Making the diagnosis of frontotemporal lobar degeneration.
In the last 10 to 15 years, awareness of the frontotemporal dementia (FTD) has increased. In fact, in demented individuals younger than age 65, FTD and AD have the same prevalence. (10) Frontotemporal dementia can be separated into 2 broad categories: behavioral variant FTD and primary progressive aphasia. (11,12) Further consideration of the clinical details of FTD is beyond the scope of this article. However, FTD can be inherited in up to 50% of cases, and in order to perform targeted genetic analysis of the patient and potential affected family members, and to investigate biomarkers that will allow antemortem diagnosis upon which to base future targeted therapy, determination of the specific pathologic subtype is important. (13) Currently, brain autopsy remains the gold standard for diagnosis of the specific pathologic and molecular FTLD subtype. (14,15) (Note: FTD refers to the clinical syndrome and FTLD to the pathologic diagnosis. See the Table for definitions of clinical and pathologic subtypes. Note that this is a fairly comprehensive list of all possible pathologic subtypes and includes many that are uncommon or rare.)
EVALUATING THE DEMENTIA BRAIN
A careful gross examination can reveal a good deal about the likely final neuropathologic diagnosis. Brain weight should of course be recorded, and regional cortical atrophy, as well as atrophy of caudate, hippocampus, brainstem, and cerebellum, should be semiquantitated. The cerebellar dentate nucleus should be examined for atrophy/degeneration, and the pigmented brainstem nuclei, the substantia nigra, and locus coeruleus evaluated for pallor. It should be kept in mind that pathologic AD may be the underlying pathologic process in an FTD brain, so AD must remain on the differential diagnosis. (16) In AD, atrophy is usually generalized (Figure 1), involving all cortical regions, most often with prominent atrophy of medial temporal structures including the hippocampus (Figure 2), amygdala, and inferior temporal cortex. In FTLD, cortical atrophy is naturally most often greatest in frontal and temporal lobes (Figure 3) but does not always spare other regions. The FTLD hippocampus is often, but not always, less atrophic than in AD, except in FTLD-tau (PiD), where hippocampal atrophy can be severe. (17) Caudate atrophy, often present in FTLD (Figure 4), is uncommon in AD. (18) The subthalamic nucleus is quite atrophic virtually only in progressive supranuclear palsy (FTLD-tau [PSP]) (Figure 5), and the cerebellar dentate nucleus is also generally "indistinct" (19) (Figure 6). The substantia nigra and locus coeruleus exhibit pallor in most FTLDs and AD. In AD, however, locus coeruleus pallor is usually greater than substantia nigra pallor, while in FTLD, the reverse is usually seen (personal observation) (Figure 7).
Definitions of Clinical and Pathologic Subtypes FTD = Clinical frontotemporal dementia syndrome, encompasses: bvFTD: behavioral variant FTD PPA (primary progressive aphasia) and its subtypes: PPA-G: nonfluent/agrammatic PPA PPA-S: semantic dementia (SD), also called semantic PPA PPA-L: logopenic PPA FTLD = Pathologic frontotemporal lobar degeneration, encompasses: FTLD-tau (inclusions immunolabeled with antibodies to tau); includes: More common primary diagnoses FTLD-tau (PiD): Pick disease FTLD-tau (CBD): corticobasal degeneration FTLD-tau (PSP): progressive supranuclear palsy Less common primary diagnoses FTLD-tau (AGD): argyrophilic grain disease FTLD-tau (MSTD): multiple-system tauopathy with dementia FTLD-tau (NFT-dementia): tangle predominant senile dementia FTLD-tau (WMT-GGI): white matter tauopathy with globular glial inclusions FTLD-tau (unclassifiable): unclassifiable tauopathies FTLD-U (inclusions labeled by antibodies to ubiquitin and p62); includes: FTLD-TDP Most common FTLD-U Inclusions labeled by antibodies to ubiquitin, p62, and TAR DNA-binding protein of 43 kDa (TDP-43) FTLD-FUS