Distinguishing neurocognitive deficits in adult patients with NP-C from early onset Alzheimer’s dementia

Distinguishing neurocognitive deficits in adult patients with NP-C from early onset Alzheimer’s... Background: Niemann-Pick disease type C (NP-C) is a rare, progressive neurodegenerative disease caused by mutations in the NPC1 or the NPC2 gene. Neurocognitive deficits are common in NP-C, particularly in patients with the adolescent/adult-onset form. As a disease-specific therapy is available, it is important to distinguish clinically between the cognitive profiles in NP-C and primary dementia (e.g., early Alzheimer’s disease; eAD). Methods: In a prospective observational study, we directly compared the neurocognitive profiles of patients with confirmed NP-C (n =7) and eAD (n = 15). All patients underwent neurocognitive assessment using dementia screening tests (mini-mental status examination [MMSE] and frontal assessment battery [FAB]) and an extensive battery of tests assessing verbal memory, visuoconstructive abilities, visual memory, executive functions and verbal fluency. Results: Overall cognitive impairment (MMSE) was significantly greater in eAD vs. NP-C (p = 0.010). The frequency of patients classified as cognitively ‘impaired’ was also significantly greater in eAD vs. NP-C (p = 0.025). Patients with NP-C showed relatively preserved verbal memory, but frequent impairment in visual memory, visuoconstruction, executive functions and in particular, verbal fluency. In the eAD group, a wider profile of more frequent and more severe neurocognitive deficits was seen, primarily featuring severe verbal and visual memory deficits along with major executive impairment. Delayed verbal memory recall was a particularly strong distinguishing factor between the two groups. Conclusion: A combination of detailed yet easy-to-apply neurocognitive tests assessing verbal memory, executive functions and verbal fluency may help distinguish NP-C cases from those with primary dementia due to eAD. Keywords: Niemann-Pick disease type C, Alzheimer’s disease, Dementia, Cognitive function Background > 65 years, there is a much wider range of differential Niemann-Pick disease type C (NP-C) is a rare, progres- diagnoses, including underlying inherited neurodegener- sive neurodegenerative disease caused by mutations in ative aetiologies such as NP-C. the NPC1 or the NPC2 gene, which lead to impaired NP-C shares a number of clinical and neuropatho- cholesterol metabolism [1, 2]. Neurocognitive and logical features in common with AD and other demen- neuropsychiatric deficits are commonly reported in pa- tias, including eAD, frontotemporal dementia (FTD), tients NP-C, particularly among patients with the ado- and Lewy body dementia [6–10]. Patients with EOCD lescent/adult-onset form [1, 3–5]. Early-onset cognitive and eAD have therefore been suggested as a potential decline (EOCD) is characterised by presentation of cog- clinical niche for the identification of new, as yet un- nitive impairment before the age of 65 years, and clinical detected cases of NP-C [11]. In particular, patients with diagnoses of EOCD are increasingly being reported. dementia-plus syndromes featuring concomitant psychi- Most cases are related to early Alzheimer’s disease atric symptoms, movement disorders such as degenera- (eAD). However, compared to dementia in patients aged tive ataxia and/or vertical supranuclear saccade palsy (VSSP) are also considered to have an increased likeli- hood of having NP-C [11–13]. * Correspondence: Andreas.Johnen@ukmuenster.de Department of Neurology, University Hospital of Münster, Albert-Schweitzer-Campus 1, Building A1, 48149 Münster, Germany © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Johnen et al. Orphanet Journal of Rare Diseases (2018) 13:91 Page 2 of 10 Although the burden of clinical symptoms of adult The recognition of NP-C as early as possible in the NP-C patients impacts on activities of daily living, cere- disease course is important as a current treatment bral magnetic resonance imaging (MRI) findings are (miglustat) is available in Europe and many other usually normal or show non-specific minor cerebral at- countries that may help stabilise the progression of rophy [2, 5]. Thus, cognitive deterioration among pa- neurological and neurocognitive symptoms. Intrathecal tients with adolescent/adult-onset NP-C can easily be hydroxypropyl-beta-cyclodextrin is a promising future mistaken for primary psychiatric disorders or other neu- alternative treatment that is currently undergoing clin- rodegenerative dementias [12–14]. It is therefore import- ical trials. Encouraging data with this agent were re- ant to be able to distinguish at the initial clinical level ported by Ory et al. in 2017, and further studies are between the