RESEARCH PAPER

Hereditary leukoencephalopathy with axonal
spheroids: a spectrum of phenotypes from CNS
vasculitis to parkinsonism in an adult onset
leukodystrophy series
David S Lynch,1,2 Zane Jaunmuktane,3 Una-Marie Sheerin,1 Rahul Phadke,3
Sebastian Brandner,3 Ionnis Milonas,4 Andrew Dean,5 Nin Bajaj,6 Nuala McNicholas,7
Daniel Costello,7 Simon Cronin,7 Chris McGuigan,8 Martin Rossor,9 Nick Fox,9
Elaine Murphy,10 Jeremy Chataway,10 Henry Houlden1,11
▸ Additional material is
published online only. To view
please visit the journal online
(http://dx.doi.org/10.1136/
jnnp-2015-310788).
For numbered affiliations see
end of article.
Correspondence to
Dr David S Lynch, Department
of Molecular Neuroscience,
The National Hospital for
Neurology and Neurosurgery,
UCL Institute of Neurology,
Queen Square, London WC1N
3BG, UK;
david.lynch.13@ucl.ac.uk
Received 11 March 2015
Revised 31 March 2015
Accepted 6 April 2015
Published Online First
2 May 2015

ABSTRACT
Background Hereditary diffuse leukoencephalopathy
with neuroaxonal spheroids (HDLS) is a hereditary, adult
onset leukodystrophy which is characterised by the
presence of axonal loss, axonal spheroids and variably
present pigmented macrophages on pathological
examination. It most frequently presents in adulthood
with dementia and personality change. HDLS has
recently been found to be caused by mutations in the
colony stimulating factor-1 receptor (CSF1R) gene.
Methods In this study, we sequenced the CSF1R gene
in a cohort of 48 patients from the UK, Greece and
Ireland with adult onset leukodystrophy of unknown
cause.
Results Five pathogenic mutations were found,
including three novel mutations. The presentations
ranged from suspected central nervous system (CNS)
vasculitis to extrapyramidal to cognitive phenotypes. The
case histories and imaging are presented here, in
addition to neuropathological findings from two cases
with novel mutations.
Conclusion We estimate that CSF1R mutations
account for 10% of idiopathic adult onset
leukodystrophies and that genetic testing for CSF1R
mutations is essential in adult patients presenting with
undefined CNS vasculitis or a leukodystrophy with
prominent neuropsychiatric signs or dementia.

INTRODUCTION
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To cite: Lynch DS,
Jaunmuktane Z,
Sheerin U-M, et al. J Neurol
Neurosurg Psychiatry
2016;87:512–519.
512

Hereditary diffuse leukoencephalopathy with neuroaxonal spheroids (HDLS) is an autosomal dominant, adult onset leukodystrophy which typically
presents with early onset cognitive or personality
change. It is characterised by a distinct neuropathological appearance consisting of axonal loss in the
cerebral white matter, axonal spheroids and variably present pigmented microglia. In 2011, it was
discovered that heterozygous mutations in the
colony stimulating factor-1 receptor (CSF1R) gene
cause HDLS.1 In addition, it was shown that pigmented orthochromatic leukodystrophy (POLD) is
also caused by CSF1R mutations and that POLD
and HDLS exist on a spectrum.2 Previous studies
have estimated that CSF1R mutations account

