Current Concepts in the Classification and Diagnosis of Frontotemporal Lobar Degenerations

Current Concepts in the Classification and Diagnosis of Frontotemporal Lobar Degenerations Frontotemporal lobar degenerations are clinically, genetically, and molecularly heterogeneous diseases characterized by mainly frontal and temporal atrophy and affecting behavioral, language, cognitive, and motor functions. The term frontotemporal dementia incorporates 3 distinct clinical syndromes seen in frontotemporal degenerations: behavioral variant of frontotemporal dementia, progressive nonfluent aphasia, and semantic dementia. Progressive supranuclear palsy syndrome, corticobasal syndrome, and motor neuron disease syndrome are also associated with frontotemporal lobar degenerations. The neuropathologic hallmark of frontotemporal lobar degenerations is accumulation of abnormal proteins in the cytoplasm and nuclei of neurons and glial cells. Proteins involved in pathologic processes that represent the basis for frontotemporal lobar degeneration classification are tau protein, transactive response DNA-binding protein of 43 kda, and fused in sarcoma protein. The aim of this review is to provide a summary of practical approaches for neuropathologic diagnostics of the rapidly evolving classifications of frontotemporal lobar degenerations. (Arch Pathol Lab Med. 2014;138:132 138; doi: 10.5858/ arpa.2012-0510-rs) CLINICAL FEATURES Frontotemporal lobar degeneration (FTLD) is a rather rare cause of dementia; however, it is a common cause of dementia in individuals younger than 65 years, second only to early-onset Alzheimer disease. Its prevalence ranges from 3.6 to 9.4 per 100 000 depending on age of onset. 1 Disease duration varies according to type, from 2.3 years in FTLD Accepted for publication March 9, 2013. From the Department of Pathology and Molecular Medicine, Thomayer Hospital, and the Department of Pathology, Third Faculty of Medicine, Charles University, Prague, Czech Republic. The authors have no relevant financial interest in the products or companies described in this article. Reprints: Radoslav Matej, MD, PhD, Department of Pathology and Molecular Medicine, Thomayer Hospital, Videnska 800, 14059 Prague 4 Krc, Czech Republic (e-mail: radoslav.matej@ftn.cz). A Practical Approach Zdenek Rohan, MD; Radoslav Matej, MD, PhD associated with motor neuron disease (MND) to 10.4 years in Pick disease. 2 The exact cause of FTLD remains unknown. The genetic component of FTLD is significant, since approximately 40% of patients with FTLD have a positive family history. 3 Disease-associated mutations are located in genes encoding tau protein (MAPT), progranulin (PGRN), valosin-containing protein (VCP), charged multivesicular body protein 2b (CHMP2B), 3 and the recently described hexanucleotide repeat in the intronic region of chromosome 9, open reading frame 72 (C9ORF72). 4,5 Of these, C9ORF72 and MAPT are the most common. A recent worldwide crosssectional study showed that C9ORF72 is responsible for nearly 40% of familial amyotrophic lateral sclerosis (ALS) cases, 25% of familial frontotemporal dementia (FTD) cases, nearly 10% of sporadic ALS cases, and 6% of sporadic FTD cases. 6 This makes C9ORF72 the most probable candidate for genetic risk analysis in both familial and sporadic FTLD and MND cases. Familial forms of progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) have also been linked to mutations in the MAPT gene; however, sporadic forms are more common. Familial forms of Pick disease are rare and are also associated with MAPT mutations. No hereditary form of argyrophilic grain disease (AGD) has been described to date. 7 The term frontotemporal dementia incorporates 3 distinct clinical syndromes: behavioral variant of FTD, progressive nonfluent aphasia, and semantic dementia. 