cognitive profile of patients with NP-C and ongoing [14, 16, 22–25]. those with common dementia subtypes such as eAD. The advent of biochemical laboratory markers and the However, there are few published studies on valid neuro- increasing availability of next-generation gene sequen- cognitive tests that could be used to distinguish adult cing methods are major advances for the identification NP-C patients from those with other neurodegenerative of new cases of NP-C. However, these methods are only dementia aetiologies [15]. applied in patients or patient groups considered at high A wide range of neurocognitive symptoms are encoun- risk of NP-C. Clinical methods of defining the level of tered among NP-C patients, but published data on the risk or suspicion of NP-C are necessary to direct such specific neurocognitive profile of NP-C are based on further diagnostic investigations. The characterization studies adopting a range of methodologies, resulting in and delineation of the neurocognitive profile of NP-C inconsistent or incomplete findings [12, 16–19]. Early may help clinicians to achieve earlier diagnoses, particu- signs of cognitive impairment have been reported to larly when combined with approaches that help distin- comprise reduced executive function, processing speed, guish potential cases from another primary degenerative and verbal memory due to frontal-subcortical neural disease such as eAD. dysfunction [3, 17, 19]. Continued disease progression In this study, we used a detailed neurocognitive test leads to further general cognitive decline, progressive de- battery to assess whether there is a recognizable, specific terioration in abilities to perform daily tasks, highly dimin- profile of deficits in adult patients with genetically ished memory, and behavioural impairment [5, 17, 20, 21]. proven NP-C. We were particularly interested in Based on findings from a pilot study in 10 patients whether neurocognitive tests from attentional and ex- with NP-C, Klarner et al. [17] reported impairments in ecutive domains identified by previous studies as useful fine motor skills, language, attention, working memory, in the detection of NP-C (e.g., TMT-A and B, verbal flu- and visuospatial functions. A number of deficits similar ency tests) were able to differentiate NP-C from eAD. to those seen in eAD were observed, including verbal Importantly and in contrast to previous studies [17], the episodic memory impairment. Appropriate neurocogni- neurocognitive test battery used here was geared to- tive tests incorporating disease staging were recom- wards the typical age span of patients with adult NP-C mended to detect NP-C: the Trail Making tests (TMT) and eAD instead of senile dementia, in which ceiling ef- A & B and verbal fluency tests were judged as most use- fects must be expected. Thus, we conducted the first dir- ful in patients with mild disease, and The Mini-Mental ect comparison of the observed NP-C neurocognitive Status Examination (MMSE), Corsi Block-tapping, Find profile with a reference group of adults with confirmed Similarities, and Clock Drawing Tests were considered eAD, the most frequent aetiology of EOCD. more appropriate in patients with more advanced dis- ease. Other, separate studies have reported frontal im- Methods pairments and decreases in executive functions and Study design attention [5, 16]. A systematic literature review of case This was a prospective observational cohort study includ- reports based on 23 separate patients has also reported ing consecutive patients encountered at the Memory executive dysfunction as the most frequent cognitive Disorder Unit at the Department of Neurology, University deficit in adult NP-C [15], possibly due to neuropathol- Hospital Münster, Germany between 2012 and 2016. All ogy in cerebellar regions and deep grey matter nuclei participants had confirmed pathogenic NPC1 genotypes. (e.g., the thalamus and striatum). Overall, the current lit- Included patients underwent neurological and psychi- erature points towards attentional and executive dys- atric examination by a physician trained in the assess- functions as the hallmark of neurocognitive impairment ment of patients suffering from dementia. Lumbar in patients with NP-C. However, it remains unclear puncture, electroencephalography, event-related poten- whether the previously recommended tests assessing tials (P300), 3.0 Tesla brain MRI, and comprehensive these cognitive domains could help distinguish NP-C pa- neurocognitive testing were also performed. Within the tients from other dementia subtypes such as eAD. eAD group, all patients were classified as having Johnen et al. Orphanet Journal of Rare Diseases (2018) 13:91 Page 3 of 10 probable eAD according to McKhann criteria [26], with ‘impairment’ was defined when