Neurodegenerative Diseases

Macroscopic Pathology

Diffuse cerebral atrophy is the defining macroscopic finding in AD brains ( Fig. 6.1 ). Brain weights are frequently between 1000 and 1200 g, even in advanced AD. The most common pattern of atrophy in AD is symmetric frontotemporal atrophy with sparing of the sensorimotor (perirolandic) and visual cortices. The circumscribed, “knife-edge” atrophy of FTLD is atypical in routine AD, and the transition between atrophic and non-atrophic brain is fairly subtle. The pattern of cerebral atrophy may follow variant clinical features of the disease, including occipital atrophy in posterior cortical atrophy.

Sectioning of the AD cerebrum confirms the frontotemporal atrophy and often reveals moderate to severe dilatation of the ventricular system—hydrocephalus ex vacuo—sometimes presenting clinically as normal-pressure hydrocephalus. In addition, sections of brain show atrophy of entorhinal cortex and amygdala. Entorhinal cortex atrophy is observed by identifying the collateral sulcus on cut sections of temporal lobe and following the sulcus rostrally to the level of the uncus and mid-amygdala and temporal horn of the lateral ventricle (usually enlarged). In AD brains a histologic section from this site is useful in sampling the amygdala, entorhinal and transentorhinal cortex, and neocortex lateral to collateral sulcus. Hippocampal atrophy may be more subtle in AD, especially in the absence of concomitant hippocampal sclerosis. In the setting of AD, markedly atrophic hippocampi, out of proportion to whole brain atrophy and brain weight, is strongly suggestive of comorbid hippocampal sclerosis (LATE) with associated inclusions of TAR DNA-binding protein 43 kDa (TDP-43). The volume of thalamus, subthalamic nuclei, and basal ganglia are typically preserved in AD. Examination of the brainstem usually reveals pallor of locus ceruleus and substantia nigra due to neurofibrillary pathology and neuron loss.

Microscopic Pathology

Pathologic confirmation of AD requires a combination of Aβ deposits and tau pathology in the form of neurofibrillary tangles (NFTs). Both pathologies are first recognized on hematoxylin and eosin (H&E) stains ( Fig. 6.2 ). The severity and extent of the pathologies is subsequently documented by immunohistochemical (IHC) methods, silver staining-based methods (Gallyas, modified Bielschowsky), fluorescence-based methods (thioflavin S), or a combination of these techniques. Other special stains, such as Congo red, may highlight a subset of amyloid deposits but, in general, this is not utilized.

Parenchymal Aβ plaques are a critical element of AD neuropathology. Patients with AD typically have frequent mature, or “cored,” parenchymal plaques that exceed the number seen in non-demented patients. These plaques comprise extracellular deposits containing dense central cores of Aβ, typically associated with neuronal loss and microglial activation. The term neuritic plaque refers to the same structure with the addition of tau-positive, plaque-associated dystrophic neurites. In neuritic plaques microglia are also integrated into the structure at its periphery. At low and intermediate power magnification, H&E stains reveal mature plaques by their disruption of parenchyma, densely eosinophilic amyloid cores, and associated microglia. Evaluation of Aβ plaque distribution and density requires IHC or other methods. A variety of antibodies to Aβ may be applied to tissue sections of interest, often following a brief pre-treatment of tissue with formic acid for antigen retrieval. With this approach, AD brains reveal more extensive Aβ that can be identified on H&E or silver stain-based methods alone. This is because non-neuritic, diffuse deposits of Aβ are detected, often in a band-like and subpial distribution. So-called primitive plaques may also be seen, referring to an intermediate stage of Aβ plaque, between diffuse and mature, and typically characterized only by dense Aβ deposits.

