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Rinnakkaistallenteet Terveystieteiden tiedekunta
2019
Prevalence of C9ORF72 Expansion in a Large Series of Patients with
Idiopathic Normal-Pressure Hydrocephalus
Korhonen, VE
S. Karger AG
Tieteelliset aikakauslehtiartikkelit
© S. Karger AG All rights reserved
http://dx.doi.org/10.1159/000497306
https://erepo.uef.fi/handle/123456789/7919
Downloaded from University of Eastern Finland's eRepository
Prevalence of the C9ORF72 expansion in a large series of patients with
1
idiopathic normal pressure hydrocephalus
2
Korhonen VEa*, Remes AMb,c,d,e, Helisalmi Sb, Rauramaa Tf ,Sutela Ag, Vanninen Rg, Suhonen NMc, e, 3
Haapasalo Ah, Hiltunen Mi, Jääskeläinen Ja, Soininen Hb, Koivisto AMb,d and Leinonen Va 4
5
a Department of Neurosurgery, Kuopio University Hospital and University of Eastern Finland, 6
Kuopio, Finland 7
b Institute of Clinical Medicine - Neurology, University of Eastern Finland, Kuopio, Finland.
8
c Medical Research Center, Oulu University Hospital, Oulu, Finland 9
d Department of Neurology, Kuopio University Hospital, Kuopio, Finland 10
e Unit of Clinical Neuroscience, Neurology, University of Oulu, Oulu, Finland 11
f Institute of Clinical Medicine - Pathology, School of Medicine, University of Eastern Finland and 12
Department of Pathology, Kuopio University Hospital, Kuopio, Finland.
13
g Department of Radiology, Kuopio University Hospital and University of Eastern Finland, Kuopio, 14
Finland 15
hA.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland 16
i Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland 17
*Corresponding author 18
Keywords: C9ORF72, FTLD, iNPH, 19
Running title: The C9ORF72 and idiopathic normal pressure hydrocephalus 20
Funding: The study was supported by research grants from the Academy of Finland, the Kuopio 21
University Hospital VTR Fund (5252614), Sigrid Juselius Foundation, the Finnish Medical 22
Foundation, Olvi Foundation, Kuopio University Hospital Research Foundation, Emil Aaltonen 23
Foundation, and the Finnish cultural foundation – North-Savonia regional Fund.
24
Acknowledgements: We wish to acknowledge BLS Marjo Laitinen for her expert assistance with 25
the laboratory analysis, RN Marita Parviainen for her kind technical assistance, Anna M. Järvinen, 26
PhD, for editing the English language, Tiina Suominen, PhD (University of Tampere) and prof.
27
Bjarne Udd (University of Tampere) for verifying the genotyping results.
28
29
Abstract:
30
Background: The C9ORF72 expansion is so far known to cause frontotemporal lobar degeneration 31
(FTLD) and amyotrophic lateral sclerosis (ALS). Objective: To identify the prevalence of the 32
C9ORF72 expansion in idiopathic normal pressure hydrocephalus (iNPH) Methods: We analysed 33
the C9ORF72 expansion in a large cohort of patients with possible iNPH (n=487) and cognitively 34
intact elderly controls (n=432; age > 65 years). Results: While the C9ORF72 expansion was 35
detected in 1.6 % (n=8/487) of cases with possible iNPH, no control subject was found to carry the 36
mutation. The mean age at onset of symptoms of C9ORF72 expansion carriers was 59 years (range:
37
52-67 years), 11 years less than non-carriers (p=0.0002). The most frequent initial/main symptom 38
pertained to gait difficulties. Despite identified mutation only three of the patients fulfilled the 39
criteria for behavioral variant frontotemporal dementia (bvFTD). Clinically significant shunt 40
response was detected in 6 out of 7 shunted C9ORF72 expansion carriers. However, the shunt 41
response showed a tendency towards diminishing during the follow-up period (mean 7.4 years).
