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Review
Pathology of neurodegenerative disease for the general neurologist
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  1. Patrick W Cullinane1,2,
  2. Sarah Wrigley1,2,
  3. Jacy Bezerra Parmera2,3,
  4. Fernanda Valerio4,
  5. Thomas O Millner4,
  6. Karen Shaw1,2,
  7. Eduardo De Pablo-Fernandez1,2,
  8. Thomas T Warner1,2,
  9. Zane Jaunmuktane1,2,4
  1. 1 Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London, UK
  2. 2 Queen Square Brain Bank for Neurological Disorders, UCL Queen Square Institute of Neurology, London, UK
  3. 3 Department of Neurology, Hospital das Clínicas, Universidade de São Paulo, São Paulo, Brazil
  4. 4 Division of Neuropathology, National Hospital for Neurology and Neurosurgery, University College London Hospitals NHS Foundation Trust, London, UK
  1. Correspondence to Dr Patrick W Cullinane, Queen Square Brain Bank for Neurological Disorders, UCL Queen Square Institute of Neurology, London, UK; patrick.cullinane.15{at}ucl.ac.uk; Dr Zane Jaunmuktane, Queen Square Brain Bank for Neurological Disorders, UCL Queen Square Institute of Neurology, London, UK; z.jaunmuktane{at}ucl.ac.uk

Abstract

Neurodegeneration refers to progressive dysfunction or loss of selectively vulnerable neurones from brain and spinal cord regions. Despite important advances in fluid and imaging biomarkers, the definitive diagnosis of most neurodegenerative diseases still relies on neuropathological examination. Not only has careful clinicopathological correlation shaped current clinical diagnostic criteria and informed our understanding of the natural history of neurodegenerative diseases, but it has also identified conditions with important public health implications, including variant Creutzfeldt-Jakob disease, iatrogenic amyloid-β and chronic traumatic encephalopathy. Neuropathological examination may also point to previously unsuspected genetic diagnoses with potential implications for living relatives. Moreover, detailed neuropathological assessment is crucial for research studies that rely on curated postmortem tissue to investigate the molecular mechanisms responsible for neurodegeneration and for biomarker discovery and validation. This review aims to elucidate the hallmark pathological features of neurodegenerative diseases commonly seen in general neurology clinics, such as Alzheimer’s disease and Parkinson’s disease; rare but well-known diseases, including progressive supranuclear palsy, corticobasal degeneration and multiple system atrophy and more recently described entities such as chronic traumatic encephalopathy and age-related tau astrogliopathy.

  • DEMENTIA
  • MOVEMENT DISORDERS
  • NEUROPATHOLOGY

Data availability statement

No data are available.

https://doi.org/10.1136/pn-2023-003988

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    Introduction

    Most adult-onset neurodegenerative diseases are considered proteinopathies because they are characterised by misfolding of native peptides and proteins such as amyloid-β (Aβ) peptide, tau, α-synuclein, transactive DNA-binding protein 43 (TDP43) and prion proteins, which then assemble into larger filaments before aggregating to form morphologically distinct cellular inclusions or extracellular parenchymal plaques (figure 1). More than 50 diseases are associated with misfolded protein pathology1 including well-established clinicopathological conditions such as Alzheimer’s disease (AD) and Parkinson’s disease (PD), as well as more recently identified neuropathological entities of uncertain clinical significance such as age-related tau astrogliopathy (ARTAG) and limbic-predominant age-related TDP43 encephalopathy (LATE). In most neurodegenerative diseases there is topographical spreading of misfolded protein pathology between synaptically-connected brain regions with different conformations of the same misfolded protein generally leading to specific patterns of regional and cellular vulnerability. Pathology may also develop in situ because of cell autonomous factors such as high metabolic demand and genetic risk factors (including possible somatic mutations) that render some neurones more susceptible to protein misfolding.2 Whatever the mechanism, the clinical features are generally determined by the anatomical distribution of neuropathology, meaning that similar clinical phenotypes may result from several different proteinopathies. Due to this phenotypic overlap, the accurate diagnosis of many neurodegenerative diseases in life is challenging and neuropathology remains the gold standard for diagnosis. Consequently, systematic brain banking and clinicopathological correlation have been the cornerstone of clinical diagnostic criteria for all the major neurodegenerative diseases.

