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Core curriculum of Neuropathology

Cell types & networks
Staining methods
Cellular pathology

Cellular pathology / Neuronal process

Anterograde degeneration

Anterograde degeneration refers to the process in which an axon is damaged, followed by secondary anterograde degeneration, subsequently progressing away from the cell body (soma). This is also called Wallerian degeneration. For example, when a motor neuron axon and the surrounding sheath are damaged as a result of cerebral infarction near the basal ganglia, subsequent degeneration of the distal cerebral peduncle, pyramid of the medulla oblongata, and lateral/anterior funiculus of the spinal cord can occur; however, this is just an example of anterograde degeneration.

Retrograde degeneration

Degeneration toward a cell body that has incurred axonal damage is called retrograde degeneration. This is also referred to as the dying back phenomenon. For example, when the lateral funiculus is damaged as a result of spinal cord injury, the phenomenon in which degeneration progresses centrally with respect to the damaged area is called retrograde degeneration. In this instance, distal anterograde degeneration will also occur.

Tract degeneration

Degeneration of specific nerve tracts is called tract degeneration. It is not distinguished according to anterograde or retrograde degeneration. It includes primary degeneration resulting from degenerative disease and nutritional disturbance as well as secondary degeneration resulting from trauma.

Transneuronal degeneration

Transneuronal degeneration is neuronal degeneration that is passed on to other connected neuronal fibers. This is the spread of degeneration via synapses and is also referred to as transsynaptic degeneration. In addition, such gradual spread of degeneration via a chain reaction is called chain degeneration.

Axonal reaction

This term indicates various reactive changes that occur as a result of axonal damage. It most commonly indicates retrograde damage toward the neuronal cell body (soma), particularly following axonal damage, and the resultant neuronal swelling is referred to as central chromatolysis. Although rather outdated, the German term primäre Reizung is also used.

Diffuse axonal injury

Diffuse axonal injury is not a type of nonmissile head injury that causes brain damage such as cerebral contusion and hemorrhage but is a blunt external force to the head that shakes the brain within the skull and results in damage of fibers of the corpus callosum and superior cerebellar peduncle. In diffuse axonal injury, the axon breaks and damages the myelin sheath, causing various secondary reactions. Axonal swelling (spheroids) also form, which are called retraction balls. Diffuse axonal injury is the diagnostic name for head injury commonly used in clinical practice; however, whether the name indicates “pathological” diffuse axonal injury remains unknown.

Axonal dystrophy

Axonal dystrophy indicates diseases in which dystrophic changes are made to axons and is one specific type of axonal swelling (spheroids) characteristic to the distal axon terminal. This is also referred to as neuroaxonal dystrophy, or it may be given a disease-specific name such as infantile neuroaxonal dystrophy. In general, it is a pathological axonal change; however, age-related changes in the nucleus gracilis of the medulla oblongata have been observed. Axons with such lesions are called dystrophic axons.

Axonal atrophy and loss

Images of axon terminals in primary and secondary axonal injury include axonal atrophy and loss. However, while it is relatively easy to assess the presence of lesions if there is a complete or high degree of loss, a mild loss requires morphological measurements. Axonal loss often leads to the destruction of the myelin sheath, and the appearance of macrophages (lipid granular cells) that ingest these destroyed components is a useful marker for mild lesions.

With H&E staining, atrophic axonal lesions are rarely observed; however, can be detected with silver staining such as Bodian staining. For example, the spinocerebellar tract consists of large fibers, whereas many small fibers can indicate atrophic axons. The lateral funiculus of the spinal cord consists of large and small fibers, and in ALS, for example, motor neuron fibers, which are large in diameter, become atrophic or lost, thereby reducing the ratio of large fibers in the lateral funiculus of the spinal cord.