42
Conclusion: This is the first study cohort identifying the underlying C9ORF72 expansion in 43
patients with possible iNPH providing evidence for the potential comorbidity between iNPH and 44
bvFTD. Further characterization of the C9ORF72 expansion in iNPH cohorts may enlight the 45
potential shared mechanisms underpinning iNPH and FTLD-ALS spectrum. FTLD should be 46
considered as a differential diagnostic possibility in iNPH. Analysis of the C9ORF72 expansion 47
should be considered for patients with probable iNPH presenting with frontal atrophy and 48
personality changes or other severe psychiatric symptoms.
49
Running title: Prevalence of C9ORF72 expansion in iNPH 50
Keywords: Behavioural variant Frontotemporal Dementia, C9ORF72, Dementia, FTLD, Idiopathic 51
Normal Pressure Hydrocephalus 52
53 54 55 56 57 58 59
Introduction
60 61
Idiopathic normal pressure hydrocephalus (iNPH) and frontotemporal lobar degeneration (FTLD) 62
are neurodegenerative diseases presenting with overlapping clinical features. INPH is characterized 63
by a triad of core symptoms, namely gait difficulties, cognitive impairment, and urinary 64
incontinence. The symptoms are progressive in nature, and patients may express the triad only 65
partially or fully 1,2. In iNPH, ventricular enlargement comprises a key radiological finding 66
alongside the observable characteristic clinical symptoms 3,4 and the observed cognitive impairment 67
is usually characterized by psychomotor slowness, impairment in frontal executive functions, as 68
well as other symptoms reflecting frontal-subcortical dysfunction 1,4,5. By contrast, FTLD is a 69
clinically heterogeneous group of syndromes that includes behavioural variant frontotemporal 70
dementia (bvFTD), semantic variant primary progressive aphasia (svPPA), and non-fluent variant 71
primary progressive aphasia (nfvPPA). BvFTD is the most common clinical subtype of FTLD, 72
which presents with progressive changes in personality and behaviour, together with deficits in 73
executive functions 6. Genetic background of FTLD is also heterogeneous. Hexanucleotide repeat 74
expansion in the C9ORF72 is the most common genetic cause of bvFTD 7,8. Brain atrophy linked to 75
the C9ORF72 expansion-associated bvFTD typically focuses symmetrically on the frontal and 76
temporal cortices. However, pronounced cortical and central atrophy has also been reported in such 77
cases 9,10. Although amyotrophic lateral sclerosis (ALS) represents the most frequent motor 78
symptom in patients with the C9ORF72 expansion, extrapyramidal symptoms have also been 79
documented 11,12. 80
On the basis of the similarity of clinical symptoms in bvFTD and iNPH, it was hypothesized that 81
bvFTD may demonstrate comorbidity with iNPH. Importantly, we have previously documented a 82
bvFTD case suffering from comorbid iNPH 13. To this end, the aim of the study was to evaluate the 83
role of the C9ORF72 expansion in a large cohort of iNPH patients. To our knowledge, this is the 84
first study addressing systematically the prevalence of the C9ORF72 expansion in iNPH.
85
86
Methods
87
All experimental procedures complied with the standards of the Declaration of Helsinki and further, 88
the Kuopio University Hospital Research Ethics Board approved the study. All patients provided 89
informed consent. The clinical cohort comprised of 487 patients with possible iNPH (Fig. 1; Table 90
1). The control group consisted of 432 subjects (mean age at evaluation 72 ± 3.4; range 66-87; 159 91
male), who underwent a thorough evaluation by an experienced neurologist specialized in memory 92
disorders, to rule out neurodegenerative diseases.
93
94
INPH diagnosis was carried out by neurologist in accordance with the Relkin et al. (2005)1 criteria.
95
The diagnosis of bvFTD was based on the Rascovsky et al. (2011)6 criteria. Patients who 96
simultaneously presented with at least one of the three core symptoms associated with iNPH, 97
together with enlarged ventricles disproportionate to the size of the sulci of the cerebral convexities 98
(Evan’s index >0.30) (14) based on CT or MRI scans, were referred to a neurosurgeon.
