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UNDERSTANDING NEURODEGENERATIVE DISEASE PATHOLOGY: A GUIDE
FOR GENERAL NEUROLOGISTS
Ergasheva Husnora Fakhriddinovna
Assistant at the Alfraganus University
Email: xusnoraergashova@gmail.com
Orcid Id: 0009-0003-6262-5145
https://doi.org/10.5281/zenodo.14545657
Abstract:
Neurodegeneration involves the progressive dysfunction or loss of selectively
vulnerable neurons in the brain and spinal cord. Despite significant advancements in fluid and
imaging biomarkers, the definitive diagnosis of most neurodegenerative diseases still depends
on neuropathological examination. Careful clinicopathological correlation has been
instrumental in shaping clinical diagnostic criteria, enhancing our understanding of disease
progression, and uncovering conditions with substantial public health relevance, such as
variant Creutzfeldt-Jakob disease, iatrogenic amyloid-β deposition, and chronic traumatic
encephalopathy. Neuropathological analysis can also reveal previously undetected genetic
conditions with potential implications for family members. Additionally, detailed postmortem
tissue examination plays a vital role in research aimed at uncovering molecular mechanisms
of neurodegeneration and developing or validating biomarkers. This review highlights the
hallmark pathological features of neurodegenerative diseases commonly encountered in
general neurology, including Alzheimer’s disease and Parkinson’s disease; rarer but
recognized disorders like progressive supranuclear palsy, corticobasal degeneration, and
multiple system atrophy; as well as emerging entities such as chronic traumatic
encephalopathy and age-related tau astrogliopathy.
Keywords
: Neurodegenerative diseases, proteinopathies, amyloid-β (Aβ), tau protein,
α-synuclein, transactive DNA-binding protein 43 (TDP-43), prion proteins, Alzheimer’s
disease (AD), Parkinson’s disease (PD), dementia with Lewy bodies (DLB).
Introduction
Adult-onset neurodegenerative diseases are commonly classified as proteinopathies, as
they are characterized by the misfolding of native peptides and proteins, such as amyloid-β
(Aβ), tau, α-synuclein, transactive DNA-binding protein 43 (TDP-43), and prion proteins.
These misfolded proteins assemble into larger filaments, which subsequently aggregate into
morphologically distinct cellular inclusions or extracellular parenchymal plaques (Figure 1).
More than 50 diseases are linked to protein misfolding pathology, including well-established
conditions like Alzheimer’s disease (AD) and Parkinson’s disease (PD), as well as newly
recognized entities with uncertain clinical significance, such as age-related tau astrogliopathy
(ARTAG) and limbic-predominant age-related TDP-43 encephalopathy (LATE).
In most neurodegenerative diseases, misfolded protein pathology spreads
topographically through synaptically connected brain regions, with distinct conformations of
the same misfolded protein causing specific patterns of regional and cellular vulnerability.
Additionally, pathology may arise in situ due to cell-intrinsic factors, such as high metabolic
demand or genetic risk factors—including somatic mutations—that increase the susceptibility
of certain neurons to protein misfolding. Regardless of the underlying mechanism, clinical
manifestations are largely dictated by the anatomical distribution of neuropathology.
Consequently, similar clinical phenotypes can result from different proteinopathies.
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This phenotypic overlap often makes accurate diagnosis during life challenging, and
neuropathology remains the gold standard for definitive diagnosis. Systematic brain banking
and clinicopathological correlation have been fundamental to establishing diagnostic criteria
for major neurodegenerative diseases, ensuring consistency and accuracy in clinical practice.
A Practical Guide to Neuropathological Diagnosis of Neurodegenerative Diseases
The neuropathological diagnostic process begins with macroscopic examination,
typically after weighing the brain. The dura, leptomeninges, and cerebral vasculature are
inspected for lesions or surface abnormalities, including gyral atrophy patterns. The
hemispheres are then separated along the midline. In brain bank settings, one hemisphere is
generally fixed in formalin for sectioning, while the other is dissected fresh and flash-frozen.
The formalin-fixed hemisphere is dissected systematically. The brainstem and
cerebellum are removed first, followed by slicing the hemisphere coronally, the cerebellum
sagittally, and the brainstem transversely. This process allows for the identification of focal or
diffuse pathology, such as regional atrophy or depigmentation of the substantia nigra and
locus coeruleus.
Approximately 20 brain regions are routinely sampled for histological analysis, with
additional regions examined based on the clinical history or observed macroscopic
abnormalities. This detailed and systematic approach ensures a thorough assessment, aiding
in the accurate diagnosis and understanding of neurodegenerative diseases.
Established Clinicopathological Diseases
Alzheimer’s Disease (AD)
AD is the most prevalent neurodegenerative disease, typically presenting as an amnestic
syndrome. However, less common phenotypes include posterior cortical atrophy, behavioral
and dysexecutive syndromes, logopenic variant primary progressive aphasia, and corticobasal
syndrome. Although the majority of AD cases are sporadic, 5–10% of early-onset cases
(occurring before 65 years) are linked to identifiable autosomal dominant mutations in the
presenilin
(
PSEN1
and
PSEN2
) or
amyloid precursor protein (APP)
genes, or APP duplication.
The possibility of iatrogenic transmission of amyloid-β (Aβ) neuropathology has been
recognized, particularly in cases where high levels of Aβ were found in individuals who died
of iatrogenic Creutzfeldt-Jakob disease decades after receiving cadaver-derived human
growth hormone. This has raised concerns about potential Aβ transmission during medical
procedures involving contaminated dura mater grafts or neurosurgical instruments.