Current guidelines for the diagnosis of AD, released in 2012 by a working group convened by the National Institute of Aging (NIA) and Alzheimer’s Association (AA), requires documentation of the extent and severity of Aβ and neuritic plaque pathologies, respectively. These 2012 criteria in turn evolved from the earlier NIA/Reagan criteria (1997), which generated probabilistic scores for AD neuropathologic change based on Aβ and tau pathologies. The NIA/AA 2012 system uses an ABC scoring system for amyloid extent (Thal phase for a myloid, or “A”), NFT stage ( B raak and Braak stage, or “B”) and neuritic plaque frequency ( C ERAD score, or “C”).

Thal phase describes the stereotypic progression of Aβ in pathologic aging and AD. The Thal phase does not depend on plaque subtype, and IHC methods are essential to identify the diffuse and primitive plaques that are predominant in subcortical nuclei, brainstem, and cerebellum. Five Thal phases are recognized. In Thal phase 1, Aβ pathology is limited to the cerebral cortex—a very common finding in human aging and in other non-AD NDDs. In Thal phase 2, Aβ deposits are detected in structures of the limbic region, particularly amygdala and hippocampus. Thal phase 3 is characterized by deposits in subcortical nuclei, such as striatum, thalamus, and basal forebrain, as well as in select brainstem structures (tectum). Thal phase 4 examples have Aβ in each of the preceding regions, and additionally, within characteristic brainstem nuclei, such as substantia nigra, tegmental gray of the midbrain and pons, locus ceruleus, and inferior olive. In Thal phase 5, diffuse deposits of Aβ are found in the molecular and granular cell layers of cerebellar cortex ( Fig. 6.3 ). It should be noted that CAA is common in leptomeningeal arterioles of the cerebrum and cerebellum in AD, and care must be taken not to confuse vessel wall deposits with parenchymal Aβ deposits. In the 2012 NIA/AA system the Thal phases are assigned A scores of 0–3 as follows: 0 (No Aβ deposits), 1 (Thal phases 1–2), 2 (Thal phase 3), and 3 (Thal phases 4–5).

In addition to Thal phase, the NIA/AA 2012 criteria require the frequency of neuritic plaques to be characterized. This is based on the neuropathologic assessment outlined by the Consortium to Establish a Registry for AD (CERAD) criteria. As originally proposed, the CERAD criteria employed silver stain-based methods to assess the density of neuritic plaques in designated neocortical areas (in practice, this may be estimated using Aβ and tau staining). Based on neuritic plaque frequency, levels of “none,” “sparse,” “moderate,” or “frequent” are assigned. The neocortical site with the highest neuritic plaque frequency is then used in the final CERAD designation. In the 2012 NIA/AA system, the CERAD neuritic plaque frequency is assigned a C score of 0–3 as follows: 0 (none), 1 (sparse), 2 (moderate), or 3 (frequent).

In addition to Aβ deposits, tau-positive NFTs are the other major component of AD pathology and the one that correlates best with cognitive impairment. NFTs comprise insoluble, fibrillar deposits of hyperphosphorylated tau in neurons, and these may be identified in virtually all brain regions. Ultrastructural examination has shown that pathologic tau deposits comprise paired helical filaments ( Fig. 6.4 ). Normal tau protein is a microtubule-associated and organelle-stabilizing protein essential to the integrity of the cytoskeleton. Tau is the product of the microtubule-associated protein tau ( MAPT ) gene on chromosome 17 with alternative splicing leading to both three-repeat (3R) and 4R isoforms of tau, based on the number of microtubule-binding domains present (discussed later in the chapter). In AD, tau is cleaved and phosphorylated and dissociates from microtubules.

