Mcanism B Neurodegenerative

Pract Neurol: first published as 10.1136/pn-2023-003988 on 16 December 2023. Downloaded from http://pn.bmj.com/ on January 2, 2024 at Gr.T.
Popa University of Medicine and Pharmacy

Review
Pathology of neurodegenerative
disease for the general neurologist
Patrick W Cullinane,1,2 Sarah Wrigley,1,2 Jacy Bezerra Parmera ‍ ‍ ,2,3
Fernanda Valerio,4 Thomas O Millner,4 Karen Shaw,1,2
Eduardo De Pablo-Fernandez ‍ ‍ ,1,2 Thomas T Warner,1,2
Zane Jaunmuktane1,2,4
► Additional supplemental ABSTRACT larger filaments before aggregating to form

material is published online
Neurodegeneration refers to progressive morphologically distinct cellular inclu-
only. To view, please visit
the journal online (http://dx. dysfunction or loss of selectively vulnerable sions or extracellular parenchymal plaques
doi.org/10.1136/pn-2023- neurones from brain and spinal cord regions. (figure 1). More than 50 diseases are asso-
003988). Despite important advances in fluid and ciated with misfolded protein pathology1
1
Department of Clinical and
imaging biomarkers, the definitive diagnosis including well- established clinicopatholog-
Movement Neurosciences, of most neurodegenerative diseases still relies ical conditions such as Alzheimer’s diseases
UCL Queen Square Institute of on neuropathological examination. Not only (AD) and Parkinson’s disease (PD), as well as
Neurology, London, UK has careful clinicopathological correlation more recently identified neuropathological
2
Queen Square Brain Bank for
Neurological Disorders, UCL shaped current clinical diagnostic criteria and entities of uncertain clinical significance such
Queen Square Institute of informed our understanding of the natural as age-related tau astrogliopathy (ARTAG)
Neurology, London, UK
3
history of neurodegenerative diseases, but it and limbic-predominant age-related TDP43
Department of Neurology,
of Iasi. Protected by copyright.

has also identified conditions with important encephalopathy (LATE). In most neurode-
Hospital das Clínicas,
Universidade de São Paulo, São public health implications, including variant generative diseases there is topographical
Paulo, Brazil Creutzfeldt-Jakob disease, iatrogenic amyloid-β spreading of misfolded protein pathology
4
Division of Neuropathology, and chronic traumatic encephalopathy. between synaptically-
connected brain
National Hospital for Neurology
and Neurosurgery, University
Neuropathological examination may also regions with different conformations of the
College London Hospitals NHS point to previously unsuspected genetic same misfolded protein generally leading
Foundation Trust, London, UK diagnoses with potential implications for living to specific patterns of regional and cellular
relatives. Moreover, detailed neuropathological vulnerability. Pathology may also develop in
Correspondence to
Dr Patrick W Cullinane assessment is crucial for research studies that situ because of cell autonomous factors such
and Dr Zane Jaunmuktane, rely on curated postmortem tissue to investigate as high metabolic demand and genetic risk
Queen Square Brain Bank for the molecular mechanisms responsible factors (including possible somatic muta-
Neurological Disorders, UCL
Queen Square Institute of
for neurodegeneration and for biomarker tions) that render some neurones more
Neurology, London, UK; discovery and validation. This review aims to susceptible to protein misfolding.2 What-
p atrick.cullinane.15@ucl.ac.uk, elucidate the hallmark pathological features ever the mechanism, the clinical features
z .jaunmuktane@ucl.ac.uk of neurodegenerative diseases commonly are generally determined by the anatomical
Accepted 11 November 2023
seen in general neurology clinics, such as distribution of neuropathology, meaning that
Alzheimer’s disease and Parkinson’s disease; similar clinical phenotypes may result from
rare but well-known diseases, including several different proteinopathies. Due to this
progressive supranuclear palsy, corticobasal phenotypic overlap, the accurate diagnosis
degeneration and multiple system atrophy and of many neurodegenerative diseases in life is
more recently described entities such as chronic challenging and neuropathology remains the
traumatic encephalopathy and age-related tau gold standard for diagnosis. Consequently,
astrogliopathy. systematic brain banking and clinicopath-
ological correlation have been the corner-
© Author(s) (or their stone of clinical diagnostic criteria for all the
employer(s)) 2023. No major neurodegenerative diseases.
commercial re-use. See rights INTRODUCTION
and permissions. Published Most adult-onset neurodegenerative diseases
by BMJ.
are considered proteinopathies because they A practical guide to the neuropathological
To cite: Cullinane PW, are characterised by misfolding of native diagnosis of neurodegenerative diseases
Wrigley S, Bezerra Parmera J, peptides and proteins such as amyloid-β After weighing the brain, the process begins
et al. Pract Neurol Epub ahead
of print: [please include Day (Aβ) peptide, tau, α-synuclein, transactive with macroscopic examination (online
Month Year]. doi:10.1136/pn- DNA- binding protein 43 (TDP43) and supplemental video 1), assessing the dura/
2023-003988 prion proteins, which then assemble into leptomeninges and cerebral vasculature
Cullinane PW, et al. Pract Neurol 2023;0:1–13. doi:10.1136/pn-2023-003988 1

Pract Neurol: first published as 10.1136/pn-2023-003988 on 16 December 2023. Downloaded from http://pn.bmj.com/ on January 2, 2024 at Gr.T.Popa University of Medicine and Pharmacy
Review

Figure 1 Formation of misfolded protein pathology and overview of pathological classification of neurodegenerative disease.
TDP43, transactive DNA-binding protein 43.
noting any surface lesions or gyral patterns of atrophy 3. α-synuclein.