Rare Inclusions immunopositive for fused in sarcoma protein (FUS), ubiquitin, and p62, and negative for TDP-43 Includes: FTLD-FUS (aFTLD-U): atypical FTLD-U FTLD-FUS (NIFID): neuronal intermediate filament inclusion disease FTLD-FUS (BIBD): basophilic inclusion body disease FTLD-UPS Very rare Inclusions labeled by ubiquitin and p62 and negative for tau, TDP-43, and FUS UPS is ubiquitin protease system Includes: FTLD-UPS (FTD-3): familial FTLD associated with CHMP2B mutations FTLD-UPS (sporadic): possibly some sporadic cases of TDP-43 and FUS-negative FTLD-U FTLD-ni Very rare No inclusions seen on immunostains with tau, ubiquitin, p62, TDP-43, or FUS
The recent National Institute on Aging-Alzheimer's Association (NIA-AA) revision of criteria for the pathologic diagnosis of AD recommends a minimum of 13 histologic sections to evaluate for Alzheimer disease neuropathologic change (ADNC), Lewy body disease (LBD), vascular brain injury, microvascular lesions, and hippocampal sclerosis. (5,6) These same 13 sections may be used for the evaluation of FTLD. The sections include (1) middle frontal gyrus; (2) superior and middle temporal gyri; (3) inferior parietal lobule; (4) occipital cortex; (5) anterior cingulate gyrus; (6) amygdala; (7) hippocampus with dentate gyrus and entorhinal cortex; (8) basal ganglia at the level of the anterior commissure with caudate, putamen, globus pallidus, and the nucleus basalis of Meynert; (9) thalamus with subthalamic nucleus; (10) cerebellar cortex and dentate nucleus; (11) midbrain with substantia nigra; (12) pons with locus coeruleus; (13) and medulla with dorsal motor nucleus of the vagus and hypoglossal nucleus. Figure 8 shows where these sections should be taken. All sections should be stained with routine hematoxylin-eosin (H&E) and evaluated according to NIA-AA revised criteria for regional neuronal loss and gliosis, vascular brain injury, microvascular lesions, and hippocampal sclerosis. (5,6) Whereas in AD the most striking neuronal loss and gliosis is in the entorhinal cortex and hippocampus, nucleus basalis, locus coeruleus, and neocortex, neuronal loss and gliosis in FTLD generally parallels the gross atrophy. Neocortical neuronal loss and gliosis is usually most prominent in frontal and temporal regions, but in corticobasal degeneration (FTLD-tau [CBD]), for example, there is often prominent, and sometimes asymmetric, parietal and motor cortex neuronal loss and gliosis as well. (20) In most FTLDs, hippocampal neuronal loss and gliosis is less striking than in AD, unless there is also hippocampal sclerosis, which is most often found in frontotemporal lobar degeneration with TAR DNA-binding protein of 43 kDa (TDP-43) proteinopathy (FTLD-TDP). (21) The other exception is FTLD-tau (PiD), which may have severe hippocampal neuronal loss and gliosis. (17) In FTLD-tau (PSP), there is notable neuronal loss and gliosis in the subthalamic nucleus, lateral thalamic nucleus, globus pallidus, and cerebellar dentate nucleus, where grumose degeneration of presynaptic terminals around dentate neurons is often prominent and can be demonstrated with immunostains for synaptophysin. (19)
Special Stains and Immunostains
Alzheimer Disease and LBD Pathology.--In addition to evaluating regional neuronal loss and gliosis, microvascular lesions, vascular brain injury, and hippocampal sclerosis, the dementia brain should always be investigated for AD and LBD pathology, regardless of the specific clinical diagnosis. There is often some degree of ADNC in the elderly brain, and combined pathologic processes are not infrequent. Alzheimer disease neuropathologic change can be semiquantitated with Bielschowsky or Gallyas silver or thioflavin-S fluorescent stains of hippocampus and neocortical sections, and the degree of ADNC reported. (5,6) Amyloid-[beta] can be demonstrated with an immunostain of hippocampus. If the section includes parahippocampal gyrus, the Thal phase of amyloid deposition