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Neurodegeneration: 2024 update 

John F. Crary 

Department of Pathology, Nash Family Department of Neuroscience, Department of Artificial Intelligence & Human 
Health, Neuropathology Brain Bank & Research CoRE, Ronald M. Loeb Center for Alzheimer's Disease, Friedman 
Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA 

Corresponding author: 
John F. Crary · Icahn School of Medicine at Mount Sinai · 1 Gustave L. Levy Place Box 1194 · New York, NY 10029 · USA 
john.crary@mountsinai.org 

Submitted: 09 September 2024 · Accepted: 18 November 2024 · Copyedited by: Jerry Lou · Published: 09 December 2024 

Abstract 

This review highlights a collection of both diverse and highly impactful studies published in the previous year 
selected by the author from the neurodegenerative neuropathology literature. As with previous reviews in this 
series, the focus is, to the best of my ability, to highlight human tissue-based experimentation most relevant to 
experimental and clinical neuropathologists. A concerted effort was made to balance the selected studies across 
neurodegenerative disease categories, approaches, and methodologies to capture the breadth of the research 
landscape. These studies employ a range of classical and state-of-the-art methodologies ranging from clinical 
pathoanatomical correlative studies to single-cell RNA sequencing, artificial intelligence, and patient-derived hu-
man induced pluripotent stem cell models. Key studies include demonstration of the earliest pathological 
changes in young patients with repetitive head impacts (RHI), elucidation of the longitudinal trajectory of extra- 
pyramidal symptoms in Lewy body disease subtypes, mapping of cell-type specific polygenic risk in Alzheimer’s 
disease to neuropathology, a novel measure of histological brain age acceleration using artificial intelligence, 
trends in cerebrovascular pathologies over 25 years, associations between RHI and TDP-43 / hippocampal scle-
rosis, microglia / T-cell interaction in neurodegeneration, the impact of viral exposures on neurodegenerative 
disease risk, and polyglutamine repeat expansion disorders. This sampling of the literature collectively displays 
the breadth of the progress being made in the neuropathology of neurodegenerative diseases. 
 

Keywords: Neurodegeneration, Neuropathology, Aging, Alzheimer’s disease, Tauopathy, α-synucleinopathy, TDP-43 proteinopathy, 
Traumatic brain injury 

 

 

 

Review 

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1. Chronic traumatic encephalopathy 
in young athletes’ post-repetitive head 
impacts 

Concussions are extremely prevalent, espe-
cially among individuals exposed to repetitive head 
impacts (RHIs) through contact sports, military ser-
vice, intimate partner violence, and other means. 
While these impacts may be symptomatic or asymp-
tomatic in the short term, long-term exposure can 
lead to severe neurological outcomes, including 
chronic traumatic encephalopathy (CTE), a degener-
ative brain disease with varied clinical and neuropa-
thological features. Most research on RHI has  
focused on older populations, leaving a critical gap 
in our understanding of how RHIs affect younger  
individuals. Investigating changes in young athletes 
is crucial, as it may uncover underlying mechanisms 
for neuropsychiatric symptoms and identify early 
triggers for tau accumulation and associated tox-
icity, potentially informing preventive strategies and 
interventions. 

A study by McKee et al. published in JAMA Neu-
rology investigates the neuropathologic and clinical 
consequences of repetitive head impacts (RHIs) in 
young contact sport athletes (McKee et al., 2023). 

Analyzing data from 152 brain donors younger than 
30 years from the UNITE Brain Bank, the study char-
acterized the presence and extent of chronic trau-
matic encephalopathy (CTE) and other neuropatho-
logic abnormalities. The authors found that 41.4 % 
of the athletes showed neuropathological changes 
diagnostic for CTE, predominantly mild (stages I or 
II). Notably, athletes with CTE were more likely to be 
older and have longer exposure to RHI, particularly 
American football. CTE positive subjects showed key 
neuropathologic features, including ventricular en-
largement, cavum septum pellucidum, thalamic 
notching, and the presence of perivascular pigment-
laden macrophages in the frontal white matter  
(Figure 1). Further, the study also examined the  
clinical symptoms reported by informants using 
standardized scales, showing that cognitive, behav-
ioral, and mood disturbances were prevalent among 
the brain donors, regardless of CTE status. Common 
symptoms included executive dysfunction, impulse 
control issues, depression, and apathy. This study 
provides critical insights into the early manifesta-
tions of CTE and other brain pathologies in young 
athletes, emphasizing the need for prospective  
studies to better understand the specific impacts of 
RHIs. The study's findings are potentially pivotal for  
developing strategies to mitigate the long-term  
effects of RHIs in contact sports.