8 Other typical syndromes associated with FTLD are progressive supranuclear palsy syndrome, corticobasal syndrome, and MND. 9 Generally, symptoms have a gradual onset and are progressive during the disease course. Typical symptoms of behavioral variant of FTD include behavioral and cognitive changes that can be described as disinhibition syndrome, apathetic syndrome, and dysexecutive syndrome, and lead to impaired social interactions, and are often accompanied by a depression-like syndrome and cognitive symptoms caused by executive dysfunction. 10 These symptoms can be variably severe in different patients, but more or less follow the topographic involvement of the frontal and temporal cortex. Disinhibition syndrome is connected with orbitofrontal atrophy, 11 apathetic syndrome with atrophy of anterior cingulate, 11 and dysexecutive syndrome with dorsolateral prefrontal atrophy. 12 Semantic dementia is characterized as fluent aphasia with loss of vocabulary and word meaning and inability to associate semantically related 132 Arch Pathol Lab Med Vol 138, January 2014 Pathology of Frontotemporal Lobar Degenerations Rohan & Matej

objects. In progressive nonfluent aphasia, the ability to match semantically related objects is preserved, but nonfluent speech, phonemic paraphasias (word substitutions), and agrammatism occur. 8 Concurrent asymmetric cortical and extrapyramidal signs, including limb apraxia, so-called alien limb phenomenon, rigidity, and dystonia, are typical of corticobasal syndrome. 13 Progressive supranuclear palsy syndrome is characterized by symmetric akinetic syndrome, axial rigidity with falls, and vertical supranuclear gaze palsy. 9 Motor neuron disease is characterized by atrophy of the upper and lower motor neurons leading to spastic and flaccid paralysis, bulbar symptoms, and profound muscle atrophy with fasciculations, with ALS being the most common example. 14 As part of a differential diagnostic workup, a thorough history of illness assessment, neuropsychologic examination, and biochemical and other laboratory tests should be performed to exclude other neurodegenerative, psychiatric, neoplastic, and metabolic disorders as well as infectious causes. Basic biochemical laboratory findings are usually unremarkable and no reliable biomarker has been found so far; nevertheless, the pathogenic proteins themselves, inflammatory cytokines, and various neuropeptides are strong candidates for potential biomarkers. 15 Widely used cerebrospinal fluid biomarkers (Ab 42, total tau, and phosphorylated tau) may help to differentiate Alzheimer disease from FTLD. 15,16 Electroencephalography and imaging studies are generally used to exclude other organic causes; however, high-resolution magnetic resonance imaging (MRI) can be helpful in the diagnosis of FTLD by revealing typical asymmetrical focal brain atrophy. Advanced MRI studies, such as diffusion tensor imaging, may also be used to support a diagnosis of FTLD. 17 Moreover, diagnostic procedures can be supported by nuclear imaging studies that can detect typical patterns of hypoperfusion or hypometabolism in the affected brain areas. 15 However, negative MRI findings or negative findings from other methods do not exclude the FTLD pathology; a definite diagnosis, as in cases of other neurodegenerative disorders, still remains neuropathologic. None of the described clinical syndromes are limited to a certain neuropathologic entity and owing to this clinicopathologic variability and the possibility of mixed neurodegenerative etiologies, 16 a detailed neuropathologic examination is necessary for a definite diagnosis and subtyping of FTLD. PRACTICAL APPROACH TO BRAIN EXAMINATION AND DISSECTION A neuropathologic examination should begin by obtaining the valid clinical data mentioned in the previous section. Although a full autopsy is optimal, it is usually sufficient to remove the brain and preserve it in 10% buffered formalin. In MND cases, the spinal cord should also be removed by using an anterior or posterior approach and fixed; additionally, samples from skeletal muscles (minimally, muscles from upper and lower extremities, intercostal muscle, and diaphragm) should be preserved. The brain, in fixative, can (if necessary) be shipped to a referral neuropathology center