99
Subsequently, a 24-hour intraventricular pressure (IVP) monitoring, spinal tap, or lumbar infusion 100
test was performed by a neurosurgeon.
101
102
A ventriculoperitoneal shunt was placed in 409 patients, out of whom 44% (n=181) were shunted 103
on the basis of the results of the 24-hour IVP monitoring. The remaining patients were shunted 104
according to the following protocol: 32% (n=132) of patients were shunted based on a positive tap- 105
test (at least 20% increase in walking speed in a 20-meter test, including one turn); 16% (n=66) 106
based on a pathological finding (conductance ≤10) in a lumbar infusion test; and 7% (n=30) based 107
on the combination of clinical evaluation and radiological findings.
108
109
Shunt response was defined as an improvement in at least two of the classical triad of symptoms, or 110
improvement in one classical symptom accompanied with a significant improvement in headaches, 111
vertigo, and/or balance. Additionally, objective shunt response evaluation, where pre and post-shunt 112
gait speed was used as a determining variable, was available for some of the patients. Gait speed 113
improvement over 20 % was considered significant (Table 2).
114
115
The patients’ cognitive functioning was evaluated by the Consortium to Establish a Registry for 116
Alzheimer's Disease Neuropsychological Battery (CERAD-NB) or MMSE. In some cases, a full 117
neuropsychological evaluation was available. Behavioral symptoms were evaluated by Frontal 118
Behavioural Inventory (FBI). Additionally, extensive follow-up data and medical records were 119
carefully re-evaluated.
120
121
The patients’ first-degree family history was carefully mapped and history of iNPH, ALS, dementia, 122
or psychiatric diseases were evaluated (reported in table 2).
123
124
Brain biopsy was extracted from 425 patients from the right frontal cortex during the insertion of 125
the ventricular catheter for shunt or IVP monitoring. One biopsy was excluded from the cohort due 126
to technical problem (#6). A neuropathologist evaluated immunohistochemistry for beta-amyloid 127
(6F/3D), hyperphosphorylated tau (AT8), p62, and TDP-43.
128
129
Previous MRI (1.5T or 3T) (n=6) or CT-scans (n=2) of all C9ORF72 expansion carriers were re- 130
evaluated by an experienced neuroradiologists, in order to both characterize and quantify the 131
apparent morphological changes of the brain described in Table 3.
132
133
The presence of the C9ORF72 repeat expansion was detected utilizing the Repeat-Primed PCR 134
(RP-PCR) 8. The results of the RP-PCR were confirmed using the Amplicon length analysis 14, and 135
verified in a collaborating laboratory, where the analysis was repeated in a blinded manner. ApoE 136
genotype was determined by polymerase chain reaction using TaqMan genotyping assays (Applied 137
Kommentoinut [VL1]: Taulukot pitäisi numeroida siihen järjestykseen, jossa niihin viitataan, tässä voisi toki viitata myös taulukkoon 2, jolloin asia on olisi ok.
Biosystems (ABI), Foster City, CA, USA) for two single-nucleotide polymorphisms (rs429358 and 138
rs7412), and an allelic discrimination method on the ABI 7000 platform 15. 139
140
All of the identified living cases with the C9ORF72 repeat expansion were clinically re-evaluated 141
by an experienced neurologist (AMR) specialized in FTLD (patient #3 deceased during the follow- 142
up period).
143
144
Results
145
The C9ORF72 expansion was detected in 1.6% (8/487) of cases with possible iNPH. Seven of them 146
fulfilled the clinical diagnostic criteria for probable iNPH, who subsequently underwent the 147
shunting procedure. (Table 2). Additionally, one identified iNPH case with the C9ORF72 expansion 148
failed to fully fulfil the diagnostic criteria for probable iNPH, thus having finally an unlikely iNPH 149
status. The patient in question suffered from severe and widespread cognitive impairment and was 150
diagnosed with both clinically and neuropathologically (#3) confirmed Alzheimer’s disease (AD);
151
thus, ventriculoperitoneal shunt was not placed in this case. One shunted patient was retrospectively 152
diagnosed to be suffering from neuropathologically confirmed FTLD (#7). None of the control 153
subjects was found to carry the C9ORF72 expansion.