 

 

Figure 1. Neuropathological changes in young contact sports athletes. A. Immunohistochemistry for hyperphosphorylated tau showing 
the pathognomonic perivascular lesion. B. LH&E showing robust perivascular hemosiderin deposition in the white matter. C. LH&E demon-
strating white matter rarefaction. D. Activated microglial clusters are prominent. Reproduced with modifications under the terms of the 
CC-BY License (http://creativecommons.org/licenses/by/4.0/). 

 

 

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2. Hippocampal sclerosis with TDP-43 
inclusions following repetitive head 
impacts 

Hippocampal sclerosis of aging, characterized 
by neuronal loss and gliosis primarily in the CA1  
region and occurring independently of hypoxic- 
ischemic injury, is prevalent in the aging population. 
Most cases also exhibit inclusions positive for trans-
active response DNA-binding protein with 43 kDa 
(TDP-43), a protein that, since its identification as 
the primary inclusion in amyotrophic lateral sclero-
sis (ALS) and frontotemporal lobar degeneration 
(FTLD), has been linked to other disorders including 
Alzheimer's disease (AD), limbic age-related TDP-43 
encephalopathy neuropathologic change (LATE-NC), 
and chronic traumatic encephalopathy (CTE). The 
association with CTE is particularly notable and  
understudied, raising questions about whether 
these conditions represent co-morbidities or if they 
have synergistic effects. 

A study by Nicks et al. published in Acta Neuro-
pathologica directly addresses the neuropatholo- 
gical association between repetitive head impacts 
(RHI), chronic traumatic encephalopathy (CTE), and 
the presence of TDP-43 inclusions and hippocampal 
sclerosis (HS) (Nicks et al., 2023). The researchers 
analyzed brain samples from 401 participants with a 
history of RHI and neuropathologically diagnosed 
CTE and compared them with 33 individuals diag-
nosed with HS without CTE. The study found that HS 
was present in 23.4 % of the CTE cases and that  
TDP-43 inclusions were present in 43.3 % of the CTE 
cases. Notably, HS in CTE occurred at a younger 
mean age (77 years) and was significantly associated 
with a longer history of contact sports exposure 
compared to CTE without HS. TDP-43 inclusions 
were frequently observed in the frontal cortex and 
often co-occurred with limbic TDP-43 pathology. 
Structural equation modeling demonstrated a signi-
ficant association between years of RHI exposure 
and the presence of hippocampal TDP-43 inclusions 
through increased CTE stage. The study also showed 
that TDP-43 inclusions in CTE were predominantly 
limbic but also involved the frontal cortex, distin-
guishing it from typical age-related TDP-43 patho- 
logies such as LATE-NC. The presence of TDP-43 
inclusions in the hippocampus was significantly  

associated with HS in CTE, suggesting a pathogenic 
link between repetitive head impacts, CTE patho- 
logy, and the development of TDP-43 proteinopathy 
and HS. These findings highlight the importance of 
considering RHI history in the assessment of hippo-
campal sclerosis and suggest potential therapeutic 
targets for mitigating the effects of RHI on neuro-
degeneration. 

3. Longitudinal motor decline in  
diffuse Lewy body disease, Parkinson’s 
disease with dementia, and 
Alzheimer’s disease 

Lewy bodies, a common neuropathological 
finding, are the hallmark of Parkinson's disease (PD) 
when localized to the substantia nigra, but they can 
progress to a diffuse pattern leading to Parkinson's 
disease dementia (PDD). When Lewy bodies are 
found in the neocortex and associated with  
dementia as the presenting symptom, this condition 
is termed diffuse Lewy body disease (DLBD). In  
patients with DLBD, extrapyramidal parkinsonian 
features may or may not develop. Lewy bodies are 
also seen in Alzheimer's disease (AD). However, the 
extent to which the rates of extrapyramidal motor 
decline progress in these different contexts is  
unclear due to the limited number of longitudinal 
studies with neuropathological endpoints, which are 
crucial for prognostication, clinical trial design, and 
further research. 

