Dementias

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31

Dementias

INTRODUCTION

Diseases causing dementia are among the commonest neurologic conditions encountered in clinical practice (Table 31.1). The importance of establishing a neuropathologic diagnosis dementia can be linked to the following:

Table 31.1

Prevalence of dementia at different ages

Age (years) Prevalence (%)
<75  4
80 12
85 27
90 40

image DEMENTIA

Definition

image Dementia can be defined as an impairment of previously attained occupational or social functioning due to an acquired and persistent impairment of memory associated with an impairment of intellectual function in one or more of the following domains: language, visuospatial skills, emotion, personality, or cognition, in the presence of normal consciousness.

image The concept that a person has previously attained a high degree of occupational and social functioning separates dementia from mental retardation.

image Impairment of consciousness, such as occurs in delirium or a confusional state, precludes a clinical diagnosis of dementia.

image Involvement of multiple domains of cognitive function separates dementia from focal neurobehavioral disorders (e.g. isolated amnesia due to bilateral hippocampal damage, or isolated dysphasia due to a localized infarct).

image Dementia is predominantly caused by degenerative processes that evolve over many years (Table 31.2). Different diseases preferentially affect different brain regions and so distinctive clinical patterns of dementia can be recognized (Fig. 31.1). With progression of the disease, more of the cortical areas tend to be affected and a global deterioration in intellectual function ensues.

Table 31.2

Causes of dementia

Neurodegenerative diseases

Common

Less common

Rare

Cerebrovascular disease

Hydrocephalus

Toxic, metabolic, and nutritional disorders

Immune-mediated syndromes

Mitochondrial encephalopathy

Demyelinating and dysmyelinating diseases

Head injury

Prion disease

Infective disorders

Neoplasia

Certain clinical patterns of dementia are suggestive of particular disorders

Clinical diagnosis

image The degenerative processes that cause cortical pathology may also affect subcortical structures and lead to other neurologic dysfunction, the most common of which is the development of parkinsonism. Identification of associated neurologic abnormalities may therefore help in establishing an accurate diagnosis.

image Several clinical bedside tests of cognitive function have been developed to assist in the diagnosing of dementia, but these mainly detect dysfunction of the temporal and parietal lobes, and are less sensitive to frontal lobe dysfunction. A commonly used bedside test is the mini-mental state examination (MMSE).

image The clinical term ‘mild cognitive impairment’ (MCI) is used when patients have evident clinical cognitive problems, but have no impairment in activities of daily living. Follow-up studies show that patients deteriorate and develop dementia at a rate of about 10–15% per year.

TEMPOROPARIETAL AND FRONTOTEMPOROPARIETAL DEMENTIAS

ALZHEIMER’S DISEASE (AD)

AD is the commonest cause of dementia and increases in incidence with age. It accounts for 50–75% of all cases of dementia, the precise figure depending on the criteria used to establish the diagnosis. There are five main groups, with different molecular genetic associations (see p. 628):

About 10–20% of patients have a first-degree relative with dementia.

image CLINICAL FEATURES OF ALZHEIMER’S DISEASE

MACROSCOPIC APPEARANCES

The brain shows atrophy and the weight is usually in the range of 900–1200 g. There is shrinkage of cerebral gyri and widening of sulci, most prominently in the medial temporal regions (particularly the hippocampus) but also in the frontal and parietal regions. Generally, the occipital lobe and the motor cortex are relatively spared. This pattern of atrophy occurs in several dementing diseases and is not specific for AD (Fig. 31.2).

In slices of fixed brain, the cortical mantle may appear thinned (Fig. 31.3). The white matter is of normal color and texture, but reduced in volume. There may be significant dilatation of the ventricular system, especially of the temporal horn of the lateral ventricles. In the midbrain, the substantia nigra is usually normally pigmented but can appear pale. The locus ceruleus is often paler than normal. Cerebral infarcts or hemorrhages may be encountered and can be related to cerebrovascular amyloid deposition or coexistent arteriosclerotic disease.

HISTOPATHOLOGY OF ALZHEIMER’S DISEASE

AD is characterized by several histologic abnormalities, none of which is specific to this disease. Special stains are required for evaluation (Table 31.3).

Table 31.3

Stains used in the histologic assessment of Alzheimer’s disease

Much of the pathology associated with Alzheimer’s disease cannot be easily seen without special stains

Sections stained with H&E are used for general morphology and can be used to evaluate neuronal loss as well as any general morphological changes, e.g. associated areas of infarction. Granulovacuolar degeneration and Hirano bodies are also easily seen (Figs 31.5, 31.6)

Silver stains are still used in diagnosis and can be divided into:

Methods that are very sensitive for amyloid (e.g. modified methenamine silver techniques). These detect all plaques and a minority of tangles (Fig. 31.7)

Methods that are very sensitive for the detection of tangles and the abnormal nerve processes around plaques but do not tend to stain amyloid (e.g. the Gallyas technique, several modifications of the Palmgren silver impregnation (Fig. 31.8), and some modifications of Bodian and Bielschowsky methods)

Methods that are optimized to detect both plaques and tangles. These tend to underestimate the density of either plaques or tangles. This is true of most modified Bodian and Bielschowsky techniques, which underestimate the total amount of amyloid in sections

In most laboratories, specific staining of plaques and tangles is now performed by immunohistochemistry with commercially-available antisera:

Plaques are detected with antisera to Aβ peptide after formic acid pretreatment of sections. This will also detect vascular amyloid (Fig. 31.9)

Tangles, plaque neurites and neuropil threads are detected by immunostaining for phosphorylated tau protein, the main protein constituent of tangles (Fig. 31.9)

Major pathologic changes are:

Associated pathologic changes are:

image Amyloid (also derived from Aβ peptide) deposition in arteries and arterioles in the cerebral and cerebellar cortex and leptomeninges (congophilic angiopathy/cerebral amyloid angiopathy) is demonstrable in over 90% of cases, although the extent of this is very variable (Fig. 31.4). Small amounts of Aβ may also accumulate in the walls of small veins.

image Granulovacuolar degeneration (Fig. 31.5) affects greater numbers of hippocampal pyramidal neurons in AD than in age-matched controls and may also be seen in subcortical nuclei. These represent autophagic activity.

image Hirano bodies, composed of actin-binding proteins, tend to be more numerous in AD than in age-matched controls in neurons in the hippocampal CA1 field and subiculum (Fig. 31.6).

image There is increased accumulation of lipofuscin in neurons (see Chapter 1).

image Corpora amylacea may be seen in large numbers (see Chapter 1).

The structural changes seen in AD can be found in the brains of cognitively normal elderly individuals in low density or restricted distribution. The diagnosis of AD is based on the presence of lesions in high density and extended distribution in a patient with clinical evidence of dementia (see Pathologic diagnostic criteria for AD, below).

Diffuse Aβ deposits

Diffuse deposits of Aβ peptide are seen on immunostaining as loose structures with irregular, ill-defined margins. In this form of deposit, the majority of protein is not aggregated as amyloid filaments (Table 31.4). Diffuse deposits are the main type of plaque seen in normal aging. Some diffuse Aβ deposits are described as fleece- or lake-like. Diffuse deposits may be seen in the subpial region in the cerebral cortex.

Focal Aβ deposits

Amyloid plaques are extracellular proteinaceous deposits composed of Aβ peptide, largely as amyloid filaments. Neuronal processes that traverse the plaque region show variable abnormalities and are termed plaque-associated dystrophic neurites. Plaques associated with abnormal neurites are termed neuritic plaques.

There are three main types of focal plaque deposit:

It is believed that there is progression from diffuse, through primitive to classic and finally burnt-out plaques, but there is no direct evidence for this. Plaques are widely distributed in the brain in AD. The neocortex and hippocampus are always involved. As disease progresses, plaques may also be present in the basal ganglia (where the great majority are diffuse), hypothalamus, the tegmentum of the midbrain and pons, the cerebellum (where all are diffuse), and the subcortical cerebral white matter.

Neuritic changes in plaques

Neuritic plaques include tau-immunoreactive dystrophic neurites (see Neuritic abnormalities in AD, below, and Fig. 31.11). In some neuritic plaques there are dystrophic neurites that contain chromogranin A and ubiquitin, but not tau protein; of the sparse neuritic plaques that may be present in the brains of cognitively normal elderly subjects, this form predominates. A variety of other plaque amyloid-related proteins can be demonstrated immunohistochemically, including apolipoprotein E (apoE), α1-antichymotrypsin, serum amyloid-P protein, growth factors, heparin sulfate, and complement factors.

image MOLECULAR PATHOLOGY OF PLAQUE Aβ

image APP is a normal transmembrane glycoprotein. The gene is located on chromosome 21, and several different mRNAs are generated by alternative splicing. The predicted structure of APP consists of three domains (Fig. 31.10): a small cytosolic domain, a transmembrane domain, and a large extracellular domain.

image The function of APP is uncertain, but suggestions center around its action as a cell surface receptor with roles in cell–cell and cell–matrix interactions.

image In normal cells APP is mainly processed in a non-amyloidogenic pathway by several proteases. Enzymes called α-secretases cut APP near the middle of the Aβ region, precluding the generation of Aβ (Table 31.4). α-secretase activity is linked to several proteases, including those of the ADAM (A Disintegrin And Metalloproteinase) family. The N-terminus of the peptide is generated when another enzyme complex, with so-called γ-secretase activity, cleaves APP within its transmembrane domain. The activity of γ-secretase is linked to the function of the presenilins (Fig. 31.11).

image A second, amyloidogenic pathway for cleavage of APP is involved in the pathogenesis of AD (Figs 31.12 and 31.13). This involves the action of two proteolytic activities, β-secretase and γ-secretase. β-Secretase activity is mediated by an enzyme called β-site APP-cleaving enzyme (BACE). Subsequent γ-secretase cleavage yields Aβ peptide fragments of different lengths, the main products comprising 40 or 42 amino acids. Aβ peptide in plaques is mainly a 42-residue form of Aβ (Aβ42) (Fig. 31.14). Aβ42 is believed to be more amyloidogenic than Aβ40.

image The formation of small amounts of Aβ is a normal event, occurring throughout life. The Aβ is normally cleared from the brain by proteolytic breakdown (e.g. by the enzyme neprilysin), microglial phagocytosis, transport across cerebrovascular endothelial cells into the bloodstream, drainage in interstitial fluid along the perivascular extracellular matrix, probably to cervical lymph nodes, and via CSF pathways.

image THE AMYLOID CASCADE HYPOTHESIS OF AD

image Several lines of evidence point to a primary role for Aβ amyloid in the pathogenesis of AD:

image The amyloid cascade model (Fig. 31.15) proposes a central role for Aβ amyloid in the pathogenesis of AD. The link between Aβ generation and the formation of NFTs is not yet known. It is also unclear as to what extent the development of AD may depend on the accumulation of soluble forms of Aβ – particularly that in the form of small, soluble aggregates (oligomers) – rather than (or in addition to) the fibrillar forms that form plaques.

image Arguments against the amyloid cascade model of AD are that cognitively normal individuals can have very large numbers of neocortical plaques (although predominantly of diffuse type), and only sparse NFTs, and also that the correlation between plaque density and the severity of dementia is relatively weak. Plaque formation in AD may be secondary to another, more fundamental, cellular pathologic process.