before the hemispheres are separated along the midline. 4. TDP43.
In a brain bank setting, one hemisphere is typically fixed Other commonly used antibodies target ubiquitin
in formalin before sectioning and the other is dissected and p62 proteins, which accumulate in diverse patho-
fresh and flash frozen. The formalin-fixed hemisphere is logical inclusions and can be a clue to certain degener-
dissected by first removing the brainstem and cerebellum. ative processes. Depending on the clinical scenario and
The hemisphere is sliced coronally, the cerebellum is cut initial histological findings, immunohistochemistry for
in the sagittal plane and the brainstem is sectioned trans- other proteins such as prion (PrPSC) or fused in sarcoma
versely while looking for any focal or diffuse pathology, (FUS) are performed. Pathological lesions detected on
including any regional atrophy and depigmentation of the H&E and immunohistochemistry are classified based
substantia nigra and locus coeruleus. Approximately 20 on their location (extracellular or intracellular), the
brain regions are routinely sampled for histological exam- cell types affected (neurones, astrocytes, oligoden-
ination with additional regions included if indicated by drocytes), their morphology and regional distribution
the clinical history or macroscopic examination. before the final neuropathological diagnosis is made in
Formalin- fixed paraffin embedded tissue sections the context of the clinical history (figure 1).
are prepared from each region for histological exam-
ination. H&E is used for visualising the tissue cytoar- ESTABLISHED CLINICOPATHOLOGICAL DISEASES
chitecture, and distinguishing neuronal loss due to Alzheimer’s disease
ischaemia or degeneration. It can also detect certain AD is the most common neurodegenerative disease.
relevant proteinaceous structures such as extracel- It typically presents as an amnestic syndrome but less
lular amyloid plaques and intraneuronal Lewy bodies, common phenotypes include posterior cortical atrophy,
although these are now better identified with specific behavioural and dysexecutive syndromes, logopenic
antibodies by using immunohistochemistry. Proteins variant primary progressive aphasia and corticobasal
routinely tested by immunohistochemistry in neurode- syndrome.3 Although most cases of AD are sporadic,
generative cases include: early onset (<65 years) AD comprises 5–10% of all
1. Aβ peptide. cases, of whom 5–10% have an identifiable autosomal
2. Tau. dominant mutation in the presenilin (PSEN1 and
2 Cullinane PW, et al. Pract Neurol 2023;0:1–13. doi:10.1136/pn-2023-003988

Review

Figure 2 Morphology of Alzheimer’s disease-related tau inclusions and Aβ plaques. Aβ, amyloid-β.
PSEN2) or amyloid precursor protein (APP) genes or the appearance of neuritic plaques. This hypothesis is
APP duplication.4 The observation of high amounts of based on the finding that mutations in the APP, PSEN1
Aβ in the parenchyma and vasculature of patients who or PSEN2 genes, which result in primary abnormalities
died from iatrogenic Creutzfeldt-Jakob disease several of Aβ metabolism, can cause young-onset AD whereas
decades after receiving cadaver-derived human growth mutations in the microtubule-associated protein tau
hormone treatment,5 has led to widespread recogni- (MAPT) gene responsible for primary tauopathies do
tion that iatrogenic transmission of Aβ neuropathology not cause AD.7 Paramount for AD histological diag-
is also possible during surgical procedures involving nosis is phosphorylated tau aggregation in neuronal
contaminated dura mater grafts used in a wide range bodies leading to the appearance of pretangles, which
of medical interventions, or involving contaminated mature into neurofibrillary tangles, and following cell
neurosurgical instruments. death remain as ghost tangles. Although Aβ may be
responsible for the initiation of tau misfolding in AD,
Macroscopic features
the degree of cortical atrophy and clinical features
In typical amnestic cases, cortical atrophy tends to be
correlate with the density of tau pathology rather than
more pronounced in multimodal association cortices
that of Aβ.8 For most cases of AD, the topographical
and medial temporal structures, particularly the amyg-
spread of neuropathology follows the model proposed
dala and hippocampus, with relative sparing of the
by Braak and Braak, beginning in the medial temporal
primary motor and somatosensory cortices.6 Loss of
neuromelanin pigmentation in the locus coeruleus is structures before extending into neocortical struc-
also common. tures9 with the exceptions of rare limbic-predominant
and hippocampal-sparing AD. Currently, the neuro-
Histological features pathological diagnosis of AD is based on the National
AD is a mixed proteinopathy because misfolded Aβ and Institute on Aging-Alzheimer’s Association guidelines
tau pathology are found together in neuritic plaques using semi-quantitative assessments of regional Aβ
(figure 2). Initially, extracellular Aβ plaques are diffuse pathology (Thal phase), regional neurofibrillary tangle
but as they mature, they develop a dense central core. presence (Braak and Braak stage) and cortical neuritic
In line with the widely accepted amyloid- cascade plaque (CERAD score) density10 to indicate the likeli-
hypothesis, dense core plaques initiate tau aggregation hood of dementia being due to AD neuropathological
within surrounding dystrophic neurites culminating in change.