for examination or fixed for 3 to 4 weeks. Before fixation, a sample of fresh brain tissue (approximately 1 cm 3 ) should be stored at 808C for both molecular-genetic and biochemical assays. Since neurodegenerative diseases causing dementia seem to affect the cortex more or less diffusely, there is no strict rule regarding sampling sites. Nevertheless, sampling should be standardized for all cases. In the context of FTLD, as well as Alzheimer disease or Lewy body dementia, a sample from the right frontal lobe (Brodmann area 9) should be obtained. One should also try to obtain a sample with highest proportion of cortical ribbon relative to the underlying white matter, since lipid-based substances from the white matter may interfere with subsequent assays. Some institutions prefer sampling from different sites (eg, cerebellum), so it may be useful to discuss this issue with the collaborating referral center. In cases where a metabolic storage disease is suspected, lipid staining should be considered before fixing the brain. A basic macroscopic assessment of brain pathology includes weighing the brain and examining (1) brain coverings, (2) arteries of the circle of Willis and vertebrobasilar arteries, and (3) superficial brain veins. Examination of the external surface of the brain and cerebellum may show changes in gyral and sulcal proportions mainly diffuse or focal atrophy or edema, softening, herniations, or hemorrhages. In cases of FTLD, variably severe, symmetric or asymmetric atrophy with a frontal and temporal predilection can be present. Moreover, cranial nerves, spinal nerve roots, and spinal vasculature should be carefully examined as well. Any macroscopically detected pathologic process should be carefully documented; photographic documentation can be very beneficial. Dissection of the fixed brain should always be standardized and basic sampling for dementia evaluation should include blocks from the frontal, parietal, and temporal cortex; occipital cortex around the calcarine fissure; the hippocampus at the level of lateral geniculate body; the striatum; the mesencephalon at the level of the oculomotor nerve; the pons at the level of the locus coeruleus; the medulla oblongata at the level of the inferior olives; and the cerebellum and dentate nucleus. Spinal cord sampling should include at least 1 block from the cervical, thoracic, and lumbar segments. If concomitant vascular dementia is suspected, blocks minimally including periventricular white matter from the parietal lobe should also be collected. Any macroscopically suspicious lesions should be embedded as well. Recently, the BrainNet Europe II Consortium suggested optimal brain sampling protocols for dementia and MND that are available on the BrainNET Europe Web site (http://www. brainnet-europe.org/index.php?option=com_content&view= article&id=99&itemid=99; accessed February 20, 2013; Brain- NET Europe II, Munich, Germany. 18 Basic staining methods include hematoxylin-eosin and silver staining methods (Bielschowsky, Gallyas). Myelin stain (eg, luxol blue) should be used for spinal cord samples to evaluate possible white matter lesions mainly in lateral and anterior corticospinal tracts since there are significant associations between FTLD and MND. A basic immunohistochemical panel for neurodegenerative disease diagnostics includes antibodies against phosphorylated tau protein (AT8 being the most commonly used), b-amyloid, a- synuclein, and antibody against the phosphorylated form of transactive response DNA-binding protein with a molecular weight of 43 kda (TDP-43). Using these antibodies, a diagnosis of FTLD-TDP, FTLD-tau, Alzheimer disease, and Lewy body dementia, as well as other synucleinopathies, can be established. However, to subtype FTLD-tau, antibodies against 3R (RD3) and 4R (RD4) tau isoforms are required. Antibodies against ubiquitin and p62 generally yield positive results in FTLD; however, cases that Arch Pathol Lab Med Vol 138, January 2014 Pathology of Frontotemporal Lobar Degenerations Rohan & Matej 133