Neurofibrillary tangles

Neurofibrillary tangles are neuronal inclusions composed largely of filamentous aggregates of hyperphosphorylated tau proteins that are variably ubiquitylated and glycated. In sections stained with hematoxylin and eosin, intracellular NFTs are faintly basophilic and extracellular NFTs appear eosinophilic (Fig. 31.16). In sections stained by silver impregnation, or when immunostained, several morphologic forms of NFT can be identified, the shape of the NFT probably being determined by that of the neuron containing it. A multi-stage model of NFT formation has been proposed (Fig. 31.17). Ultrastructural investigation reveals that NFTs are composed of paired helical filaments (PHFs) with a maximum diameter of 20 nm and a periodic narrowing to 10 nm every 80 nm (Fig. 31.18). A small proportion of filaments is straight, with a diameter of 15 nm. Detailed examination of PHF preparations shows that the filaments have a dense core region with a surrounding fuzzy coat.

NFTs are readily detected by antisera directed against phosphorylated tau protein (Fig. 31.19). Many NFTs are immunoreactive for ubiquitin or P62 (Fig. 31.20). Neurofibrillary tangles can be seen in elderly brains in low density and restricted distribution as well as in a variety of other conditions. Hence, they are not specific to AD (Table 31.5). In AD, the density of NFTs is closely related to the severity of dementia.

Table 31.5

Disorders associated with neurofibrillary tangles

Progressive supranuclear palsy (PSP)

Down syndrome

Dementia pugilistica

Postencephalitic parkinsonism

Parkinsonism dementia complex of Guam

Subacute sclerosing panencephalitis

Niemann–Pick disease type C

Familial British dementia

Myotonic dystrophy

Kufs’ disease

Neuronal brain iron accumulation type-1

Gerstmann–Straüssler–Scheinker syndrome

Cockayne syndrome

Neuritic abnormalities in AD. There are two main forms:

image Plaque-related dystrophic neurites, which are abnormally distended nerve cell processes running through Aβ plaque deposits. Some of the neurites contain increased amounts of lysosome-related dense bodies, but no PHFs, and immunostain for chromogranin A and ubiquitin, but not tau protein. Other neurites contain PHFs ultrastructurally and are immunoreactive both for tau protein and variably for ubiquitin (Fig. 31.11).

image Neuropil threads (NTs), which are fine, distorted, and twisted nerve cell processes that are immunoreactive for tau protein (Fig. 31.21) and variably for ubiquitin. Ultrastructural examination shows nerve cell processes that contain a mixture of PHFs and straight filaments (Fig. 31.18).

Perisomatic granules. Immunostaining for ubiquitin reveals densely-labeled round bodies adjacent to pyramidal neurons representing distended, retracted synaptic boutons. These are termed perisomatic granules (Fig. 31.21).

Tangle-associated neuritic clusters in AD. Tau immunostaining may show shows filamentous aggregates in the pyramidal cell region of the hippocampus. Although these superficially resemble plaque neurites, there is no associated focal accumulation of Aβ. These clusters represent ingrowth of tau-containing cell processes into a region previously occupied by a NFT (Fig. 31.22).

Neuronal and synaptic loss in AD. A 30–40% loss of neocortical neurons can be demonstrated in advanced AD, particularly in young-onset patients. The neuronal loss is associated with astrocytic gliosis and, in some cases, cortical microvacuolation, the latter often termed status spongiosus (Fig. 31.23). This pattern of vacuolation is coarser than that typically seen in prion disease and is largely confined to the outer cortical layers. In AD, synaptic loss of 30–50% can be demonstrated by quantitation of synapse-related proteins in affected cortical regions. The most widely used marker is synaptophysin, a glycoprotein associated with synaptic vesicles. The degree of synaptic loss correlates well with clinical scores of the severity of dementia.

Glial pathology in AD. Reactive astrocytes occur in and around neuritic plaques, and in areas of neuronal loss and cortical microvacuolation. Microglial activation occurs in relation to plaque amyloid. This close association has led to speculation that microglia are responsible for amyloidogenic processing of Aβ peptide. Aβ-induced activation of microglia may also lead to secretion of cytokines which are potentially neurotoxic.

image MOLECULAR PATHOLOGY OF TAU PROTEIN IN NFTs

image NEUROCHEMICAL PATHOLOGY OF AD

image Neurochemical analysis of brains has shown widespread transmitter defects in the brains of patients with AD.

image There is a marked loss of acetylcholine from the cerebral cortex in AD. This is related to loss of neurons from the nucleus basalis of Meynert (in the basal forebrain), which is the major cholinergic input nucleus to the cerebral cortex. Several treatments that augment cholinergic transmission are being used or tested in AD.

image There is loss of neurotransmitters associated with intrinsic neurons in the cerebral cortex (e.g. GABA), in-keeping with neuronal and synaptic loss from these regions.

image 5-hydroxytryptamine (5-HT; serotonin) input to the cerebral cortex is reduced. This is related to a loss of neurons from the serotoninergic dorsal raphe nuclei and may correlate with depression in AD.

image Noradrenergic input to the cortex is reduced as a consequence of the variable loss of neurons from the locus ceruleus.

White matter pathology in AD. Pallor of myelin staining of central hemispheric white matter is quite common in AD. In some cases this is related to microvascular changes of coincidental arteriolosclerosis. In other cases pallor of myelin occurs in the absence of vascular abnormalities.

Subcortical involvement in AD. Many subcortical regions are involved by plaques, NFTs, or NTs in AD (Table 31.6). Some regions, such as the dorsal raphe nucleus, are affected at an early stage of disease. Involvement of the nucleus basalis of Meynert is especially important, as this is the cholinergic projection nucleus to the cerebral cortex. Cell loss from this nucleus results in a severe cholinergic deficit in the cerebral cortex in AD.

Pathologic staging of AD

The evolution of pathologic changes in AD is fairly predictable and was subdivided into several stages by Braak and Braak, originally using silver staining and subsequently on the basis of immunohistochemistry for hyperphosphorylated tau protein.

Plaque stages correlate poorly with the severity of dementia (Fig. 31.24) and are:

NFT stages correlated well with the severity of dementia (Fig. 31.25). The Braak staging of neurofibrillary degeneration is incorporated in the 2012 National Institute on Aging–Alzheimer’s Association (NIA-AA) guidelines for the neuropathologic assessment of Alzheimer’s disease neuropathologic criteria for diagnosis of AD (p. 625). The BrainNet Europe Consortium has validated a scheme incorporating immunohistochemistry for hyperphosphorylated tau instead of silver staining for staging of neurofibrillary changes in AD (Fig. 31.26).

Pathologic diagnostic criteria for AD

Difficulties in making a pathologic diagnosis of AD occur because the histologic changes are not entirely pathognomonic and overlap those in the cognitively normal elderly. The diagnosis of AD should be restricted to cases with both plaques and NFTs in the hippocampus and neocortex (extending at least to Braak stage 4), and a clinical history of dementia.

Several different criteria have been proposed for the pathologic diagnosis for AD:

image The Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) guidelines for the diagnosis of AD have been widely used and are based on semi-quantitative assessment of neuritic plaque density by comparison with standard reference illustrations (Tables 31.7–31.9, Figs 31.24, 31.25). This has been shown to have good reproducibility between different laboratories. The patient’s age and the clinical history of dementia are taken into account in determining the diagnostic category for each case. The CERAD scheme specifies silver staining or fluorescent dye staining, which has prompted workers to evaluate equivalent immunohistochemical staining methods for evaluation of cases.

Table 31.7

CERAD protocol for diagnosis of Alzheimer’s disease

Macroscopic appearance

The following features are noted:

brain weight

regional neocortical atrophy and ventricular enlargement (rated semiquantitatively as none, mild, moderate, or severe)

atrophy of the hippocampus and entorhinal cortex (present or absent)

pallor of the substantia nigra and locus ceruleus (present or absent)

atherosclerosis, significant obstruction or aneurysms of cerebral blood vessels (present or absent)

lacunar infarcts, regional infarcts, hemorrhages (number, size, frequency, distribution, and laterality recorded)

Histologic sampling and staining

A minimum of six anatomic regions is designated for histologic examination (Fig. 31.26):

middle frontal gyrus

superior and middle temporal gyri

anterior cingulate gyrus

inferior parietal lobule

hippocampus and entorhinal cortex

midbrain including the substantia nigra

Paraffin-embedded sections are cut at a thickness of 6–8 μm and stained with:

Hematoxylin and eosin (H&E)

A silver stain, such as the modified Bielschowsky impregnation, for the detection of neuritic plaques and neurofibrillary tangles

Thioflavin-S stained sections viewed under UV light can be used to assess plaques, tangles, and vascular amyloid

A Congo red stain can be used for evaluating vascular amyloid

Diagnostic classification

The CERAD classification is performed in three steps:

A semiquantitative assessment is made of the density of neuritic plaques (i.e. that include thickened, silver-impregnated neurites) in the sections of the neocortex. The density is scored by comparison with reference photomicrographs and diagrams as none, sparse, moderate, or frequent (Fig. 31.27). The density of tangles is also estimated but this does not contribute to the diagnostic classification in the CERAD protocol

An age-related plaque score is obtained by relating the maximum plaque density in sections of frontal, temporal, or parietal cortex, to the age of the patient at death (in the ranges <50, 50–75, or >75 years) (Table 31.8)

The age-related plaque score is then integrated with the clinical presence or absence of dementia to allow cases to be categorized as normal with respect to AD, probable AD, or definite AD (Table 31.9)

Table 31.9

CERAD diagnostic groups

Normal (with respect to Alzheimer’s disease or other dementing processes) if:

Either

No histologic evidence of Alzheimer’s disease (0 score), and no clinical history of dementia, and absence of other neuropathologic lesions likely to cause dementia

Or

An A age-related plaque score and no clinical history of dementia

CERAD NP definite Alzheimer’s disease

C age-related plaque score, and clinical history of dementia, and presence or absence of other neuropathologic lesions likely to cause dementia

CERAD NP probable Alzheimer’s disease

B age-related plaque score, and clinical history of dementia, and presence or absence of other neuropathologic lesions likely to cause dementia

CERAD NP possible Alzheimer’s disease if:

Either

A age-related plaque score, and clinical history of dementia, and presence or absence of other neuropathologic lesions likely to cause dementia

Or

B or C age-related plaque score and absence of clinical manifestations of dementia

image The Thal plaque phase is a scheme that stages the regional involvement of accumulation of Aβ in the brain into five phases. Aβ detected exclusively in neocortex (phase 1), additionally in allocortex (phase 2), extending to diencephalon and striatum (phase 3), involving brainstem (phase 4), and present in cerebellum (phase 5).

image The NIA-AA criteria were developed in recognition that AD has to be defined as a clinico-pathologic entity and that within that clinical diagnostic group there may be pathologic variation. It is recommended that finding pathologic changes of AD in the brain at autopsy are reported as ’AD neuropathologic changes’.

image Aβ plaques are staged according to the Thal Phase scheme (A).

image NFT stage is determined according to the Braak criteria (B).

image Neuritic plaques are scored according to the CERAD scheme (C) (Fig. 31.27, Table 31.10).