On H&E examination of the AD brain, NFTs appear as either flame-shaped, basophilic cytoplasmic inclusions ( Fig. 6.2 ), or as round aggregates filling the cell body (globose NFTs). Whereas pyramidal neurons of neocortex and hippocampus frequently contain NFTs of the flame-shaped variety, neurons with round cell bodies, such as in amygdala, basal forebrain, and brainstem, frequently contain globose NFTs. NFTs may also be identified by silver staining methods and thioflavin S, which is useful because both techniques simultaneously detect neuritic plaque pathology. Another approach to identify NFTs is to use antibodies to tau, such as clone AT8, which targets tau that is phosphorylated at its serine 202 and threonine 205 residues. This IHC approach has the additional advantage that non-fibrillar, granular deposits of phospho-tau may be detected in neurons as pretangles that are not readily visualized by other methods ( Fig. 6.5 ). In addition to accumulating in the neuronal cell body to form an NFT, or as plaque-associated neurites, tau accumulates in neuronal dendrites as “neuropil threads.” These may be numerous in neocortex, even when NFT pathology is mild.

In regard to tau pathology, the NIA/AA 2012 criteria require the extent of NFT pathology to be documented using the staging system published in 1991 by Heiko and Eva Braak. With a few notable exceptions, such as the rare variant of hippocampal-sparing AD, this staging system is robust and strongly predictive of cognitive status. Patients with Braak and Braak NFT stages of V and VI rarely, if ever, have normal cognition. Likewise, patients with clinical AD but Braak and Braak NFT stages of ≤III have other underlying pathologies contributing to their cognitive impairment. Therefore an accurate and unbiased determination of NFT stage is a critical element in the evaluation of an AD patient at autopsy.

In contrast to the progression of Aβ deposits in aging and AD, the earliest tau pathology appears within brainstem nuclei and in the transentorhinal and entorhinal regions adjacent to collateral sulcus (stages I–II). As the NFT pathology progresses, there is more extensive involvement of amygdala, hippocampal formation, basal forebrain, subcortical nuclei, and eventually neocortex/isocortex (stages III–IV). The neocortical involvement begins in the association cortex with significant NFT pathology in primary visual, auditory, and sensorimotor cortices only occurring in Braak and Braak stage VI. The NFT stages are summarized as follows:

• Stages I–II, “transentorhinal”: In stage I, tau pathology is limited to transentorhinal cortex. Stage II is characterized by involvement of large multipolar neurons in lamina II of the entorhinal cortex and early involvement of other limbic structures. Full-thickness involvement of the entorhinal cortex and significant involvement of the hippocampal formation are not seen in stage II. Stages I and II constitute a B score of 1 in the 2012 NIH/AA system.

• Stages III–IV, “limbic”: Stage III NFT pathology is indicated by a band-like involvement of hippocampal regions CA2 and CA1, early involvement of CA4, full-thickness involvement of transentorhinal and entorhinal cortex, and neuron loss in superficial entorhinal cortex. The last of these is confirmed on H&E stains, and extracellular “ghost” tangles ( Fig. 6.6 ) occupy the position of the large multipolar neurons that formerly occupied lamina II. Stage IV is characterized by more severe involvement of all limbic regions, including anterior cingulate cortex, involvement of large cholinergic neurons of basal forebrain, and patchy but mild neocortical involvement by NFTs. Although neocortical NFTs are not numerous in stage IV, neuropil threads and plaque-associated neurites may be numerous. Together these limbic stages (III–IV) may correlate with mild cognitive impairment (MCI) in some patients but in isolation are insufficient to account for mild AD or more severe forms of cognitive impairment. Stages III and IV constitute a B score of 2 in the 2012 NIH/AA system.

  

• Stages V–VI, “isocortical”: In stage V, frontal, parietal, and temporal association cortices have more advanced NFT pathology as do the peristriate (Brodmann area 19) and parastriate (Brodmann area 18) areas of occipital lobe. In contrast, the primary visual/striate cortex (BA 17), as well as other primary cortical areas, has little or no NFT pathology. In addition, cases with stages V and VI have a predictable pattern of lamina II, III, and V NFT pathology across patients and cortical regions that is readily identified on low power examination of an AT8 or other suitable stain. Stage VI is characterized by involvement of all preceding regions and more substantial NFT pathology in primary sensorimotor, auditory, and visual cortices. Identification of stage VI thus requires appropriate sampling of motor cortex, Heschl’s gyrus (with auditory cortex), and striate cortex along the calcarine sulcus. Stages V and VI constitute a B score of 3 in the 2012 NIH/AA system.