can easily be determined, as amyloid plaques appear early in neocortex (phase 1), later in CA1 and the subiculum (phase 2), still later in the fascia dentata (phase 3), then in CA4 (phase 4), and finally in cerebellum and brainstem (phase 5). (5,6,22) The LBD pathology can be semiquantitated on H&E sections of brainstem and [alpha]-synuclein immunohistochemistry of amygdala. If the amygdala has Lewy bodies, additional [alpha]-synuclein immunostaining should be performed on anterior cingulate gyrus, and if Lewy bodies are seen in the cingulate, then additional [alpha]-synuclein immunostaining should be performed on frontal, temporal, and parietal neocortex for grading of the Lewy body pathology. (5,6)
Frontotemporal Lobar Degeneration Pathology.--For initial FTLD screening, tau, ubiquitin or p62, and TDP-43 immunostaining should be performed on hippocampus and frontal cortex. Recommended antibodies are the following: for tau, AT8 (Pierce-Endogen, Rockford, Illinois) or PHF-1 (available from Peter Davies, PhD, at Albert Einstein College of Medicine by request); for p62, anti-p62Lck ligand (BD Biosciences, San Jose, California); and for TDP-43, polyclonal antibody to normal TARDBP (Proteintech, Chicago, Illinois) or polyclonal to phosphorylated TARDBP (pS409/410-2) (Cosmo Bio Co, Ltd, Tokyo, Japan). Tau immunostains will highlight the abnormally phosphorylated tau deposits in neurons and glia that are found in FTLD-tau; ubiquitin or p62 immunostains will highlight the abnormal protein deposits in neurons and glia found in FTLD-U; and TDP-43 will demonstrate whether or not the ubiquitin or p62 immunopositive, tau-negative inclusions are those of FTLD-TDP, the most common FTLD-U. (14,15)
For more specific classification, refer to recent articles describing FTLD subtypes. (14,15) Briefly, tau inclusions associated with a specific FTLD-tau, most commonly corticobasal degeneration (FTLD-tau [CBD]), FTLD-tau (PSP), or FTLD-tau (PiD), can be morphologically distinguished. In FTLD-TDP, the antibody to normal TDP-43 will show normal positivity in nuclei of neurons that have no abnormal TDP-43-positive inclusions, and "negative" nuclei in neurons that have inclusions, while the phosphorylated TDP-43 antibody will highlight inclusions only. Should immunostains show ubiquitin- or p62-positive inclusions that are TDP-43 negative, or no tau- or ubiquitin-positive inclusions at all, an additional immunostain can be considered, using an antibody to FUS (also known as FUS/TLS, fused in sarcoma/translocated in liposarcoma protein). If FUS staining is positive, the diagnosis is FTLD-FUS, and the possible, more specific, diagnoses include atypical FTLD-U (FTLD-FUS [aFTLD-U]), neuronal intermediate filament inclusion disease (FTLD-FUS [NIFID]), or basophilic inclusion body disease (FTLD-FUS [BIBD]). If FUS staining is negative, the diagnosis is FTLD involving the ubiquitin proteasome system (FTLD-UPS), and more specifically, it may be associated with mutations in the CHMP2Ba gene (FTD-3) or possibly a FUS-negative sporadic FTLD-UPS. There is also a chance that tau, ubiquitin or p62, and TDP-43 results will all be negative, in which case the possibility that prion disease is responsible for the FTLD should be considered.
The results of the initial screening with these 3 antibodies (tau, ubiquitin or p62, and TDP-43) on 2 sections each, frontal cortex and hippocampus, will in most cases allow the general pathologist to subclassify the FTLD. At this point, screening will likely have indicated the major FTLD disease protein present. In some cases, and certainly for more detailed delineation of the complete pathology present in the case, immunostaining on sections from additional regions may be required. However, the additional sections need only be immunostained with antibodies to the major disease protein. Figure 9 is a flowchart showing the sequence of stains and immunostains that can be followed in working up a case for FTLD.