Table 31.10

ABC scoring scheme for AD neuropathologic change

image

Modified from National Institute on Aging-Alzheimer’s Association guidelines for the neuropathologic assessment of Alzheimer’s disease, 2012.

Combining these three scores (‘ABC scoring’) allows the pathologist to allocate a probability that AD-associated abnormalities accounted for the patient’s dementia in life. AD lesions seen in the post-mortem brain from cognitively normal elderly people are considered pathologic rather than a part of a normal aging process. The likelihood that clinical dementia has been caused by AD lesions in the brain is stratified on the basis of the post-mortem neuropathologic findings, as follows (Table 31.11):

Patients who have plaques and NFTs in a very restricted density or distribution or who are not clinically demented are best classified as having ‘Alzheimer’s disease neuropathologic change’, as this does not pre-judge the nature of their disease.

Patients who have a restricted distribution of tau immunoreactive structures not meeting criteria for a specific tauopathy and not fitting with a Braak stage can be designated as having ‘Stage + neurofibrillary change’.

In applying earlier NIA–Reagan criteria, it became apparent that many laboratories had moved away from use of silver-stained preparations in evaluating AD pathology and that alternate approaches were desirable. The BrainNet Europe group published staging criteria based on evaluation of tau-labeled histologic sections from four brain regions (Figs 31.27–31.30).

DIFFICULTIES IN DIAGNOSING AD

In some patients with dementia, neuropathologic examination reveals NFTs in cortical and subcortical areas in the absence of significant numbers of plaques.

image Specific tauopathies such as PSP (see Chapter 28) and CBD (see Chapter 28, and later in this chapter) may present as a dementia syndrome or a syndrome of parkinsonism and dementia. A search for the characteristic abnormalities should be made of subcortical structures known to be affected in these disorders. Cortical regions should be assessed for swollen neurons characteristic of CBD, and both cortex and white matter should be examined for tau-immunopositive glial inclusions.

image Tangle-only dementia (see below) is an uncommon but increasingly recognized disorder.

Some patients have an abundance of plaques but very few NFTs.

Some patients have Alzheimer changes in a restricted distribution or associated with other pathologic features. Consider the following:

image Limbic AD, characterized by clinical dementia and large numbers of NFTs restricted to the amygdala and hippocampus but with large numbers of neocortical plaques.

image Two pathologic subtypes of AD have been suggested: typical AD (~75% cases) and hippocampal sparing or limbic-predominant AD (~25% of cases).

image Asymmetric AD. The changes of AD may rarely be asymmetric so that one hemisphere is preferentially affected.

image Posterior AD. Severe disease preferentially affecting the occipital and visual-association areas with pathologic features of AD has been reported.

image Frontal AD. AD pathology may be most marked frontally and associated with the clinical features of frontotemporal dementia.

image Swollen neurons in AD. In a few cases swollen cortical neurons are a feature of disease that would otherwise be pathologically typical of AD. Care should be taken to ensure that the case does not meet criteria for CBD (see Chapter 28, and below) and that grain pathology is not present (p. 639).

image AD with other degenerative diseases. AD pathology can occur in association with other degenerative diseases such as Parkinson’s disease, Huntington’s disease, Pick’s disease or prion disease.

image AD with vascular disease. There may be ischemic or hemorrhagic disease due to the cerebral and cerebellar amyloid angiopathy in AD (see Chapter 10), and AD is often associated with atherosclerotic and/or arteriosclerotic vascular disease of the brain; a diagnosis of mixed AD and vascular dementia is appropriate in some cases.

LEWY BODIES IN DEMENTIA SYNDROMES

The routine use of antibodies to α-synuclein, which detects Lewy bodies, has shown that dementia can be associated with Lewy bodies in different brain regions, as follows:

image Some patients have a primary clinical dementia syndrome, characterized by fluctuation, early visual hallucinations, extrapyramidal tremor, which meets clinical criteria for dementia with Lewy bodies (DLB). These patients typically have Lewy bodies in brain stem and midbrain nuclei as well as widespread involvement of neocortex and limbic cortex by Lewy bodies. Many have AD-type pathology.

image Some patients present with pure motor Parkinson’s disease (PD) but later develop dementia when the condition is termed Parkinson’s disease dementia (PDD). They have changes as seen in classical PD with Lewy bodies in midbrain and brain stem nuclei. They also commonly show widespread involvement of neocortex and limbic cortex by Lewy bodies and many have AD-type pathology.

image In a significant proportion of patients with clinical and neuropathologically confirmed AD, use of immunohistochemistry for α-synuclein shows Lewy bodies restricted to neurons in the amygdala (AD with amygdala Lewy bodies).

image GENETIC FACTORS IN ALZHEIMER’S DISEASE

Down syndrome and Alzheimer’s disease

Patients with Down syndrome (trisomy 21) develop pathologic lesions of Alzheimer’s neuropathology with age. Clinical dementia typically develops by 40 years. This is believed to be related to triplication of the APP gene on Chr 21 and aligns strongly with the amyloid cascade hypothesis. The earliest changes are deposition of Aβ as diffuse plaques with later development of tau pathology as neuritic plaques and neurofibrillary tangles.

Familial Alzheimer’s disease

A small number of kindreds worldwide have autosomal dominant forms of AD. Three genes have been linked, those for APP (APP), presenilin-1 (PSEN1) and presenilin-2 (PSEN2). Affected patients typically develop early-onset AD. In some patients with PSEN mutations, there is spastic paraparesis.

Genetic risk factors for late onset sporadic Alzheimer’s disease

Genome-wide association studies as well as earlier linkage studies have identified several genes that increase the risk of development of AD and which now account for about 50% of the genetic risk in late-onset sporadic AD. Four main pathways can now be suggested as being linked to AD risk by a small set of genes. There is probably significant interplay between each pathway.

image

Familial AD is rare and caused by mutations in a small number of genes linked to APP handling and formation of amyloid. Late onset sporadic AD is common and is probably linked to several genes as part of four main pathways leading to disease. These pathways interact with each other and also environmental factors, e.g. head injury, and may then result in development of AD. How these genes and pathways cause lesions of AD is not yet known.

CLU, clusterin; PICALM, phosphatidylinositol-binding clathrin assembly protein; CR1, complement receptor 1; BIN1, bridging integrator 1; ABCA7, ATP-binding cassette subfamily A, member 7; MS4A cluster, membrane-spanning 4-domains subfamily A; CD2AP, CD2-associated protein; CD33, sialic-acid-binding immunoglobulin-like lectin; EPHA1, ephrin receptor A1.

(Adapted from Morgan K. The three new pathways leading to Alzheimer’s disease. Neuropathol Appl Neurobiol 2011; 37(4):353–357.

DEMENTIA WITH LEWY BODIES (DLB)

DLB is now recognized as a common form of dementia. In several hospital-based series, this form of dementia accounts for 10–25% of all cases. The incidence of DLB in the community is unclear. The high frequency in hospital series may reflect a referral bias (e.g. due to frequent falls resulting in early hospitalization). The term DLB is a clinical one, the pathologic correlate being the finding of Lewy bodies in affected brain, a hallmark of the disease is the presence of cortical Lewy bodies (see below). In most affected patients there are also pathologic features of AD.

image CLINICAL DIAGNOSIS OF DLB

image The central requirement is progressive cognitive decline of sufficient magnitude to interfere with normal social or occupational function. Prominent or persistent memory impairment may not necessarily occur in the early stages, but is usually evident with progression. Deficits may be prominent on testing of attention and frontal subcortical skills, and visuospatial ability.

image In addition, two of the following are required for a probable, and one for a possible, diagnosis of DLB: fluctuating cognition with pronounced variation in attention and alertness; recurrent visual hallucinations (typically, these are well-formed and detailed); spontaneous motor features of parkinsonism.

image Features supportive of the diagnosis are: repeated falls, syncope or transient loss of consciousness, neuroleptic sensitivity, systematized delusions, and non-visual hallucinations.

image A diagnosis of DLB is less likely in the presence of stroke disease, evident as focal neurologic signs or on brain imaging, or if there is evidence of any physical illness or other brain disorder sufficient to account for the clinical picture.

MICROSCOPIC APPEARANCES

The defining feature of DLB is the presence of Lewy bodies in several brain regions (Table 31.12). As in idiopathic PD, there is almost invariably a significant loss of neurons from the substantia nigra and locus ceruleus, but many of the residual neurons contain classic Lewy bodies (Fig. 31.32). There are also Lewy bodies in the cerebral cortex. Cortical Lewy bodies can be seen in sections stained with H&E (Fig. 31.33a–c) but are better demonstrated by immunochemistry for α-synuclein, P62 or ubiquitin (Fig. 31.33d).

Table 31.12

Pathologic features of dementia with Lewy bodies

Essential for diagnosis of DLB

Lewy bodies

Associated but not essential

Lewy-related neurites

Plaques (all morphological types)

Neurofibrillary tangles

Regional neuronal loss – especially brain stem (substantia nigra and locus ceruleus) and nucleus basalis of Meynert

Microvacuolation (spongiform change) and synapse loss

Neurochemical abnormalities and neurotransmitter deficits.