    Figure 1
    Figure 1

    Formation of misfolded protein pathology and overview of pathological classification of neurodegenerative disease. TDP43, transactive DNA-binding protein 43.

    A practical guide to the neuropathological diagnosis of neurodegenerative diseases

    After weighing the brain, the process begins with macroscopic examination (online supplemental video 1), assessing the dura/leptomeninges and cerebral vasculature noting any surface lesions or gyral patterns of atrophy before the hemispheres are separated along the midline. In a brain bank setting, one hemisphere is typically fixed in formalin before sectioning and the other is dissected fresh and flash frozen. The formalin-fixed hemisphere is dissected by first removing the brainstem and cerebellum. The hemisphere is sliced coronally, the cerebellum is cut in the sagittal plane and the brainstem is sectioned transversely while looking for any focal or diffuse pathology, including any regional atrophy and depigmentation of the substantia nigra and locus coeruleus. Approximately 20 brain regions are routinely sampled for histological examination with additional regions included if indicated by the clinical history or macroscopic examination.

    Supplementary video

    Formalin-fixed paraffin embedded tissue sections are prepared from each region for histological examination. H&E is used for visualising the tissue cytoarchitecture, and distinguishing neuronal loss due to ischaemia or degeneration. It can also detect certain relevant proteinaceous structures such as extracellular amyloid plaques and intraneuronal Lewy bodies, although these are now better identified with specific antibodies by using immunohistochemistry. Proteins routinely tested by immunohistochemistry in neurodegenerative cases include:

    1. Aβ peptide.

    2. Tau.

    3. α-synuclein.

    4. TDP43.

    Other commonly used antibodies target ubiquitin and p62 proteins, which accumulate in diverse pathological inclusions and can be a clue to certain degenerative processes. Depending on the clinical scenario and initial histological findings, immunohistochemistry for other proteins such as prion (PrPSC) or fused in sarcoma (FUS) are performed. Pathological lesions detected on H&E and immunohistochemistry are classified based on their location (extracellular or intracellular), the cell types affected (neurones, astrocytes, oligodendrocytes), their morphology and regional distribution before the final neuropathological diagnosis is made in the context of the clinical history (figure 1).

    Established clinicopathological diseases

    Alzheimer’s disease

    AD is the most common neurodegenerative disease. It typically presents as an amnestic syndrome but less common phenotypes include posterior cortical atrophy, behavioural and dysexecutive syndromes, logopenic variant primary progressive aphasia and corticobasal syndrome.3 Although most cases of AD are sporadic, early onset (<65 years) AD comprises 5–10% of all cases, of whom 5–10% have an identifiable autosomal dominant mutation in the presenilin (PSEN1 and PSEN2) or amyloid precursor protein (APP) genes or APP duplication.4 The observation of high amounts of Aβ in the parenchyma and vasculature of patients who died from iatrogenic Creutzfeldt-Jakob disease several decades after receiving cadaver-derived human growth hormone treatment,5 has led to widespread recognition that iatrogenic transmission of Aβ neuropathology is also possible during surgical procedures involving contaminated dura mater grafts used in a wide range of medical interventions, or involving contaminated neurosurgical instruments.

    Macroscopic features

    In typical amnestic cases, cortical atrophy tends to be more pronounced in multimodal association cortices and medial temporal structures, particularly the amygdala and hippocampus, with relative sparing of the primary motor and somatosensory cortices.6 Loss of neuromelanin pigmentation in the locus coeruleus is also common.