between 10% and 25% of adult onset leukodystrophies, depending on the population studied.3 4
The clinical phenotype of patients with HDLS is
variable, but the most common symptoms include
cognitive decline, personality change and depression. Additional symptoms occur frequently and
include parkinsonism, spasticity and seizures.
Median age of onset is 45 years, although patients
with onset as young as 18 have been described.
Median life expectancy is 6 years but this is also
variable, and some patients have survived for up to
29 years after symptom onset.3 5
All mutations identified to date have been found
in the tyrosine kinase domain of the protein (exons
12–21) with exons 18, 19 and 20 containing the
majority of the mutations (see figure 1 and online
supplementary table S1). CSF1R is a cell surface
receptor that is highly expressed on cells of the
myeloid lineage including the microglia of the
central nervous system (CNS).6 It is activated by
the cytokines colony stimulating factor-1 (CSF1)
and interleukin-34. The receptor consists of an
extracellular ligand binding domain, a transmembrane domain and an intracellular tyrosine kinase
domain.6 Binding of CSF1 to the CSF1R receptor
results in receptor homodimerisation and the
autophosphorylation of a number of tyrosine residues in the intracellular domain. This is followed
by activation of several signalling pathways including Src,7 AKT, Erk and phospholipase C-γ.8 CSF1R
activation therefore regulates microglial survival,
proliferation and differentiation.

METHODS
Patients
Patients with adult onset (>16 years) leukodystrophy of unknown cause were recruited nonconsecutively from the National Hospital for
Neurology and Neurosurgery, London; University
College Cork, Ireland; St Vincent’s University
Hospital, Ireland; and Aristotle University of
Thessaloniki, Greece, as part of the inception
cohort of the adult onset leukodystrophy group
multidisciplinary clinical service.9 10 The main
inclusion criterion was MRI white matter abnormalities consistent with leukodystrophy, that is,

Lynch DS, et al. J Neurol Neurosurg Psychiatry 2016;87:512–519. doi:10.1136/jnnp-2015-310788

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Figure 1 Schematic representation of the colony stimulating factor-1 receptor (CSF1R) gene illustrating new and previously described mutations.

symmetric confluent T2 hyperintensity but excluding those with
asymmetric/atypical features more likely associated with small
vessel disease or multiple sclerosis. All patients had MRI and
routine biochemical (including very long chain fatty acids),
haematological, infectious and immune screening. Informed
consent was obtained for genetic research sequencing and the
project was carried out with institutional ethical approval from
all centres.

Genetic analysis
The CSF1R gene was sequenced in all 48 patients as follows.
The entire coding region of CSF1R was PCR-amplified using
flanking intronic primers ( primer sequences available on
request). The PCR product was purified and then sequenced in
both directions using Big Dye Terminator V.3.1 Cycle
Sequencing Kit (Applied Biosystems). Sequencing products were
purified and read on an ABI 3730 DNA Analyzer (Applied
Biosystems). Sequences were analysed using Seqscape V.3 software (Applied Biosystems). Variants are described with reference
to Ensembl Transcript ENST00000286301 of the CSF1R gene.
In silico prediction was performed using Polyphen-211 and
Provean.12

Neuropathological analysis
Formalin-fixed, paraffin-embedded tissue was cut to 4 mm thick
sections (14 mm for Luxol fast blue), mounted on glass slides and
stained with routine H&E, periodic acid-Schiff (PAS) and Luxol
fast blue/cresyl violet histochemical stains. Sections were examined
by immunohistochemistry with the following antibodies: glial
fibrillar acid protein (GFAP) ( polyclonal, 1:2500, Dako), phosphorylated neurofilaments (clone SMI31, 1:5000, Sternberg), neurofilament cocktail (clone 2F11, 1:500, Dako/Cappel), myelin
basic protein (clone SMI94, 1:2000, Sternberger), amyloid precursor protein (clone 22C11, 1:800, Chemicon/Millipore), amyloid-β
(clone 6F3D, 1:100, Dako), ubiquitin (polyclonal, 1:1200, Dako),

p62 (3/P62LCK Ligand, 1:100, BD Transduction), α-synuclein
(clone KM51, 1:50, Leica/Novocastra), hyperphosphorylated τ
(clone AT8, 1:1200, INNOGENETICS), TDP-43 (clone 2E2-D3,
1:3000, Abnova), CD68 (clone PG-M1, 1:100, Dako), CD3
(LN10, 1:100, Leica/Novocastra), CD20 (clone 7D1, 1:200,
Dako). Immunohistochemistry was carried out on a BondMax
autostainer (Leica Microsystems) using 3,3-diaminobenzidine as
chromogen. Appropriate positive controls were used for all immunohistochemical studies. Negative controls were treated identically
except that the primary antibody was omitted. Negative control
sections were examined for pigment deposits under bright light,
including assessment of digital negative image with total inversion
of the light (LEICA SCN400 scanner at ×40magnification and
65% image compression setting (LEICA UK)).