Table 1. Overview of Frontotemporal Lobar Degenerations (FTLDs) a FTLD Type Associated Pathologic Protein Associated Disease Entity Associated Genetic Background Clinical Syndrome b FTLD-tau Tau 3R PiD, FTDP-17 MAPT FTD, CBS, PSPS, 4R CBD, PSP, AGD, MST, FTDP-17 dementia 3R þ 4R c DNTC, FTDP-17 FTLD-TDP TDP-43 FTLD types: A, B, C, D C9ORF72, PGRN, VCP, TARDBP FTD, dementia, MND, IBMPFD d FTLD-FUS FUS aftld-u, BIBD, NIFID FUS FTD, MND FTLD-UPS Ubiquitin FTD-3 CHMP2B FTD FTLD-ni No detectable inclusions Abbreviations: aftld-u, atypical FTLD with ubiquitin-immunoreactive inclusions; AGD, argyrophilic grain disease; BIBD, basophilic inclusion body disease; CBD, corticobasal degeneration; CBS, corticobasal syndrome; CHMP2B, charged multivesicular body protein 2b; C9ORF72, chromosome 9 open reading frame 72; DNTC, diffuse neurofibrillary tangle dementia with calcifications; FTD, frontotemporal dementia; FTD-3, frontotemporal dementia associated with mutations on chromosome 3; FTDP-17, frontotemporal dementia and parkinsonism linked to chromosome 17; FTLD-FUS, FTLD with fused in sarcoma immunoreactive inclusions; FTLD-ni, FTLD with no immunoreactivity; FTLD-tau, FTLD with tauimmunoreactive inclusions; FTLD-TDP, FTLD with transactive response DNA-binding protein immunoreactive inclusions; FTLD-UPS, FTLD with immunoreactivity against ubiquitin-proteasome system; FUS, fused in sarcoma; IBMPFD, inclusion body myositis, Paget disease of the bone and frontotemporal dementia; MND, motor neuron disease; MST, multisystem atrophy with globular inclusions; NIFID, neuronal intermediate filament inclusion disease; PGRN, progranulin; PiD, Pick disease; PSP, progressive supranuclear palsy; PSPS, progressive supranuclear palsy syndrome; TARDBP, TAR DNA binding protein; TDP-43, transactive response DNA-binding protein of 43 kda; VCP, valosin-containing protein. a Data derived from Sieben et al, 7 Josephs et al, 9 Mackenzie et al, 20 and Mackenzie et al. 30 b Combinations and atypical variants do exist. c Although Alzheimer disease also presents with 3R þ 4R tau isoforms, it is not generally regarded as primary tauopathy. d Associated with FTLD-TDP type D with VCP mutation. are ubiquitin and p62 positive and phosphorylated TDP-43 negative need further evaluation in a specialized neuropathologic center. Moreover, ubiquitin often reacts with neurofibrillary tangles and dystrophic neurites, which are hallmarks of Alzheimer disease. Antibodies against fused in sarcoma RNA-binding protein (FUS) and other proteins (currently referred to as the FET family of proteins) and C9ORF72 are being introduced into practice as well. Both embedded blocks and immunoblank slides can be shipped to a referral neuropathologic center for further evaluation. In these cases, proper brain sampling, detailed macroscopic documentation, and high-quality clinical data are essential supplements needed by the referral center. CLASSIFICATION OF FTLD In the past there has been a certain amount of confusion regarding the classification of FTLD, but recently, newly proposed classification schemes seem to have clarified this dynamically evolving issue. 19,20 Detection of pathologically accumulated proteins allows classification of FTLD as FTLD-tau (tau is microtubule assembly protein tubulin-associated unit), FTLD-TDP with TDP-43, and FTLD-FUS with FUS as the third member. In cases where only ubiquitin-immunoreactive inclusions are found, FTLD-UPS (UPS standing for ubiquitin-proteasome system) is used. This group includes hereditary frontotemporal dementia associated with a mutation in the CHMP2B gene on chromosome 3 (FTD- 3). If MND is confirmed clinically, along with symptoms of FTD, progressive supranuclear palsy syndrome, or corticobasal syndrome, and if pathologic inclusions are found during the postmortem examination of motor neurons, then the designation FTLD-MND is appropriate. FTLD-ni (no immunoreactivity) is reserved for rare cases that do not meet the parameters of FTLD-tau, FTLD-TDP, FTLD-FUS, and FTLD-UPS and replaces the older name dementia lacking distinctive histopathology. 