154
The mean onset age of symptoms in patients with the C9ORF72 expansion was 59±8.8 [range 47- 155
67] years. The mean Evan’s Index was 0.43. Disproportion between the sylvian and suprasylvian 156
subarachnoid spaces was present in all but one (#8) of the patients, with the results ranging from 157
mild (#2, #3, #4, #6) to severe (#1, #5, #7) (Table 3, Fig 2).
158
Six patients were found to present with the full classical triad of symptoms associated with iNPH 159
together with the enlarged ventricles as indicated by brain imaging. In five out of the eight patients, 160
gait difficulty was the leading symptom. The mean pre-operative MMSE score of the sample was 161
20.8/30 [14-25, median 22]. Results from the CERAD-NB overall showed that five patients were 162
found to exhibit mild to moderate cognitive impairment (#1, #4, #6, #7 and #8), with one remaining 163
patient demonstrating unimpaired cognition (#2), and the other remaining patient showing profound 164
deficits due to severe dementia (#5) (Table 4). Moreover, two patients suffered from mild 165
depression. The mean follow-up time was 7.4 years.
166
The FBI data were available for three out of the five patients, with two patients demonstrating mild 167
behavioral changes, and one patient displaying moderate deterioration of behaviour. Out of the 168
eight patients, only three cases fulfilled the clinical diagnostic criteria for bvFTD6, with one of the 169
remaining patients being diagnosed with ALS based on ENMG (#1). All patients had a family 170
history of symptoms linked to iNPH, ALS, dementia, or psychiatric diseases (Table 2).
171
Positive clinically verified or objectively measured shunt response was detected in almost all cases 172
when evaluated during multiple follow-ups. (Table 2). The most frequent benefit attributable to the 173
shunt pertained to improvement in gait followed by improvement in urinary incontinence. Some of 174
the patients showed a modest improvement in both episodic memory and executive functions (#1, 175
#6, #7) even though no clinically relevant shunt response was evident in their cognitive abilities.
176
The patient’s cognitive abilities showed a tendency to deteriorate over the follow-up period of 6.6 177
years but some of the patients remained cognitively stable (Table 4).
178
Beta-amyloid reactivity was common but only one patient presented with both beta-amyloid and tau 179
protein concomitantly (#3), with the patient subsequently being diagnosed with AD. All of the 180
patients testing positive for beta-amyloid were ApoE4 carriers. P62 and TDP-43 181
immunohistochemistry were frequently detected but not in all cases (table 2, figure 3).
182
183
Discussion
184
This is the first known study addressing the presence of the C9ORF72 repeat expansion in an iNPH 185
cohort. Surprisingly, the C9ORF72 expansion was found in 1.6 % of patients primarily diagnosed 186
with possible iNPH. Six of the cases with the C9ORF72 expansion had fulfilled the criteria for 187
probable iNPH and undergone a ventriculoperitoneal shunt procedure 1. In re-examination, three of 188
the C9ORF72 expansion carriers fulfilled the clinical diagnostic criteria for bvFTD. One patient 189
was diagnosed with AD and one patient as bvFTD without comorbid iNPH.