    Histological features

    AD is a mixed proteinopathy because misfolded Aβ and tau pathology are found together in neuritic plaques (figure 2). Initially, extracellular Aβ plaques are diffuse but as they mature, they develop a dense central core. In line with the widely accepted amyloid-cascade hypothesis, dense core plaques initiate tau aggregation within surrounding dystrophic neurites culminating in the appearance of neuritic plaques. This hypothesis is based on the finding that mutations in the APP, PSEN1 or PSEN2 genes, which result in primary abnormalities of Aβ metabolism, can cause young-onset AD whereas mutations in the microtubule-associated protein tau (MAPT) gene responsible for primary tauopathies do not cause AD.7 Paramount for AD histological diagnosis is phosphorylated tau aggregation in neuronal bodies leading to the appearance of pretangles, which mature into neurofibrillary tangles, and following cell death remain as ghost tangles. Although Aβ may be responsible for the initiation of tau misfolding in AD, the degree of cortical atrophy and clinical features correlate with the density of tau pathology rather than that of Aβ.8 For most cases of AD, the topographical spread of neuropathology follows the model proposed by Braak and Braak, beginning in the medial temporal structures before extending into neocortical structures9 with the exceptions of rare limbic-predominant and hippocampal-sparing AD. Currently, the neuropathological diagnosis of AD is based on the National Institute on Aging-Alzheimer’s Association guidelines using semi-quantitative assessments of regional Aβ pathology (Thal phase), regional neurofibrillary tangle presence (Braak and Braak stage) and cortical neuritic plaque (CERAD score) density10 to indicate the likelihood of dementia being due to AD neuropathological change.

    Figure 2
    Figure 2

    Morphology of Alzheimer’s disease-related tau inclusions and Aβ plaques. Aβ, amyloid-β.

    Synucleinopathies

    The synucleinopathies can be divided into two pathological entities: (1) Lewy body disease and (2) multiple system atrophy (MSA). Lewy body disease comprises PD and dementia with Lewy bodies (DLB), which are akinetic–rigid syndromes classically separated by the timing of dementia onset, which may occur any time >1 year after the onset of motor symptoms in PD but occurs before or contemporaneously with motor symptoms in DLB. Despite this clinical distinction, PD and DLB likely represent the same clinicopathological continuum. MSA typically presents with autonomic failure and either cerebellar ataxia (MSA-C) or parkinsonism (MSA-P). While there are numerous monogenic causes (eg, SNCA, PRKN, PINK-1, DJ-1, VPS35 mutations) and susceptibility genes (LRRK2, GBA) associated with PD, MSA is largely a sporadic disease, although combined α-synucleinopathy comprising neuropathological features of both PD and MSA is characteristic of G51D mutations in the SNCA gene.11

    Macroscopic examination

    The macroscopic findings in PD and DLB are pallor and atrophy of the substantia nigra and locus coeruleus with variably prominent frontal and medial temporal lobe atrophy.12 In MSA, atrophy usually extends beyond the substantia nigra in olivopontocerebellar- (OPCA) or striatonigral- (SND) predominant patterns that broadly correspond to the MSA-C and MSA-P clinical subtypes, respectively. In rare cases, referred to as minimal change MSA, atrophy is limited to the substantia nigra despite more widespread misfolded α-synuclein pathology.13

    Histological examination

    PD and DLB are characterised by the accumulation of α-synuclein fibrils in the cytoplasm and processes of neurones forming Lewy bodies and Lewy neurites (figure 3). Lewy pathology tends to evolve in a stereotyped pattern described by Braak and colleagues with characteristic caudal–rostral propagation from the brainstem, through limbic regions to the neocortex.14 More recently, amygdala-predominant and olfactory-restricted patterns of Lewy pathology have been recognised. PD and DLB cannot be distinguished on an individual level at autopsy, consistent with the recent finding that the electron cryo-microscopy structures of α-synuclein filaments from patients with these conditions are identical.15 In MSA, α-synuclein aggregation characteristically occurs in both neurones and oligodendrocytes forming neuronal and glial cytoplasmic inclusions (figure 3). Inclusions also occur less frequently within the nuclei of glial cells and neurones. Lewy pathology may be present in 10–20% of MSA cases but the structure of α-synuclein filaments in MSA is distinct from that seen in PD/DLB.16

    Figure 3
    Figure 3

    Morphology of α-synuclein inclusions in Parkinson’s disease and multiple system atrophy.