19 Table 1 gives an overview of the basic concepts in FTLD classification. HISTOPATHOLOGY AND DIFFERENTIAL DIAGNOSIS OF FTLD Frontotemporal Lobar Degeneration tau This group includes FTLD with tau-immunoreactive inclusions. Further subclassification of FTLD-tau is based on the existence of different isoforms of tau protein that differ in the number of phosphate-binding domain repeats: 3R with 3 repeats and 4R with 4 repeats. 21 According to the predominant tau isoform, tauopathies are divided into 3R, 4R, and 3R þ 4R tauopathies. Pick disease is a typical 3R tauopathy; CBD, PSP, AGD, and multisystem atrophy with globular inclusions belong to 4R tauopathies; and diffuse neurofibrillary tangle dementia with calcifications, to 3R þ 4R tauopathies. 9 These tau isoforms can be comfortably detected immunohistochemically by 3R- or 4R-specific antibodies RD3 and RD4, respectively. For the purpose of this short review, only Pick disease, PSP, CBD, and AGD as the representatives of the most frequent tauopathies will be further discussed, with basic differential diagnostic markers being shown in Table 2. 3R Tauopathy: Pick Disease. The macroscopic examinations of brains with Pick disease often show severe, circumscribed lobar frontal and temporal atrophy that may be either symmetric or asymmetric. Microscopically, loss of neurons and gliosis, often in a pancortical pattern, in the neocortex of frontal and temporal lobes is found. Neuronal atrophy and gliosis usually spares the hippocampus and is found to a minimal extent in the brainstem and cerebellum. Typical neuropathologic findings are Pick bodies, which are neuronal cytoplasmic inclusions that stain slightly basophilic on routine hematoxylin-eosin staining and are strongly argyrophilic after Bielschowsky or Bodian silver staining but do not stain with Gallyas silver stain. Immunohistochemistry testing reveals Pick bodies that are tau, RD3, p62, and ubiquitin immunoreactive and RD4, a-synuclein, and TDP- 43 negative (Figure 1, a and b). The cortical distribution of Pick bodies typically involves neurons in the dentate gyrus. Other cortical areas include the cornu Ammonis of the hippocampus, presubiculum, cingulate gyrus, insula, inferior 134 Arch Pathol Lab Med Vol 138, January 2014 Pathology of Frontotemporal Lobar Degenerations Rohan & Matej

Table 2. temporal lobe, and the inferior parietal lobule. Subcortical and brainstem distribution of Pick bodies is less prominent. Another typical finding is Pick cells or so-called swollen chromatolytic neurons. Glial pathology in Pick disease is less pronounced than in other tauopathies, with glial inclusions often showing atypical 3R and 4R positivity. 22 4R Tauopathies. Progressive Supranuclear Palsy. Gross examination of the brain affected by PSP may be unremarkable or show mild cortical and midbrain atrophy with mildly dilated ventricles. The subthalamic nucleus is often atrophied and the substantia nigra is depigmented. Probably the most characteristic gross finding in PSP is atrophy of the superior cerebellar peduncle due to loss of neurons in the dentate nucleus. In PSP, neuronal loss with gliosis in subcortical regions (basal ganglia, subthalamic nucleus, and substantia nigra) and dentate nucleus is typical. Neuronal pathology presents with typical finding of cytoplasmic, globose 4R-tau immunoreactive inclusions and diffuse granular cytoplasmic inclusions immunoreactive for tau (so-called pretangles) (Figure 2, a and b). Glial lesions include tufted astrocytes and oligodendroglial coiled bodies. Tufted astrocytes contain argyrophilic and tau-immunoreactive inclusions located toward the center of astrocytes in contrast to astrocytic plaques found in CBD (see below and Table 2). Oligodendroglial coiled bodies are tau-immunoreactive, rounded, cytoplasmic inclusions. Tau-immunoreactive neuropil threads are also found in PSP, but to a lesser extent than in CBD. 22 A scoring system for PSP, based on the distribution and extent of tau pathology, has been proposed by Williams et al. 23 