Spheroid is the general term for pathological swelling of neuronal processes, particularly axons, which is also referred to as axonal swelling. Various causes can lead to the formation of spheroids in the proximal to distal portion of the axon. Of these, relatively small (20 μm or smaller in diameter) spheroids may have to be distinguished from globules; however, there is essentially no difference. With H&E staining, spheroids are eosinophilic, and with silver staining such as Bodian staining, they are more clearly visualized. The argyrophilic intensity varies depending on the amount of fibrous components in the spheroid. In general, more fibrous components (such as neurofilaments) are assocoiated with stronger argyrophilia, whereas if there is a large amount of organelles, including granular structures and mitochondria, the argyrophilia is weak and the cells often appear light stained and foamy. With KB and LFB staining of the myelin sheath, the area surrounding the spheroid is stained densely blue, representing a spheroid on the myelinated nerve fiber; if unstained, it is identified as a nonmyelinated nerve fiber spheroid.


Spheroids that develop on the most proximal portion of the axon of Purkinje cells are called torpedoes. They form relatively more often in the Purkinje cells near the granule cell layer of the cerebellar cortex and appear spindle shaped, suggestive of a torpedo. They form as a result of Purkinje cell degeneration following injury to the cerebellar cortex from various causes. In addition, long-term use of antiepileptic agents can cause severe loss of Purkinje cells; in such instances, a large number of torpedoes are observed. They appear eosinophilic with H&E staining and argyrophilic with Bodian staining.

Dystrophic axon

When a specific type of spheroid develops on the most distal portion of the axon, this axon is called dystrophic axon. While dystrophic axons also physically develop in the nucleus gracilis of the medulla oblongata, the disease in which dystrophic axons extensively develop throughout the brain is called neuroaxonal dystrophy. Typically, neuronal dystrophy includes Hallervorden–Spatz disease, in which spheroids mainly form in the substantia nigra and pallidum, and infantile neuroaxonal dystrophy, in which spheroids extensively form throughout the gray matter of the brain. The term dystrophic axon often indicates the presence of these specific diseases. The formation of dystrophic axons in the nucleus gracilis of the medulla oblongata also results from aging and long-term use of antiepileptic agents.

Terminal button

The “terminal” is the distal end of the axon, and “terminal button” refers to the state where the axon terminal exhibits button-shaped swelling. As suggested by the name “button,” the swelling is not large. The term is also used to indicate idiopathic swelling of the axon terminal of Purkinje cells that form synapses surrounding the dentate neurons. With H&E staining, each individual terminal button cannot be distinguished.

Axonal retraction ball

Following axonal damage from head injury, spheroids form on the axons at the site of injury. These spheroids are called axonal retraction balls. They appear as eosinophilic, round, elliptical, swollen masses with H&E staining and are argyrophilic.


Cactus spike-like protrusions found extending outward from the surface of the dendrite or cell body of Purkinje cells are called “cactus” formations. Changes such as this have been described in Menkes kinky hair disease and generally represent changes of Purkinje cells that exhibit degeneration and loss of cerebellar granule cells. They appear as short, light-colored, dendritic formations with H&E staining and are more clearly visualized with Bodian silver staining.

Asteroid bodies or dendritic expansions

Purkinje cell dendrites can swell within the molecular layer. Such changes appear to look like asteroids (hence the name asteroid bodies or dendritic expansions). They are often seen with Purkinje cell cactus formations as aggregated structures that extend like a stretched hand near the eosinophilic portion and are more clearly visualized with silver staining.

Intraneuritic corpora amylacea

Corpora amylacea generally form in astrocyte dendrites but can also form in neuronal dendrites. Therefore, corpora amylacea observed on the brain surface, surrounding blood vessels and cerebroventricular walls, are on astrocytic dendrites; however, they are often found in the gray matter and, in particular, the substantia nigra. They exhibit the same slight hematoxylinophilic characteristics as astrocytic dendrites. Corpora amylacea are positively stained with PAS staining. With KB or LFB staining, the presence of a surrounding myelin sheath indicates that it is in a neuronal dendrite; however, the absence of a myelin sheath does not necessarily indicate the opposite. Therefore, proper care is required when interpreting results of these stains.