• Atypical patterns of tau pathology, including deposits within astrocytes, at the depths of sulci, within white matter, or aberrant deposits in lamina I, suggest comorbid pathologies and are not AD pathologies changes per se. These are discussed elsewhere in the chapter.

Per NIA/AA 2012 guidelines, the combinations of Thal phase (A score), CERAD neuritic plaque frequency (B score), and Braak and Braak NFT stage (C score) are placed together in a matrix to determine whether the patient has “no,” “low,” “intermediate,” or “high” AD neuropathologic change (ADNC). Two very simple rules of thumb can be derived from this approach. First, a designation of high ADNC requires fairly advanced Aβ + NFT/tau pathology. Second, Thal phase and neuritic plaque frequency alone cannot be used to assign a high ADNC score in the absence of an isocortical NFT stage. In this way, the ABC scoring system relies heavily on the association between tau pathology and cognitive impairment.

Other pathologies common in ADNC are CAA, and other cellular inclusions, such as Hirano bodies and granulovacuolar degeneration (GVD). CAA comprises deposits of Aβ in the tunica media and adventitia of arterioles in leptomeninges and cortex ( Fig. 6.7 ). CAA is most readily seen in leptomeningeal vessels of occipital cortex, cerebellum, and within the depths of the collateral sulcus in the temporal lobe. Mild CAA is seen as diffuse and patchy deposits not occupying the entire vessel wall and is readily detected by immunostains to Aβ. In moderate and severe CAA forms, the Aβ deposits are full thickness, giving rise to a “lead pipe” appearance of arterioles (in the absence of perfusion pressure after death, typical cortical arterioles would collapse). This lead pipe appearance of CAA is best appreciated on low and intermediate power examination of H&E stains and is confirmed by Aβ immunostaining. Severe CAA is also associated with perivascular hemosiderin deposits and microhemorrhages detected premortem by gradient echo MRI. Frequently, patients with severe CAA also have Aβ deposits in adjacent perivascular parenchyma—a pattern termed dyshoric CAA . Capillary CAA is another notable form of Aβ deposits, particularly because this is enriched in carriers of the APOE ε4 allele. This capillary CAA is most readily detected in capillaries of deep cortical laminae. Cerebral white matter and associated vessels in white matter are typically negative for Aβ deposits. Like Thal phase for parenchymal Aβ deposits, a hierarchical progression of CAA has been described beginning in occipital and cerebellar regions and culminating in vessels of the vertebrobasilar system (an uncommon finding). It should be noted that not all CAA is Aβ-derived. Rare pathologies leading to non-Aβ CAA include amyloidosis with deposits of gelsolin, protease-resistant prion protein, or transthyretin. Likewise amyloid angiopathy in the region of pituitary and sella turcica reflects systemic amyloidosis (e.g., senile-type transthyretin or AA or AL-type amyloid), not Aβ. Therefore negative stains for Aβ in the setting of an H&E appearance of amyloid angiopathy should prompt other screening techniques (e.g., Congo red).

Hirano bodies and GVD are nonspecific findings and are most abundant within the hippocampal formation of AD patients ( Fig. 6.8 ). Hirano bodies consist of arrays of actin filaments on ultrastructural examination and by H&E appear as rod-shaped and refractile eosinophilic structures adjacent to the cell bodies of pyramidal neurons in the hippocampal formation. Hirano bodies are actually neuronal cytoplasmic inclusions despite their appearance as extracellular structures. GVD consists of cytoplasmic, basophilic granules with associated vacuoles in neurons. Foci of GVD frequently accompany pyramidal neurons with Hirano bodies in the hippocampal formation. The pathogenesis of GVD is not known, and studies have shown these deposits may be derived from lysozymes.