RESULTS
We sequenced the CSF1R gene in the 48 patients presenting
with adult onset leukodystrophy of unknown cause from the
UK, Greece and Ireland and identified five patients carrying
mutations in the gene (including 3 novel mutations), indicating
that CSF1R mutations account for approximately 10% of adult
onset leukodystrophies in our cohort. A summary of identified
mutations and clinical spectrum is given in table 1. Sequence
alignment and in silico pathogenicity predictions for the novel
V596M, A763P and E825K mutations are provided in online
supplementary figure S1. We did not identify any discriminating
clinical feature that could predict whether a CSF1R mutation
would be found (see online supplementary table S2 for a
summary of the negative cases).

Case 1
This patient had struggled at school with learning difficulties
and developed sensory symptoms in the limbs at age 25 years.
She was involved in a car accident at age 31 years, following
which she developed mild cognitive symptoms and executive

Lynch DS, et al. J Neurol Neurosurg Psychiatry 2016;87:512–519. doi:10.1136/jnnp-2015-310788

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Neurogenetics

5

4

3

AS, axonal spheroids; CSF1R, colony stimulating factor-1 receptor; DWI, diffusion weighted imaging; NA, not applicable; TCC, thinning of the corpus callosum; WML, white matter lesions.

NA
WML, cortical atrophy
Falls, cognitive decline
No

29

NA

Parkinsonism, apraxia, pyramidal signs

NA
WML, atrophy, TCC
Parkinsonism, apraxia
Depression
No

43

Alive

Apraxia, tremor
Ataxia, cognitive decline
Alive
Yes

42

Depression, personality change

c.2287G>A
p. A763P
c.2473G>A
p. E825K
c.2442+1
G>A
c.1987G>A
E633K
2

No

45

51

Parkinsonism, apraxia, seizures

WML, atrophy, TCC

Myelin/axonal loss in deep WM with
frequent AS and pigmented macrophages
NA

Subcortical AS and astrogliosis,
pigmented macrophages

WML, changing DWI
positivity
suggesting vasculitis
WML
Sensory symptoms, cognitive
decline
c.1786G>A
p. V596M
1

No

25

35

Supranuclear gaze palsy, seizures, pyramidal
signs

Neuropathology
MRI
Additional symptoms
Initial symptoms
Age at
death
Age at
onset
Family
history
Mutation
Case

Summary of the clinical characteristics and investigations of patients with CSF1R mutations
Table 1
514