Corticobasal Degeneration. The typical form of CBD that accompanies corticobasal syndrome presents as an asymmetric focal atrophy of the frontal and parietal lobes and atrophy of the corpus callosum. Atrophy of subcortical regions is usually not prominent and the brainstem and cerebellum are often spared; however, loss of pigmented neurons in the substantia nigra may occur. In the CBD variant associated with olivopontocerebellar atrophy, the pons and cerebellum are markedly atrophied. Spherical Differential Diagnosis of Selected Tauopathies a Pick Disease CBD PSP AGD Tau isoform 3R 4R 4R 4R Neurons Pick bodies Corticobasal bodies, Globose NFTs, pretangles Ballooned neurons Pick cells pleomorphic NIs, in limbic pretangles, ballooned neurons structures Astrocytes Tau-positive inclusions Astrocytic plaques Tufted astrocytes Tau-positive grains may be detectable b Oligodendrocytes Tau-positive inclusions AT8þ coiled bodies less AT8þ coiled bodies AT8þ coiled bodies Tau-positive neuropil threads may be detectable b Variable dense than in PSP Numerous in both cortical and subcortical grey and white matter numerous Variable, mainly subcortical, less than in CBD Variable Neuronal loss and gliosis Cortical areas Very severe Severe Subtle Minimal Subcortical areas Thalamus, caudate nucleus Mainly substantia nigra, less in subthalamic Severe in subthalamic and thalamic nuclei, pallidum Minimal nucleus and substantia nigra Cerebellum Minimal Minimal c Atrophy of dentate nucleus Minimal Abbreviations: AGD, argyrophilic grain disease; CBD, corticobasal degeneration; NFTs, neurofibrillary tangles; NIs, neuronal inclusions; PSP, progressive supranuclear palsy. a Data derived from Dicksonet et al, 22 Williams et al, 23 Dickson et al, 24 and Saito et al. 25 b Glial inclusions show 4R-tau predominance in Pick disease. c Atypical variant of corticobasal degeneration with prominent olivopontocerebellar atrophy presents with predominant atrophy of hindbrain structures. corticobasal bodies (also so-called Pick-like inclusions) may be found in neurons. These corticobasal bodies can be stained with Gallyas, are tau-4r immunoreactive, and are found mostly in the frontal and parietal cortex, in contrast to Pick bodies in Pick disease. A dominant, and in the case of CBD a characteristic, finding are numerous Gallyas- and tau-immunoreactive threads in the neuropil of affected gray matter structures and adjacent white matter. Typical features, although difficult to find, are swollen chromatolytic neurons (sometimes called ballooned neurons ). Another characteristic, and also a reliable diagnostic marker of CBD, is the presence of astrocytic lesions called astrocytic plaques with typical peripheral Gallyas- and tau-4r immunoreactive inclusions in astrocytes. 22,24 Argyrophilic Grain Disease. Gross findings in AGD are usually unremarkable, although mild medial temporal lobe atrophy may be visible. The diagnostic hallmark of AGD is argyrophilic grains that can be demonstrated with Gallyas silver stain, Bodian and Bielschowsky stains, and by a positive immunohistochemical reaction for tau protein, its 4R isoform, and p62. Argyrophilic grains are scattered throughout the neuropil in both cortical and subcortical areas. Most susceptible are limbic structures, mainly transentorhinal and entorhinal cortex. The spread of argyrophilic grains follow temporal and anatomic patterns that are also the basis for AGD staging. 25 Gallyas- and tau-immunoreactive oligodendroglial coiled bodies can also be found in AGD but are considered to be nonspecific as they occur in other tauopathies. Another nonspecific feature of AGD is ballooned neurons, found mainly in the limbic lobe. The dominant neuronal pathology presents with diffuse cytoplasmic Gallyas-negative, tau-4r immunoreactive deposits. Even though AGD can present with Alzheimer disease like pathologic changes (AT8-immunoreactive neuronal cytoplasmic inclusions), it is regarded as a distinct neuropathologic entity. Since AGD can often coexist with another neurodegenerative disease (eg, Alzheimer disease), a careful examination and potentially the use of RD4 antibody may be needed to recognize AGD. Arch Pathol Lab Med Vol 138, January 2014 Pathology of Frontotemporal Lobar Degenerations Rohan & Matej 135