A study by Choudhury et al. published in  
Alzheimer’s & Dementia investigates the progres-
sion of motor deficits in dementia with Lewy bodies 
(DLB), Parkinson’s disease dementia (PDD), and  
Alzheimer’s disease dementia (AD) using data from 
the Arizona Study of Aging and Neurodegenerative 
Disorders (Choudhury et al., 2023). The study  
included 193 participants with autopsy-confirmed 
diagnoses: 98 with PDD, 48 with DLB, and 47 with 
AD. Within the DLB cohort, participants were further 
categorized into those with parkinsonism (DLB+) 
and without parkinsonism (DLB-). The researchers 
utilized the Unified Parkinson’s Disease Rating Scale 
(UPDRS) parts II and III to assess motor function over 
an eight-year period, employing non-linear mixed 
effects models to analyze the data. The results  
revealed that motor deficits progressed most rapidly 

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in the DLB+ group, with significant worsening in gait 
and limb bradykinesia compared to PDD and other 
groups (Figure 2). The study found that baseline  
UPDRS-II and III scores were highest in the PDD 
group, followed by DLB+, AD, and DLB-. Over time, 
the DLB+ group showed a faster progression in  
UPDRS-III scores compared to PDD, driven by  
significant declines in gait and limb bradykinesia. 
The study also highlighted that the presence of  
parkinsonism in DLB (DLB+) was associated with 
more rapid motor decline than in DLB- or AD,  

emphasizing the importance of recognizing and 
monitoring these symptoms for better clinical  
management and prognostication. The findings  
underscore the need for targeted interventions to 
address motor deficits and suggest that patients 
may benefit from specific therapeutic strategies 
aimed at mitigating motor decline. The research 
provides valuable insights into the differential  
progression of motor impairments in neurodegener-
ative dementias, with implications for clinical trial 
design and patient care.

 

 

Figure 2. UPDRS-III total scores during off stage examination for each participant and their trajectories for groups: PDD (A), DLB+ (B), DLB− 
(C), and AD (D). Each point represents one movement exam visit and corresponding score. Blue lines depict each participant. Red line 
represents a mixed model fit line. The shaded area (funnel) surrounding red fit line represents 95 % confidence interval for the mixed 
model fitted curves. AD, Alzheimer’s disease; DLB+, DLB with parkinsonism; DLB−, DLB without parkinsonism; DLB, dementia with Lewy 
bodies; PDD, Parkinson’s disease dementia. Reproduced with modifications under the terms of the CC-BY License (http://creativecom-
mons.org/licenses/by/4.0/). 

 

 

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4. Cell-type-specific Alzheimer’s poly-
genic risk scores 

Large-scale genetic studies have uncovered  
numerous genetic loci associated with Alzheimer's 
disease (AD), but understanding how the corre-
sponding causal genes contribute to the cellular and 
molecular mechanisms driving AD remains a major 
challenge. Since neurodegeneration in AD is a com-
plex, non-cell autonomous process involving inter-
actions between multiple cell types, deciphering 
how these genes act across different cells is essen-
tial for identifying therapeutic targets. Genes  
expressed by microglia and astrocytes are notably 
over-represented in genome-wide association  
studies (GWAS) of AD. However, how these cell-spe-
cific genetic changes connect to the neuropatholo- 
gical hallmarks of AD, such as neurofibrillary tangles 
and amyloid plaques, and ultimately to cognitive  
decline, remains unclear—a critical gap in our 
knowledge. 