Additional pathologies in AD brain include TDP-43 deposits, described later, and amygdala-predominant Lewy bodies. Amygdala-predominant Lewy bodies are fibrillar deposits of α-synuclein, often colocalized with NFTs and tau, in large neurons of the corticomedial and basolateral amygdala. Lewy neurites are uncommon in this setting, and these patients lack the widespread Lewy body pathology of DLB and PD. The significance of amygdala-limited Lewy bodies in the setting of AD was previously unclear. However, recent studies have shown that patients with advanced AD path (A3 B3 C3), amygdala-predominant Lewy bodies, and TDP-43 inclusions form a unique subset of dementia patients with a quadruple proteinopathy (Aβ + α-synuclein + tau + TDP-43). Longitudinal studies of these patients have shown a shorter time interval between mild cognitive impairment and conversion to dementia, as well as more rapid disease progression with more significant cognitive impairment.

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Differential Diagnosis

The differential diagnosis of AD depends on the patient’s age and clinical presentation. Patients with EOAD, as described above, may present with a unusual mix of behavioral variant and motor symptoms, leading to clinical diagnoses of FTD. Autopsy is thus critical in early-onset dementias to clarify the final diagnosis. Conversely, clinical diagnoses of a behavioral variant of AD, or a primary progressive aphasia variant of AD, may prove to be FTLD with TDP-43 inclusions (FTLD-TDP). Rare 4R tauopathies such as CBD may also present with executive dysfunction and memory disturbance, mimicking a variant of AD before parkinsonian or other disease features become prominent. In current practice, the combination of neuroimaging studies (structural MRI, PET for tau, Aβ, and glucose metabolism) and CSF biomarkers and even genetic studies often clarifies the differential of EOAD. The differential diagnosis of patients with LOAD does not frequently include atypical and rare diseases, such as FTLD. Instead, a different set of common, age-related pathologies are in the differential diagnosis. Among these, hippocampal sclerosis of aging with TDP-43 pathology, now termed LATE, commonly mimics AD in the oldest old patients (≥85 years). In addition, cerebrovascular lesions and, in particular, small-vessel disease significantly impacts the clinical expression of AD.

Macroscopic Findings

Examination of DLB brains at autopsy reveals only mild frontal atrophy, and brain weights are frequently greater than 1300 g ( Fig. 6.9 ). There is no distinct parieto-occipital or temporal lobe atrophy visible on external examination in the absence of comorbid pathologies. As with prion diseases, patients with profound cognitive impairment in DLB may come to autopsy and brain removal yields a fairly unremarkable cerebrum. The major pathologic finding noted in virtually all DLB cases is loss of pigmentation in substantia nigra and locus ceruleus. Ventricle enlargement and medial temporal lobe atrophy are mild, if even present. The basal ganglia, midbrain tectum and tegmentum, basis pontis, cerebellar peduncle volumes, and cerebellum typically appear within normal limits, in contrast to uncommon entities with parkinsonism.

Microscopic Findings

On H&E examination, the characteristic feature of DLB is the presence of LBs in the neocortex, large cholinergic neurons of the nucleus basalis in the basal forebrain, and limbic regions such as the anterior cingulate cortex, amygdala, hippocampal formation including subiculum, and entorhinal cortex. Neocortical LBs occur mainly in deep cortical laminae (V, VI) and are rarely seen superficial to those laminae. By H&E, cortical LBs are recognized by the eccentric displacement of the nucleus and cytoplasm containing homogeneous-appearing and vaguely fibrillary eosinophilic inclusions. Unlike brainstem LBs, or those in large neurons of nucleus basalis or amygdala, cortical LBs lack a halo of surrounding cytoplasm and/or pigment. Their presence is confirmed using antibodies to α-synuclein or its phosphorylated form. In contrast to AD, the extent of α-synuclein pathology is greatly underestimated by H&E findings alone ( Fig. 6.10 ). As such, cases with any limbic or cortical Lewy body pathology on H&E examination require special stains to document their extent. Brainstem nuclei typically involved in PD and PDD are also frequently diseased in DLB cases. These include substantia nigra, albeit often without severe neuron loss, reticular gray of midbrain, raphe nuclei, locus ceruleus, dorsal nucleus of X, and the reticular formation of medulla. As with PD/PDD, fibers of the glossopharyngeal nerve in the medulla are frequently α-synuclein-positive ( Fig. 6.11 ). LBs and neurites may also be found in the peripheral nervous system, including within neurons of cardiac ganglia, adrenal medulla, and celiac ganglia.