190
The differential diagnostics in iNPH is based on clinical and radiological findings. Response to 191
shunt plays a significant role in confirming the diagnosis, which causes most likely both missed and 192
false diagnoses 4,16. It should be noted that ventriculomegaly can be an early sign of 193
neurodegeneration even when parasagittal sulci are obliterated. In the current study, all shunted 194
patients fulfilled the criteria for probable iNPH but only three of the C9ORF72 expansion carriers 195
were determined to additionally suffer from comorbid bvFTD or ALS. It could be that the clinical 196
spectrum of C9ORF72 expansion is variable and the current clinical criteria for bvFTD might not 197
be sensitive enough to identify atypical bvFTD patients 6,17. However, interestingly all five shunted 198
C9ORF72 expansion carriers in the study cohort were observed to demonstrate a clinically verified 199
shunt response, suggesting that the presence of the C9ORF72 expansion did not hamper the shunt 200
response. The results further indicated that the most common and significant shunt response 201
pertained to improved gait, followed by improvement in urinary incontinence; however, the shunt 202
surgery failed to significantly impact upon the patients cognitive functioning. Although all shunted 203
C9ORF72 expansion carriers clearly displayed initial benefits from the shunting, the shunt response 204
showed a tendency toward diminishing during the follow-up period, with the average duration of 205
7.4 years. These findings are in line with previous reports on the shunt response. More specifically, 206
according to the existing literature, gait improvement appears to be the most common and 207
significant response to the shunt that is observable in the majority of patients, while improvements 208
in both cognition and urinary incontinence are markedly less frequently observed 18,19. Studies 209
focusing on the long-term outcomes of shunt surgery are scarce. However, the handful of existing 210
studies suggest that at the one-year follow-up, the shunt response is still observable in 75-84% of 211
iNPH patients 18,20,21, and three years post-surgery, 73% of patients continue to exhibit benefits from 212
the shunt 20. 213
In the present study, a neuropathological evaluation of the frontal cortical biopsies was available for 214
four of the shunted cases carrying the C9ORF72 expansion. Unfortunately, neuropathological 215
analyzes were not systematically performed for p62 and TDP-43 pathology thereby diminishing 216
both the validity and the generalizability of the current results. The C9ORF72 expansion has been 217
associated with TDP-43 pathology with or without p62 immunoreactive inclusions 22. In the current 218
cohort, p62 immunoreactive inclusions were detected more frequently as compared to TDP-43 219
pathology, which may either be due to the small size of the frontal cortical biopsy, and/or some 220
phenomena associated with the C9ORF72 expansion. It has previously been shown that the 221
presence of ubiquitin together with p62 positive and TDP-43 negative neuronal inclusions, 222
especially in the cerebellum, hippocampus and thalamus, are highly specific to the C9ORF72 223
expansion 22,23. However, TDP-43 pathology associated with the C9ORF72 expansion has been 224
identified in diverse neuroanatomical regions of the brain and the spinal cord, including the frontal 225
and temporal cortex, hippocampus, and pyramidal motor system. However, although TDP-43 226
immunoreactive lesions are seen throughout the neuraxis in FTLD, their distribution and frequency 227
are erratic 24. It is noteworthy here that in the current study, the frontal cortical biopsies were 228
approximately 1mm x 3-5mm in size. Thus, it is plausible that the small size of the frontal cortical 229
biopsies in our study did not allow for the full detection of the typical TDP-43 pathology in at least 230
all of the cases.
231
In the current study, AD-related neuropathology characterized by beta-amyloid plaques without tau- 232
pathology was observed in several cases. Each of the beta-amyloid positive cases was an ApoE4 233
allele carrier. It has been previously reported that AD-associated neuropathology is at least 234
occasionally linked to the C9ORF72-associated FTLD 25. In addition, similarly to the AD patients, 235
abnormally low CSF Aβ1-42 levels have been identified in over 20% of the FTLD patients with the 236
C9ORF72 expansion 26. As AD and vascular dementia are the most frequent neurodegenerative 237
diseases showing comorbidity with iNPH, the pathologic features perceived in iNPH most 238
commonly represent both vascular and AD-related changes 27. In addition, other forms of dementias 239
are also frequently observed in iNPH patients 28. Thus, the current results are consistent with the 240
previous evidence of typical TPD-43- and p62-positive inclusions in patients with the C9ORF72 241
expansion. Furthermore, the present findings provide supporting evidence to the assumption that 242
mixed neuropathology may be present both in cases with the C9ORF72 expansion, as well as in 243
iNPH patients.