A study by Yang et al. published in Nature  
Communications investigates how cell-type-specific 
polygenic risk scores (ADPRS) for AD are associated 
with distinct pathological processes (Yang et al., 
2023). By deriving ADPRS from large-scale genome-
wide association studies (GWAS) and leveraging  
single nucleus RNA sequencing (snRNA-seq) data, 
the researchers assessed the impact of genetic risk 
localized to different brain cell types, focusing on  
microglia and astrocytes, on various AD endopheno-
types. Using data from the Religious Orders Study 
and the Rush Memory and Aging Project (ROSMAP), 
as well as the Anti-Amyloid Treatment in Asympto-
matic Alzheimer’s (A4) study, the study found that 
astrocytic ADPRS were primarily associated with  
amyloid-β (Aβ) pathology, while microglial ADPRS 
were linked to both Aβ and tau pathologies, as well 
as cognitive decline. The findings suggest that  
genetic risks associated with astrocytes contribute 
to early Aβ accumulation, whereas microglial  
genetic risks drive later-stage pathological changes 
and cognitive impairment. 

Yang et al. utilized causal modeling to map the 
contributions of cell-type-specific ADPRS to the  
sequence of AD pathophysiology. The study sug-
gests that astrocytic genetic risks affect AD primarily 

through Aβ accumulation in diffuse and neuritic 
plaques, whereas microglial genetic risks have 
broader effects on neuritic plaques, tau neurofibril-
lary tangles, and cognitive decline. This was sup-
ported by data from the A4 study, which showed 
that microglial ADPRS were significantly associated 
with in vivo tau PET measures, indicating an early 
role in tau pathology. The research underscores the 
importance of considering cell-type-specific genetic 
risks in understanding the progression of AD and 
highlights potential targets for therapeutic interven-
tions. These insights pave the way for future studies 
to explore genetically guided approaches to AD 
treatment, focusing on modulating specific glial cell 
functions to mitigate disease progression. 

5. Histological brain age acceleration 
using digital neuropathology and 
artificial intelligence 

Understanding mechanisms of human brain  
aging is increasingly important as the elderly popu-
lation grows, given the complexity of structural 
changes that arise from a spectrum of normal and 
pathological processes affecting functional impair-
ment. One highly effective approach to studying  
aging is through biological clocks, initially developed 
using DNA methylation analysis. DNA methylation 
clocks estimate biological age by measuring methyl-
ation patterns at specific CpG sites in the genome, 
reflecting cellular aging processes. This method can 
be used to reveal discrepancies between biological 
and chronological age, providing insights into age 
acceleration or deceleration that can be linked to 
environmental and genetic factors. 

In a study by Marx et al. published in Acta  
Neuropathologica, and led by the author of this  
review, the authors leverage digital pathology to  
deploy multiple instance learning (MIL) to estimate 
brain age from histopathological whole slide images 
(Marx et al., 2023). Employing an attention-based 
deep MIL model, the team analyzed digitized post-
mortem hippocampal sections to develop an ad-
vanced brain age estimation tool, achieving a mean 
absolute error of 5.45 years (Figure 4). The integra-
tion of spatially resolved graph convolutional net-
works (GCNs) allowed the model to consider neuro-  

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Figure 3. Association of cell-type-specific AD polygenic risk scores. ROSMAP, Religious Orders Study/Memory and Aging Project; AD, Alz-
heimer disease; PRS, polygenic risk score; Ex, Exitatory neurons; In, Inhibatory neurons; Ast, astrocytes; Mic, microglia; Oli, Oligodendro-
cytes; Opc, Oligodendrocyte precursors. Reproduced in under a Creative Commons Attribution 4.0 International License (http://crea-
tivecommons.org/licenses/by/4.0/) 

 

anatomical context, resulting in a significant im-
provement over traditional methods. Marx et al. 
identified robust associations between histopatho-
logic brain age acceleration and clinical and patho-
logical outcomes, which were not evident with gold 
standard epigenetic measures. Attention heatmaps 
generated by the model highlighted aging-vulnera-
ble brain regions, such as specific white matter areas 
and hippocampal subfields, as critical for accurate 
age estimation. This study emphasizes the potential 
of histopathological markers to provide deeper  
insights into brain aging mechanisms. Additionally, 
the combination of MIL with GCNs presents a novel 
methodology for predicting brain age, offering 
promising implications for understanding and diag-
nosing neurodegenerative diseases and their pro-
gression. This innovative approach paves the way 
for more precise and informative assessments of 
age-related neuropathological changes. In this  
context, HistoAge represents a cutting-edge ad-
vancement—an AI-driven digital neuropathology 
tool designed to study brain aging more precisely, 
leveraging advanced computational techniques to 
enhance our understanding of age-related changes 
in the brain. 