The inclusions are mainly concentrated in small neurons of the deep cortical layers. The limbic, insular, temporal, parietal, and frontal cortices may be involved, in decreasing order of frequency. The amygdaloid nuclei are usually affected. So too is the nucleus basalis of Meynert, which shows marked loss of neurons; this causes a severe cholinergic deficit in the cerebral cortex in DLB.

Lewy-related neurites demonstrable by immunostaining for α-synuclein or ubiquitin but not generally for tau may be present in the CA2–3 region of the hippocampus (Fig. 31.34) and in the subcortical nuclei affected by cell loss. Transcortical microvacuolation resembling that in prion disease is seen in the mesial temporal cortex in a small proportion of patients (Fig. 31.35).

Overlap with the pathology of AD is as follows:

A small proportion of DLB patients have cortical and brain stem Lewy body pathology in the complete absence of AD changes. This pattern is sometimes referred to as the pure form of DLB, while the more frequent combination of cortical and brain stem Lewy bodies in the presence of AD changes is referred to as the common form of DLB. The pathologic assessment of DLB is summarized in Figure 31.37.

image NEUROCHEMICAL PATHOLOGY OF DLB

image GENETICS OF DLB

FRONTOTEMPORAL LOBAR DEGENERATIONS, INCLUDING TAUOPATHIES

This is a group of degenerative dementing diseases that share several clinical features and are characterized by selective frontal and temporal lobe atrophy. They account for 12–20% of cases of dementia. Clinical presentation is variable between cases and includes the behavioral variant of frontotemporal dementia (bvFTD), semantic dementia (SD), and progressive nonfluent aphasia (PNFA). Some patients have an associated movement disorder, either parkinsonism or motor neuron disease. Historically, diseases falling into this category were grouped together as ‘Pick’s disease’. However, insights from immunohistochemical and molecular studies have revealed several distinct types of frontotemporal degeneration. The term Pick’s disease is now restricted to cases of frontotemporal degeneration with widespread Pick bodies, as discussed below.

image CLINICAL FEATURES OF FTLD

image There are three main clinical syndromes associated with FTLD:

1. Behavioral variant of frontotemporal dementia (bvFTD) is associated with cognitive decline leading to changes in social and personal conduct associated with difficulty in regulating behavior. Patients may present with neglect of personal hygiene, ‘uncaring’ incontinence, impaired judgment, disinhibition, and stereotyped behavior. Patients typically lack insight into their cognitive decline. Imaging commonly shows that prefrontal and anterior temporal regions are atrophic.

2. Progressive nonfluent aphasia (PNFA) – patients present with problems in word retrieval (expression) but have preservation of comprehension. This pattern is typically associated with atrophy of peri-Sylvian regions in the dominant hemisphere. Imaging commonly shows that the dominant frontotemporal region is atrophic.

3. Semantic dementia – patients have impairment of that realm of memory that relates to the meaning of verbal or visual inputs (semantic memory) but have preservation of episodic memory. This pattern is typically associated with anterior temporal atrophy, particularly in the dominant hemisphere. Imaging commonly shows that temporal regions are atrophic.

image Patients may have a movement disorder, usually parkinsonism or motor neuron disease.

image Frontal release signs such as forced grasping and palmomental, sucking, and rooting reflexes may be present.

image Neuroimaging shows variable cerebral atrophy. Patterns of atrophy have some correlation with underlying pathology and molecular cause of disease (Fig. 31.38).

PATHOLOGIC SUBTYPES OF FTLD

There are five main pathologic groups in the frontotemporal lobar degenerations (Table 31.13).

Table 31.13

Pathologic subtypes of FTLD

Tauopathies (FTLD-tau) (sporadic or inherited) – 50% cases

Frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP) (sporadic or inherited) 45%

Frontotemporal lobar degeneration with FUS pathology (FTLD-FUS) 5%

Frontotemporal lobar degeneration with ubiquitin pathology (FTLD-UPS) <1%

Frontotemporal lobar degeneration with no inclusions seen (FTLD-ni) <1%

When a frontotemporal degeneration is suspected pathologically, it is essential to perform immunohistochemical studies to enable an appropriate disease categorization. A staged examination of the brain will typically involve immunostaining for phosphorylated tau, the UPS (ubiquitin or P62), TDP43, and FUS.

image GENETICS OF FTLD

In approximately 50% of patients, FTLD has an autosomal dominant pattern of inheritance, but there is often phenotypic variability among different members of the same kindred.

Chromosome 3-linked FTLD

Mutations in the CHMP2B (charged multivesicular body protein 2B) gene is linked to a rare form of FTLD. This is part of the endosomal ESCRTIII complex. Involved in the endosomal pathway and causes a pattern of FTLD-UPS.

Chromosome 9-linked FTLD

There are two genes located on chromosome 17 which are linked to different forms of FTLD:

THE TAUOPATHIES INCLUDING FTLD-TAU

The tauopathies represent a group of neurodegenerative diseases dominated by the pathologic accumulation of tau protein in neurons and glial cell. Some present clinically as a movement disorder (usually parkinsonism), some with a dementia syndrome, and some with a mixed clinical picture.

The tauopathies can be divided into two main groups:

image The majority of patients with a tauopathy do not have a family history and have one of the conditions that are regarded as sporadic tauopathies.

image In a small number of kindreds the tauopathy is inherited, associated with mutation in the tau gene, MAPT (Tables 31.14, 31.15).

Table 31.14

Sporadic and inherited tauopathies

Sporadic tauopathy

Alzheimer’s disease

Parkinsonism-dementia complex of Guam

Postencephalitic parkinsonism

Dementia pugilistica

Familial British dementia

Progressive supranuclear palsy (PSP)

Corticobasal degeneration (CBD)

Argyrophilic grain disease (AGD)

Pick’s disease

Inherited tauopathy

Frontotemporal lobar degeneration with Parkinsonism linked to chromosome 17 tau (FTDP-17tau)

FTLD-tau pattern

Progressive supranuclear palsy pattern

Corticobasal degeneration pattern

Pick’s disease pattern

Table 31.15

Tau accumulation in different conditions

Western blot of insoluble brain extracts Predominant tau isoform Diseases
Tau triplet
60, 64 & 68 kDa		 4R & 3R Alzheimer’s disease
Parkinsonism-dementia Complex of Guam
Postencephalitic parkinsonism
Dementia pugilistica
Familial British dementia
FTDP-17tau
Tau doublet
64 & 69 kDa		 4R Progressive supranuclear palsy
Corticobasal degeneration
Argyrophilic grain disease
FTDP-17tau
Tau doublet
60 & 64 kDa		 3R Pick’s disease
FTDP-17tau

This section will consider both familial and sporadic tauopathies.

image BIOLOGY AND BIOCHEMISTRY OF TAU

image Tau protein is one of a family of microtubule-associated proteins (MAPs). Tau is abundant in axons, where it functions to stabilize microtubules.

image The tau gene, MAPT, is located on chromosome 17. Alternate splicing of transcripts of MAPT leads to the synthesis of six main isoforms of tau, all containing tandem repeat regions that are encoded by exons 9–12 and serve as microtubule-binding domains. Three of the isoforms include exon 10 and have four microtubule-binding repeat domains (4Rtau). Three of the tau isoforms lack exon 10 and have three microtubule-binding repeat domains (3Rtau). The tau isoforms range from 352 to 441 amino acids in length, with molecular weights of 45–65 kDa (Table 31.15).

image Tau protein in the tauopathies is typically hyperphosphorylated and shows a change in solubility causing formation of filamentous intracellular aggregates in neurons and glia.

PICK’S DISEASE: CLINICAL FEATURES

This is the least common of the tauopathies. While most cases are sporadic, familial cases of Pick’s disease due to MAPT mutations are described. The clinical presentation is typically a frontotemporal dementia syndrome with onset between 45 and 65 years and lobar atrophy seen on imaging.

MACROSCOPIC APPEARANCES

In Pick’s disease atrophy of the frontal and temporal lobes is typically very severe, in some cases producing ‘blade-like’ or ‘knife-edge’ gyri (Fig. 31.39). The posterior part of the superior temporal gyrus is usually spared. In some cases of Pick’s disease, atrophy is only moderate.

MICROSCOPIC APPEARANCES

The cardinal histologic abnormality is the presence of Pick bodies. These are spherical inclusions in neuronal cell bodies. In contrast to Lewy bodies, Pick bodies are slightly basophilic and have a crisp margin (Fig. 31.40a). They are strongly argyrophilic (Fig. 31.40b,c) and may be seen in pyramidal neurons and dentate granule cells in the hippocampus and in affected regions of neocortex. They may be present in low density in subcortical nuclei (Fig. 31.40d).

Electron microscopy of Pick bodies shows that they contain 15 nm straight filaments, and some 22–24 nm twisted filaments appearing similar to the PHF in AD. Entrapped vesicular structures are also present. Immunohistochemistry shows reactivity for phosphorylated tau protein (Fig. 31.41), ubiquitin, tubulin, and chromogranin-A. The tau protein in Pick’s disease differs from that in other tau disorders in that only 3Rtau isoforms are present, from transcripts lacking exon 10.

Swollen neurons are typical of Pick’s disease, when they are termed Pick cells, but vary in number in relation to the severity of the neuronal loss. Swollen neurons are argyrophilic and can be stained with antisera to phosphorylated neurofilament protein or αB-crystallin (Fig. 31.42). Tau immunoreactivity is often also present in swollen neurons.

Neuronal loss relates to the degree of cortical atrophy present. In severe cases neuronal loss in affected regions of cortex is virtually complete, resulting in status spongiosus (Fig. 31.43). In cases with moderate cortical atrophy there is microvacuolation in Layer II of the cortex and restricted neuronal loss. Astrocytic gliosis is present in areas of cortical neuronal loss and in underlying white matter. Granulovacuolar degeneration is commonly seen in remaining neurons.

Cases of frontotemporal dementia lacking Pick bodies were in the past designated as ‘atypical’ Pick’s disease. Review of such cases with immunohistochemical staining for ubiquitin or P62, tau, TDP-43, FUS, and neurofilament protein or α-internexin usually leads to a diagnosis of one of the other defined types of FTLD.

FRONTOTEMPORAL DEGENERATION AND PARKINSONISM LINKED TO CHROMOSOME 17 TAU (FTDP-17TAU)

Patients develop frontotemporal dementia with prominent parkinsonism, and amyotrophy. The disorder is linked to chromosome 17, and mutations in the tau gene. MAPT mutations are detectable in 6–18% of FTLD patients. Around 40 MAPT mutations in 100 families have been identified, with phenotypic variability for the different mutations.