Review
Synucleinopathies clinical subtypes, respectively. In rare cases, referred
The synucleinopathies can be divided into two patho- to as minimal change MSA, atrophy is limited to the
logical entities: (1) Lewy body disease and (2) multiple substantia nigra despite more widespread misfolded
system atrophy (MSA). Lewy body disease comprises α-synuclein pathology.13
PD and dementia with Lewy bodies (DLB), which
are akinetic–rigid syndromes classically separated by
Histological examination
the timing of dementia onset, which may occur any
time >1 year after the onset of motor symptoms in PD PD and DLB are characterised by the accumulation
but occurs before or contemporaneously with motor of α-synuclein fibrils in the cytoplasm and processes
symptoms in DLB. Despite this clinical distinction, PD of neurones forming Lewy bodies and Lewy neurites
and DLB likely represent the same clinicopathological (figure 3). Lewy pathology tends to evolve in a stereo-
continuum. MSA typically presents with autonomic typed pattern described by Braak and colleagues with
failure and either cerebellar ataxia (MSA-C) or parkin- characteristic caudal–rostral propagation from the
sonism (MSA- P). While there are numerous mono- brainstem, through limbic regions to the neocortex.14
genic causes (eg, SNCA, PRKN, PINK-1, DJ-1, VPS35 More recently, amygdala-predominant and olfactory-
mutations) and susceptibility genes (LRRK2, GBA) restricted patterns of Lewy pathology have been
associated with PD, MSA is largely a sporadic disease, recognised. PD and DLB cannot be distinguished
although combined α-synucleinopathy comprising on an individual level at autopsy, consistent with
neuropathological features of both PD and MSA is the recent finding that the electron cryo-microscopy
characteristic of G51D mutations in the SNCA gene.11 structures of α-synuclein filaments from patients
with these conditions are identical.15 In MSA, α-sy-
Macroscopic examination nuclein aggregation characteristically occurs in both
The macroscopic findings in PD and DLB are pallor neurones and oligodendrocytes forming neruonal and
and atrophy of the substantia nigra and locus coeruleus glial cytoplasmic inclusions (figure 3). Inclusions also
with variably prominent frontal and medial temporal occur less frequently within the nuclei of glial cells

lobe atrophy.12 In MSA, atrophy usually extends and neurones. Lewy pathology may be present in
beyond the substantia nigra in olivopontocerebellar- 10–20% of MSA cases but the structure of α-synu-
(OPCA) or striatonigral- (SND) predominant patterns clein filaments in MSA is distinct from that seen in
that broadly correspond to the MSA-C and MSA-P PD/DLB.16
Figure 3 Morphology of α-synuclein inclusions in Parkinson’s disease and multiple system atrophy.

Review
Case 1 involving the right hand, dysphagia, symptoms sugges-
A 58-year-old man presented with a 1-year history of tive of REM-sleep behaviour disorder, left-hand utilisa-
difficulty getting in and out of his bed and car, incom- tion behaviour and alien limb, episodes of stridor and
plete bladder emptying, poor stream, double voiding and recurrent chest infections. He died at age 71 following
hesitancy. Within a few months he developed a shuffling a disease duration of 3.5 years and with a final clinical
gait and a tendency to drag his left foot leading to several diagnosis of corticobasal syndrome. Neuropatholog-
falls. This was followed by tremor of his left hand, ical examination revealed widespread glial cytoplasmic
hypophonia, constipation, erectile dysfunction, ortho- inclusion and neuronal α-synuclein pathology consistent
static lightheadedness and emotional lability. Examina- with a diagnosis of MSA (figure 4), which very rarely
tion identified normal eye movements, a mild resting presents as a corticobasal syndrome. Despite the prom-
tremor of the left hand with cogwheel rigidity and brady- inent cortical signs, there was no apparent macroscopic
kinesia. He walked with a stooped posture, reduced arm atrophy in any grey or white matter regions, in keeping
swing and a shuffling gait. There was some improve- with minimal change MSA, which is a rare subtype that
ment of his tremor with levodopa. Repeat examination may be associated with more rapid clinical progression.13
18 months into the illness showed mild dysarthria, ideo-
motor apraxia and impaired two-point discrimination Tauopathies
and astereognosis affecting his left hand and apraxia of The primary tauopathies comprise Pick’s disease,
his left leg. There was further rapid progression over the progressive supranuclear palsy, corticobasal degener-
next 6 months with increasing falls, ideomotor apraxia ation, globular glial tauopathy and chronic traumatic
Figure 4 Macroscopic and microscopic findings in a case of minimal change multiple system atrophy. Compared with the of Iasi. Protected by copyright.
significant lateral putaminal atrophy seen in a case of MSA-SND (A2, blue arrowhead), there is no macroscopic atrophy of the basal
ganglia structures (A1). Similarly, there is no atrophy of the pontine base (A3, vertical line) compared with the severe reduction in the
height of this structure in a case of MSA-OPCA (A4, vertical lines). In contrast to atrophy and gliosis of the inferior olivary nucleus
in a case of MSA-OPCA (A6, purple arrow), this structure is of normal bulk and well demarcated in this case (A5, blue arrow). The
cerebellar white matter is also preserved (A8, green arrow) compared with severe cerebellar white matter atrophy seen in MSA-
OPCA (A7, yellow arrow (note good preservation of superior cerebellar peduncle, shown with blue asterisk). Histological examination
reveals an α-synucleinopathy with pathological inclusions seen in both glial and neuronal cells. The morphology of glial cytoplasmic
inclusions is typical of MSA. Glial cytoplasmic inclusions are seen within pencil fibres of Wilson in the putamen (B1), pontine base
white matter (B2), the inferior olivary nucleus (B3) and the cerebellar white matter (B4). While on macroscopic examination, neither
striatonigral nor olivopontocerebellar regions show any apparent atrophy, on histological examination, the lateral part of the
posterior putamen shows mild gliosis and neuronal depletion (not shown). Therefore, the pathology corresponds best to minimal
change MSA with histological evidence of striatal (posterior putaminal) atrophy. Moderately severe hyaline arteriolosclerosis was also
seen in occasional blood vessels in the cerebral white matter and there was focal cerebral amyloid angiopathy in the occipital lobe
involving the occipital cortex and overlying leptomeninges (not shown). Scale bar: B1, 75 µm; B2 and B4, 300 µm; B3, 100 µm. AC,
anterior commissure; Cau, caudate nucleus; CC, corpus callosum; GP, globus pallidus; IC, internal capsule; MC, minimal change;
MSA, multiple system atrophy; OPCA, olivopontocerebellar; Put, putamen; SND, striatonigral.