6. Decline in cerebrovascular patholo-
gies over 25 years 

Recently, several studies have suggested that 
the incidence rate of dementia may be declining, of-
fering hope that improved healthcare and lifestyle 
factors are influencing this global challenge. How-
ever, dementia remains a highly complex disease 
with multiple underlying causes that are difficult to 
diagnose in the clinical setting. Both genetic and en-
vironmental risk factors play significant roles in the 
development of dementia, and understanding their 
interplay over time is critical. Across birth epochs, an 
enormous number of factors have changed, any of 
which could potentially influence dementia risk. 
These include environmental exposures (e.g., air 
pollution, pesticides), infectious diseases (e.g., her-
pes, HIV), socioeconomic shifts (e.g., malnutrition), 
medical advances, dietary and lifestyle trends, tech-
nological changes, genetic variations, access to 
healthcare, longevity, and even epigenetic modifica-
tions. Despite recent findings pointing toward de-
clining dementia rates, the precise neuropathologi-
cal underpinnings of these trends remain unclear. 
This gap in knowledge presents a major barrier to 

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Figure 4. The “HistoAge” pipeline. a. Digital whole slide images were broken up into smaller tiles, then run through a neural network that 
extracts features. These features were linked to adjoining tiles using graph structure. b. The features were then used to train a new neural 
network that predicted age, which was compared to chronological age to estimate age acceleration. Reproduced under the Creative 
Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/). 

 

developing targeted interventions and public health 
strategies, particularly as the population continues 
to age and the global burden of dementia grows. 

A study by Grodstein et al. published in JAMA 
Neurology examines trends in postmortem neuro-
degenerative and cerebrovascular neuropathologies 
over 25 years using data from the Religious Orders 
Study and the Rush Memory and Aging Project 
(Grodstein et al., 2023). This comprehensive investi-
gation includes 1,554 deceased participants with 
complete brain autopsies and neuropathologic eval-
uations. The study analyzes four birth cohorts span-
ning from 1905 to 1930 to assess changes in neuro-
pathological outcomes such as Alzheimer's disease 
(AD), amyloid load, tau tangles, neocortical Lewy 
bodies, limbic-predominant age-related TDP-43  
encephalopathy, atherosclerosis, arteriolosclerosis, 
and brain infarcts. Strikingly, they found no signifi-
cant differences in the prevalence of pathologic AD 

diagnoses across birth cohorts, with age-standard-
ized prevalence ranging between 62 % and 68 %. 
Similarly, there were no marked changes in global 
AD pathology or other neurodegenerative patholo-
gies over time. However, an increase in tau tangle 
density was noted in more recent birth cohorts, sug-
gesting a potential rise in this specific pathology. In 
contrast, the authors found a dramatic decrease in 
cerebrovascular pathologies, particularly athero-
sclerosis and arteriolosclerosis, over the observed 
period. Age-standardized prevalence of moderate to 
severe atherosclerosis decreased from 54 % in the 
earliest cohort (1905–1914) to 22 % in the latest  
cohort (1925–1930). Arteriolosclerosis showed a 
similar decline. These findings highlight the impact 
of improved vascular health on brain aging and sug-
gest that reductions in clinical dementia observed in 
other studies may be associated with enhanced  
resilience to neuropathology rather than a decrease 
in the underlying neurodegenerative pathologies. 

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Additionally, the study emphasizes the importance 
of considering both neurodegenerative and cere-
brovascular factors in understanding dementia 
trends and developing public health strategies to  
address the growing aging population. The results 
underscore the need for continued efforts to  
improve vascular health as a means to mitigate the 
impact of dementia. 