MICROSCOPIC APPEARANCES

Histology reveals astrocytic gliosis and variable neuronal loss from affected cortical regions. In some cases, swollen neurons are present in the atrophic cerebral cortex. There is regional atrophy of the cerebral cortex, the severity varying from superficial microvacuolation to severe neuronal loss with transcortical microvacuolation. The basal ganglia and substantia nigra usually show neuronal loss and gliosis. Globose tangles may be seen in neurons in the midbrain. In some cases the pathology resembles that of progressive supranuclear palsy or corticobasal degeneration, or round intraneuronal inclusions may be present as occur in classic Pick’s disease.

Immunohistochemical staining is the key to establishing a diagnosis, and reveals extensive accumulation of phosphorylated tau in neurons and glial cells, both astrocytes and oligodendrocytes (Fig. 31.44). Diffuse tau-immunoreactivity within neurons in the form of so-called pretangles is the dominant component of neuronal pathology. Tau-immunoreactive glial lesions are frequently seen and include tufted astrocytes and astrocytic plaques. Oligodendroglial coiled bodies are common. Myelin loss and astrocytic gliosis of white matter are seen in some cases.

The tau pathology shows some correlation with the type of underlying MAPT mutation:

DEMENTIA WITH CHANGES OF CBD OR PSP

Some patients who develop a clinical frontotemporal dementia syndrome have pathologic changes of a tauopathy with the pattern of either CBD or PSP. These conditions have been discussed in Chapter 28 as examples of extrapyramidal movement disorders. Review has shown a proportion of such cases to have a mutation in MAPT and therefore to fall within the spectrum of FTDP-17tau.

Progressive supranuclear palsy

PSP usually presents with an extrapyramidal movement disorder (described in Chapter 28) but cognitive impairment is common and in some patients can be the presenting feature. Tauopathy with features of PSP has also been seen underlying clinical primary progressive aphasia and corticobasal syndrome. Histologic features are those of PSP.

TANGLE-ONLY DEMENTIA

Dementia may rarely be associated with NFTs in the hippocampal region, brain stem, and substantia nigra, in the absence of Aβ plaques – a condition termed neurofibrillary tangle predominant dementia (NFTPD). Most patients are female. The average age at onset is 80 years, and at death, 85 years. In most reported cases, the ante-mortem diagnosis has been AD. About 10% of patients have had parkinsonism.

MACROSCOPIC AND MICROSCOPIC APPEARANCES

Numerous 3R and 4R tau-immunoreactive NFTs and NTs are present in the hippocampus, entorhinal cortex, and amygdala, corresponding to Braak stage III, with many tangles being ‘ghost tangles’ (Fig. 31.45). In about 60% of reported cases plaques have been absent. In others there have been only a few diffuse Aβ deposits, consistent with aging. The substantia nigra typically shows neuronal loss and NFT formation. In making this diagnosis, a search should be made to exclude diagnostic features in other defined tauopathies such as PSP, and argyrophillic grain disease (AGD).

RARE GEOGRAPHICALLY RESTRICTED TAUOPATHIES

A tau disorder associated with extensive calcification of the basal ganglia, hippocampus, deep nuclei of the cerebellum and, occasionally, the frontal white matter termed ‘diffuse neurofibrillary tangles with calcification’ (DNTC). This condition is almost exclusively confined to Japanese patients. In addition to a tangle-predominant dementia associated with extensive mineralization of the basal ganglia, there are numerous neuronal and astrocytic inclusions that are immunopositive for α-synuclein, together with TDP-43 inclusions. The pathogenetic interrelationship of these overlapping entities remains to be determined.

Although it is unlikely to cause diagnostic confusion in most clinical settings, the ALS-parkinsonism-dementia complex is also characterized by NFTs in a wide distribution but has been reported among the Chamorro population on Guam and the Kii peninsula in Japan.

ARGYROPHILIC GRAIN DEMENTIA (AGD)

This condition was initially described in a pathologic survey of patients diagnosed clinically as having AD. Such pathologic changes have since been described in approximately 5% of all brains examined in the elderly, independent of the presence of dementia, raising the possibility that grain pathology may not always cause clinical abnormalities. Grain pathology may be seen as a pure form or more commonly associated with a wide range of other neurodegenerative diseases. The accumulated tau is restricted to four-repeat isoforms and use of 4R tau-specific antibodies has been advocated as a sensitive way to detect pathology. Antibodies to the ubiquitin binding protein, P62, also detect the grain-like structures, preferentially to other tau pathologies.

MACROSCOPIC AND MICROSCOPIC APPEARANCES

Small, spindle-shaped, argyrophilic grains and coiled bodies or filaments are found in the hippocampus, entorhinal cortex and surrounding regions, and in some subcortical nuclei (Fig. 31.46). These argyrophilic structures are composed of tau-immunoreactive straight filaments with a diameter of about 9 nm. Many pyramidal neurons in these same regions show coarse granular accumulation of phosphorylated tau within the cell body and dendrites, but NFTs and NTs are relatively sparse. Tau reactive astrocytes, oligodendroglial coil bodies and occasional interfascicular threads may be seen, mainly in the parahippocampal white matter. There may also be occasional astrocytic tau plaques of the type seen in CBD but restricted to the anterior temporal cortex. Aβ plaques are often present but tend to be predominantly diffuse. Ballooned neurons may be seen in nearby temporal cortex.

FRONTOTEMPORAL LOBAR DEGENERATION WITH TDP-43 PATHOLOGY (FTLD-TDP)

This is the commonest pathologic type of frontotemporal dementia. While most cases are not associated with a family history of disease, familial cases have been linked to mutations in GRN (progranulin), VCP (valosin-containing protein) TARDBP (TDP-43) or C9orf72 genes.

MICROSCOPIC APPEARANCES

In early disease, neuronal loss and astrocytic gliosis are restricted to the superficial neocortical laminae, which show microvacuolation (Fig. 31.48). Variable numbers of swollen neurons may be present. Severe disease is characterized by virtually complete transcortical loss of neurons from affected regions, with status spongiosus (Fig. 31.49). In patients with associated amyotrophic lateral sclerosis/motor neuron disease, loss of upper or lower motor neurons can be seen together with variable loss of corticospinal tracts. There is usually rarefaction and gliosis of white matter in the affected regions. Neuronal loss and astrocytic gliosis may involve the basal ganglia and substantia nigra.

Three main histologic abnormalities are seen on immunohistochemistry for ubiquitin, P62, and TDP-43. Several authors have proposed conceptually similar classification systems for FTLD-TDP cases based on these pathologic findings, which have been reconciled into four groups, A–D, in a consensus proposal (Table 31.16).

image Neuronal cytoplasmic inclusions (NCI) can be seen in neocortical neurons and in dentate granule cells of the hippocampus. A range of morphological types of NCI have been described. Hippocampal involvement varies in particular types of FTLD-TDP (Figs 31.50–31.52, Table 31.16).

image Dystrophic neurites (DN) seem to be of two qualitatively different types and most prominent in regions of cortical microvacuolation. Long, linear neurites are mainly in outer cortical layers while shorter, comma-shaped neurites occur in all cortical layers. The different types of neurite are associated with different types of disease (Figs 31.53, 31.54, Table 31.16).

image Neuronal intranuclear inclusions (NII) are seen in a proportion of cases. These are typically elongated and lenticular in shape. There are particularly prominent in patients with VCP mutations but may be seen in lower density in other types of FTLD-TDP (Fig. 31.55 and Table 31.16).

Hippocampal sclerosis is seen in some cases, as detailed in Table 31.16. It is now recognized that certain forms of hippocampal sclerosis previously classified as representing an isolated (‘pure’) abnormality are in reality cases of TDP-43 proteinopathy.

If immunohistochemical investigation fails to reveal TDP-43-positive inclusions yet ubiquitin or P62 immunostaining shows NCI, then it is important to look for FUS pathology (see p. 643).

image BIOLOGY AND SIGNIFICANCE OF TDP-43 IMMUNOSTAINING

Transactive response DNA-binding protein of 43 kDa (TDP-43), is a RNA- and DNA-binding protein, which is normally involved in gene transcriptional regulation and RNA processing, including splicing.

Immunostaining normally shows a widespread neuronal and glial nuclear localization. In pathologic states, the normal diffuse nuclear immunoreactivity is lost and there is labeling of cytoplasmic inclusions or neurites, and in some instances of discrete intranuclear inclusions.

TDP-43 is the main component of the inclusions seen in ALS/MND (p. 641) and certain types of frontotemporal lobar degeneration characterized by ubiquitin-immunoreactive inclusions (FTLD-TDP group). These are classed as TDP-43 proteinopathies.

TDP-43 in inclusions undergoes truncation, phosphorylation, and ubiquitination.

A small proportion of familial cases of ALS/MND are linked to mutations in the gene for TDP-43, TARDP.

In some contexts, neuronal TDP-43 accumulation is thought to be secondary. TDP-43-immunopositive neuronal inclusions can be seen as a component of other neurodegenerative diseases, especially Alzheimer’s disease, in which such inclusions can be found in about 50% of cases.

TDP-43 inclusions have been reported in about 3% of elderly neurologically normal patients.

C9orf72 and chromosome 9-linked FTLD (C9FTD/ALS)

Genetic studies have established that expansion of a GGGGCC hexanucleotide repeat in the C9orf72 gene coding for a protein of unknown function on chromosome 9 can be a cause of ALS as well as FTLD. Early neuropathologic studies suggest that this is a TDP-43 proteinopathy (types B or A) but that there is a disproportionate presence of TDP-43 − ve extramotor inclusions detected only by antibodies to the ubiquitin proteasome system (UPS), e.g. using P62, including:

image FRONTOTEMPORAL DEMENTIA WITH MOTOR NEURON DISEASE

A proportion of patients with MND develop a frontotemporal dementia syndrome. In a reverse situation, a proportion of patients who present with bvFTD, PNFA, SD or CBS may develop motor neuron signs. This condition has been referred to as FTD-MND to describe the clinical association, however understanding of the disease pathogenesis in such patients would put the majority of cases into the group of FTLD-TDP. Motor neuron disorders (MND) are discussed in Chapter 27. In patients with pure MND it is possible to see extramotor pathology of the type described in FTLD.