Case 1: FTLD-tau (PiD)
The decedent was a 72-year-old man with an 8-year history of primary progressive aphasia. Brain autopsy revealed asymmetric atrophy of the inferior frontal gyrus with moderate atrophy on the left (Broca region) and mild atrophy on the right. There was also asymmetry of the hippocampal atrophy, which was severe on the left and mild on the right (Figure 10, A). Microscopic examination of H&E sections revealed numerous round, discrete, bluegray cytoplasmic inclusions in the hippocampal dentate gyrus approximately the size of dentate gyrus neuronal nuclei, compatible with Pick bodies (Figure 10, B). Some of the Pick bodies were labeled with ubiquitin (Figure 10, C). All of them were immunolabeled with antibodies to phosphorylated tau (Figure 10, D). There was severe neuronal loss and gliosis in the left inferior frontal gyrus (Broca region) (Figure 10, E) and ballooned neurons were seen in several cortical and subcortical regions (Figure 10, E, inset). Tau immunostains also labeled Pick bodies and glial inclusions in the frontal cortex (Figure 10, F). Pick bodies were also present in temporal and parietal cortex, caudate and putamen, substantia nigra, locus coeruleus, and pontine nuclei (not shown). They were positive with antibodies to 3R but not 4R tau (not shown). (23) TDP-43 immunostaining of frontal cortex and hippocampus was negative.
Case 2: FTLD-tau (CBD)
A brain autopsy was performed on a 67-year-old woman who died after an 8-year history of primary progressive aphasia. Gross examination revealed absent to mild symmetric cortical and hippocampal atrophy and moderate dilatation of the lateral ventricles (Figure 11, A). Hematoxylin-eosin sections revealed neuronal loss and gliosis that was greatest in language regions, and numerous ballooned neurons in cortical and subcortical regions and brainstem nuclei (Figure 11, B) that were labeled with antibodies to phosphorylated tau (Figure 11, C). There were numerous tau-positive threads in cortex (Figure 11, C) and white matter (Figure 11, D). Astrocytic plaques and threads in cortex were also highlighted by Gallyas stains (Figure 11, E). A higher-power image of a tau-labeled astrocytic plaque and neuronal inclusion is seen in Figure 11, F. TDP-43 immunostaining of frontal cortex and hippocampus was negative.
Case 3: FTLD-tau (PSP)
A 74-year-old man with a 9-year history of FTD died, and brain autopsy revealed moderate frontal atrophy, severe ventricular dilatation, severe atrophy of the head of the caudate, and mild atrophy and yellowish discoloration of the globus pallidus (Figure 12, A). Sections of globus pallidus immunostained with tau showed neuronal inclusions and tufted astrocytes (Figure 12, B). A H&E section of cerebellar dentate nucleus showed moderate neuronal loss and gliosis (Figure 12, C) and a synaptophysin immunostain of this section highlighted "grumose" degeneration (Figure 12, C, inset). (24) Only rare dentate nucleus neurons were tau positive (Figure 12, D). There were tau-positive neurons and tufted astrocytes in frontal, temporal, parietal, and motor cortex (Figure 12, E; positive with Gallyas stain in Figure 12, E, inset), nucleus basalis, caudate, putamen (Figure 12, F), globus pallidus, thalamus, subthalamic nucleus (Figure 12, G), and many brainstem nuclei. In some regions, such as the putamen, tufted astrocytes predominated (Figure 12, F), while in others, such as the subthalamic nucleus, tau-positive neurons predominated (Figure 12, G). Tau inclusions were labeled with anti bodies to 4R but not 3R tau (not shown). (23) TDP-43 immunostaining of frontal cortex and hippocampus was negative.
Case 4: FTLD-TDP
An autopsy of the brain of a 63-year-old man who had a 6-year history of FTD with corticobasal syndrome revealed marked asymmetry of frontal, temporal, and parietal atrophy--severe on the right and mild to moderate on the left, with relative sparing of motor and sensory gyri (Figure 13, A and B). Coronal sections at the level of the anterior hippocampus also showed severe right and moderate left ventricular dilatation (Figure 13, C). Tau immunostaining of frontal cortex and hippocampus was negative. A TDP-43 immunostain of frontal cortex showed cytoplasmic and intranuclear inclusions and short dystrophic neurites predominantly in upper layers of cortex (Figure 13, D). There were sparse cytoplasmic inclusions in hippocampal dentate gyrus (not shown). This is an example of FTLD-TDP type A, as described in the recent article on the "harmonized" classification scheme for FTLD-TDP. (25) For comparison, Figure 13, E and F, shows FTLD-TDP type B; and Figure 13, G, shows FTLD-TDP type C.