7. Microglia-T cell interaction in Alz-
heimer’s disease and tauopathy 

The immune system's involvement in neuro-
degeneration continues to gain increasing attention, 
with compelling evidence pointing to its critical role 
in disease progression. The innate immune system, 
particularly through the activation of microglia, has 
been at the forefront of research efforts, with these 
cells being implicated in the inflammatory processes 
that contribute to neuronal damage. However, a sig-
nificant gap remains in understanding the role of the 
adaptive immune system, which, despite being  
central in autoimmune and infectious diseases, has 
been comparatively understudied in neurodegener-
ative disorders. T cells, key players in the adaptive 
immune response, have received far less focus in 
neurodegenerative diseases like Alzheimer's. This 
oversight represents a critical barrier to fully under-
standing the immune-mediated mechanisms of  
neurodegeneration. Although not as abundant as in 
conditions such as multiple sclerosis, T cells may still 
play an important role in these diseases, offering a 
potential but underexplored therapeutic target. 

A study by Chen et al. at the Washington Uni-
versity School of Medicine published in Nature  
investigated the relationship between microglia, 
T cells, and tau-mediated neurodegeneration (Chen 
et al., 2023). Using mouse models of amyloid depo-
sition and tau aggregation, they systematically com-
pared the immune responses in the brains of trans-
genic mice and humans, revealing that tauopathy, 
but not amyloid deposition, triggers a unique adap-
tive immune response. Depletion of either microglia 
or T cells significantly blocked tau-mediated neuro-
degeneration, suggesting a critical role these im-
mune cells play in the disease process. The study 
identified a marked increase in T cells, especially  

cytotoxic T cells, in regions with tau pathology in 
both mice and human Alzheimer's disease brains, 
correlating with neuronal loss and dynamic transfor-
mations from activated to exhausted states. The  
researchers utilized single-cell RNA sequencing 
(scRNA-seq) and single-cell TCR sequencing (scTCR-
seq) to map the cellular and molecular signatures of 
immune cells in the brain. They found that in 
tauopathy, T cells and microglia formed an immune 
hub characterized by increased expression of inter-
feron-γ and PDCD1 signaling pathways. Notably,  
inhibiting these pathways significantly reduced 
brain atrophy. The study also highlighted the role of 
microglia in presenting antigens to T cells, promot-
ing their infiltration and activation. This interaction 
was found to be critical in driving neurodegenera-
tion, as evidenced by the reduction in tau pathology 
and brain atrophy upon depletion of T cells. These 
findings underscore the potential of targeting micro-
glia and T cell interactions as a therapeutic strategy 
for tauopathies and Alzheimer's disease, offering 
new avenues for treatment by modulating the im-
mune response. 

8. Viral exposures linked to neuro-
degeneration 

Growing evidence has increasingly spotlighted 
the potential causal role of viruses in neurodegener-
ative diseases (NDDs). Historical examples, such as 
post-encephalitic parkinsonism, first hinted at this 
link, and subsequent research has suggested associ-
ations with viruses like herpes simplex virus (HSV). 
The COVID-19 pandemic further intensified specula-
tion regarding viral contributions to neurodegener-
ation. Most notably, recent studies have strongly 
linked Epstein-Barr virus (EBV) to multiple sclerosis 
(MS). This connection is significant because viral  
infections can be mitigated through vaccination or 
treated with antivirals, presenting vast new possibil-
ities for preventing or slowing neurodegenerative 
processes. However, the specific mechanisms by 
which viral exposures contribute to NDDs remain 
unclear, representing a critical gap in our under-
standing and a barrier to developing targeted inter-
ventions. 

A study published in Neuron by Levine et al.  
examines the association between viral exposures 