Macroscopic Features
In typical amnestic presentations, cortical atrophy is most pronounced in multimodal
association cortices and medial temporal structures, particularly the hippocampus and
amygdala. In contrast, the primary motor and somatosensory cortices are relatively spared.
Additionally, loss of neuromelanin pigmentation in the locus coeruleus is a common
macroscopic finding.
Histological Features
AD is considered a mixed proteinopathy due to the presence of both misfolded Aβ and
tau proteins within neuritic plaques. Initially, extracellular Aβ plaques are diffuse but mature
over time to form dense central cores. According to the amyloid-cascade hypothesis, these
plaques initiate tau aggregation in surrounding dystrophic neurites, resulting in the formation
of neuritic plaques. Mutations in
APP
,
PSEN1
, and
PSEN2
, which affect Aβ metabolism, are
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linked to early-onset AD, whereas mutations in the
MAPT
gene, which causes primary
tauopathies, do not lead to AD.
Phosphorylated tau aggregation is a hallmark histological feature of AD. Tau initially
accumulates in neuronal bodies as pretangles, which mature into neurofibrillary tangles and,
following cell death, persist as ghost tangles. While Aβ plays a role in initiating tau misfolding,
clinical features and the extent of cortical atrophy correlate more strongly with tau pathology
density than with Aβ burden.
The spread of neuropathology in most cases of AD follows the Braak and Braak model,
beginning in the medial temporal lobe structures and progressively extending to neocortical
areas. Exceptions include limbic-predominant and hippocampal-sparing subtypes.
The neuropathological diagnosis of AD is guided by the National Institute on Aging-
Alzheimer’s Association (NIA-AA) guidelines. This involves semi-quantitative assessments of:
1.
Regional Aβ pathology (Thal phase)
2.
Regional neurofibrillary tangle presence (Braak and Braak stage)
3.
Cortical neuritic plaque density (CERAD score)
These parameters collectively estimate the likelihood of dementia being attributable to
AD neuropathological changes.
Synucleinopathies
Synucleinopathies are neurodegenerative diseases characterized by the pathological
aggregation of α-synuclein protein. They can be divided into two main pathological entities:
1.
Lewy Body Disease
: This includes Parkinson’s disease (PD) and dementia with Lewy
bodies (DLB). These disorders are akinetic–rigid syndromes distinguished by the timing of
dementia onset. In PD, dementia typically occurs more than one year after the onset of motor
symptoms, while in DLB, cognitive decline precedes or coincides with motor symptoms.
Despite this clinical distinction, PD and DLB are likely part of the same clinicopathological
spectrum.
2.
Multiple System Atrophy (MSA)
: MSA commonly presents with autonomic dysfunction
and either cerebellar ataxia (MSA-C) or parkinsonism (MSA-P). While PD has numerous
monogenic causes (e.g.,
SNCA
,
PRKN
,
PINK-1
,
DJ-1
,
VPS35
mutations) and susceptibility genes
(e.g.,
LRRK2
,
GBA
), MSA is primarily sporadic. However, G51D mutations in the
SNCA
gene can
lead to combined α-synucleinopathy, exhibiting neuropathological features of both PD and
MSA.
Macroscopic Examination
PD and DLB
: Key findings include pallor and atrophy of the substantia nigra and locus
coeruleus, often accompanied by varying degrees of frontal and medial temporal lobe atrophy.
MSA
: Atrophy extends beyond the substantia nigra, involving olivopontocerebellar
(OPCA) or striatonigral (SND) regions, which correspond to MSA-C and MSA-P clinical
subtypes, respectively. Rarely, in minimal-change MSA, atrophy is confined to the substantia
nigra despite widespread α-synuclein pathology.
Histological Examination
PD and DLB
: Both are characterized by the accumulation of α-synuclein fibrils in
neurons, forming Lewy bodies and Lewy neurites. The progression of Lewy pathology
typically follows a caudal-to-rostral pattern, as described by Braak and colleagues, spreading
from the brainstem through the limbic regions to the neocortex. Recent studies have
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identified amygdala-predominant and olfactory-restricted patterns of Lewy pathology. At the
microscopic level, PD and DLB cannot be distinguished at autopsy, as the electron cryo-
microscopy structures of α-synuclein filaments are identical in both conditions.
MSA
: α-synuclein aggregation occurs in both neurons and oligodendrocytes, forming
neuronal and glial cytoplasmic inclusions. Less frequently, inclusions are found in the nuclei
of glial cells and neurons. While Lewy pathology may be present in 10–20% of MSA cases, the
structure of α-synuclein filaments in MSA is distinct from that observed in PD/DLB.
This distinction between Lewy div disease and MSA highlights the variability in clinical
presentation and pathology across the synucleinopathies, reflecting differences in the
structure and distribution of α-synuclein aggregates.
Conclusion
Neuropathological examination remains the definitive gold standard for diagnosing
most neurodegenerative diseases. Beyond diagnosis, it holds significant implications for the
relatives of affected individuals and broader public health. Emerging pathological entities
continue to require detailed clinicopathological correlation, underscoring the dynamic nature
of this field. Advances in molecular biology techniques further reinforce the value of
neuropathological studies, even for well-characterized conditions like Alzheimer’s disease
(AD) and Parkinson’s disease (PD). Such examinations are vital for advancing high-quality
research into the molecular mechanisms underlying these diseases and for the discovery and
validation of tissue-based biomarkers.
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