Frontotemporal lobar degenerations with FUS pathology (FTLD-FUS)

There are three main conditions associated with pathologic accumulation of FUS in cellular inclusions:

Clinicopathologic studies have shown some overlap between these condition but also distinct clinical and neuropathologic features that justify their continued identification as separate entities.

image MOLECULAR PATHOLOGY AND SIGNIFICANCE OF FUS

The fused-in-sarcoma (FUS) protein is encoded by the FUS gene on chromosome 16 and is a 526-residue protein with a molecular weight of 53 kDa.

FUS is involved in RNA–protein interactions and transcriptional activation.

Mutations in FUS are linked to familial amyotrophic lateral sclerosis type 6 and juvenile onset basophil inclusion body disease (p. 641)

No FUS mutations have been found in patients with FUS accumulation in FTLD-FUS.

Other members of the FET protein family (FUS, EWS, and TAF15) as well as Transportin-1 have also been detected in the inclusions of FTLD-FUS, raising the possibility of a pathway defect linking similar conditions.

Atypical FTLD with ubiquitin-only immunoreactive changes

This condition is the commonest of the FTLD-FUS group and was defined as a pathologic entity following the discovery that some cases formerly classified as FTLD-U did not show TDP-43 pathology. These were termed atypical FTLD with ubiquitin-only pathology (aFTDP-U). The inclusions in these cases are immunopositive for FUS.

Clinically, patients present with a subtype of bvFTD that has been termed the stereotypic form of FTD, dominated by obsessional, repetitive, ritualistic behavior associated with social withdrawal and hyperorality.

Macroscopically there is moderate frontal and temporal atrophy. Caudate atrophy is usually prominent and severe to a point where it has been suggested as being predictive of the aFTLD-U pattern of disease, especially if patients have onset under 40 years. In most cases hippocampal sclerosis is also present.

Histologically, there are ubiquitin- or P62-positive, tau/TDP-43-negative neuronal cytoplasmic inclusions (NCI) which are strongly immunoreactive for FUS. The majority of NCI appear as small, compact, round or oval inclusions, which sit next to the nucleus and are rarely larger than it. These bean-shaped inclusions are commonly seen in outer layers of the cerebral cortex (Fig. 31.56), hippocampal dentate fascia (Fig. 31.57) and periaqueductal gray matter. In addition to bean-shaped FUS inclusions, crescentic NCI can also be seen in the striatum. A coarse granular pattern of FUS accumulation is demonstrable in pyramidal neurons in some cases. Neuritic pathology is not evident although rare fine FUS-positive filaments may be seen. A small proportion of lower motor neurons contain inclusions, some of which may have a skein appearance.

Another prominent abnormality is the presence of neuronal intranuclear inclusions (NII) which are long and thin, and may either appear to run straight across the nucleus as a rod or to be curved around the nuclear margin (vermiform NII). These are present in the hippocampus, especially in dentate granule cells (Fig. 31.58).

NEURONAL INTERMEDIATE FILAMENT INCLUSION DISEASE (NIFID)

This is a rare condition usually with onset between 23–56 years and clinically characterized by bvFTD with parkinsonism, or a pyramidal movement disorder.

Macroscopically, there is frontotemporal atrophy and variable caudate atrophy. The hippocampus is typically preserved in size.

Histologically, affected cortical regions show neuronal loss, superficial microvacuolation and astrocytic gliosis. Neuronal cytoplasmic inclusions can be seen in neocortex, hippocampus and basal ganglia. Some of the inclusions are usually visible on H&E staining (Fig. 31.59a,b) but these represent but a small subset of those that are demonstrable immunohistochemically. It is important to note that one cannot rely on ubiquitin IHC to screen for these inclusions as they typically show only weak labeling (Fig. 31.59f).

Immunohistochemistry for FUS shows many more inclusions than are seen in H&E sections. Neocortical NCI are of varied morphology: crescent shaped, annular, flame-shaped, or forming small, round Pick-like inclusions. Rod-shaped and curved vermiform neuronal intranuclear inclusions are present (Fig. 31.59c,d). A subset of cortical inclusions is also immunoreactive for neurofilament protein (NF) (Fig. 31.59e) and/or α-internexin. Hippocampal dentate granule cells contain FUS-positive rounded NCI as well as vermiform or annular intranuclear inclusions. Occasional FUS-positive oligodendroglial inclusions have been noted.

BASOPHILIC INCLUSION BODY DISEASE (BIBD)

This neurodegenerative condition was originally characterized pathologically by the presence of neuronal cytoplasmic inclusions which were well defined and basophilic on H&E staining: basophilic inclusions (BI) (Fig. 31.60). BIBD may be associated with sporadic ALS/MND (including, in particular, juvenile ALS), ALS/MND with dementia and a form of pure frontotemporal dementia (FTD). Since the discovery that these inclusion bodies contain FUS as well as related proteins, BIBD is now classed as one of the TDP-FUS group.

On immunostaining for FUS, cytoplasmic inclusions can be seen in neocortical neurons, hippocampal pyramidal cells and dentate granule cells, neurons in the globus pallidus and thalamus. Inclusions are also present in the midbrain, pons and medulla (including the hypoglossal nuclei) and in LMN of the spinal cord. Neuronal cytoplasmic inclusions appear as one of three main types (Fig. 31.37):

FUS labeling also reveals a small number of DN and glial cytoplasmic inclusions have been described. In contrast to other forms of FTLD-FUS, NII are rarely seen.

Frontotemporal lobar degenerations with UPS pathology (FTLD-UPS)

During the evolution of terminology used to classify FTLD cases, the main tool was use of antibodies to ubiquitin leading to the designation of a group called FTLD-U. With discovery of TDP-43 and FUS and the application of antibodies to other components of the ubiquitin proteasome system (UPS), especially P62, cases which show ubiquitin-only pathology are now termed FTLD-UPS. One defined set of cases in this group is linked to mutations in CHMP2B, the gene for charged multivesicular body protein 2b. In other cases, mutation in this gene has been excluded. It seems likely that other associated proteins will be discovered that will remove cases from this group of FTLD and define new subgroups based underlying protein abnormalities.

HIPPOCAMPAL SCLEROSIS

‘Pure’ hippocampal sclerosis is defined as severe degeneration and gliosis of the CA1 sector and subiculum of the hippocampal formation in the absence of any demonstrable underlying cause of disease. The anatomic location of damage predicts an amnesic component to cognitive decline. In considering a cause, the clinical context is also important as hippocampal sclerosis (medial temporal sclerosis) can be associated with epilepsy or seen as a manifestation of hypoxic-ischemic damage following an episode of severe hypotension or severe hypoxia. It can also be part of the pattern of brain damage associated with prolonged hypoglycemic damage. The changes can be seen in H&E preparations but it is important to perform a range of immunochemical stains to exclude a primary neurodegenerative cause. In addition to being seen in some patients with AD, it is now realized that this pattern of disease can be part of the spectrum of some forms of FTLD.

Macroscopically, the hippocampal region shows atrophy. Histologically, loss of hippocampal pyramidal cells is seen in CA1 and the subiculum (Fig. 31.61)

FAMILIAL BRITISH DEMENTIA AND FAMILIAL DANISH DEMENTIA

Familial British Dementia (FBD) is linked to a point mutation in the integral membrane protein 2B gene, ITM2B, on chromosome 13q14 and inherited as an autosomal dominant condition. Clinically, disease typically starts in the sixth decade when affected patients develop a variable combination of dementia, cerebellar ataxia and spastic tetraparesis.

MICROSCOPIC APPEARANCES

The characteristic findings are of severe widespread amyloid angiopathy with parenchymal amyloid plaques. The amyloid is composed of a 24-amino-acid peptide (ABRI) and antibodies to this peptide can be used in diagnosis (Fig. 31.62). Immunohistochemistry for phosphorylated tau reveals NFTs and NTs in a distribution corresponding approximately to Braak stage II but also clustered around amyloid-laden parenchymal blood vessels.

Familial Danish Dementia (FDD) is a related condition in which affected patients develop progressive ataxia and dementia associated with cataracts and deafness. It is caused by a different mutation in the same ITM2B gene and the abnormal 4-kDA peptide is termed ADAN. Pathologic findings are similar to those seen in FBD but there are no parenchymal amyloid plaques.

DEMENTIA WITH NEUROSERPIN ACCUMULATION

Familial encephalopathy with neuroserpin inclusion bodies (FENIB) is a rare autosomal dominant condition that usually presents with dementia, commencing between the 2nd and the 5 h decade. Early-onset cases tend to develop intractable myoclonic epilepsy in addition to cognitive abnormalities. Disease is caused by mutation in the gene for neuroserpin, SERPINI1. The SER49PRO point mutation detected in later-onset FENIB kindred is predicted to cause less functional disruption of the protein than the SER52ARG mutation identified in a kindred with a younger age of onset, and epilepsy.

DEMENTIA ASSOCIATED WITH OTHER DEGENERATIVE DISEASES

Several diseases typically present as early onset degenerative diseases of the nervous system but can present with a dementia syndrome in adult life (Table 31.17).

Table 31.17

Degenerative diseases that cause dementia and usually present in childhood

Mitochondrial cytopathy

Neuronal intranuclear inclusion disease

Lafora body disease

Neuronal ceroid lipofuscinosis

Wilson’s disease

Fabry’s disease

Krabbe’s disease

Metachromatic leukodystrophy

Alexander’s disease

Cerebrotendinous xanthomatosis

Nasu–Hakola disease

Adrenoleukodystrophy

GM1 gangliosidosis type III

GM2 gangliosidosis

Gaucher’s disease

Niemann–Pick disease type C

Mucopolysaccharidosis type IIIB

VASCULAR DEMENTIA

Vascular dementia (VaD) can be defined as an acquired intellectual impairment resulting from damage to the brain by cerebrovascular disease. A major problem in establishing a pathologic diagnosis of vascular dementia is that vascular lesions are commonly seen in cognitively normal patients (vascular pathology has been reported in about 60% of brains from older adults). Clinical, imaging and pathologic studies have now led to development of the concept of vascular cognitive impairment (VCI), which extends from patients with mild cognitive impairment (MCI) that does not meet an operational definition of dementia through to patients who have a full clinical dementia. Two broad groups can be considered, as follows:

image RISK FACTORS FOR VASCULAR DEMENTIA

Risk factors for vascular dementia can be divided into five main groups: demographic, atherosclerotic, stroke-related, poor cerebral perfusion, and genetic (Table 31.18).

