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Core curriculum of Neuropathology

Cell types & networks
Staining methods
Cellular pathology

Cellular pathology / Neuronal cell body

Central chromatolysis

In KB staining, the destruction of Nissl bodies (the rough endoplasmic reticulum) observed in senile plaques is called chromatolysis. During this, the process of swelling of the central part of the perinuclear cytoplasm and peripheral displacement of dissolved Nissl bodies is called medullary lysis of tigroid substances. The term “tigroid” was derived from KB-stained images of Nissl bodies, which resemble tiger stripes; thus, their disintegration is called tigrolysis or chromatolysis. While tigrolysis typically begins from the central part of the cell, on rare occasions, it can begin from the margin. Tigrolysis is observed in toxic diseases.

Ballooned neurons and achromasia

Ballooned neurons and achromasia have been described in pellagra, Pick’s disease, Creutzfeldt–Jakob disease, corticobasal degeneration (CBD), and progressive supranuclear palsy (PSP); however, whether the same mechanism and intracellular changes are exhibited in these diseases remains unclear. These neurons are often called ballooned neurons. Some of these neurons lack Nissl bodies, which is called achromasia. Neurons of the cerebral cortex in CBD present with achromasia, which is diagnostically significant, and many show swelling.

Neuronal swelling due to axonal damage

Neuronal axon damage can lead to retrograde damage to the cell body (soma) and consequently cause somal swelling. When this occurs, Nissl bodies are dissolved from the cell center and peripherally displaced along with the nucleus; this is referred to as central chromatolysis. This change when expressed in mechanistic and not morphological terms is also called axonal reaction. This change has been found to be a reaction secondary to axonal damage caused by degenerative disease, trauma, and other causes.

Metabolic disease-induced swelling due to accumulation of abnormal metabolic products

Various diseases cause abnormal metabolic products to accumulate in the cell, which leads to swelling. Histochemical staining enables the assessment of the constituents of accumulated products.

Degenerative disease-induced swelling due to accumulation of abnormal cytoskeletal components

In some degenerative diseases, the accumulation of abnormal tau and synuclein causes swelling of the cell body (soma). For example, the formation of Alzheimer’s NFTs and Lewy bodies within the cell can cause general swelling. In such instances, the swelling is termed “neuronal ballooning” in some degenerative diseases, and neurons exhibiting such changes are referred to as ballooned neurons. Furthermore, Nissl bodies may be lacking in swollen neurons (neuronal achromasia), and such cells are called achromatic neurons.

Atypical cellular components due to dysplasia

With regard to brain malformations, some diseases exhibit atypical cellular components that can cause the neuron to increase in size; this is typically observed in focal cortical dysplasia. Similarly, abnormally large neurons are observed in the cortical nodules in tuberous sclerosis, which is referred to as neuronal cytomegaly or cytomegalic neurons. The cytoskeleton of the cell body (soma) mainly consists of neurofilaments.

Neuronal atrophy

Neurons physically shrink with age, which is conventionally referred to as simple atrophy. Changes in which neurons disappear in the same manner as the surrounding tissue are called homogenizing cell changes; however, this term is rarely used at present. An atrophic change where the entire cytoplasm becomes eosinophilic (red) as a result of a sudden ischemic attack is called an ishemic or hypoxic change. This change weakens neurons in Ammon’s horn of the hippocampus and cerebellar Purkinje cells, and if the ischemia is particularly strong, it extends throughout the entire brain. Deposition of calcium, pseudocalcium, and iron in the degenerate atrophic neurons can occur as a result of cell death and is called calcification, pseudocalcification, and ferrugination, respectively; collectively, this is also referred to as mineralization.


Lipofuscin is the pigment-containing accumulated residue within the neuron that increases with age and degeneration. The accumulated amount, time, and micromorphology vary depending on the nucleus. In Purkinje cells, lipofuscin within the dentate and inferior olivary nuclei accumulates in postmitotic cells. Lipofuscin has little diagnostic significance. Lipofuscin appears as yellow to yellowish–brown granules with H&E staining and as green granules with KB staining.