    Case 1

    A 58-year-old man presented with a 1-year history of difficulty getting in and out of his bed and car, incomplete bladder emptying, poor stream, double voiding and hesitancy. Within a few months he developed a shuffling gait and a tendency to drag his left foot leading to several falls. This was followed by tremor of his left hand, hypophonia, constipation, erectile dysfunction, orthostatic lightheadedness and emotional lability. Examination identified normal eye movements, a mild resting tremor of the left hand with cogwheel rigidity and bradykinesia. He walked with a stooped posture, reduced arm swing and a shuffling gait. There was some improvement of his tremor with levodopa. Repeat examination 18 months into the illness showed mild dysarthria, ideomotor apraxia and impaired two-point discrimination and astereognosis affecting his left hand and apraxia of his left leg. There was further rapid progression over the next 6 months with increasing falls, ideomotor apraxia involving the right hand, dysphagia, symptoms suggestive of REM-sleep behaviour disorder, left-hand utilisation behaviour and alien limb, episodes of stridor and recurrent chest infections. He died at age 71 following a disease duration of 3.5 years and with a final clinical diagnosis of corticobasal syndrome. Neuropathological examination revealed widespread glial cytoplasmic inclusion and neuronal α-synuclein pathology consistent with a diagnosis of MSA (figure 4), which very rarely presents as a corticobasal syndrome. Despite the prominent cortical signs, there was no apparent macroscopic atrophy in any grey or white matter regions, in keeping with minimal change MSA, which is a rare subtype that may be associated with more rapid clinical progression.13

    Figure 4
    Figure 4

    Macroscopic and microscopic findings in a case of minimal change multiple system atrophy. Compared with the 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.

    Tauopathies

    The primary tauopathies comprise Pick’s disease, progressive supranuclear palsy, corticobasal degeneration, globular glial tauopathy and chronic traumatic encephalopathy. Argyrophilic grain disease, primary age-related tauopathy and age-related tau astrogliopathy are common pathologies seen in ageing brains and are described below. Progressive supranuclear palsy classically presents with Richardson’s syndrome, but other clinical phenotypes include parkinsonian and cortical variants. Corticobasal degeneration can manifest as corticobasal syndrome, primary progressive aphasia and even Richardson’s syndrome, while globular glial tauopathy presents with varying degrees of frontotemporal dementia (FTD) and upper motor neurone features with or without parkinsonism. Pick’s disease typically presents as behavioural variant FTD (bvFTD) but rarely manifests as primary progressive aphasia or corticobasal syndrome.17 Chronic traumatic encephalopathy occurs in people with a history of repetitive head impacts and is characterised by progressive episodic memory and/or executive dysfunction, with or without neurobehavioral dysregulation.18 19 Mutations in the MAPT gene produce tauopathies that often have histological features that allow them to be differentiated from the sporadic diseases mentioned above.

    Macroscopic examination

    The typical macroscopic findings in progressive supranuclear palsy are atrophy and pallor of the substantia nigra, and atrophy of the subthalamic nucleus, cerebellar dentate nucleus and superior cerebellar peduncle. There may also be variable atrophy of the neocortex, with characteristic emphasis in the frontal lobe. The pattern of regional atrophy is more variable in corticobasal degeneration but asymmetric focal cortical atrophy and depigmentation of the substantia nigra are the most common findings. ‘Knife edge’ atrophy localised to the frontal and temporal lobes with an anteroposterior gradient is classically associated with Pick’s disease. Chronic traumatic encephalopathy is not associated with a distinct macroscopic atrophy pattern but there may be medial temporal lobe atrophy and a cavum septum pellucidum is frequently present.

