining in the neuronal ytoplasm, usually assoiated with eentri displaement of the nuleus. The Lewy bodies are best visualised immunohistohemially, with antibody to a-synulein (fig 7). Lewy neurites these are nerve ell proesses that ontain aggregates of a-synulein (fig 6). These abnormal strutures an our in both DLB/PDD and idiopathi Parkinson s disease and are most numerous in the CA2/3 region of the hippoampus and in the substantia nigra. Other abnormalities: A high proportion of patients with DLB/PDD (about three quarters) also have AD-type neuropathologial abnormalities. Although diffuse plaques may be abundant, in many ases there are too few neuriti plaques or neurofibrillary tangles to fulfil CERAD or other diagnosti riteria (for example, those of the NIA and Reagan Institute) for a diagnosis of definite AD or high probability of AD. However, in a signifiant proportion Figure 7 Lewy bodies in the erebral ortex. These Lewy bodies in the ingulated gyrus have been immunostained for a-synulein. Note the sattered fine Lewy neurites in the surrounding neuropil that are also immunopositive for a-synulein. of ases a diagnosis of ombined AD and DLB/PDD is appropriate. Some patients with DLB show mirovauolation of the erebral ortex, predominantly in the medial temporal regions. This an lead to misdiagnosis of prion disease. DEMENTIA CAUSED BY CEREBROVASCULAR DISEASE The development of dementia as a result of ishaemi erebrovasular disease is relatively ommon. However, while the pathologial features in dementia aused by severe erebrovasular disease are well reognised, they form a ontinuum with abnormalities that an our in the absene of dementia. There are no objetive neuropathologial riteria to indiate the threshold for making this diagnosis. Ishaemi abnormalities of mild to moderate severity are often found in onjuntion with hanges of AD or DLB and may ontribute to the dementia in many patients with those diseases. Gross examination of the brain typially reveals mild to moderate, often asymmetrial, dilatation of the lateral ventriles. The basal arteries are often atheromatous but this may be quite mild, with the bulk of the pathology related to small vessel disease (see below). The white matter usually appears irregularly pitted or granular and ontains ill defined foi of yellow or grey disoloration. Sattered launar infarts are almost always present. In some ases the brain ontains one or more larger infarts; these may our in the watershed regions between the perfusion territories of the major erebral arteries. In a few patients, the dementia is aused by hippoampal slerosis, and the hippoampi may appear greyish brown, shrunken, and granular. Rarely bilateral infarts involving the hippoampus or thalamus are the ause of dementia. Mirosopially, erebrovasular dementia is assoiated with: Degenerative hange of small blood vessels, espeially in the deep erebral white matter and basal ganglia. Small arteries and arterioles have thikened, hyaline walls with replaement of smooth musle by ollagen. There is often enlargement of perivasular spaes. Rarefation of white matter, due to a ombination of nerve fibre degeneration, gliosis, and pathy demyelination. Small foi of avitation, and lipid laden marophages are usually present. Miroinfarts in the erebral ortex. Sparsely sattered miroinfarts are a ommon finding in erebrovasular dementia. Oasionally the ortial miroinfarts are quite numerous. Other abnormalities: These an inlude foi of old haemorrhage (with lusters of haemosiderin laden marophages), erebral amyloid angiopathy (sometimes severe), and hippoampal slerosis. NORMAL PRESSURE HYDROCEPHALUS The lassial linial triad omprises early disturbane of gait, urinary inontinene, and impaired ognition, the last of these usually manifesting later than the other features. Features of frontal lobe dysfuntion are ommon. Gross examination of the brain reveals dilatation of the lateral and third ventriles. The leptomeninges may show fibrous thikening. On mirosopy, there are multiple large gaps in the ependymal lining, the periventriular region is glioti, and the deep white matter often ontains ishaemi lesions. v13