Hirano bodies (eosinophilic rod-like structures)

Hirano bodies, first reported by A. Hirano in New York (NY, USA), are structures that frequently develop in pyramidal cell layers of the hippocampus with aging. Alternatively, they are also called eosinophilic rod-like structures, and as the name suggests, they appear as somewhat refractile, rod-shaped, elliptical masses within neurons, dendrites, and surrounding areas. These structures are also eosinophilic (red) with H&E staining and frequently appear with physical aging as well as in Alzheimer’s disease.

Granulovacuolar degeneration

Granulovacuolar degeneration involves the accumulation of several small vacuoles that are 2–3 μm in diameter in granular structures. These vacuoles are somewhat basophilic (blue) with H&E staining and are found within the cell body (soma) of pyramidal neurons of the hippocampus with aging and in Alzheimer’s disease.

Eosinophilic round structures

Round bodies of the size of red blood cells (approximately 8 μm in diameter) that are eosinophilic (red) with H&E staining are occasionally observed in the stroma of pyramidal neurons of the hippocampus. Eosinophilic round bodies tend to increase with age and consist of a structureless electron-dense material that accumulates within the axon terminal. They were first reported by M. Hara of Yokoyama while in New York (NY, USA).

Alzheimer’s NFTs

Dementia such as Alzheimer’s disease and normal aging cause the accumulation of insoluble phosphorylated tau proteins, which accumulate as abnormal fiber formations called NFTs. NFTs are divided into flame-shaped and globose-shaped NFTs according to the presence of argyrophilic and morphological content. They are also divided by intracellular and extracellular locale. With H&E staining, they appear as relatively refractile fiber bundles; however, old tangles may appear eosinophilic. NFTs have strong argyrophilic properties. With GB staining, they are clearly stained black and are therefore very easily detected. However, care should be taken because GB stained-substances are not always NFTs. In addition to aging and dementia, NFTs appear in patients with subacute sclerosis pancencephalitis, sequelae of perinatal brain damage, elderly patients with Nieman–Pick disease type C, and patients with delayed head trauma (boxer’s dementia)

Pick’s argyrophilic bodies

These are argyrophilic round bodies formed within hippocampal neurons in Alzheimer’s and Pick’s disease, a presenile dementia, and are characteristically found in the apical dendrites of neurons. These spherical structures are diagnostically significant for Pick’s disease; thus, they are also called Pick’s argyrophilic bodies. Although not as clear as Pick’s bodies, round bodies that seem rather bloated with extremely swollen neuronal cytoplasm are called Pick’s cells. These cells are often found in the dentate gyrus and subiculum of the hippocampus. Pick’ bodies are highly argyrophilic and are formed by abnormal phosphorylated tau proteins.

In patients clinically diagnosed with Pick’s disease, Pick’s bodies are often not found on pathological tests. Such patients are clinicopathologically diagnosed with “Pick’s disease without Pick’s bodies,” and attention must be paid to the absence of biological markers in such diagnoses. On the other hand, it is thought that only patients with Pick’s bodies should be diagnosed with Pick’s body disease.

Polyglucosan bodies

Corpuscles consisting of glucose polymers are called polyglucosan bodies, and they include Lafora, myoclonic, and Bielschowsky bodies. Polyglucosan bodies accumulate in the neuronal cell body (soma), cell processes, and glial cells. Of these, Lafora bodies generally accumulate in the soma. They are round, hematoxyphilic, and have slits inside, which sometimes make them appear as petals. They can be clearly detected with PAS staining and are used as a marker of Lafora disease. Polyglucosan bodies are formed in neurons as well as in astrocytic processes; this is described in a separate section.