244
Differential diagnosis between iNPH and bvFTD can be challenging due to the overlapping clinical 245
and imaging features. For example, psychomotor slowness and deficits in executive functions 246
represent typical features of both diseases 1,4–6. Difficulties with gait and balance form the core 247
symptomatology of iNPH 1, and bvFTD patients also may suffer from extrapyramidal symptoms, 248
such as gait impairment, bradykinesia, urinary incontinence, and tremor. Moreover, psychiatric 249
symptoms are commonplace in bvFTD patients resulting in erroneous diagnoses of psychiatric 250
disease at the beginning of the disease course 6. It is possible that also iNPH is associated with a 251
constellation of psychiatric manifestations, including aggression, disturbances of impulse control, 252
and even psychosis 1,3. Furthermore, Schizophrenia may be an over-represented comorbidity in 253
iNPH 29. The diagnostic process is further complicated by the fact that neuroradiological differential 254
diagnostics are not clear in all cases. Ventricular enlargement is a key radiological finding in iNPH 255
1, which may also be present in the C9ORF72 expansion-associated bvFTD 10,11. In the present 256
study DESH was evident in 7 out of 8 patients with C9ORF72 expansion.
257
Despite the growing evidence, the etiology of iNPH remains elusive. However, accruing literature 258
suggests that iNPH likely is associated with a genetic component 30–34. It has been suggested that 259
the copy number loss in SFMBT1 gene may play a role in the development of iNPH 30,35. 260
Interestingly, the segmental copy number loss in SFMBT1 gene has previously been reported in 261
Japan to be present both in 50% of patients, who concomitantly present with enlarged ventricles and 262
clinical features of iNPH 30, as well as in 25% of shunted iNPH patients 35. The current findings 263
showing that the C9ORF72 expansion is associated with the iNPH phenotype in a subset of 264
patients, appears to represent a further genetic variation with potential linkages to iNPH. Normal 265
ventricular wall – ependyma – is covered by motile cilia and primary ciliary dyskinesias have been 266
linked with congenital hydrocephalus 36. The C9ORF72 expansion could, through yet unknown 267
mechanisms, relate to ependymal dysfunction or the impaired clearance of harmful metabolites and 268
therefore advance the progression of iNPH.
269
Despite the occurrence of the C9ORF72 expansion being a novel finding in iNPH, this etiology 270
remains relatively rare.
271
The main strengths of the current study include the large cohort of iNPH patients, which provides a 272
unique opportunity to capture even the rather sporadic potential comorbid features that may be 273
shared between iNPH and other neurodegenerative disorders. Secondly, the study protocol included 274
evaluations derived from multiple domains of medical specialty enabling a thorough diagnosing and 275
characterizing of the clinical phenotypes. An assessment of the shunt response combined with the 276
evaluation of clinical characteristics of iNPH allows for reliable diagnosis of probable iNPH.
277
Moreover, brain biopsies from the frontal cortex offer a rare albeit a powerful window into the 278
neuropathological changes in the living brain tissue. The current study has also significant 279
limitations including a potential for type one error due to the low frequency of the C9ORF72 280
expansion and the absence of the genetic alteration in the cognitively healthy elderly population.
281
Additionally, the shunt response was not evaluated in all cases objectively and the Hawthorne effect 282
should be taken into account in patients #1, #2, and #5, when evaluating the current results.
283
However, the diagnosis of bvFTD and iNPH was based on the evaluation of a neurologist and a 284
neurosurgeon and there was a consensus on the diagnoses regarding all six patients. Furthermore, 285
the shunt response was evaluated objectively for three patients and for the remaining patients the 286
shunt response was evaluated by different neurosurgeons during multiple follow-ups as well as 287
questionnaires reducing the Hawthorne effect.