Figure 1. Pick disease showing granular neurons of the dentate fascia of the hippocampus with tau-immunoreactive cytoplasmic inclusions (a). The inclusions show 3R-tau predominance as demonstrated by RD3-specific antibody (b) (AT8, original magnification 3400 [a]; RD3, original magnification 3200 [b]). Figure 2. Progressive supranuclear palsy, mesencephalon. Antibodies against hyperphosphorylated tau protein (a), and 4R-tau isoform (b) reveal neuronal cytoplasmic inclusions and neuropil threads of variable length and thickness (AT8, original magnification 3200 [a]; RD4, original magnification 3200 [b]). Figure 3. FTLD TDP (Frontotemporal lobar degeneration transactive response DNA-binding protein) type A showing temporal cortex with TDP-43immunoreactive neuronal cytoplasmic inclusions and numerous neuropil threads found predominantly in layer II of the neocortex (a). FTLD-MND (FTLD motor neuron disease) showing spinal motor neuron with TDP-43-immunoreactive neuronal cytoplasmic skeinlike inclusions (b) (phosphorylated TDP-43, original magnifications 340 [a] and 3600 [b]; contrast and brightness enhanced with Adobe Photoshop CS4 software [Adobe Systems Inc., San Jose, California]). 136 Arch Pathol Lab Med Vol 138, January 2014 Pathology of Frontotemporal Lobar Degenerations Rohan & Matej

Frontotemporal Lobar Degeneration TDP In healthy brains, TDP-43 immunohistochemistry shows diffuse nuclear staining. In FTLD-TDP brains, pathologically misfolded TDP-43 can be detected in neuronal nuclear inclusions, neuronal cytoplasmic inclusions (NCIs), and neurites. According to the pattern and distribution of TDP- 43 inclusions and neurites, FTLD-TDP can be divided into 4 types. 20,26,27 In type A (Mackenzie type 1, Sampathu type 3) numerous NCIs, predominantly in layer II of the neocortex, and many short dystrophic neurites, are observed (Figure 3, a). Type B (Mackenzie type 3, Sampathu type 2) has a moderate amount of NCIs and few dystrophic neurites distributed in all neocortical layers. Type C (Mackenzie type 2, Sampathu type 1) is characterized by few NCIs and many long dystrophic neurites that can be found predominantly in neocortical layer II. Type D (type 4 described by Forman et al 28 ) has a typical appearance with many lenticular neuronal nuclear inclusions with few NCIs and many short dystrophic neurites in all layers of neocortex. The neuropathology of most cases of sporadic ALS is characterized by cytoplasmic neuronal and glial TDP-43 positivity in the primary motor cortex, brainstem motor nuclei, and anterior horn motor neurons (Figure 3, b). This provides strong evidence that FTLD-TDP and ALS (FTLD-MND) form a clinicopathologic spectrum of TDP-43 proteinopathies. 29 Frontotemporal Lobar Degeneration FUS The third abnormal protein described in FTLD and ALS with tau- and TDP-43 negative inclusions is FUS. 30 Deposits of FUS can be found in the cytoplasm and nuclei of both neurons and glia. Three entities are usually associated with FTLD-FUS: basophilic inclusion body disease, neuronal intermediate filament inclusion disease, and atypical FTLD with ubiquitinated inclusions. 19,30 These 3 entities have aggregated FUS protein in common; however, each can be observed as a different pathologic entity. In basophilic inclusion body disease, basophilic inclusions, seen with hematoxylin-eosin staining, are the hallmark. Neuronal intermediate filament inclusion disease is unique in that variably shaped eosinophilic intracellular inclusions seen with hematoxylin-eosin staining are often immunoreactive with antibody prepared against neuronal intermediate filaments (a-internexin). In contrast, atypical FTLD with ubiquitinated inclusions is characterized by inclusions that cannot be visualized with hematoxylin-eosin staining and are immunoreactive only with ubiquitin and FUS. 30 PROGNOSIS AND TREATMENT Frontotemporal lobar degenerations still remain incurable with mean survival times of 2 to 10 years, 2 depending on the FTLD type. The lowest survival rates are those associated with MND. 2 Owing to the typical gradual onset of symptoms and lack of reliable diagnostic tools, early diagnosis of FTLD is rather uncommon. As is true for other neurodegenerative disorders, fully developed symptoms are markers of irreversible damage to involved brain areas and, therefore, treatment is nonspecific (selective serotonin reuptake inhibitors, antipsychotics, memantine) and of palliative character. 