    Histological examination

    Despite the clinical overlap between these conditions, they can be distinguished by differences in the morphology (figure 5) and regional distribution of tau pathology. Pick’s disease is characterised by neuronal cytoplasmic inclusions known as Pick bodies with fewer globular inclusions in glial cells, whereas progressive supranuclear palsy, corticobasal degeneration and globular glial tauopathy are defined by the morphology of their astrocytic tau inclusions. In progressive supranuclear palsy, tau accumulates within astrocytic cell bodies resulting in lesions known as tufted astrocytes, whereas tau accumulates in distal astrocytic processes in corticobasal degeneration leading to astrocytic plaques. Globular glial tauopathy gets its name from the characteristic globular tau inclusions seen in astrocytes and oligodendrocytes. The pathognomonic feature of chronic traumatic encephalopathy is the presence of neuronal and astrocytic tau pathology distributed around small blood vessels at the depths of cortical sulci, where the greatest mechanical deformation is predicted to occur during head impacts.20 Neuronal tau pathology also occurs in progressive supranuclear palsy, corticobasal degeneration, globular glial tauopathy and chronic traumatic encephalopathy in the form of neurofibrillary tangles and pretangles. Tauopathies can also be classified by the relative abundance of 3-repeat and 4-repeat tau isoforms; progressive supranuclear palsy, corticobasal degeneration and globular glial tauopathy have a strong predominance of 4-repeat tau whereas Pick’s disease neuronal inclusions mainly comprise 3-repeat tau. Mixed tauopathies include chronic traumatic encephalopathy and AD, which have both 3-repeat and 4-repeat tau pathology.21 A classification scheme based on the electron cryo-microscopy structure of tau filaments from the different tauopathies has also been proposed.22

    Figure 5
    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.

    Case 2

    An 84-year-old man presented with confusion and a 4–5 month history of reduced mobility.23 He had symmetrical rigidity in the arms more than the legs, difficulty performing finger and foot tapping tasks, and his gait was shuffling and unsteady. It was thought that his cognitive symptoms were exacerbated by prochlorperazine, which had been started 2 months earlier for vertigo. He was diagnosed with DLB and rivastigmine was started. He subsequently developed low mood with suicidal ideation, anxiety, headaches, pain and tingling in both feet and recurrent falls. There was also fluctuating cognition, disturbed sleep and physically aggressive behaviour. He died from his illness at the age of 86. At autopsy, there was no Lewy pathology but rather there was tau pathology consistent with chronic traumatic encephalopathy (figure 6). The patient was a former professional association football player and was likely exposed to repetitive head impacts. Although neuropathological examination is required to confirm the diagnosis, this case highlights the importance of seeking a history of repetitive head impacts. Identifying such cases is crucial for determining genetic and environmental factors that may predispose certain people to this potentially avoidable condition.

    Figure 6
    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.

    TDP43 proteinopathies

    Frontotemporal lobar degeneration (FTLD) is characterised by alterations in behaviour/personality and language dysfunction, with relative preservation of episodic memory. Clinically, it can be subdivided into bvFTD and primary progressive aphasia. TDP43 pathology underpins approximately 45% of FTLD cases, with various tauopathies being responsible for most of the remaining cases.24 Motor neurone diseases (MND) including amyotrophic lateral sclerosis and primary lateral sclerosis, comprise the other major group of conditions associated with TDP43 pathology. There is considerable clinical overlap between FTLD-TDP43 and amyotrophic lateral sclerosis corresponding to the distribution of TDP43 pathology.25 Specifically, about 15% of people with FTLD develop MND, while executive dysfunction may occur in 20–25% of amyotrophic lateral sclerosis cases and non-executive cognitive impairment in 5–10%.26

    Macroscopic examination

    The macroscopic findings in the MND spectrum disorders include atrophy of the motor cortex, spinal cord and anterior spinal nerve roots, while macroscopic examination of FTLD shows atrophy of the frontal and temporal regions, often accompanied by atrophy and pallor of the substantia nigra.

    Histological examination

    On microscopic examination there is loss of Betz cells in the motor cortex and neuronal loss and gliosis in the 12th cranial nerve nucleus, anterior horns, and gliosis in the corticospinal tracts in the brain and lateral columns of the spinal cord.