288
Conclusion 289
This study provides the first known systematic evidence of the C9ORF72 expansion among iNPH 290
patients. To this end, the current findings strongly support clinical similarity or even potential 291
comorbidity between iNPH and FTLD-ALS spectrum in a subset of patients carrying the C9ORF72 292
expansion. The clinical symptomatology associated with iNPH and bvFTD appear overlapping, 293
which complicates the differential diagnostics of these two diseases. However, in the current study, 294
the positive shunt response supports the idea of potential comorbidity, rather than unsuccessful 295
differential diagnostics between iNPH and bvFTD. On the basis of the current evidence, clinicians 296
are encouraged to routinely inquire their patients about the existence of possible behavioral and/or 297
psychiatric problems, together with a family history of ALS/FTLD, to allow for the consistent 298
evaluation of the potential role of bvFTD in iNPH patients. It is additionally recommended that 299
iNPH patients with cortical atrophy and personality changes, severe neuropsychiatric and/or 300
psychiatric symptoms, would be submitted to an analysis for the potential presence of the C9ORF72 301
expansion. On the other hand, bvFTD patients with enlarged ventricles and severely impaired gait 302
should be evaluated by a neurosurgeon for a potential shunt benefit. Despite the fact that the 303
presence of the C9ORF72 expansion in iNPH patients appears quite rare, the frequency of the 304
C9ORF72 expansion in the present iNPH cohort was unexpectedly high. Thus, further 305
investigations into the potential role of the C9ORF72 expansion in other iNPH cohorts are 306
warranted. Advances in the characterization of the association of the C9ORF72 expansion with 307
iNPH may ultimately lead to a more accurate differential diagnostics but potentially provide an 308
enhanced understanding of the potential comorbidity and underlying mechanisms underpinning 309
bvFTD and iNPH.
310
Supplementary material
311
No supplementary material.
312
313
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426
Fig 1: Flowchart 427
Flow chart of 487 consecutive patients suspected with iNPH 428
Fig 2: Neuroradiology 429
CT or MR images of the 6 C9ORF72 expansion carriers. All patients (a, b, c, d, e, f) showed 430
enlarged ventricles with Evan’s index of 0.36-0.50. Evident frontotemporal (g, same patient as in 431
b), and frontoparietal cortical atrophy (h, same patient as in d).
432
433
Figure 3: Neuropathology 434
p62 immunopositivity (A, B), thin TDP-43 immunoreactive neuritis (C) and moderate amount of Aβ- 435
immureactive plaques (D). Arrows marking example neuropathological changes.
436
437
Table 1: Demographics of the study cohort and controls 438
Table 2: Clinical characteristics and pathological findings of the iNPH patients with the C9ORF72 439
expansion 440
Table 3: Neuroradiological features of the C9ORF72 expansion carriers 441
Table 4: Cognitive profile of the C9ORF72 expansion carriers 442
443
444 445
Table 1. The demographics on the study cohort and the controls 446
Variable C9ORF72 expansion
carriers
Study cohort non- carriers
Neurologically healthy controls
Cases, n 8 479 432
Gender, Male (%) 3 (37.5) 229 (47.9) 159 (37.3)
Age at onset* 59.3± 8.8 70.2± 8.2** -
Age at control evaluation
- - 72 ± 3.9
C9ORF72 expansion, n (%)
8 (100) 0 (0.0) 0 (0)
The sample mean ± SD is given for the age at onset and the age at control evaluation
*Statistically significant difference (95% CI 5.1-16.7, p=0.0002)
**Available for 460 447
448