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and the risk of developing neurodegenerative  
diseases (NDDs) using large-scale biobank data from 
FinnGen and the UK Biobank (Levine et al., 2023). 
The researchers identified 45 significant viral-NDD 
associations in the discovery phase with FinnGen, 
and successfully replicated 22 of these associations 
in the replication phase using the UK Biobank.  
Notably, the strongest association was observed  
between viral encephalitis (not elsewhere classi-
fied/unspecified) and Alzheimer’s disease (AD), with 
a hazard ratio of 30.72 in FinnGen and an odds ratio 
of 22.06 in the UK Biobank. Other significant associ-
ations included influenza with pneumonia, which 
was linked to an increased risk of five of the six  
studied NDDs, including AD, amyotrophic lateral 
sclerosis (ALS), dementia, Parkinson's disease (PD), 
and vascular dementia (VAS). The analysis high-
lighted the long-term impact of viral exposures, 
showing that some associations persisted up to 15 
years prior to NDD diagnosis. The study also repli-
cated the association between Epstein-Barr virus 
(EBV) and multiple sclerosis (MS). Importantly, the 
findings suggest that vaccination against certain  
viruses, such as influenza and varicella-zoster, might 
reduce the risk of developing NDDs. It is important 
to note that the reverse causality has not been  
eliminated. The possibility that patients in the pre-
symptomatic phases of neurodegenerative disease 
might be at risk for viral infection needs to be  
addressed more closely. The study emphasizes the 
need for more research into the role of viral infec-
tions in the pathogenesis of neurodegenerative  
diseases and suggests that leveraging vaccination 
and antiviral strategies might offer new avenues for 
prevention and treatment. These findings under-
score the importance of considering viral exposure 
history in NDD risk assessments and highlight the 
potential for public health interventions to mitigate 
these risks. 

9. Polyglutamine (polyQ) diseases:  
ribosomal proteins and tauopathy 

Polyglutamine (polyQ) diseases, such as Hun-
tington's disease (HD) and various spinocerebellar 
ataxias, represent an important yet understudied 
group of neurodegenerative disorders. These  
diseases are caused by CAG-repeat expansions in 

different genes and are characterized by neuronal 
intranuclear inclusions (NIIs), which play a key role 
in disease pathology. NIIs are not only central to 
polyQ disorders but are also observed in normal  
aging, as evidenced by Marinesco bodies in the  
substantia nigra and locus coeruleus. However, the 
formation of NIIs and their precise role in neuro-
degeneration remain poorly understood, represent-
ing a critical gap in knowledge. Addressing this gap 
through focused research on polyQ disorders and 
related inclusions is essential for advancing our  
understanding of these complex diseases and their 
broader implications for neurodegeneration. Few 
neuropathological studies focusing specifically on 
polyQ disorders are published each year, but two 
notable studies were recently conducted. 

One study by Yagita et al. published in Neuro-
pathology investigated the ribosomal protein SA 
(RPSA) in neuronal intranuclear inclusions (NIIs)  
associated with polyglutamine (polyQ) diseases and 
Marinesco bodies (MBs) in normal aging brains 
(Yagita et al., 2024). Utilizing immunohistochemical 
and biochemical analyses, the researchers examined 
brain samples from patients with Huntington  
disease (HD), spinocerebellar ataxia type 3 (SCA3), 
and normal elderly controls (NCs). The study  
revealed that RPSA is a common component of NIIs 
in polyQ diseases and MBs in normal aging. In polyQ 
diseases, RPSA co-localizes with polyQ aggregations 
and other proteins such as p62, ubiquitin, and  
huntingtin, forming a mosaic-like distribution within 
the NIIs. The nuclear fraction of HD patients' brain 
samples contained higher levels of RPSA compared 
to NCs, suggesting an upregulation of RPSA in the 
diseased state. In contrast, cytoplasmic RPSA  
expression was reduced in neurons with NIIs, which 
could imply sequestration of RPSA into the inclu-
sions, leading to its depletion in the cytoplasm. The 
study also identified that MBs in the substantia nigra 
of NCs share similar protein components with NIIs, 
including RPSA and p62, indicating common mecha-
nisms may drive the formation of these intranuclear 
inclusions. These findings highlight the role of ribo-
somal dysfunction in both neurodegenerative  
diseases and normal aging, providing new insights 
into the pathogenesis of polyQ diseases and the  
potential impact of ribosomal proteins in neuronal 
health and disease. 

https://doi.org/10.17879/freeneuropathology-2024-


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Figure 5. Tauopathy in SCA8. (A) In the dentate nucleus of the cerebellum, grumose degeneration was observed. (B–H) Immunohisto- 
chemistry for p-tau demonstrateed numerous globose-type NFTs, threads, and tufted astrocytes in the dentate nucleus (B), internal glo-
bus pallidus (C), subthalamic nucleus (D), precentral gyrus (E, F), and cerebellum (G, H). In the precentral gyrus, Betz cells were diffusely 
granular positive for p-tau (F). Purkinje cells were also positive for p-tau (H). HE staining (A); immunohistochemistry for p-tau (B–H). Scale 
bars: 100 μm in (A–D), 500 μm in (E, G), 25 μm in (F, H). Reproduced under the Creative Commons Attribution 4.0 International License 
(http://creativecommons.org/licenses/by/4.0/). 