    There is diffuse nuclear immunopositivity for TDP43, an RNA/DNA-binding protein under physiological conditions. In pathogenic states, TDP43 becomes hyperphosphorylated and ubiquitinated, and is mislocalised from the nucleus to the cytoplasm where it forms inclusions (figure 7).24 Neuronal cytoplasmic inclusions dominate in both FTLD and MND cases, but there may also be rarer neuronal intranuclear and glial inclusions.27 FTLD-TDP43 is subdivided into five subtypes (type A–E) based on the patterns of cytoplasmic or intranuclear pathology and the cortical distribution.28 29 Type A, which typically presents as progressive non-fluent aphasia or bvFTD, is characterised by numerous short dystrophic neurites, compact or crescentic neuronal cytoplasmic inclusions and neuronal intranuclear inclusions that concentrate in layers II and III of the neocortex. Type B is the most frequent subtype seen in FTLD cases with MND and features compact neuronal cytoplasmic inclusions that are diffusely distributed throughout all cortical layers, with relatively few dystrophic neurites. Type C tends to cause semantic dementia and is characterised by long, thick dystrophic neurites seen in superficial cortical layers and well-circumscribed neuronal cytoplasmic inclusions in the hippocampus, amygdala and basal ganglia. Numerous neuronal intranuclear inclusions occur in cortical and subcortical regions in Type D, which is associated with the syndrome of inclusion body myositis, Paget’s disease of bone and FTLD. Finally, type E causes rapidly progressive FTD or MND with granulofilamentous neuronal cytoplasmic inclusions seen against a background of grain-like TDP43 deposits in neocortical and subcortical regions. Mutations in the progranulin (GRN) and C9orf72 genes can produce both type A and type B pathology, while p62 and valosin-containing protein (VCP) gene mutations can lead to type D pathology. No genetic substrate for type C and E pathology has been identified to date.

    Figure 7
    Figure 7

    Morphology of cellular inclusions in TDP43 proteinopathies. TDP43, transactive DNA-binding protein 43.

    Case 3

    A 64-year-old man presented with episodic memory problems, anomia and subtle semantic language deficits. His mother had been diagnosed with AD aged 72 but there was no other known family history of neurological disease. Neuropsychometric testing identified poor verbal recognition memory, impaired naming, reduced semantic fluency and impaired executive function. MR scan of his brain showed generalised volume loss that was more pronounced in both hippocampi. He was diagnosed with AD and enrolled in an Aβ monoclonal antibody trial. Within 2 years, he developed behavioural change with prominent aggression. He died at the age of 73 years. Neuropathological examination revealed widespread TDP43 pathology in keeping with Type A TDP43 proteinopathy. In addition, there were diffuse TDP43 ‘star-like’ perinuclear inclusions and widespread perinuclear p62 immunoreactive inclusions, which outnumbered TDP43 inclusions in the dentate gyrus and cerebellar granule cells (figure 8). These histological features strongly suggest a C9orf72 hexanucleotide repeat expansion, which was subsequently confirmed by genetic sequencing. FTLD is highly heritable with approximately 18% of FTD cases in one series having a monogenic cause.30 Genetic causes of FTLD include mutations in MAPT (tauopathies), GRN, VCP and C9orf72 repeat expansions (TDP43 proteinopathies). This case demonstrates how recognising a distinctive pattern of pathology led to a postmortem genetic diagnosis that was unsuspected in life but had implications for the patient’s family.

    Figure 8
    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.

    Prion diseases

    Approximately 85–90% of prion diseases are sporadic, with the remaining familial cases caused by autosomal dominant mutations in the PRNP gene that encodes the PrPC protein.31 Fewer than 1% of cases are acquired through iatrogenic transmission from PrPSc-contaminated surgical instruments, cadaveric transplant of dura mater tissue, medical treatment with cadaver-derived growth hormone or dietary exposure to pathological bovine PrP through consumption of contaminated meat (bovine spongiform encephalopathy transmission to humans causing variant CJD) or ritual cannibalism (kuru).31

    Sporadic Creutzfeldt-Jakob disease, the most common clinical manifestation of prion disease, typically presents as a rapidly progressive dementia variably associated with ataxia, myoclonus, pyramidal and extrapyramidal features. In most cases, death occurs within 1 year. Several atypical presentations are recognised including the Heidenhain visual variant. Genetic cases due to mutations in the PRNP gene may present with ataxia (Gerstmann-Sträussler-Scheinker syndrome) or sleep impairment and distal pain with or without autonomic symptoms (familial fatal insomnia).