dysfunction. By age 35 years, there was progressive immobility,
cognitive decline and urinary incontinence. Aged 36 years she
rapidly deteriorated over a 3-month period, with anarthria, loss
of mobility and worsening dementia. Her father had died of
motor neuron disease aged 65 years after an 18-month illness.
Her mother had been treated for alcoholism and was still alive
with a number of physical and cognitive problems.
Examination revealed a supranuclear gaze palsy and a brisk
jaw jerk. There was an asymmetric spastic quadriparesis
and left-sided inattention. She was abulic with a frontal
subcortical pattern of cognitive impairment. Mini-Mental State
Examination was 8/30.
Neuroimaging: The first MRI of the brain at age 31 years was
reported as showing an acute parietal infarct with restricted diffusion; however, subsequent imaging showed progressive extensive signal change with patches of restricted diffusion and
volume loss in the superficial and deep white matter with relative sparing of the subcortical U fibres (see figure 2). There was
disproportionate volume loss and T2-weighted hyperintensity of
the splenium of the corpus callosum extending to the posterior
limb of both internal capsules and corticospinal tracts at the
level of the mid brain. There was no abnormal contrast
enhancement and MR angiogram was normal. These imaging
findings were thought to be suspicious for cerebral vasculitis.
CSF examination, nerve conductions studies and echocardiogram were normal. EEG showed generalised background
slowing. A right frontal brain biopsy was performed to investigate the possibility of cerebral vasculitis.
Neuropathology (figure 3): Demonstrated well-preserved hexalaminar architecture of the neocortex with no obvious balloon
cells (figure 3A). The leptomeninges were unremarkable. In the
subcortical white matter, there were frequent eosinophilic
axonal swellings, which showed positive labelling for phosphorylated neurofilaments, p62, amyloid precursor protein,
amyloid-β (figure 3E, G–I) and ubiquitin. Sparse numbers of
PAS and CD68 positive pigmented cells were evident in the
white matter (figure 3F, K, L). Immunostaining for GFAP
revealed severe reactive stellate and chronic fibrillar astrogliosis
in the subcortical white matter and to a lesser extent in the
cortex (figure 3B). In spite of frequent axonal spheroids, myelin
pallor or significant reduction in density of axons were not
apparent (figure 3C, D). There were no α-synuclein (figure 3J),
TDP43 or hyperphosphorylated τ positive inclusions in the
cortex or white matter, and T lymphocytes and B lymphocytes
were very sparse.
The patient died suddenly of a massive pulmonary embolus
aged 36.
Genetic analysis: CSF1R sequencing revealed a novel heterozygous c.1786G>A mutation leading to a V596M substitution
in exon 13.

Case 2
This patient presented at age 47 years with a 2-year history of
depression and personality change, including increasing use of
illicit drugs. He made reckless financial decisions and became
violent at home. Progressive cognitive deterioration followed
and within 2 years of presentation he required long-term care.
He developed frequent generalised seizures following a right
frontal brain biopsy and gradually became mute and uncommunicative. There was no family history of similar illness.
On examination, there was upper limb apraxia and a parkinsonian gait with prominent freezing. Later examination findings
included severe rigidity in the left upper limb, a rest tremor and
stimulus-sensitive myoclonus. Eye movements were affected by
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Figure 2 FLAIR (A) and diffusion weighted imaging (DWI) (C) imaging of case 1 aged 34 years demonstrating restricted diffusion and FLAIR
hyperintensity in the right parietal lobe. At age 36 imaging findings had progressed as can be seen in FLAIR (B) and DWI (D) images. The number
of lesions showing restricted diffusion raised the possibility of central nervous system vasculitis. Case 2 imaged at age 48 shows extensive white
matter hyperintensities on FLAIR (E) and T2-weighted imaging (F and G). There is reduced fluorodeoxyglucose (FDG) uptake in the frontal and right
parietal lobes as seen in this FDG-positron emission tomography scan (H).
slow saccades, visual impersistance and a mild vertical supranuclear gaze palsy.
MRI demonstrated extensive symmetrical T2 high signal in
the cerebral white matter involving the frontal, parietal and posterior temporal lobes (figure 2). The lateral and third ventricles
were enlarged due to cerebral volume loss. A DaTscan was
normal and fluorodeoxyglucose/positron emission tomography
scan of the brain demonstrated reduced tracer uptake in the
frontal and right parietal lobes. There was no contrast enhancement or diffusion weighted imaging (DWI) positivity and
imaging appearances remained stable after 1 year.
Neuropathology (figure 4): A right frontal brain biopsy
revealed unremarkable leptomeninges and well-preserved
hexalaminar cytoarchitecture of the cortex (figure 4A).
Myelin pallor and axonal loss (figure 4C, D) were evident in the
deeper part of the white matter where frequent axonal spheroids and moderate numbers of pigmented cells were seen.
Axonal spheroids contained neurofilaments, amyloid precursor
protein and ubiquitin (figure 4E–G). Pigmented cells, which
showed yellow-brown colour of the cytoplasm on H&E stained
sections, showed positive labelling for CD68 (figure 4H).
Immunostainings for hyperphosphorylated τ and α-synuclein
were negative and amyloid-β immunoreactivity was restricted to
some of the axonal spheroids.
Genetic analysis: CSF1R sequencing demonstrated a novel
heterozygous c.2287G>A mutation resulting in an A763P substitution in exon 19.