Review
encephalopathy. Argyrophilic grain disease, primary neocortex, with characteristic emphasis in the frontal
age-related tauopathy and age-related tau astrogliop- lobe. The pattern of regional atrophy is more variable
athy are common pathologies seen in ageing brains in corticobasal degeneration but asymmetric focal
and are described below. Progressive supranuclear cortical atrophy and depigmentation of the substantia
palsy classically presents with Richardson’s syndrome, nigra are the most common findings. ‘Knife edge’
but other clinical phenotypes include parkinsonian atrophy localised to the frontal and temporal lobes
and cortical variants. Corticobasal degeneration can with an anteroposterior gradient is classically associ-
manifest as corticobasal syndrome, primary progres- ated with Pick’s disease. Chronic traumatic encepha-
sive aphasia and even Richardson’s syndrome, while lopathy is not associated with a distinct macroscopic
globular glial tauopathy presents with varying degrees atrophy pattern but there may be medial temporal lobe
of frontotemporal dementia (FTD) and upper motor atrophy and a cavum septum pellucidum is frequently
neurone features with or without parkinsonism. Pick’s present.
disease typically presents as behavioural variant FTD
(bvFTD) but rarely manifests as primary progressive Histological examination
aphasia or corticobasal syndrome.17 Chronic traumatic Despite the clinical overlap between these condi-
encephalopathy occurs in people with a history of tions, they can be distinguished by differences in
repetitive head impacts and is characterised by progres- the morphology (figure 5) and regional distribution
sive episodic memory and/or executive dysfunction, of tau pathology. Pick’s disease is characterised by
with or without neurobehavioral dysregulation.18 19 neuronal cytoplasmic inclusions known as Pick bodies
Mutations in the MAPT gene produce tauopathies that with fewer globular inclusions in glial cells, whereas
often have histological features that allow them to be progressive supranuclear palsy, corticobasal degen-
differentiated from the sporadic diseases mentioned eration and globular glial tauopathy are defined by
above. the morphology of their astrocytic tau inclusions. In
progressive supranuclear palsy, tau accumulates within
Macroscopic examination astrocytic cell bodies resulting in lesions known as

The typical macroscopic findings in progressive supra- tufted astrocytes, whereas tau accumulates in distal
nuclear palsy are atrophy and pallor of the substantia astrocytic processes in corticobasal degeneration
nigra, and atrophy of the subthalamic nucleus, leading to astrocytic plaques. Globular glial tauopathy
cerebellar dentate nucleus and superior cerebellar gets its name from the characteristic globular tau inclu-
peduncle. There may also be variable atrophy of the sions seen in astrocytes and oligodendrocytes. The
Figure 5 Morphology of cellular inclusions in various tauopathies. AGD, argyrophilic grain disease; ARTAG, age-related tau
astrogliopathy; CBD, corticobasal degeneration; FAs, fuzzy astrocytes; GGT, globular glial tauopathy; PiD, Pick's disease; PSP,
progressive supranuclear palsy; TSAs, thorn-shaped astrocytes; 3R, 3-repeat; 4R, 4-repeat.

Review
pathognomonic feature of chronic traumatic enceph- (MND) including amyotrophic lateral sclerosis, and
alopathy is the presence of neuronal and astrocytic primary lateral sclerosis, comprise the other major
tau pathology distributed around small blood vessels group of conditions associated with TDP43 pathology.
at the depths of cortical sulci, where the greatest There is considerable clinical overlap between
mechanical deformation is predicted to occur during FTLD-TDP43 and amyotrophic lateral sclerosis corre-
head impacts.20 Neuronal tau pathology also occurs in sponding to the distribution of TDP43 pathology.25
progressive supranuclear palsy, corticobasal degener- Specifically, about 15% of people with FTLD develop
ation, globular glial tauopathy and chronic traumatic MND, while executive dysfunction may occur in
encephalopathy in the form of neurofibrillary tangles 20–25% of amyotrophic lateral sclerosis cases and
and pretangles. Tauopathies can also be classified by non-executive cognitive impairment in 5–10%.26
the relative abundance of 3-repeat and 4-repeat tau
isoforms; progressive supranuclear palsy, cortico- Macroscopic examination
basal degeneration and globular glial tauopathy have The macroscopic findings in the MND spectrum disor-
a strong predominance of 4-repeat tau whereas Pick’s ders include atrophy of the motor cortex, spinal cord
disease neuronal inclusions mainly comprise 3-repeat and anterior spinal nerve roots, while macroscopic
tau. Mixed tauopathies include chronic traumatic examination of FTLD shows atrophy of the frontal
encephalopathy and AD, which have both 3- repeat and temporal regions, often accompanied by atrophy
and 4-repeat tau pathology.21 A classification scheme and pallor of the substantia nigra.
based on the electron cryo-microscopy structure of tau
filaments from the different tauopathies has also been Histological examination
proposed.22 On microscopic examination there is loss of Betz cells
in the motor cortex and neuronal loss and gliosis in the
Case 2 12th cranial nerve nucleus, anterior horns, and gliosis
An 84- year-
old man presented with confusion and in the corticospinal tracts in the brain and lateral
a 4–5 month history of reduced mobility.23 He had columns of the spinal cord.