    Macroscopic examination

    There may be some enlargement of the ventricles along with variable atrophy of the cortex and thalamus and in genetic prion disease with predominant ataxia, the cerebellar cortex shows marked atrophy. However, compared with other more protracted neurodegenerative diseases, the degree of cerebral atrophy is typically mild.

    Histological examination

    The hallmark of CJD is spongiform neuropil vacuolation across the grey matter regions. Definitive diagnosis requires demonstration of the abnormal prion protein (referred to as PrPSc) in the brain or cerebrospinal fluid. Depending on the codon 129 variant in PRNP and the abnormal prion protein conformation it may be distributed in a perineuronal or diffuse synaptic pattern, or as dense-core plaques in grey matter. Variant CJD may be distinguished by unique involvement of the lymphoreticular system and the presence of distinct misfolded prion protein aggregates in the brain.

    Incidental and concomitant proteinopathies

    Except for prion protein, variable amounts of the other above-described misfolded proteins/peptide can develop in ageing brains and, in addition to the primary pathology, most neurodegenerative cases will have varying amounts of one or more other misfolded protein pathologies of uncertain clinical relevance.32 The prevalence of co-pathology increases with increasing age and may also be associated with APOE ɛ4 genotype.32

    Incidental Lewy body disease

    Community-based population studies indicate that the prevalence of incidental Lewy body disease ranges from 15% in those aged over 60 years to 40% in those aged over 85 years.33 34 In two-thirds of these cases the pattern of Lewy pathology follows the typical caudal-rostral pattern while another one-third of cases have an amygdala-predominant pattern, which is influenced by the APOE ε4 genotype. Incidental Lewy body disease is associated with reduction in dopaminergic nigral neurones and striatal dopamine levels suggesting that it may represent premotor PD.33

    Primary age-related tauopathy

    Primary age-related tauopathy refers to neurofibrillary tangle pathology that is histologically and structurally indistinguishable from that seen in AD but in the absence of any significant amyloid-β pathology.35 Primary age-related tauopathy is largely restricted to the medial temporal lobes, basal forebrain, brainstem, olfactory bulb and cortex.35 Compared with AD, primary age-related tauopathy cases tend to have considerably less tau pathology outside the medial temporal lobe, lower frequency of APOE ε4 risk allele, higher frequency of the protective APOE ε2 allele and less severe cognitive impairment.36

    Age-related tau astrogliopathy

    Age-related tau astrogliopathy is a spectrum of astroglial tau pathology mainly seen in people aged over 60.37 It may coexist with other primary tauopathies and is characterised by two distinct patterns of astrocytic tau pathology, referred to as fuzzy/granular and thorn-shaped astrocytes, which can develop in grey and white matter regions. Thorn-shaped astrocyte pathology in particular can be observed in subpial and perivascular distributions and in isolation, closely mimics the astrocytic tau pathology seen in chronic traumatic encephalopathy.37 In one series, thorn-shaped astrocytes were identified in the frontotemporoparietal subcortical white matter in the majority of pathologically-confirmed AD cases with primary progressive aphasia, suggesting that age-related tau astrogliopathy may be associated with this clinical variant of AD.38

    Argyrophilic grain disease

    Argyrophilic grain disease is characterised by the presence of small, grain-like inclusions that are within neuronal dendrites and axons and contain abnormal 4-repeat tau filaments. They are commonly seen in the brains of older individuals, most frequently in the medial temporal lobes, but in advanced cases, they can also extend to cortical and brainstem regions.39 Argyrophilic grain disease is rarely the sole pathology in those with neurological symptoms, rather it tends to coexist with other neurodegenerative diseases, particularly progressive supranuclear palsy and corticobasal degeneration. In the context of AD, it has been suggested that coexisting argyrophilic grain disease may lower the threshold for AD pathology to manifest with clinical symptoms.40 As the sole pathology, argyrophilic grain disease may be responsible for mild cognitive impairment, behavioural and psychiatric symptoms in older people and rarely, FTD.39