Case 3
The patient developed symptoms at age 42 years. The first
symptom was impaired balance and unsteadiness when walking

and she was referred to a neurologist for investigation of ataxia.
Cognitive symptoms developed over the following 9 months
with disinhibition, abulia and short-term memory impairment.
Urinary incontinence also developed. There was a family history
of a similar illness. The patient’s mother died at age 42 years
with swallowing, memory and walking difficulties. Two maternal
uncles were similarly affected.
On examination, there was evidence of a global intellectual
decline, with frontal and subcortical predominance. There
was mild ideomotor and constructional apraxia. There was a
postural and action tremor in the limbs with bilateral
Gegenhalten.
Neuroimaging: MRI revealed gross white matter signal abnormality and cortical volume loss, more significant in the frontal
lobe with thinning of the corpus callosum. The lateral ventricles
were grossly dilated secondary to cerebral white matter loss.
Follow-up MRI 2 years later showed progression of the frontal
lobe white matter lesions. There was no contrast enhancement
or DWI-positive lesions.
Genetic analysis: CSF1R sequencing revealed a novel heterozygous c.2473G>A mutation causing an E825K substitution in
exon 19.

Case 4
This 45-year-old patient worked as a manager at a hotel and
presented with a 1–2-year history of depression and increasing
difficulty at work. They had become withdrawn and lost confidence in their ability to solve problems, resulting in being made
redundant. The family doctor treated the patient for depression
without success.

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Figure 3 Full thickness brain biopsy of case 1. The H&E stained section (A) shows frequent axonal swellings in the subcortical white matter
(inset). Immunostaining for glial fibrillar acid protein (B) reveals a severe chronic fibrillar and reactive stellate astrogliosis in the subcortical white
matter and in the cortex. Immunostaining for myelin basic protein with SMI94 antibody (C) and of axons with SMI31 antibody (D) reveals no
apparent myelin or axon loss. SMI31 immunoreactive axonal spheroids are frequent (E) while periodic acid-Schiff (PAS) positive pigmented glial cells
(F, red arrowhead) are sparse. Axonal spheroids are positive for p62 (G), amyloid precursor protein (H) and amyloid-β (I), and negative for
α-synuclein ( J). Occasional scattered PAS-positive cells in the white matter (K, red arrowhead) show positive labelling for the macrophage lysosome
marker CD68 (L). A negative control section (M) highlights the yellow-brown pigment in the cytoplasm of these monocyte-derived cells (brown
arrowheads), which appears blue in a negative—complete colour inversion image (N, blue arrowheads). Scale bar: 1 mm in A–D, 10 mm inset in A,
50 mm in E–F, 50 mm in G–N.

516

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Figure 4 Full thickness brain biopsy of case 2. The H&E stain (A), immunostaining for glial fibrillar acid protein (B), axons (neurofilament cocktail)
(C) and myelin (Luxol fast blue/cresyl violet) (D) shows a mild pallor of the myelin and reduction of axon density towards the deep white matter
(separated by a yellow dotted line in D) where frequent axonal spheroids are seen (inset in E). The axonal spheroids label with antibodies for
neurofilaments (E), amyloid precursor protein (F) and ubiquitin (G). Increased numbers of CD68 positive microglial cells are present in the deeper
white matter (H), which show yellow-light brown cytoplasm on H&E and negative control sections and appear blue when viewed as a negative
colour inversion image (insets in H). Scale bar: 1 mm in A–D, 5 mm in E–H, 10 mm insets in E and H.