Lewy bodies

Lewy bodies are eosinophilic (red) bodies found in the neuronal cytoplasm of nerve nuclei in the brain stem, including the substantia nigra, locus ceruleus, and dorsal nucleus of vagus, of elderly individuals and in idiopathic Parkinson’s disease. There are smaller Lewy bodies that are almost of the same size as the nucleus and larger bodies that are as large as the entire cytoplasm. Typical Lewy bodies have a highly stainable core surrounded by a belt-shaped halo with weak stainability. These are called brain stem-type Lewy bodies. They are not always spherical but can be sinuous, rod-shaped inclusions. In addition, they can be hidden in nuromelanin granules within the cytoplasm; therefore, care is required to observe them. Lewy bodies are also formed in neurons in the cerebral cortex and appear as rather swollen, slightly eosinophilic globular substances; these are called cortical Lewy bodies.

Parkinson’s disease was first described in 1817 by Parkinson and was subsequently named Parkinson’s disease in 1868 by Charcot. Later, in 1912, Lewy bodies were described by Lewy, and in 1917, Tretiakoff coined the term corpus de Lewy in French. It has been commonly used since then. Lewy bodies are structures with diagnostic significance, for example, for Lewy body disease, which is characterized by the appearance of Lewy bodies. When Lewy bodies are ubiquitinated, they can be clearly detected using antiubiquitin antibodies. Furthermore, similar positive findings are exhibited with antibodies for α-synuclein; thus, the concept of α-synucleinopathy has recently been proposed to describe the disease group in which Lewy bodies characteristically appear.

Bunina body

Bunina bodies are abnormal structures that appear in motor neurons of the spinal cord and brain stem in ALS and are specific markers used to diagnose this disease. In patients with a high degree of neuronal loss, Bunina bodies may not be detected by normal tests but can only be detected with more thorough testing. At present, they have been known as ALS-specific structures and have only been described in ALS reports. The term Bunina body was coined after the Russian pathologist Bunina. H&E staining reveals Bunina bodies as eosinophilic (red to orange in color), small, round structures that are approximately of the size of red blood cells and exist as two or three bodies connected within neurons. They are often found in the cytoplasm where there is abundant lipifuscin. Bunina bodies also clearly stain with anticystatin C antibodies; however, this antibody may also positively stain other organelles; therefore, proper care is required when interpreting results. In motor neurons in ALS, somewhat irregular eosinophilic granular structures are often observed and suspected of being Bunina bodies.

Skein-like inclusions

Lower motor neurons in sporadic or hereditary ALS have aggregates of tubular, eosinophilic, filament-shaped structures called skein-like inclusions, named because of their skein-like appearance. Although they are filament bundles, they are characteristically stained only slightly; therefore, they can be difficult to observe with H&E staining. At a glance, they can be mistaken for Bunina bodies; thus, proper care is required when interpreting results. Because they are highly ubiquitinated, they test positive with antiubiquitin antibodies. In a recent study of several cases, the exclusion of motor neuron disease resulted in a relatively high incidence of skein-like inclusions in PSP, CBD, and Pick’s disease as well as in the brain of elderly individuals; therefore, it is thought that skein-like inclusions have little disease specificity.

Round hyaline inclusions or spherical inclusions

Eosinophilic globular substances of filaments with higher aggregation density than skein-like inclusions can be found in the anterior horn cells of the spinal cord in ALS. These are called round hyaline or spherical inclusions.

Lewy body-like hyaline inclusions

Lewy body-like inclusions are slightly colored glass-like round inclusions that appear similar to Lewy bodies and are occasionally found in the motor neurons of the anterior horn of the spinal cord and brain stem in ALS. These inclusions were first mentioned in familial ALS; however, they have also been observed in sporadic cases. Furthermore, some believe that inclusions should be divided into hereditary and sporadic. They are highly ubiquitinated and test positive with antiubiquitin antibodies.

Ubiquitinated neuronal inclusions in the dentate fascia (UNID) appearing in ALS with dementia

In ALS with dementia, ubiquitin-positive neuronal inclusions develop in the granule cells of the hippocampus dentate gyrus and neurons of the cortical temporal lobe. They typically appear as small round inclusions, and slightly-colored positive findings are also observed in the cytoplasm surrounding the nucleus. Ubiquitinated neuronal inclusions are hardly detected by routine H&E and silver stains, and they test positive with antiubiquitin antibodies. Therefore, when performing pathological screening for ALS, immunostaining using antiubiquitin antibodies is indispensable. Ubiquitinated neuronal inclusions cannot be visualized with GB staining and differ from hippocampal granule cell inclusions in the dentate gyrus with multiple system atrophy, as described below.