symmetrical rigidity in the arms more than the legs, There is diffuse nuclear immunopositivity for
difficulty performing finger and foot tapping tasks, TDP43, an RNA/DNA- binding protein under phys-
and his gait was shuffling and unsteady. It was thought iological conditions. In pathogenic states, TDP43
that his cognitive symptoms were exacerbated by becomes hyperphosphorylated and ubiquitinated,
prochlorperazine, which had been started 2 months and is mislocalised from the nucleus to the cytoplasm
earlier for vertigo. He was diagnosed with DLB and where it forms inclusions (figure 7).24 Neuronal cyto-
rivastigmine was started. He subsequently developed plasmic inclusions dominate in both FTLD and MND
low mood with suicidal ideation, anxiety, headaches, cases, but there may also be rarer neuronal intranu-
pain and tingling in both feet and recurrent falls. clear and glial inclusions.27 FTLD-TDP43 is subdivided
There was also fluctuating cognition, disturbed sleep into five subtypes (type A–E) based on the patterns of
and physically aggressive behaviour. He died from his cytoplasmic or intranuclear pathology and the cortical
illness at the age of 86. At autopsy, there was no Lewy distribution.28 29 Type A, which typically presents as
pathology but rather there was tau pathology consis- progressive non-fluent aphasia or bvFTD, is character-
tent with chronic traumatic encephalopathy (figure 6). ised by numerous short dystrophic neurites, compact
The patient was a former professional association foot- or crescentic neuronal cytoplasmic inclusions and
ball player and was likely exposed to repetitive head neuronal intranuclear inclusions that concentrate in
impacts. Although neuropathological examination is layers II and III of the neocortex. Type B is the most
required to confirm the diagnosis, this case highlights frequent subtype seen in FTLD cases with MND and
the importance of seeking a history of repetitive head features compact neuronal cytoplasmic inclusions
impacts. Identifying such cases is crucial for deter- that are diffusely distributed throughout all cortical
mining genetic and environmental factors that may layers, with relatively few dystrophic neurites. Type C
predispose certain people to this potentially avoidable tends to cause semantic dementia and is characterised
condition. by long, thick dystrophic neurites seen in superficial
cortical layers and well-circumscribed neuronal cyto-
TDP43 proteinopathies plasmic inclusions in the hippocampus, amygdala and
Frontotemporal lobar degeneration (FTLD) is char- basal ganglia. Numerous neuronal intranuclear inclu-
acterised by alterations in behaviour/personality and sions occur in cortical and subcortical regions in Type
language dysfunction, with relative preservation of D, which is associated with the syndrome of inclusion
episodic memory. Clinically, it can be subdivided body myositis, Paget’s disease of bone and FTLD.
into bvFTD and primary progressive aphasia. TDP43 Finally, type E causes rapidly progressive FTD or
pathology underpins approximately 45% of FTLD MND with granulofilamentous neuronal cytoplasmic
cases, with various tauopathies being responsible for inclusions seen against a background of grain- like
most of the remaining cases.24 Motor neurone diseases TDP43 deposits in neocortical and subcortical regions.

Review
Figure 6 Macroscopic and microscopic findings in a case of chronic traumatic encephalopathy. There is mild global cerebral volume

loss with enlargement of the lateral ventricle (A1), marked atrophy of the hippocampus (B7) and severe pallor and neuronal loss in
the substantia nigra (B10 and B11). Immunohistological examination revealed widespread, irregularly distributed tau pathology in the
form of subpial, periventricular and perivascular thorn-shaped astrocytes, dense limbic neuronal and glial tau pathology and patchy
cortical neuropil thread, pretangle and tangle pathology particularly in the superficial cortical laminae as shown in the frontal cortex
(B1, B4 and B6). There are frequent thorn-shaped astrocytes arranged in an irregular and patchy manner in the cortex, including
around cortical blood vessels (B3, red asterisk), with some emphasis at the depths of cortical sulci (B1, blue arrowheads, and B2).
Subpial thorn-shaped astrocytes are seen in the neocortex (B5), midbrain (B13) and pons (not shown). Thorn-shaped astrocytes
are also present in the subependymal white matter adjacent to the lateral and fourth ventricles (not shown). Numerous pretangles
and occasional tangles are seen in the dentate gyrus (B9) and pretangles and tangles with proximal dendritic swellings are seen in
the CA4 region (B8). Occasional tangle, pretangle and thread pathology can also be seen in the substantia nigra (B12). Occasional
TDP43 immunoreactive neuronal cytoplasmic inclusions were present in the dentate gyrus (not shown). There was also widespread
amyloid-β pathology corresponding to Thal phase 5 (not shown). SFG: superior frontal gyrus; MFG: middle frontal gyrus; IFG: inferior
frontal gyrus; CC: corpus callosum; Cau: caudate nucleus; IC: internal capsule; Put: putamen; PHG: parahippocampal gyrus; FG:
fusiform gyrus; CA1-4: cornu Ammonis 1–4; CP: cerebral peduncle; MGN: medial geniculate nucleus; SN: substantia nigra; RN: red
nucleus; SC: superior colliculus. Scale bar: B1, 5 mm; B2, 940 µm; B3, 65 µm; B4, 750 µm; b5, 470 µm; B6, 570 µm; B7, 6 mm; B8 and
B9, 70 µm; B10, 6 mm; B11, 300 µm; B12, 70 µm; B13, 210 µm.
Mutations in the progranulin (GRN) and C9orf72 monoclonal antibody trial. Within 2 years, he devel-
genes can produce both type A and type B pathology, oped behavioural change with prominent aggression.
while p62 and valosin-containing protein (VCP) gene He died at the age of 73 years. Neuropathological
mutations can lead to type D pathology. No genetic examination revealed widespread TDP43 pathology in
substrate for type C and E pathology has been identi- keeping with Type A TDP43 proteinopathy. In addi-
fied to date. tion, there were diffuse TDP43 ‘star-like’ perinuclear
inclusions and widespread perinuclear p62 immuno-
Case
reactive inclusions, which outnumbered TDP43 inclu-
A 64-year-old man presented with episodic memory
sions in the dentate gyrus and cerebellar granule cells
problems, anomia and subtle semantic language defi-
cits. His mother was diagnosed with AD aged 72 but (figure 8). These histological features strongly suggest a
there was no other known family history of neuro- C9orf72 hexanucleotide repeat expansion, which was
logical disease. Neuropsychometric testing identified subsequently confirmed by genetic sequencing. FTLD
poor verbal recognition memory, impaired naming, is highly heritable with approximately 18% of FTD
reduced semantic fluency and impaired executive func- cases in one series having a monogenic cause.30 Genetic
tion. MR scan of his brain showed generalised volume causes of FTLD include mutations in MAPT (tauop-
loss that was more pronounced in both hippocampi. athies), GRN, VCP and C9orf72 repeat expansions
He was diagnosed with AD and enrolled in an Aβ (TDP43 proteinopathies). This case demonstrates how