Case 5: FTLD-FUS (BIBD)
The decedent was a 55-year-old man with a 7-year history of FTD. Brain autopsy revealed moderate to severe right frontal (Figure 14, A) and mild left frontal atrophy (Figure 14, B). Distinct basophilic inclusions were seen in frontal, motor, and parietal cortex, red nucleus, hypoglossal nucleus, pontine nuclei, and superior colliculus. One such inclusion in motor cortex is shown in Figure 14, C. Basophilic inclusions stained negatively with ubiquitin immunostain (Figure 14, D) and antibodies to tau and TDP-43 (not shown). FUS immunostains strongly labeled basophilic inclusions (Figure 14, E) and also demonstrated numerous cytoplasmic inclusions in superficial cortical layers that were not seen on H & E stains (Figure 14, F), as has been described in basophilic inclusion body disease. (26)
SUMMARY OF THE PATHOLOGIC APPROACH
Pathologic classification of the FTLD brain can be approached in a logical, stepwise manner by using immunohistochemistry and the morphologic characteristics of the inclusions and their distribution. Using tau, ubiquitin or p62, and TDP-43 immunostains of frontal cortex and hippocampus, the pathologist will in most cases be able to classify the FTLD into either a tauopathy or a non-tau FTLD. Approximately one-half of FTLDs are tauopathies and the other half, TDP-43 proteinopathies.
In the case of a tauopathy, the presence of round, tau-positive Pick bodies characterizes the case as FTLD-tau (PiD). If tau-positive inclusions, but not Pick bodies, are present, the most common alternative tauopathies are FTLD-tau (CBD) and FTLD-tau (PSP). Both have tau positive neuronal and astrocytic inclusions. The distinguishing astrocytic inclusions are the astrocytic plaques of FTLD-tau (CBD) and tufted astrocytes of FTLD-tau (PSP). Astrocytic plaques are characterized by small, homogeneously sized tau-positive inclusions in peripheral astrocytic processes, and the central astrocytic nucleus may or may not be seen in the plane of the section. The parts of the astrocytic processes close to the nucleus are not tau positive. In contrast, tau positivity in tufted astrocyte processes is strongest closest to the astrocytic nucleus and becomes weaker in the distal processes before it disappears, and the nucleus is generally visible. In FTLD-TDP, tau staining is negative, and TDP-43 immunostains label neuronal cytoplasmic inclusions, intranuclear inclusions, and short dystrophic neurites in type A; predominantly cytoplasmic inclusions in type B; and predominantly long dystrophic neurites in type C. In FTLD-FUS, tau and TDP-43 staining is negative. Ubiquitin staining is usually positive in FTLD-FUS (aFTLD-U), is positive in some of the inclusions found in FTLD-FUS (NIFID), and is usually negative in FTLD-FUS (BIBD). FUS inclusions are generally strongly positive in all these cases. However, all types of FTLD-FUS are rare.
Pathology of the FTLD brain is not easily subclassified in every case, but in most cases the approach is straightforward and logical. In most cases, the results of the workup will allow the general pathologist to synthesize the pathologic diagnosis of a specific FTLD subtype (Figure 15). Hopefully, this article will be a useful reference when faced with the autopsy of a decedent with frontotemporal dementia.
This work was supported in part by NIA grant AG 13854. We would like to thank the patients and their families who, through their generous participation, make studies like this possible.
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Eileen H. Bigio, MD
Accepted for publication March 7, 2012.
From the Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, Illinois.
The author has no relevant financial interest in the products or companies described in this article.
Reprints: Eileen Bigio, MD, Northwestern University Feinberg School of Medicine, 710 N Fairbanks Ct, Olson 2-458, Chicago, IL 60611 (e-mail: email@example.com).
Please note: Illustration(s) are not available due to copyright restrictions.
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|Author:||Bigio, Eileen H.|
|Publication:||Archives of Pathology & Laboratory Medicine|
|Date:||Mar 1, 2013|
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