Lewy neurites are α-synuclein-positive structures seen in DLB and are not visible by H&E staining. These are thick, tortuous structures frequently seen in association with intra- and extracellular Lewy bodies by α-synuclein ( Fig. 6.10 ). Lewy neurites and LBs together are used in the pathologic grading schema recommended by McKeith and colleagues. Notable in this grading scheme is that the number of LBs and Lewy neurites are recorded together at low power magnification and are used to provide a designation of severity per region. In contrast to AD, wherein NFTs may be innumerable in neocortex, cases of DLB with pathologic LBD diffuse/neocortical have LB counts that are readily enumerated.

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Differential Diagnosis

The most common differential diagnosis of DLB at the time of autopsy is AD. As described above, some AD pathologies are typical in DLB. However, neocortical NFT pathology is sparse in most cases. Amyloid pathology is seen in almost all DLB patients, often in the form of non-neuritic, diffuse Aβ deposits, CAA involving arterioles, and sparse to moderate neuritic plaque pathology. In patients with dementia, amyloid-positive neocortical samples with sparse neuritic plaques and NFTs should be closely reviewed for neocortical Lewy bodies.

Atypical parkinsonian syndromes may also enter the differential of DLB, as patients with multiple system atrophy (MSA), PSP, and CBD may have cognitive impairment. Neuropathologic examination of DLB cases reveals only minimal white matter pathology and none of the characteristic striatal, basis pontis, nigral, or cerebellar atrophy of MSA. In addition, there are no readily identified oligodendroglial cytoplasmic inclusions by α-synuclein staining in DLB cases, further differentiating it from MSA. LB and Lewy body-like neuronal inclusions are not uncommon in MSA samples, especially in long-lived patients with cognitive impairment. However, these MSA cases have the typical distribution of striatonigral and/or olivopontocerebellar atrophy (OPCA), neuronal inclusions, and abundant oligodendroglial cytoplasmic inclusions, or “glial cytoplasmic inclusions” (GCIs).

Macroscopic Findings

As described above, ARTAG is a common finding in aging and common age-related dementias. It is also one of the most common comorbid pathologies in rare NDDs that are not primary tauopathies, such as ALS with TDP-43 inclusion pathology. If there is comorbid neuropathology, the macroscopic findings are those of the predominant disease process.

Microscopic Findings

The two most common types of astrocytic tau inclusions in aging are termed thorn-shaped astrocytes (TSA) and granular or fuzzy astrocytes . As discussed below, these are differentiated from less common astrocytic inclusions in rare NDDs, including ramified astrocytes (Pick disease), astrocytic plaques (CBD), and tufted astrocytes (PSP).

The thorn-shaped astrocyte, or TSA, is a phospho-tau–positive astrocyte that may be located in the subependymal, subpial, perivascular, and white and gray matter regions ( Fig. 6.12 ). In white matter, TSAs are most common in superficial white matter at the interface with overlying cortex, as well as in the perivascular region. Subpial TSAs are one of the most common forms of ARTAG, being most readily seen in autopsy sections that include basal forebrain and anterior commissure (region of anterior perforated substance), with the pial surface intact. In lobar regions, subpial TSAs may be seen in subpial cortex, including at the depths of sulci, which should not be confused with the hallmark lesions of CTE as described below. Within the brainstem, subpial TSAs are readily seen along the dorsolateral midbrain and occasionally in ventral brainstem, including at the cerebral peduncles and medullary pyramids. Subependymal TSAs are commonly seen in the amygdala region, adjacent to the temporal horn of the lateral ventricle, and in midbrain adjacent to the cerebral aqueduct. Gray matter ARTAG is characterized by both TSAs and granular or fuzzy astrocytes (GFAs), which may be seen in amygdala subnuclei, striatum, and various neocortical regions ( Fig. 6.12 ). As the name implies, GFAs are limited to gray matter, unlike TSAs.