On examination, there was upper limb apraxia and a
parkinsonian gait. Cognitive examination revealed significant
frontal lobe dysfunction and impaired short-term memory.
On examination of eye movements, pursuit was normal but
saccades were slow. There was no rigidity in the limbs, myoclonus or dystonia.
Neuroimaging: MRI revealed confluent, symmetrical T2
high signal in the frontal and parietal lobes. There was associated atrophy with ventricular dilation and thinning of the
corpus callosum. There was relative sparing of the peritrigonal regions. There was no contrast enhancement or
DWI-positive lesions. Follow-up imaging 1 year later was
unchanged.
Genetic analysis: CSF1R sequencing revealed a heterozygous
c.2442+1 G>A mutation at a splice site involving exon 18.
This mutation has previously been reported to cause HDLS.13
In addition, functional work has shown that mutations at this

splice site lead to three aberrant splice variants which exclude
exon 18.14

Case 5
This patient developed symptoms at the age of 29 years. Initial
symptoms included falls, short-term memory loss and brief,
epileptiform episodes with staring and non-responsiveness.
They suffered steady cognitive decline during the 30s and by
age 40 years was significantly dependent and incontinent with
frequent generalised seizures. There was no family history of a
similar illness.
On examination, the right upper limb was held in a flexed
dystonic posture with rigidity. Bilateral grasp reflexes and
rooting, suck and pout reflexes were present. Lower limb tone
was symmetrically increased with sustained clonus and bilateral
extensor plantar responses. There was bilateral tremor, bradykinaesia and a festinating gait.

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Neuroimaging: MRI showed predominantly anterior periventricular white matter hyperintensities and global cortical
atrophy. There was no contrast enhancement or DWI-positive
lesions. Follow-up imaging 1 year later was unchanged.
Genetic analysis: CSF1R sequencing revealed a heterozygous
c.1987G>A mutation causing an E633K substitution in exon
14. This mutation has been reported to cause HDLS previously
in a number of reports.13

individuals will help guide clinician discussions around prognostication, genetic risk in other family members and reproductive
counselling in families.
In addition, where a brain biopsy has been performed for a
suspected CNS vasculitis and a diagnosis not achieved, the
biopsy sample should be carefully examined for the presence of
axonal spheroids or pigmented glia and consideration given to
CSF1R gene sequencing.

DISCUSSION

Sharing of data and material in this report

CSF1R mutations are part of a small but growing list of
microglia-associated neurodegenerative diseases. While early
reports suggested that the mutations had a dominant-negative
effect, it has now been shown that CSF1R mutations are loss of
function. Mutant CSF1R is expressed on the cell surface and
can bind CSF1, form dimers and be internalised.15 Therefore,
heterozygous mutations result in a 75% reduction in active
CSF1/CSF1R dimers that can signal normally.
Appropriate CSF1R signalling may be essential not only for
CNS development, but also for the health of the fully developed
brain. Recently it was shown that microglia in the adult brain
are actively dependent on CSF1R signalling. Inhibition of signalling through CSF1R was found to lead to the rapid depletion
of almost all brain microglia via apoptosis, with repopulation
occurring when inhibition was withdrawn.16
The importance of microglia in maintaining a healthy CNS is
increasingly recognised. Interestingly, homozygous mutations in
TREM2, another microglial cell surface receptor, cause an early
onset dementia, Nasu-Hakola disease.17 Heterozygous variants
in TREM2 are also a significant risk factor for Alzheimer’s
disease (AD),18 and genome-wide association studies have linked
variants in the microglial receptors CD33 and IRF8 with AD
and multiple sclerosis, respectively.19 20 These findings clearly
point to the importance of microglia in the health of the CNS
and the need to further study how microglial dysfunction leads
to neuronal death.
In this study, we found that CSF1R mutations account for
approximately 10% of adult onset leukodystrophies in a mixed
cohort from the UK, Greece and Ireland. We identified a range
of phenotypes, with case 1 presenting with features suggesting a
CNS vasculitis; cases 2, 4 and 5 had early and late parkinsonian
features; and case 3 had a more classical cognitive phenotype.
There are at least 30 different leukodystrophies that can
present in adulthood, many of which have similar or even indistinguishable presentations making accurate diagnosis challenging.9 Presence of axonal spheroids, pigmented cells and white
matter degeneration in diagnostic brain biopsies is highly variable, subject to variable regional predilection for pathology, sampling bias and disease stage. Diagnostic brain biopsies should
ideally include full thickness of the cortex and underlying white
matter to reduce the sampling bias. In many cases, extensive
and expensive testing is required to make a diagnosis. Our study
confirms previous findings that CSF1R mutations are a relatively
common cause of adult onset leukodystrophy and that CSF1R
mutations can lead to diverse phenotypes and can mimic many
other neurological diseases, including CNS vasculitis.
As the phenotype of CSF1R mutations continues to be
refined, we recommend that patients who present with a possible CNS vasculitis or undiagnosed adult onset leukodystrophy
be screened early for mutations in CSF1R, and this should not
be limited to patients with typical neuropsychiatric or parkinsonian presentations. The early detection of a known pathogenic CSF1R mutation may negate the need for a brain biopsy
and its associated risks. Early genetic diagnosis in affected
518