7 v14 PRION DISEASES These diseases, of whih the most ommon form is sporadi Creutzfeldt-Jakob disease (CJD), are relatively rare auses of dementia. They are aused by the aumulation within the brain of a normal ellular protein, prion protein (PrP), in an abnormal, protease resistant onformation, PrP Res. Through a poorly understood mehanism, onversion of abnormal to normal prion protein is failitated by the presene of the abnormal form of the protein and is therefore self perpetuating. Variant CJD is a prion disease that probably resulted from the transmission of PrP Res to humans, via food, from attle with bovine spongiform enephalopathy. Iatrogeni CJD is the term given to prion disease whih results from inadvertent transmission of CJD from human to human during medial or surgial proedures. A minority of prion diseases is aused by mutation in the prion protein gene, PRNP. The importane of this group of diseases is due largely to the transmissibility of the disease and the hardiness of PrP Res, whih is resistant to onventional disinfetants and sterilisation proedures. Transmission may result from the use, for invasive surgial proedures, of instruments that have previously been in ontat with tissue ontaining PrP Res, or from the donation of blood (at least in the ase of variant CJD) or tissue from patients with linial or prelinial prion disease. The initial linial presentation of sporadi CJD is very variable and an inlude visual disturbanes and ataxia, but rapidly progressive dementia soon beomes the dominant linial abnormality. This is generally aompanied by myolonus, and periodi sharp wave omplexes in eletroenephalogram (EEG) traes. Death ours within six months of disease onset. Whereas sporadi CJD is usually a disease of the middle aged or elderly, variant CJD typially affets young adults psyhiatri and sensory symptoms are ommon early manifestations, the duration is usually in exess of 12 months, and myolonus and periodi sharp wave omplexes are often laking. On gross examination, the brain in CJD may appear entirely normal. Less often it shows obvious atrophy. Mirosopy reveals aumulation of PrP Res within affeted parts of the ortial and subortial grey matter, and spongiform hange fine vauolation of the neuropil, assoiated with neuronal loss and astroytosis. Miroglial ativation is usually pronouned but lymphoyti inflammation minimal. The preise distribution and pattern of aumulation of PrP Res varies aording to the type of prion disease, the strain of prion agent, and the sequene of the two PRNP alleles in partiular, whether either or both of the odons at position 129 enodes methionine or valine. Further information about the pathogenesis and pathology of prion diseases is inluded in the referenes at the end of this review. OTHER NEURODEGENERATIVE AND CEREBROVASCULAR CAUSES OF DEMENTIA Table 1 lists some of the other neurodegenerative and erebrovasular diseases that an ause dementia and summarises the key neuropathologial abnormalities. A wide range of other degenerative diseases, infetions, metaboli diseases and tumours an also ause dementia. For more detailed desriptions of these diseases and their linial and pathologial features, the reader should onsult the major reviews and referene texts ited in the bibliography. APPROACH TO NEUROPATHOLOGICAL DIAGNOSIS Neuropathologial diagnosis must be guided by the linial information, inluding the family history, age of onset of disease, tempo and sequene of manifestations, and the neuroradiologial and eletrophysiologial findings. For example, the approah to diagnosis of rapidly progressive dementia in an elderly person with periodi sharp waves on eletroenephalography is very different from that to a middle aged patient with a family history of strokes and dementia. There are published guidelines on the post-mortem sampling of brains for histology in dementia, and protools for the diagnosis and staging of the diseases responsible. Neuropathologial assessment is best performed in a entre with neuropathologial expertise. Diffiulties in diagnosis are most often aused by inappropriate initial handling and sampling of the tissue, inadequate fixation, and poor proessing and embedding due to the use of routine histology protools rather than the longer yles required for brain tissue. REFERENCES 1 Dikson DW. Required tehniques and useful moleular markers in the neuropathologi diagnosis of neurodegenerative diseases. Ata Neuropathol (Berl) 2005;109: Esiri MM, Lee M-Y, Trojanowski JQ. The neuropathology of dementia, 2 ed. 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