UNID appearing in multiple system atrophy

It has been reported that approximately one-third of patients with multiple system atrophy exhibit ubiquitin-positive neuronal inclusions similar to inclusions of hippocampal granule cells in the dentate gyrus observed in ALS patients with dementia. At present, the clinical significance of this remains unknown. While these inclusions cannot be visualized with H&E and silver staining, they are clearly stained with antiubiquitin antibodies as nonspherical, coil-like inclusions surrounding the nucleus. UNID in multiple system atrophy appear black with GB staining and thus differ from ubiquitinated neuronal inclusions in ALS patients with dementia, which are not stained. Ubiquitinated inclusions have been reported in granule cells of the dentate gyrus as well as neurons of the neocortex.

Pontine neuronal inclusions in multiple system atrophy in cases of multiple system atrophy

These are relatively large, irregular, argryophilic inclusions observed in residual pontine neurons in multiple system atrophy. They can be stained with antineurofilament antibodies.

Negri body

In viral infections, viral accumulation can be found in inclusion bodies in the nucleus and cell body (soma) of neurons. RNA viruses include the measles (subacute sclerosing panencephalitis and measles inclusion body encephalitis) and rabies viruses, whereas DNA viruses include herpes virus (herpes simplex encephalitis) and cytomegalovirus (cytomegalovirus encephalitis). Of these, rabies-induced eosinophilic inclusions in the cytoplasm are called negri bodies.

Marinesco bodies

Marinesco bodies are eosinophilic, relatively coarse, granular structures that are approximately of the same size as the nucleolus and have no clinical significance.

Various intranuclear viral inclusions

In viral infections, viral accumulation can be found in inclusion bodies in the nucleus and cell body (soma) of neurons. RNA viruses include the measles virus (subacute sclerosing panencephalitis and measles inclusion body encephalitis) and rabies virus (rabies), whereas DNA viruses include the herpes virus (herpes simplex encephalitis) and cytomegalovirus (cytomegalovirus encephalitis). In subacute sclerosing panencephalitis, a slow measles virus infection, intranuclear viral inclusions have a surrounding halo and are called Cowdry A type inclusions; intranuclear inclusions caused by cytomegaloviruses are also Cowdry A type.

Neuronal nuclear inclusions in multiple system atrophy

These are tubular structures observed in the nucleus of cortical neurons in multiple system atrophy. These stain as short neuropil threads with GB stain. While they are thought to indicate the existence of degeneration, at present, their significance remains unclear. These cannot be detected with conventional routine staining, including H&E staining, and can only be visualized with GB staining. Originally, it was thought that the cerebral cortex was not damaged in multiple system atrophy. However, GB staining has revealed that the presence of GCIs is disease specific and they are extensively distributed in the cerebral cortex. Therefore, attention should be paid to neuronal changes in the cerebral cortex.

Neuronal nuclear inclusions in triplet repeat diseases

The repetition of a three-base sequence is called a triplet repeat, and the groups of diseases in which overexpansion of triplet repeats is assumed to be closely involved in the cause of degenerative disease are called triplet repeat diseases. Triplet repeat diseases are generally characterized by overexpansion of the CAG three bases, and their gene product is polyglutamine. Triplet repeat diseases include spinocerebellar ataxia, Huntington’s disease, dentatorubropallidoluysial atrophy, and Machado–Joseph disease, which present with ubiquitin-positive inclusions in neuronal nuclei and cell bodies (soma). These inclusions are also stained with antibodies for the gene product polyglutamine; there seems to be no relationship with the degree of the degeneration, and staining features may vary from small to rather large granules. Moreover, staining with antiubiquitin and antipolyglutamine antibodies may also show aggregate-like formations throughout the nucleus and not inclusions.