 

 

 

https://doi.org/10.17879/freeneuropathology-2024-
http://creativecommons.org/licenses/by/4.0/


Free Neuropathology 5:31 (2024) John F. Crary 
DOI: https://doi.org/10.17879/freeneuropathology-2024-5848 page 11 of 12 
 
 

 

A second study also published in Neuropathol-
ogy by Yonenobu et al. examined tauopathy in 
spinocerebellar ataxia type 8 (SCA8), suggesting that 
this variant might display unique tauopathic  
features (Yonenobu et al., 2023). The researchers 
analyzed post-mortem brain samples from patients 
diagnosed with SCA8. SCA8 is characterized by  
neuronal loss and gliosis predominantly in the  
cerebellum and brainstem, which aligns with the 
clinical manifestations of the disease. Additionally, 
Purkinje cell loss is a consistent finding, accompa-
nied by Bergmann gliosis and dentate nucleus de-
generation. Intriguingly, the investigators uncov-
ered a unique tauopathy. Unlike other spinocerebel-
lar ataxias, SCA8 exhibited tau-positive neuronal and 
glial inclusions, particularly in the brainstem and  
cerebellum. This finding not only expands the  
neuropathological spectrum of SCA8 but also  
provides new insights into its underlying mecha-
nisms, paving the way for future research on  
targeted therapeutic strategies. Intriguingly, SCA8 is 
an atypical polyglutamine disorder, with the polyQ 
tract encoded from the anti-sense strand, raising a 
possible explanation for why the tauopathy  
described for SCA8 might be unique. The study  
emphasizes the importance of recognizing these 
unique pathological features to improve the diagno-
sis and understanding of SCA8. 

Funding statement 

This work was supported by funding from the 
NIH (R01AG054008, R01NS095252, R01AG062348, 
R01NS086736, U54NS115266, U54NS115322) as 
well as the Rainwater Charitable Trust / Tau Consor-
tium, the Alexander Saint Amand Scholar Award, the 
Karen Strauss Cook Research Scholar Award, and a 
generous gift from Stuart Katz and Dr. Jane Martin. 

Conflict of interest 

The author reports no conflicts of interest. 

Disclosure statement 

Generative artificial intelligence tools, specifi-
cally OpenAI's GPT-4, were used in the preparation 
of this manuscript. These tools assisted in drafting 
and refining portions of the text. The final content 
has been reviewed and edited by the author to  
ensure its accuracy, originality, and compliance with 
the journal's authorship and integrity guidelines. 
The author takes full responsibility for the content 
of the manuscript. 

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https://doi.org/10.17879/freeneuropathology-2024-
https://doi.org/10.1186/s40478-023-01649-z
https://doi.org/10.1111/neup.12927
https://doi.org/10.1038/s41467-023-43132-2
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	Rewiew
	1. Chronic traumatic encephalopathy in young athletes’ post-repetitive head impacts
	2. Hippocampal sclerosis with TDP-43 inclusions following repetitive head impacts
	3. Longitudinal motor decline in  diffuse Lewy body disease, Parkinson’s disease with dementia, and Alzheimer’s disease
	4. Cell-type-specific Alzheimer’s polygenic risk scores
	5. Histological brain age acceleration using digital neuropathology and artificial intelligence
	6. Decline in cerebrovascular pathologies over 25 years
	7. Microglia-T cell interaction in Alzheimer’s disease and tauopathy
	8. Viral exposures linked to neurodegeneration
	9. Polyglutamine (polyQ) diseases:  ribosomal proteins and tauopathy
	Funding statement
	Conflict of interest
	Disclosure statement
	References