Review

Figure 7 Morphology of cellular inclusions in TDP43 proteinopathies. TDP43, transactive DNA-binding protein 43.
recognising a distinctive pattern of pathology led to a Macroscopic examination

postmortem genetic diagnosis that was unsuspected in There may be some enlargement of the ventricles
life but had implications for the patient’s family. along with variable atrophy of the cortex and thalamus
and in genetic prion disease with predominant ataxia,
Prion diseases the cerebellar cortex shows marked atrophy. However,
Approximately 85–90% of prion diseases are sporadic, compared with other more protracted neurodegenera-
with the remaining familial cases caused by autosomal tive diseases, the degree of cerebral atrophy is typically
dominant mutations in the PRNP gene that encodes mild.
the PrPC protein.31 Fewer than 1% of cases are
acquired through iatrogenic transmission from PrPSc- Histological examination
contaminated surgical instruments, cadaveric trans- The hallmark of CJD is spongiform neuropil vacuo-
plant of dura mater tissue, medical treatment with lation across the grey matter regions. Definitive diag-
cadaver-derived growth hormone or dietary exposure nosis requires demonstration of the abnormal prion
to pathological bovine PrP through consumption of protein (referred to as PrPSc) in the brain or cerebro-
contaminated meat (bovine spongiform encephalop- spinal fluid. Depending on the codon 129 variant in
athy transmission to humans causing variant CJD) or PRNP and the abnormal prion protein conformation
ritual cannibalism (kuru).31 it may be distributed in a perineuronal or diffuse
Sporadic Creutzfeldt- Jakob disease, the most synaptic pattern, or as dense- core plaques in grey
common clinical manifestation of prion disease, typi- matter. Variant CJD may be distinguished by unique
cally presents as a rapidly progressive dementia vari- involvement of the lymphoreticular system and the
ably associated with ataxia, myoclonus, pyramidal presence of distinct misfolded prion protein aggre-
and extrapyramidal features. In most cases, death gates in the brain.
occurs within 1 year. Several atypical presentations are
recognised including the Heidenhain visual variant. Incidental and concomitant proteinopathies
Genetic cases due to mutations in the PRNP gene may Except for prion protein, variable amounts of the
present with ataxia (Gerstmann- Sträussler-
Scheinker other above-described misfolded proteins/peptide
syndrome) or sleep impairment and distal pain with or can develop in ageing brains and, in addition to the
without autonomic symptoms (familial fatal insomnia). primary pathology, most neurodegenerative cases will

Review
Figure 8 Macroscopic and microscopic findings in a case of FTLD-TDP Type A due to C9orf72 hexanucleotide repeat expansion.
There is severe atrophy of the hippocampus, reduction in bulk of the thalamus (A1, purple arrow), and less prominent atrophy of

the frontal lobe (A1). There was also prominent atrophy of the anterior temporal lobe with reduction in size of the amygdala, less
prominent atrophy of the parietal lobe, and reduction in bulk of the caudate nucleus and globus pallidus (not shown). Frequent
p62 immunoreactive perinuclear inclusions (green arrowheads) are seen in the superficial layers of frontal cortex (B1–2), dentate
gyrus of the hippocampus (B4–5) and in cerebellar granule cells (B7–8). Frequent short TDP43 immunoreactive neurites (B3, blue
arrowhead) were seen predominantly in the superficial cortex corresponding to layer 2. The cytoplasmic neuronal inclusions (B3 and
B6, red arrowheads) although seen in a pancortical distribution, showed emphasis in superficial cortical layers, in keeping with Type
A TDP43 proteinopathy. TDP43 and p62 pathology was also present in the parietal, lateral temporal and insular cortices, and in the
putamen and caudate nucleus (not shown). Importantly, the perinuclear, granular dot-like (also called ‘star’-like) p62 immunoreactive
inclusions (B2, B5 and B8, green arrowheads) were more frequent than TDP43 positive inclusions in the dentate gyrus (B6, red
arrowhead) and in the cerebellar granule cells where there are no pathological TDP43 immunoreactive aggregates (B9). These
histological features are highly suggestive of primary TDP43 proteinopathy due to a pathological C9orf72 hexanucleotide repeat
expansion, which was confirmed by genetic testing. There was also intermediate level Alzheimer’s disease pathological change, a
chronic cortical microinfarct (anterior medial temporal lobe), patchy cerebral cortical and leptomeningeal amyloid angiopathy and
moderate hyaline arteriolosclerosis with mild atheroma (not shown). Scale bar: B1, 5 mm; B2, B3, B5, B6, B8, B9, 25 µm; B4, 3 mm;
B7, 4 mm. FTLD, frontotemporal lobar degeneration; TDP43, transactive DNA-binding protein 43.
have varying amounts of one or more other misfolded Primary age-related tauopathy
protein pathologies of uncertain clinical relevance.32 Primary age- related tauopathy refers to neurofibril-
The prevalence of co- pathology increases with lary tangle pathology that is histologically and struc-
increasing age and may also be associated with APOE turally indistinguishable from that seen in AD but in
ɛ4 genotype.32 the absence of any significant amyloid-β pathology.35
Primary age- related tauopathy is largely restricted
Incidental Lewy body disease to the medial temporal lobes, basal forebrain, brain-
Community- based population studies indicate that stem, olfactory bulb and cortex.35 Compared with
the prevalence of incidental Lewy body disease ranges AD, primary age-related tauopathy cases tend to have
from 15% in those aged over 60 years to 40% in those considerably less tau pathology outside the medial
aged over 85 years.33 34 In two-thirds of these cases the temporal lobe, lower frequency of APOE ε4 risk allele,
pattern of Lewy pathology follows the typical caudal- higher frequency of the protective APOE ε2 allele and
rostral pattern while another one-third of cases have an less severe cognitive impairment.36
amygdala-predominant pattern, which is influenced by
the APOE ε4 genotype. Incidental Lewy body disease Age-related tau astrogliopathy
is associated with reduction in dopaminergic nigral Age-related tau astrogliopathy is a spectrum of astrog-
neurones and striatal dopamine levels suggesting that lial tau pathology mainly seen in people aged over
it may represent premotor PD.33 60.37 It may coexist with other primary tauopathies