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Differential Diagnosis

TSAs and GFAs may be present in various combinations in the same autopsy specimen and there is not a stereotypic pattern across all cases. TSAs have prominent perinuclear staining by phospho-tau stains, such as AT8, and short, stubby staining of astrocytic processes that give rise to a thorn-like appearance. GFAs also have dense, perinuclear cytoplasmic staining with phospho-tau immunostaining. Unlike TSAs, tau immunoreactivity in the processes of GFAs is more diffuse, patchier, and granular (hence the name granular/fuzzy) ( Fig. 6.12 ). Both TSAs and GFAs are variably positive by silver staining methods, such as Gallyas staining. In addition, both astrocytic lesions show immunoreactivity to antibodies to the 4R tau isoform and are negative for 3R tau. This differs from typical neuronal lesions, where both 3R and 4R isoform staining is seen. In both common and uncommon astrocytic lesions, with the exception of Pick disease, it is 4R tau that predominates. Ultrastructural studies of astrocytic tau pathology in aging (few in number) have shown the tau more closely resembles straight filaments and that the paired helical filaments of neuronal NFTs are not seen.

One of the major entities in the differential diagnosis of ARTAG is CTE, a pathologic alteration that frequently is associated with repetitive head trauma. In contrast to ARTAG, the phospho-tau pathology of CTE is present in both neurons and glia at the depths of sulci. This distinction is critical because the astrocytic pathology in CTE has the morphologic appearance of TSAs, as seen in ARTAG. The combination of perivascular neuronal and glial phospho-tau lesions, at the depths of multiple cerebral sulci, in tandem with other supporting features (described later), is diagnostic of CTE neuropathologic change. Conversely, depth of sulcus, subpial, or gray matter ARTAG limited to TSAs and GFAs should not be used for the pathologic diagnosis of CTE neuropathologic change. A recent community-based autopsy study in older adults showed ARTAG was highly prevalent in older individuals, with TSAs seen at the depths of sulci, but the pathognomonic lesion of CTE was not identified in a single case. Unlike subpial ARTAG, which is ubiquitous, the pathognomic lesion of CTE is extremely rare outside the setting of significant and repetitive head trauma. There does not appear to be a lobar predominance for this type of subpial ARTAG. The shared depth of sulcus location of ARTAG and CTE, and the involvement of astrocytes in both processes, raises the question of whether there are mechanistic links between these entities.

The unique 4R-positive astrocytic lesions of PSP (tufted astrocytes) and CBD (astrocytic plaques) are also in the differential of ARTAG on neuropathologic evaluation. Thorny astrocytes in ARTAG may strongly resemble tufted astrocytes of PSP. Furthering confusion, both astrocytic lesions are 4R-positive, both may be Gallyas stain-positive, and both may occur in frontal cortex, striatum, and limbic structures such as amygdala. A critical element in the diagnostic consideration is the presence or absence of an atypical parkinsonian disorder, or even simply parkinsonism as in less common PSP variants with a lower tau burden. In addition, PSP patients may have comorbid ARTAG, so both diagnoses may be considered in the same specimen. Indeed, one of the earliest descriptions of ARTAG was as a secondary astrocytic pathology in the setting of PSP. On phospho-tau staining, the tufted astrocytes of PSP lack the dense perinuclear staining of TSAs, instead having tau-positivity limited to thick, proximal portions of astrocytic processes. Additionally, tufted astrocytes may be ubiquitinated, staining with immunostains to ubiquitin and the polyubiquitin‐binding protein p62/sequestosome 1 (p62). In contrast, TSAs and GFAs are ubiquitin-negative and p62-negative. The astrocytic plaque of CBD is characterized by phospho-tau reactivity in thin, distal astrocytic processes with no perinuclear cytoplasmic staining, which is not likely to be confused with ARTAG pathology. Lastly, cardinal nuclei implicated in the neuropathology of both PSP and CBD are spared in the much more common astrocytic tau pathology of ARTAG. Structures such as globus pallidus, subthalamic nucleus, red nucleus, and dentate nucleus of cerebellum are rarely if ever sites of ARTAG pathology.