Genetic data, DNA samples, control data and neuropathological
slides are open access for sharing with other research groups.
Author affiliations
1
Department of Molecular Neuroscience, The National Hospital for Neurology and
Neurosurgery, UCL Institute of Neurology, Queen Square, London, UK
2
The Leonard Wolfson Experimental Neurology Centre, The National Hospital for
Neurology and Neurosurgery, UCL Institute of Neurology, London UK
3
Division of Neuropathology and Department of Neurodegenerative Disease, The
National Hospital for Neurology and Neurosurgery, UCL Institute of Neurology,
Queen Square, London, UK
4
Aristotle University of Thessaloniki, Thessaloniki, Greece
5
Department of Neuropathology, Addenbrooke’s Hospital, Cambridge, UK
6
Department of Neurology, Queens Medical Centre, Nottingham, UK
7
Department of Neurology, Cork University Hospital, Wilton, Cork, Ireland
8
University College Dublin, St. Vincent’s University Hospital, Dublin, Ireland
9
Department of Neurodegeneration, Dementia Research Centre, London, UK
10
Department of Neuroinflammation, The National Hospital for Neurology and
Neurosurgery, UCL Institute of Neurology, Queen Square, London, UK
11
Neurogenetics Laboratory, The National Hospital for Neurology and Neurosurgery,
UCL Institute of Neurology, Queen Square, London, UK
Acknowledgements The authors would like to thank all the patients in this study
for their essential help with this work. This study was supported by the Medical
Research Council, The Leonard Wolfson Experimental Neurology Centre, The
Wellcome Trust and The Brain Research Trust (BRT). This study was also supported
by the National Institute for Health Research (NIHR), University College London
Hospitals (UCLH), Biomedical Research Centre (BRC) and the NIHR Queen Square
Dementia Biomedical Research Unit. NF and MR are NIHR senior investigators.
Contributors DSL, ZJ and UMS acquired the data, performed experiments and
drafted the manuscript. RP, SB, IM, AD, NB, NM, DC, SC, CM and MR contributed
to study design and acquisition of data. NF, EM, JC and HH were involved in data
interpretation and revised the manuscript for content. HH conceived of and
supervised the study. All authors approved the final version of the manuscript.
Funding The Leonard Wolfson Experimental Neurology Centre, University College
London Hospitals (UCLH), Biomedical Research Centre (BRC) and the NIHR Queen
Square Dementia Biomedical Research Unit.
Competing interests None declared.
Ethics approval National Research Ethics Service.
Provenance and peer review Not commissioned; externally peer reviewed.
Data sharing statement Genetic data, DNA samples, control data and
neuropathological slides are open access for sharing with other research groups.
Open Access This is an Open Access article distributed in accordance with the
terms of the Creative Commons Attribution (CC BY 4.0) license, which permits
others to distribute, remix, adapt and build upon this work, for commercial use,
provided the original work is properly cited. See: http://creativecommons.org/
licenses/by/4.0/

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