31 Cholinesterase inhibitors that may alleviate symptoms of Alzheimer disease are controversial in FTLD. 31 Reliable biomarkers for early stages are not available to date; however, the rapidly growing knowledge regarding the underlying pathology and molecular-genetic associations is promising. 15 CONCLUSION The role of the pathologist in the management of FTLD is becoming increasingly important. Even though diagnostic testing performed ante mortem, using various modalities, can increase the probability of a correct diagnosis, a definite diagnosis is still based on a postmortem examination of the brain and spinal cord. Therefore, the pathologist s task is to obtain samples of both fresh and fixed tissues in a standardized manner and to either perform the required diagnostic tests in-house or send the brain and/or collected samples to a referral neuropathologic center. The significant familial link for both FTLD and MND calls for a precise neuropathologic diagnosis and categorization so that molecular-genetic testing for mutations in genes, discussed in this review, can be performed. However, with respect to the occurrence of C9ORF72 mutation in a significant proportion of sporadic cases, 6 and also to the problematic and ethically demanding issue of molecular-genetic diagnostics of neurodegenerative diseases in living relatives in general, routine clinical diagnostic testing on autopsy material is problematic and not generally available. Nevertheless, preserving fresh frozen tissue samples is of great research importance owing to rather low FTLD prevalence. The antibodies against C9ORF72, which is probably the most common genetic aberration responsible for familial FTD and ALS, will probably be introduced into routine practice in the near future. This will lead to quicker and more widely available determination of C9ORF72 status. The study has been partially funded by Grant IGA NT 12094-5 from the Czech Ministry of Health. The authors wish to thank Tom Secrest, MSc, for revisions on the English version of the article. References 1. Bird T, Knopman D, VanSwieten J, et al. Epidemiology and genetics of frontotemporal dementia/pick s disease. Ann Neurol. 2003;54(suppl 5):S29 S31. 2. Josephs KA, Knopman DS, Whitwell JL, et al. Survival in two variants of tau-negative frontotemporal lobar degeneration: FTLD-U vs FTLD-MND. Neurology. 2005;65(4):645 647. 3. Pickering-Brown SM. The complex aetiology of frontotemporal lobar degeneration. Exp Neurol. 2007;206(1):1 10. 4. Renton AE, Majounie E, Waite A, et al. A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD. Neuron. 2011; 72(2):257 268. 5. DeJesus-Hernandez M, Mackenzie IR, Boeve BF, et al. Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. Neuron. 2011;72(2):245 256. 6. Majounie E, Renton AE, Mok K, et al. Frequency of the C9orf72 hexanucleotide repeat expansion in patients with amyotrophic lateral sclerosis and frontotemporal dementia: a cross-sectional study. Lancet Neurol. 2012;11(4): 323 330. 7. Sieben A, Van Langenhove T, Engelborghs S, et al. The genetics and neuropathology of frontotemporal lobar degeneration. Acta Neuropathol. 2012; 124(3):353 372. 8. McKhann GM, Albert MS, Grossman M, Miller B, Dickson D, Trojanowski JQ. Clinical and pathological diagnosis of frontotemporal dementia: report of the Work Group on Frontotemporal Dementia and Pick s Disease. Arch Neurol. 2001;58(11):1803 1809. 9. 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