Table 31.18

Risk factors for vascular dementia

Risk category Risk factor
Demographic Age, male sex, lower educational level
Atherosclerotic Hypertension, cigarette smoking, myocardial infarction, diabetes mellitus, hyperlipidemia
Stroke-related Large cerebral infarcts, bilateral cerebral infarcts, ischemic white matter disease, strategic infarcts (thalamic, angular gyrus, or subcortical frontal infarction)
Poor cerebral perfusion or oxygenation Obstructive sleep apnea, congestive cardiac failure, cardiac arrhythmias, major surgery, orthostatic hypotension
Genetic Familial vascular encephalopathies (CADASIL)

MACROSCOPIC AND MICROSCOPIC APPEARANCES

The neuropathologic abnormalities which are potentially associated with vascular cognitive impairment can be classified according to the cause of the ischemia: large vessel disease, small vessel disease and hypoperfusion (see Chapter 9). Rarely there are specific vasculopathies leading to disease. (Table 31.19).

Table 31.19

Pathology of vascular dementia

Large vessel disease

Large volume infarcts or bilateral infarcts

Strategically placed infarcts

Small vessel disease

Lacunar infarcts

Ischemic white matter damage (leukoencephalopathy)

Cribriform change

Cortical microinfarcts

Hypoperfusion lesions

Hippocampal sclerosis

Border zone infarcts

Cortical laminar necrosis

Rare local vascular disorders

CADASIL

Cerebral amyloidosis

Cerebral vasculitis (including secondary to autoimmune disorders)

Antiphospholipid antibody syndrome

Small vessel disease: Subcortical vascular dementia (SVaD) is the term used to describe a dementia syndrome linked to small vessel disease. The most consistent finding in vascular dementia is hyaline arteriosclerosis and arteriolosclerosis affecting small vessels. This is strongly associated with hypertension and diabetes mellitus. Pathologically, patients with SVaD can show several pathologic features in which ischemic white matter degeneration (ischemic leukoencephalopathy, Binswanger’s disease) and lacunar infarcts are felt to be the main contributors to cognitive disturbance.

image Ischemic white matter degeneration. Macroscopically, the brain is usually of normal or slightly reduced weight with little external evidence of atrophy. The major cerebral arteries are usually atherosclerotic. The lateral and third ventricles are moderately dilated. The cerebral white matter often feels soft on sectioning. The cut surface appears slightly granular and may be pitted with small depressions (Fig. 31.63). When these changes are seen in life on imaging it is termed ‘leukoaraiosis’. Typically, these changes are most pronounced in the deep frontal and temporal white matter. Coexistent lacunar infarcts are usually present in the basal ganglia, thalamus, pons, and, less often, the hemispheric white matter (Fig. 31.64). Histology reveals arteriosclerosis and arteriolosclerosis – hyalinization of small arteries and arterioles with loss of smooth muscle and replacement by collagen (Fig. 31.65). The white matter shows patchy pallor on myelin staining, axonal loss, reduction in the number of oligodendrocytes, and mild astrocytic gliosis (Fig. 31.66). There is often an associated loss of axons in these areas. Dementia with these changes is now clinically termed subcortical vascular dementia (SVaD) but has also been referred to in the past as lacunar dementia and Binswanger’s disease. Note that if histologic sampling is restricted to small blocks that include only 1–2 cm of subcortical white matter, significant deep white matter disease may well be missed.

image Lacunar infarction. Lacunar infarcts are seen as very small cavities and may be present in both gray and white matter. They are most commonly found in the basal ganglia, thalamus and pons (Fig. 31.64). Clinicopathologic studies have shown a relationship with cognitive abnormality and the pattern of disease termed subcortical vascular dementia (SVaD).

image Cribriform atrophy of white matter. This appears as myriad fine pin-size holes in the white matter that are due to dilatation of perivascular spaces and most numerous in the anterior temporal and frontal regions. Histologically, hyalinized vessels are surrounded by a dilated perivascular space with surrounding myelin pallor and astrocytic gliosis that extend a small distance from the vessel (Fig. 31.67). The significance of this change and relationships with clinical features are in need of further clarification.

image Granular cortical atrophy. This is a relatively uncommon finding and its relationship with cognitive decline is in need of further clarification. Macroscopically, affected regions of cerebral cortex appear pitted by depressions 1–2 mm in diameter (Fig. 31.68). Histology shows these to correspond to numerous cortical microinfarcts, usually associated with hyaline arteriosclerosis of small vessels but sometimes associated with amyloid angiopathy. Other diseases that involve small vessels can cause this pattern of lesions, the most notable example being the microvascular thrombosis associated with the antiphospholipid antibody syndrome.

Large vessel disease: Large regional cerebral infarcts rarely contribute significantly to global cognitive decline in the setting of a clinical dementia. The term ‘multi-infarct dementia’ has been used for this clinical association. Rarely, severe cognitive dysfunction is caused by bilateral small infarcts in critical sites such as the medial thalamus or hippocampal region (Table 31.20). Other reasons for the association of large vessel disease or regional cerebral infarcts with dementia are:

The causes and consequences of various forms of large vessel disease, including atherosclerotic and embolic disease, vasculitis, and CADASIL are considered in Chapter 9.

Global cerebral hypoperfusion: Conditions leading to cerebral hypoperfusion can cause ischemic injury to the hippocampus and watershed/boundary zone regions (see Chapters 8 and 9). Hippocampal sclerosis with clinical dementia is seen in some patients after a defined episode of hypotension complicating cardiovascular disease (Fig. 31.69). Boundary zone infarcts in the frontal and parietal cortex can also lead to dementia.

image CLINICAL FEATURES OF VASCULAR DEMENTIA

image Clinical diagnosis of vascular dementia is typically based on focal neurologic signs consistent with strokes, stepwise neurologic deterioration, and declining cognitive performance that may, however, fluctuate considerably on a day-to-day basis.

image Gait difficulties, urinary incontinence, parkinsonian features, and pseudobulbar signs are commonly associated features with small vessel disease in a subtype of disease termed subcortical vascular dementia (SVaD).

image Making a clinical diagnosis of VaD is problematic in that operational criteria for dementia require memory loss. However, many patients with VaD do not have memory loss; their cognitive decline is mainly in the form of a frontal dysexecutive syndrome.

image The term vascular cognitive impairment (VCI) is used clinically to describe any cognitive impairment following stroke or attributed to vascular disease, ranging from VaD to mild cognitive impairment MCI.

image The term vascular cognitive disorder (VCD) has been proposed to describe dementia caused by vascular disease in which there is abnormal executive function, severe enough to interfere with normal functioning.

image The term post-stroke dementia (PSD) is used clinically to describe dementia occurring after stroke. Excluded from PSD are focal neurobehavioral deficits caused by a single episode, such as aphasia, apraxia or agnosia. The incidence of dementia after stroke is about 7% after 1 year and 48% after 25 years.

image CLINICAL FEATURES OF VASCULAR COGNITIVE IMPAIRMENT (VCI)

Possible VaD

There is cognitive impairment and imaging evidence of cerebrovascular disease but:

image No clear relationship (temporal, severity, or cognitive pattern) between the vascular disease (e.g. silent infarcts, subcortical small-vessel disease) and the cognitive impairment

image Insufficient information for the diagnosis of VaD (e.g. clinical symptoms suggest the presence of vascular disease, but no CT/MRI studies are available)

image Severity of aphasia precludes proper cognitive assessment (however, patients with documented evidence of normal cognitive function before the clinical event that caused aphasia could be classified as having probable VaD)

image There is evidence of other neurodegenerative diseases or conditions in addition to cerebrovascular disease that may affect cognition, such as:

Possible VaMCI

There is cognitive impairment and imaging evidence of cerebrovascular disease but:

image No clear relationship (temporal, severity, or cognitive pattern) between the vascular disease (e.g. silent infarcts, subcortical small-vessel disease) and onset of cognitive deficits

image Insufficient information for the diagnosis of VaMCI (e.g. clinical symptoms suggest the presence of vascular disease, but no CT/MRI studies are available)

image Severity of aphasia precludes proper cognitive assessment. However, patients with documented evidence of normal cognitive function before the clinical event that caused aphasia could be classified as having probable VaMCI

image There is evidence of other neurodegenerative diseases or conditions in addition to cerebrovascular disease that may affect cognition, such as:

(Adapted from AHA/ASA Scientific Statement – Vascular Contributions to Cognitive Impairment and Dementia. Stroke 2011 42(9):2672–2713.)

NEUROPATHOLOGIC ASSESSMENT IN VASCULAR DEMENTIA

An approach to neuropathologic diagnostic evaluation of VaD has been published (see below) alongside a classification for the neuropathologic diagnosis of vascular dementia into six subtypes (Table 31.21). A diagnosis of probable VaD is appropriate when cerebrovascular pathology meets criteria for one of the subtypes of VaD and other causes of dementia have been excluded. A diagnosis of possible VaD is appropriate when neuropathologic examination shows a vascular pathology which does not meets criteria for one of the subtypes of VaD.

Table 31.21

Subtypes of vascular dementia

Lesions Diagnostic group Subtype
Large infarct or several infarcts (>50 mL loss of tissue) Multi-infarct dementia I
Multiple small or microinfarcts (>3 with minimum diameter 5 mm; involving >3 coronal levels; vascular hyalinization, CAA, lacunar infarcts, perivascular changes) Small vessel vascular dementia II
Infarcts in critical areas (e.g. thalamus, hippocampus, basal forebrain) Strategic infarct dementia III
Incomplete or diffuse infarction (hippocampal sclerosis, ischemic–anoxic damage, cortical laminar necrosis, border zone infarcts involving brain tissue in at least three different coronal planes) Vascular dementia due to cerebral hypoperfusion IV
Multiple cerebral hemorrhages (lobar, intracerebral or subarachnoid) Vascular dementia due to cerebral hemorrhages V
Any of the above cerebrovascular changes with concurrent AD-type pathology (Braak stage >III) Mixed dementia VI

Adapted from Kalaria et al. (2004).