Review
and is characterised by two distinct patterns of astro- CONCLUSION

cytic tau pathology, referred to as fuzzy/granular and Neuropathological examination not only remains the
thorn-shaped astrocytes, which can develop in grey gold standard for reaching a definitive diagnosis in most
and white matter regions. Thorn- shaped astrocyte neurodegenerative diseases, but it can also have important
pathology in particular can be observed in subpial implications for living relatives as well as wider public
and perivascular distributions and in isolation, closely health implications. New pathological entities requiring
mimics the astrocytic tau pathology seen in chronic further clinicopathological correlation continue to be
traumatic encephalopathy.37 In one series, thorn- described and with advances in molecular biology tech-
shaped astrocytes were identified in the frontotem- niques, neuropathological examination of tissue from
poroparietal subcortical white matter in the majority well-established conditions such as AD and PD remains
of pathologically-confirmed AD cases with primary as important as ever to facilitate high quality research into
progressive aphasia, suggesting that age- related tau the molecular mechanisms of these diseases and for the
astrogliopathy may be associated with this clinical
discovery and validation of tissue biomarkers.
variant of AD.38
Key points
Argyrophilic grain disease
Argyrophilic grain disease is characterised by the pres- ► Most neurodegenerative diseases are characterised
ence of small, grain- like inclusions that are within by misfolding of physiological proteins leading
neuronal dendrites and axons and contain abnormal to characteristic neuronal and glial inclusions or
4-repeat tau filaments. They are commonly seen in extracellular deposits that allow these conditions to be
the brains of older individuals, most frequently in the distinguished from each other on examination of brain
medial temporal lobes, but in advanced cases, they can tissues.
also extend to cortical and brainstem regions.39 Argy- ► There is considerable overlap in clinical phenotypes
rophilic grain disease is rarely the sole pathology in determined by the regional distribution of
those with neurological symptoms, rather it tends to neuropathology and neuronal loss.

coexist with other neurodegenerative diseases, partic- ► Despite advances in neuroimaging and fluid
ularly progressive supranuclear palsy and cortico- biomarkers, neuropathological examination of the
basal degeneration. In the context of AD, it has been brain remains the gold-standard diagnosis for many
suggested that coexisting argyrophilic grain disease neurodegenerative diseases.
may lower the threshold for AD pathology to mani- ► Subject to appropriate funding, brain banks
fest with clinical symptoms.40 As the sole pathology, enable research through careful curation of high-
argyrophilic grain disease may be responsible for mild quality central nervous system and peripheral
cognitive impairment, behavioural and psychiatric organ tissues and fluids from longitudinally
symptoms in older people and rarely, FTD.39 well-c haracterised donors with and without
neurodegenerative diseases.
Limbic-predominant age-related TDP43 encephalopathy ► Neuropathological examination of the brain is not
LATE neuropathological change (LATE- NC) refers only crucial to advance our understanding of the
to TDP43 pathology in older adults, with or without pathobiological basis of disease and to establish
hippocampal sclerosis, which, as the name implies, the diagnosis in clinically difficult cases, but may
typically shows emphasis in limbic regions, but in also yield unexpected findings, which may have
advanced cases can also extend into the frontal cortex. important implications for living relatives and
LATE-NC may affect 20–50% of people aged over 80 public health.
years. It can cause an amnestic syndrome that mimics
AD and is increasingly recognised as a source of
considerable morbidity in older adults.41 Further reading
► DeTure MA, Dickson DW. The neuropathological

DONOR REFERRAL
diagnosis of Alzheimer’s disease. Molecular
Patients who would like to find out more about brain
Neurodegeneration 2019;14:32. doi:10.1186/
donation should be referred to the nearest brain bank.
s13024-019-0333-5
Locations and contact details for brain banks in the UK,
► Surmeier DJ, Obeso JA, Halliday GM. Selective
as well as useful information for potential donors, can
neuronal vulnerability in Parkinson disease. Nat
be found online (https://brainbanknetwork.ac.uk/public/
Rev Neurosci 2017;18:101–13. doi:10.1038/
donating). Donations from people without symptoms of
nrn.2016.178
a neurodegenerative disease should also be encouraged
► Kovacs GG, Ghetti B, Goedert M. Classification
as there is a shortage of brain tissue from healthy control
of diseases with accumulation of Tau protein.
donors. Moreover, increasing diversity in terms of the
Neuropathology and Applied Neurobiology
sex and race of donors will be important to ensure that
2022;48:e12792. doi:10.1111/nan.12792
research is representative of the entire population.