Neuropil thread

In the event of a pathological condition such as NFT formation in neurons in Alzheimer’s disease, NFTs surrounding thread-like argyrophilic structures may be observed. Although they cannot be distinguished with H&E staining, they can be clearly detected with silver and GB staining. Neuropil threads are mainly aggregates of abnormal phosphorylated proteins in the dendrites.

Senile plaque

While senile plaques are not all dendritic changes, they are essentially deposits of amyloid components, which lead to the accumulation of phosphorylated tau in dendrites (i.e., the formation of many dystrophic neurites in the plaque).


In the parahippocampal gyrus of the temporal lobe, rice-like grain formations are observed on rare occasions using silver stains such as Bodian and GB staining. These formations are thought to be beaded aggregates of abnormal phosphorylated tau proteins in the neuronal processes. These grains characteristically appear in grain dementia.

Glomerular structures

The inferior olivary, red, and dentate nucleus are connected by a neuropathway (Guillan–Morare’s triangle), which when damaged in some way is known to cause pseudohypertrophy of the inferior olivary nucleus. In this pseudohypertrophic pathological change to the inferior olivary nucleus, neuronal processes surrounding the residual neuron become strangely glomerular like. Cytoplasmic vacuolation is often observed in neurons with glomerular structures. Glomerular structures can be observed with H&E and silver staining.

Lewy-related neurites

Ubiquitin-positive, slightly swollen, neural protrusions found around neurons that form Lewy bodies are called Lewy-related neurites or Lewy neurites. While Lewy bodies can be clearly stained and identified on H&E staining, Lewy-related neurites are difficult be identified clearly. In contrast, immunostaining with antiubiquitin and anti-α-synuclein antibodies clearly stains them.

Ubiqitinated dot-like structures

When the central nervous system is immunostained with antiubiquitin antibodies, many positive dot-like structures are observed in the white matter even in the normal healthy brain. While this is thought to be ubiquitination within the nerve fibers, it has little pathological significance. In addition, aggregates approximately 10–20 μm in diameter, which are larger than those observed in the cortical white matter of the temporal lobe such as the parahippocampal gyrus, are often observed. These structures appear to be caused by age-related changes; however, a method of evaluating histological findings has not been investigated in detail.

Grumose degeneration of dentate nucleus

Grumose degeneration of dentate nucleus is specific degeneration of the dentate nucleus as a result of neuronal loss, while aggregates of eosinophilic cloud-like structures surrounding or slightly away from the neurons of the cerebellar dentate nucleus are observed on H&E staining. With silver staining such as Bodian, these structures are faint cloud-like formations with no stain affinity and observed as forms of argyrophilic small granules, slightly large aggregates, and ring-like formations. The cloud-like and microgranular structures are thought to be fibers sprouting from the axonal terminals of Purkinje cells, while the slightly large aggregates and ring-like structures are swollen axonal terminals.

It is difficult to assess grumose degeneration; unmyelinated axons of Purkinje cells around neurons increase in grumose degeneration; therefore, an eosinophilic band can be observed with H&E–LFB double staining. Because unmyelinated fibers touch the neuronal cell body (soma) directly, no such band is observed in the normal state.

Grumose degeneration in the dentate nucleus is often accompanied by degeneration of the hilum of the dentate nucleus and superior cerebellar peduncle and centrifugal pathways in the cerebellum. This type of degeneration is characteristic to some degenerative diseases, including PSP and dentatorubropallidoluysial atrophy. Grumose degeneration was described in 1964 by Steel et al. in the first original case report of PSP. Steel simply used the term “grumose” as an adjective with no particular meaning; however, later in Japan, the term “grumose degeneration” was used in a specific connotation. In recent years, the term “grumose degeneration” has been adopted in text books in the US and Europe.