Macroscopic Findings

Patients with LATE may have concomitant AD neuropathologic change (intermediate and high AD neuropathology). In these cases, the macroscopic features of AD neuropathologic change predominate, including frontotemporal and parietal atrophy with sparing of motor cortex. In addition, LATE and TDP-43 pathology may contribute to HS. Hippocampal sclerosis is characterized by atrophy of the hippocampi that is well out of proportion to the overall level of cerebral atrophy ( Fig. 6.13 ). Coronal sections of the brain in a plane through the posterior hippocampus and lateral geniculate nucleus reveal atrophic, firm, and white-appearing hippocampi in which the typical gray-white matter contrast of hippocampal formation is difficult to discern. In the absence of comorbid AD, LATE with HS reveals the same firm atrophic hippocampi with an even greater discrepancy between hippocampus and non-atrophic neocortical regions.

Microscopic Findings

A key microscopic finding in hippocampal sclerosis, seen in some LATE cases, is massive neuronal loss in sector CA1 and subiculum with reactive astrocytosis. In contrast, pure AD without comorbid TDP-43 pathology and/or HS does not typically have the same extent of astrocytosis. Neurons of dentate gyrus and hippocampal formation also have inclusions of TDP-43, the pathological hallmark of LATE and LATE neuropathologic change (LATE-NC) ( Fig. 6.14 ). TDP-43 is a DNA/RNA-binding protein that plays a critical role in multiple human NDDs, including ALS and FTLD. Examination of cases with LATE reveals the earliest foci of TDP-43 pathology are in the region of the amygdala, including within amygdala subnuclei proper, entorhinal and transentorhinal cortex, and in adjacent white matter. The pathologic inclusions are not stereotypic. In two of the more common appearances, TDP-43 inclusions appear fibrillary and NFT-like, colocalizing with tau inclusions in aging and AD. In another pattern, TDP-43 accumulates in neuronal cytoplasmic inclusions in lamina II of the limbic cortex associated with numerous short neurites. This pattern may appear similar to FTLD ( Fig. 6.15 ), albeit more limited in distribution and without the extensive neuronal loss and spongiosis that characterizes FTLD.

Several staging proposals exist to characterize LATE TDP-43 pathology in the setting of aging and AD pathologies. In the simplest three-tier model, TDP-43 pathology in the amygdala region is designated as stage I. More conspicuous involvement of the hippocampus has been noted in stage II, and in stage III there is involvement of other regions, including the frontal cortex. A critical knowledge gap is that the specific cell populations and structures that are vulnerable to phospho-TDP pathology are not known, even in sites of stage I pathology. Most importantly, how TDP-43 pathology impacts cognition and the patient’s functional status across different pathologic stages is poorly understood. Careful clinical-pathologic correlational studies are required using state-of-the-art pathologic approaches and diagnoses in autopsy-based samples with rich clinical datasets.

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Differential Diagnosis

Although FTLD-TDP typically affects younger patients and has greater TDP-43 pathology, the precise boundary between LATE and late-onset FTLD-TDP has yet to be defined. One major difference is that brains with LATE-NC do not have the circumscribed, frontal, and temporal atrophy that characterizes FTLD-TDP. Patients with FTLD-TDP will typically have greater neuron loss in the cortical ribbon, with a more widespread and severe TDP-43 proteinopathy, than is seen in LATE.