Review
Twitter Jacy Bezerra Parmera @JacyParmera 9 Braak H, Braak E. Neuropathological stageing of Alzheimer-
Acknowledgements We thank the patients and their families related changes. Acta Neuropathol 1991;82:239–59.
without whose generous donation this study would not have 10 Hyman BT, Phelps CH, Beach TG, et al. National institute
been possible. We thank the Queen Square Brain Bank staff on aging–Alzheimer’s association guidelines for the
for their assistance with material preparation and Professor neuropathologic assessment of Alzheimer’s disease. Alzheimers
Sebastian Brandner for his assistance producing video 1. Dement 2012;8:1–13.
Figures 1, 2, 3, 5 and 7 and some of the schematics embedded 11 Kiely AP, Ling H, Asi YT, et al. Distinct clinical and
in video 1 were created with B ioRender.com. neuropathological features of G51D SNCA mutation cases
Contributors PWC and SW drafted the manuscript. JBP, FV, compared with SNCA duplication and H50Q mutation. Mol
TOM, KS, EDP-F, TTW and ZJ revised the manuscript and Neurodegener 2015;10:41.
provided important intellectual content. 12 Dickson DW. Parkinson’s disease and parkinsonism:
Funding The authors have not declared a specific grant for this neuropathology. Cold Spring Harb Perspect Med
research from any funding agency in the public, commercial or 2012;2:a009258.
not-for-profit sectors. 13 Ling H, Asi YT, Petrovic IN, et al. Minimal change
Competing interests None declared. multiple system atrophy: an aggressive variant Mov Disord
Patient consent for publication Consent obtained directly from 2015;30:960–7.
patient(s). 14 Braak H, Del Tredici K, Rüb U, et al. Staging of brain
Ethics approval Queen Square Brain Bank protocols have pathology related to sporadic Parkinson’s disease. Neurobiol
been approved by the NHS Health Research Authority, Ethics Aging 2003;24:197–211.
Committee London-Central (REC reference 18/LO/0721) and 15 Yang Y, Shi Y, Schweighauser M, et al. Structures of
informed consent was obtained for publication.
Α-synuclein filaments from human brains with Lewy
Provenance and peer review Commissioned; externally pathology. Nature 2022;610:791–5.
reviewed by Seth Love, Bristol, UK.
16 Jellinger KA. More frequent Lewy bodies but less frequent
Data availability statement No data are available. Alzheimer-type lesions in multiple system atrophy as
Supplemental material This content has been supplied by the compared to age-matched control brains. Acta Neuropathol
author(s). It has not been vetted by BMJ Publishing Group 2007;114:299–303.
Limited (BMJ) and may not have been peer-reviewed. Any
17 Irwin DJ, Brettschneider J, McMillan CT, et al. Deep clinical
opinions or recommendations discussed are solely those of

the author(s) and are not endorsed by BMJ. BMJ disclaims and neuropathological phenotyping of pick’s disease. Ann
all liability and responsibility arising from any reliance placed Neurol 2016;79:272–87.
on the content. Where the content includes any translated 18 Katz DI, Bernick C, Dodick DW, et al. National institute
material, BMJ does not warrant the accuracy and reliability of of neurological disorders and stroke consensus diagnostic
the translations (including but not limited to local regulations,
clinical guidelines, terminology, drug names and drug dosages), criteria for traumatic encephalopathy syndrome. Neurology
and is not responsible for any error and/or omissions arising 2021;96:848–63.
from translation and adaptation or otherwise. 19 McKee AC, Stern RA, Nowinski CJ, et al. The spectrum
of disease in chronic traumatic encephalopathy. Brain
ORCID iDs
Jacy Bezerra Parmera http://orcid.org/0000-0002-3565-5328 2013;136:43–64.
Eduardo De Pablo-Fernandez http://orcid.org/0000-0003- 20 Ghajari M, Hellyer PJ, Sharp DJ. Computational
2834-2515 modelling of traumatic brain injury predicts the location
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Pract Neurol: first published as 10.1136/pn-2023-003988 on 16 December 2023. Downloaded from http://pn.bmj.com/ on January 2, 2024 at Gr.T.

Popa University of Medicine and Pharmacy

► Additional supplemental ABSTRACT larger filaments before aggregating to form

of Iasi. Protected by copyright.

Cullinane PW, et al. Pract Neurol 2023;0:1–13. doi:10.1136/pn-2023-003988 1

of Iasi. Protected by copyright.

noting any surface lesions or gyral patterns of atrophy 3. α-synuclein.

2 Cullinane PW, et al. Pract Neurol 2023;0:1–13. doi:10.1136/pn-2023-003988

of Iasi. Protected by copyright.

Cullinane PW, et al. Pract Neurol 2023;0:1–13. doi:10.1136/pn-2023-003988 3

of Iasi. Protected by copyright.

4 Cullinane PW, et al. Pract Neurol 2023;0:1–13. doi:10.1136/pn-2023-003988

Cullinane PW, et al. Pract Neurol 2023;0:1–13. doi:10.1136/pn-2023-003988 5

of Iasi. Protected by copyright.

6 Cullinane PW, et al. Pract Neurol 2023;0:1–13. doi:10.1136/pn-2023-003988

of Iasi. Protected by copyright.

Cullinane PW, et al. Pract Neurol 2023;0:1–13. doi:10.1136/pn-2023-003988 7

of Iasi. Protected by copyright.

8 Cullinane PW, et al. Pract Neurol 2023;0:1–13. doi:10.1136/pn-2023-003988

of Iasi. Protected by copyright.

recognising a distinctive pattern of pathology led to a Macroscopic examination

Cullinane PW, et al. Pract Neurol 2023;0:1–13. doi:10.1136/pn-2023-003988 9

of Iasi. Protected by copyright.

10 Cullinane PW, et al. Pract Neurol 2023;0:1–13. doi:10.1136/pn-2023-003988

and is characterised by two distinct patterns of astro- CONCLUSION

of Iasi. Protected by copyright.

► DeTure MA, Dickson DW. The neuropathological

Cullinane PW, et al. Pract Neurol 2023;0:1–13. doi:10.1136/pn-2023-003988 11

of Iasi. Protected by copyright.

12 Cullinane PW, et al. Pract Neurol 2023;0:1–13. doi:10.1136/pn-2023-003988

of Iasi. Protected by copyright.

Cullinane PW, et al. Pract Neurol 2023;0:1–13. doi:10.1136/pn-2023-003988 13

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