INTERMITTENTLY RAISED PRESSURE HYDROCEPHALUS

Dementia associated with hydrocephalus accounts for about 2% of cases of dementia. Onset is generally after 70 years of age. Often, no predisposing factor for the hydrocephalus is identified. Isolated measurements of CSF pressure at the time of lumbar puncture are typically within normal limits, so the term ‘normal pressure hydrocephalus’ has been applied to these patients. However, monitoring of CSF pressure over longer periods reveals that it is intermittently raised. The dementia associated with hydrocephalus is characterized clinically by the triad of memory disturbance, early disturbance of gait, and early urinary incontinence. CT scans reveal ventricular dilatation and low-attenuation signal in periventricular white matter, without sulcal widening or other features of cortical atrophy.

image PATHOLOGIC CHARACTERIZATION OF LESIONS IN SUSPECTED VASCULAR DEMENTIA

image Characterize lesions as ischemic or hemorrhagic infarcts.

image Note presence of lacunes and lacunar infarcts.

image Note location of infarcts: cortex, white matter, basal ganglia, brain stem, cerebellum.

image Note circulation involved: arterial territories – anterior, middle or posterior cerebral or basilar arteries.

image Note laterality: right or left.

image Determine the sizes and number of infarcts: 0–4, 5–15, 16–30, 31–50 and >50 mm; if size <5 mm, record as small or microinfarcts.

image Presence and location of small vessel disease: lipohyalinosis, fibroid necrosis, CAA.

image Presence of white matter disease: rarefaction or incomplete infarction.

image Presence of hippocampal sclerosis.

image Degree of gliosis: mild, moderate or severe.

image Presence of AD (including Braak neurofibrillary tangle staging). If Braak stage is greater than III, the case is considered mixed AD and VaD.

Adapted from Kalaria et al. (2004).

MACROSCOPIC AND MICROSCOPIC APPEARANCES

Pathology confirms these imaging features (Fig. 31.70). There is symmetric dilatation of the lateral and third ventricles and good preservation of the cerebral cortex. The cerebral white matter appears macroscopically normal, but histology may reveal mild to moderate periventricular rarefaction and gliosis. Vascular dementia and primary neurodegenerative disease should be excluded by histologic examination. If hydrocephalus is diagnosed in life a ventricular shunt is usually inserted. A frequent complication of this procedure in the elderly is the development of large subdural hematomas.

A STAGED APPROACH TO PATHOLOGIC DIAGNOSIS

Strategies for the staged examination of the post-mortem brain have been published using conventional, immunohistochemical and molecular techniques. The schematic diagram in Figure 31.71 allows a staged examination to achieve a diagnosis with appropriate use of resources.

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C9FTD/ALS

Al-Sarraj, S., King, A., Troakes, C., et al. p62 positive, TDP-43 negative, neuronal cytoplasmic and intranuclear inclusions in the cerebellum and hippocampus define the pathology of C9orf72-linked FTLD and MND/ALS. Acta Neuropathol (Berl). 2011;122(6):691–702.

Simón-Sánchez, J., Dopper, E.G., Cohn-Hokke, P.E., et al. The clinical and pathological phenotype of C9ORF72 hexanucleotide repeat expansions. Brain. 2012;135:723–735.

Snowden, J.S., Rollinson, S., Thompson, J.C., et al. Distinct clinical and pathological characteristics of frontotemporal dementia associated with C9ORF72 mutations. Brain. 2012;135:693–708.

Troakes, C., Maekawa, S., Wijesekera, L., et al. An MND/ALS phenotype associated with C9orf72 repeat expansion: Abundant p62-positive, TDP-43-negative inclusions in cerebral cortex, hippocampus and cerebellum but without associated cognitive decline. Neuropathology. 2011. [PMID: 22181065 [Epub ahead of print]].

FTLD-FUS

Brelstaff, J., Lashley, T., Holton, J.L., et al. Transportin1: a marker of FTLD-FUS. Acta Neuropathol (Berl). 2011;122(5):591–600.

Broustal, O., Camuzat, A., Guillot-Noël, L., et al. French clinical and genetic research network on FTD/FTD-MND. FUS mutations in frontotemporal lobar degeneration with amyotrophic lateral sclerosis. J Alzheimers Dis. 2010;22(3):765–769.

Huang, E.J., Zhang, J., Geser, F., et al. Extensive FUS-immunoreactive pathology in juvenile amyotrophic lateral sclerosis with basophilic inclusions. Brain Pathol. 2010;20(6):1069–1076.

Ito, H., Fujita, K., Nakamura, M., et al. Optineurin is co-localized with FUS in basophilic inclusions of ALS with FUS mutation and in basophilic inclusion body disease. Acta Neuropathol (Berl). 2011;121(4):555–557.

Josephs, K.A., Holton, J.L., Rossor, M.N., et al. Neurofilament inclusion body disease: a new proteinopathy? Brain. 2003;126(Pt 10):2291–2303.

Josephs, K.A., Whitwell, J.L., Parisi, J.E., et al. Caudate atrophy on MRI is a characteristic feature of FTLD-FUS. Eur J Neurol. 2010;17(7):969–975.

Jekyll Dr, K.H., Hyde, M.r. The Two Faces of the FUS/EWS/TAF15 Protein Family. Sarcoma. 2011, 2011. [837474].

Loy, C.T., McCusker, E., Kril, J.J., et al. Very early-onset frontotemporal dementia with no family history predicts underlying fused in sarcoma pathology. Brain. 2010;133(Pt 12):e158. [author reply e159].

Mackenzie, I.R., Ansorge, O., Strong, M., et al. Pathological heterogeneity in amyotrophic lateral sclerosis with FUS mutations: two distinct patterns correlating with disease severity and mutation. Acta Neuropathol (Berl). 2011;122(1):87–98.

Mackenzie, I.R., Munoz, D.G., Kusaka, H., et al. Distinct pathological subtypes of FTLD-FUS. Acta Neuropathol (Berl). 2011;121(2):207–218.

Matsuoka, T., Fujii, N., Kondo, A., et al. An autopsied case of sporadic adult-onset amyotrophic lateral sclerosis with FUS-positive basophilic inclusions. Neuropathology. 2011;31(1):71–76.

Menon, R., Baborie, A., Jaros, E., et al. What’s in a name? Neuronal intermediate filament inclusion disease (NIFID), frontotemporal lobar degeneration-intermediate filament (FTLD-IF) or frontotemporal lobar degeneration-fused in sarcoma (FTLD-FUS)? J Neurol Neurosurg Psychiatry. 2010;82(12):1412–1414.

Munoz, D.G., Neumann, M., Kusaka, H., et al. FUS pathology in basophilic inclusion body disease. Acta Neuropathol (Berl). 2009;118(5):617–627.

Neumann, M., Rademakers, R., Roeber, S., et al. A new subtype of frontotemporal lobar degeneration with FUS pathology. Brain. 2009;132(Pt 11):2922–2931.

Rohrer, J.D., Lashley, T., Holton, J., et al. The clinical and neuroanatomical phenotype of FUS associated frontotemporal lobar degeneration. J Neurol Neurosurg Psychiatry. 2010;82(12):1405–1407.

Snowden, J.S., Hu, Q., Rollinson, S., et al. The most common type of FTLD-FUS (aFTLD-U) is associated with a distinct clinical form of frontotemporal dementia but is not related to mutations in the FUS gene. Acta Neuropathol (Berl). 2011;122(1):99–110.

Urwin, H., Josephs, K.A., Rohrer, J.D., et al. FUS pathology defines the majority of tau- and TDP-43-negative frontotemporal lobar degeneration. Acta Neuropathol (Berl). 2010;120(1):33–41.

Yokota, O., Tsuchiya, K., Terada, S., et al. Basophilic inclusion body disease and neuronal intermediate filament inclusion disease: a comparative clinicopathological study. Acta Neuropathol (Berl). 2008;115(5):561–575.

Vascular dementia

Black, S.E. Vascular cognitive impairment: epidemiology, subtypes, diagnosis and management. J R Coll Physicians Edinb. 2011;41(1):49–56.

Caplan, L.R., Gomes, J.A. Binswanger disease – an update. J Neurol Sci. 2010;299(1–2):9–10.

Debette, S., Seshadri, S. Vascular risk factors and dementia revisited. J Neurol Neurosurg Psychiatry. 2009;80(11):1183–1184.

Enciu, A.M., Constantinescu, S.N., Popescu, L.M., et al. Neurobiology of vascular dementia. J Aging Res.. 2011;2011:401604.

Gorelick, P.B., Scuteri, A., Black, S.E., on behalf of the American Heart Association Stroke Council, Council on Epidemiology and Prevention, Council on Cardiovascular Nursing, Council on Cardiovascular Radiology and Intervention, Council on Cardiovascular Surgery and Anesthesia. Vascular Contributions to Cognitive Impairment and Dementia: A Statement for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke. 2011;42(9):2672–2713.

Jellinger, K.A. Morphologic diagnosis of “vascular dementia” – a critical update. J Neurol Sci. 2008;270(1–2):1–12.

Jellinger, K.A. The enigma of vascular cognitive disorder and vascular dementia. Acta Neuropathol (Berl). 2007;113(4):349–388.

Kalaria, R.N., Kenny, R.A., Ballard, C.G., et al. Towards defining the neuropathological substrates of vascular dementia. J Neurol Sci. 2004;226(1–2):75–80.

Matthews, F.E., Brayne, C., Lowe, J., et al. Epidemiological pathology of dementia: attributable-risks at death in the Medical Research Council Cognitive Function and Ageing Study. PLoS Med. 2009;6(11):e1000180.

Menon, U., Kelley, R.E. Subcortical ischemic cerebrovascular dementia. Int Rev Neurobiol. 2009;84:21–33.

Pantoni, L., Sarti, C., Alafuzoff, I., et al. Postmortem examination of vascular lesions in cognitive impairment: a survey among neuropathological services. Stroke. 2006;37(4):1005–1009.

Tomimoto, H. Subcortical vascular dementia. Neurosci Res. 2011;71(3):193–199.

Other dementias

Coker, S.B. The diagnosis of childhood neurodegenerative disorders presenting as dementia in adults. Neurology. 1991;41:794–798.

Davis, R.L., Shrimpton, A.E., Holohan, P.D., et al. Familial dementia caused by polymerization of mutant neuroserpin. Nature. 1999;401:376–379.

Davis, R.L., Holohan, P.D., Shrimpton, A.E., et al. Familial encephalopathy with neuroserpin inclusion bodies. Am J Pathol. 1999;155:1901–1913.

Kosaka, K. Diffuse neurofibrillary tangles with calcification: a new presenile dementia. J Neurol Neurosurg Psychiatry. 1994;57:594–596.

Leinonen, V., Koivisto, A.M., Savolainen, S., et al. Post-mortem findings in 10 patients with presumed normal pressure hydrocephalus and review of the literature. Neuropathol Appl Neurobiol. 2011;38(1):72–86.

Schott, J.M., Reiniger, L., Thom, M., et al. Brain biopsy in dementia: clinical indications and diagnostic approach. Acta Neuropathol (Berl). 2010;120(3):327–341.

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