Table 2. The clinical characteristics and the pathological findings of the iNPH patients with the 449
C9ORF72 expansion 450
Patient #1 #2 #3 #4 #5 #6 #7 #8
Final diagnosis iNPH+ALS iNPH AD iNPH+FTD iNPH+SCZ iNPH FTD iNPH+FTD
Age at onset (years) 52 47 70 67 57 67 65 58
Age at shunt (years) 55 57 NA 68 69 68 67 60
Age at re-evaluation (years) 70 62 Deceased 73 73 70 NA NA
ApoE genotype 3/4 3/4 3/4 3/3 3/4 3/3 3/4 3/4
The first and main symptoms Gait Gait Cognition Gait Gait Gait Gait Cognition
The symptom triad at the time of shunting
3/3 3/3 2/3 2/3 3/3 3/3 3/3 3/3
Gait difficulties + + - + + + + +
Cognitive impairment + + + - + + + +
Urinary incontinence + + + + + + + +
Neuropsychiatric symptoms at the time of re-evaluation
- - + - - + - +
MND in ENMG at the time of re-evaluation
+ - - - -
Family history
iNPH - - NA - + + - -
Dementia - + NA - - + + +
Psychiatric disease - - NA - + - - -
ALS - - NA + - - - +
Gait problems + - NA + + + - -
Shunt +* + - + + + + +
Shunt response evaluated at follow-up visit (3 months) post-operation
Gait + + NA + + + - +
Cognition - - NA - - - - -
Incontinence + NA NA + +** +** - +**
Improvement in gait speed after the shunt***
NA NA NA 30 % NA 22 % - 47 %
Biopsy + + + + + NA + +
Gliosis - - + + + NA - -
Beta-amyloid - + + - + NA - -
Tau - - + - - NA - -
TDP-43 - - NA + NA NA + +
p62 NA + + + NA NA + +
NA; not available 451
*Revision made 13 years after the primary shunt 452
** Cured, *** 10 meters x 2 including turn 453
Table 3. The neuroradiological features of the C9ORF72 expansion carriers 454
Patient #1 #2 #3 #4 #5 #6 #7 #8
Imaging modality MRI MRI CT MRI CT MRI MRI MRI
Evan’s Index 0.47 0.42 0.36 0.40 0.50 0.47 0.39 0.45
DESH* 1 1 1 1 1 1 1 0
Disproportion between the sylvian and suprasylvian subarachnoid spaces¶
2 1 1 1 2 1 2 0
Lateral ventricles** 3 3 3 3 3 3 3 3
Sylvian fissure** 3 3 1 3 4 4 3 3
Superior medial/convexity subarachnoid space**
0 0 0 0 0 0 0 0
Basal cistern** 1 1 1 1 1 1 2 1
Aqueductal flow void Yes Yes NA Yes NA Yes Yes Yes
Mean width of the temporal horns
9/9 mm 7/6 mm 3.6/5.0 mm 6.4/6.4 mm 7.7/7.1 mm 6/7 mm 15/10 mm 6.8/6.3 mm Periventricular and deep white
matter changes¶¶
3 1 3 1 0 3 1
Callosal angle (degrees) 49 NA NA 44 NA 47 74 59
Hippocampus atrophy (Schelten’s)
2/2 1/1 NA 1/2 NA 2/2 3/4 2/4
Cortical atrophy*** 3 1 1 2 3 3 3 3
*Absent=0, evident=1 455
** Reduced=0, normal=1, slightly enlarged=2, moderately enlarged=3, greatly enlarged=4 456
*** No atrophy=0, mild atrophy=1, moderate atrophy=2, severe atrophy=3 457
¶ Normal=0, mild=1, severe=2 458
¶¶ No changes=0, punctate foci=1, beginning confluence=2, large confluent areas=3 459
NA=Not available 460
DESH; Disproportionately Enlarged Subarachnoid-space Hydrocephalus 461
462 463 464
465
Table 4. The cognitive profile of the C9ORF72 expansion carriers 466
467 468 469
Patient #1 #2 #3 #4 #5 #6 #7 #8
CERAD-NB Pre/post-shunt Time between the tests
(months)
27 70 NA 6 NA 17 4 4
Verbal fluency 13 15 19 20 10 18 13 2 14 14 14 8 11 9
15-item naming test 13 10 14 13 8 12 14 13 6 8 10 9 9 9
MMSE 19 20 22 25 16 25 25 14 25 23 22 21 23 26
Word list learning 10 12 20 20 9 19 16 1 15 14 15 14 13 9
Constructional praxis 9 7 9 7 7 11 8 5 8 9 8 8 10 7
Word list recall 1 4 6 6 0 7 5 0 3 5 2 3 4 3
Word list recall (%) 25 80 75 75 0 100 100 0 60 83 33 50 80 75
Word list recognition 20 18 20 20 9 20 19 0 14 17 13 19 18 19
Word list recognition (%)
100 80 100 100 95 100 95 0 70 85 65 95 90 95
Delayed constructional praxis
3 2 7 7 2 11 7 2 1 4 3 3 4 4
Clock drawing 4 3 6 6 1 4 1 1 1 3 1 1 3 6
Figure 1.
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471
Figure 2.
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