    Limbic-predominant age-related TDP43 encephalopathy

    LATE neuropathological change (LATE-NC) refers to TDP43 pathology in older adults, with or without hippocampal sclerosis, which, as the name implies, typically shows emphasis in limbic regions, but in advanced cases can also extend into the frontal cortex. LATE-NC may affect 20–50% of people aged over 80 years. It can cause an amnestic syndrome that mimics AD and is increasingly recognised as a source of considerable morbidity in older adults.41

    Donor referral

    Patients who would like to find out more about brain donation should be referred to the nearest brain bank. Locations and contact details for brain banks in the UK, as well as useful information for potential donors, can be found online (https://brainbanknetwork.ac.uk/public/donating). Donations from people without symptoms of a neurodegenerative disease should also be encouraged as there is a shortage of brain tissue from healthy control donors. Moreover, increasing diversity in terms of the sex and race of donors will be important to ensure that research is representative of the entire population.

    Conclusion

    Neuropathological examination not only remains the gold standard for reaching a definitive diagnosis in most neurodegenerative diseases, but it can also have important implications for living relatives as well as wider public health implications. New pathological entities requiring further clinicopathological correlation continue to be described and with advances in molecular biology techniques, neuropathological examination of tissue from well-established conditions such as AD and PD remains as important as ever to facilitate high quality research into the molecular mechanisms of these diseases and for the discovery and validation of tissue biomarkers.

    Key points

    • Most neurodegenerative diseases are characterised by misfolding of physiological proteins leading to characteristic neuronal and glial inclusions or extracellular deposits that allow these conditions to be distinguished from each other on examination of brain tissues.

    • There is considerable overlap in clinical phenotypes determined by the regional distribution of neuropathology and neuronal loss.

    • Despite advances in neuroimaging and fluid biomarkers, neuropathological examination of the brain remains the gold-standard diagnosis for many neurodegenerative diseases.

    • Subject to appropriate funding, brain banks enable research through careful curation of high-quality central nervous system and peripheral organ tissues and fluids from longitudinally well-characterised donors with and without neurodegenerative diseases.

    • Neuropathological examination of the brain is not only crucial to advance our understanding of the pathobiological basis of disease and to establish the diagnosis in clinically difficult cases, but may also yield unexpected findings, which may have important implications for living relatives and public health.

    Further reading

    • DeTure MA, Dickson DW. The neuropathological diagnosis of Alzheimer’s disease. Molecular Neurodegeneration 2019;14:32. doi:10.1186/s13024-019-0333-5

    • Surmeier DJ, Obeso JA, Halliday GM. Selective neuronal vulnerability in Parkinson disease. Nat Rev Neurosci 2017;18:101–13. doi:10.1038/nrn.2016.178

    • Kovacs GG, Ghetti B, Goedert M. Classification of diseases with accumulation of Tau protein. Neuropathology and Applied Neurobiology 2022;48:e12792. doi:10.1111/nan.12792

    Supplemental material

    Data availability statement

    No data are available.

    Ethics statements

    Patient consent for publication

    Ethics approval

    Queen Square Brain Bank protocols have been approved by the NHS Health Research Authority, Ethics Committee London-Central (REC reference 18/LO/0721) and informed consent was obtained for publication.

    Acknowledgments

    We thank the patients and their families without whose generous donation this study would not have been possible. We thank the Queen Square Brain Bank staff for their assistance with material preparation and Professor Sebastian Brandner for his assistance producing video 1. Figures 1, 2, 3, 5 and 7 and some of the schematics embedded in video 1 were created with BioRender.com.

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    Supplementary materials

    • Supplementary Data

      This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.

    Footnotes

    • Twitter @JacyParmera

    • Contributors PWC and SW drafted the manuscript. JBP, FV, TOM, KS, EDP-F, TTW and ZJ revised the manuscript and provided important intellectual content.

    • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

    • Competing interests None declared.

    • Provenance and peer review Commissioned; externally reviewed by Seth Love, Bristol, UK.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

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