patients scored below the at least intermediate pathophysiological evidence of AD 10th percentile rank (PR) of the respective normative sam- based on cerebrospinal fluid biomarker profile and MRI ple detailed in the professional manuals for each test. The brain atrophy pattern. All patients underwent follow-up proportions of patients categorized as ‘impaired’ based on visits for ≥12 months. Functional disability was evaluated their neurocognitive profiles were compared between the in NP-C patients using a well-established and validated NP-C and eAD groups using the Chi-square test. For all disease-specific disability scale for NP-C [27], which as- between-group comparisons, statistical significance was sesses six key domains (ambulation, manipulation, lan- concluded at the p < 0.05 level. guage, swallowing, ocular movements, and epilepsy) on Cohen’s d effect-sizes for between-group differences, a composite scale with scores ranging from 0 (best) to taking into account the within-group variance and 24 (worst). homogeneity of scores, were derived for each test par- Subjects with a history of neurological disorders other ameter. Based on this analysis, receiver operating char- than eAD or NP-C such as other dementia subtypes, other acteristics (ROC) curves were used to calculate the neurodegenerative disorders (e.g., Huntington’s disease, sensitivity and specificity of the parameter with the lar- multiple system atrophy, motor neuron disease), stroke, gest effect-size for differential diagnosis between NP-C hydrocephalus, epilepsy, brain tumour, traumatic brain in- and eAD, and in test parameters previously suggested to jury, major psychiatric illness not related to dementia (e.g., be useful in detecting mild NP-C [17]. drug or alcohol abuse), and other systemic diseases known to interfere with cognitive function were excluded. Results Patients Assessments A total of nine patients with NP-C were selected for inclu- Demographic data and clinical parameters were col- sion in the study, all of whom had confirmed diagnoses lected for all patients. An extensive battery of neurocog- based on molecular genetic testing. Two NP-C patients nitive tests was applied, which assessed all major who were initially selected for the study were excluded from cognitive domains. The test battery included: the the data analysis because they were not testable due to the German equivalent of the Rey Auditory Verbal Learning severity of their motor dysfunction. Individual patient Test (RAVLT) [28] for verbal span, verbal learning effi- demographics, disease characteristics, biochemical variables ciency, verbal short-term retrieval, verbal long-term re- and disability scores of the seven included NP-C patients trieval, and verbal recognition; the Rey Complex Figure are presented in Table 1. All seven patients had been symp- Test and Recognition Trial (RCFT) [29] for visuocon- tomatic (symptom duration 6–14 years) and were on on- structive abilities and visual short-term retrieval; TMT-A going miglustat treatment for a range of 3–14 months. and -B for processing speed, and set-shifting speed, re- Ataxia was the most common symptom at initial presenta- spectively [30]; the Regensburger verbal fluency test tion (three patients), followed by cataplexy and dysarthria (RWT) [31] for lexical and semantic word fluency; and (in two patients each). None of the patients in this cohort the forwards and backwards digit span tests from the showed more than mild dementia, and no patients pre- Wechsler Memory Scale (WMS) [32] for attention and sented with epileptic seizures or psychotic symptoms. Dis- working memory capacity. Among these neurocognitive ability scores indicated relatively mild disease severity [27]. parameters, lower raw scores indicate better perform- Table 2 shows a comparison of NP-C and eAD patient ance on the TMT-A, TMT-B, RCFT time to copy, the group characteristics. The mean ± SD age of the adult/ RAVLT5–6, and RAVLT5–7 scores. Higher raw scores adolescent onset NP-C patients in this cohort (34.6 ± signify better performance for all other parameters. 12.2 years) was significantly lower than that in the reference Overall cognitive function was screened using the group of eAD patients (55.1 ± 3.4 years; p = 0.004). Patients MMSE [33], where higher scores represent less impair- in both groups had a similar level of education. ment. Frontal-executive impairment was screened using Disease biomarker levels in the eAD group confirmed the Frontal Assessment Battery (FAB), where higher that all eAD patients had notable/substantial AD path- scores also indicate less impairment [34]. ology. Amyloid-ß and total tau levels were measured in four NP-C patients. Mean total tau concentration was Data analysis significantly higher in the eAD group compared with Between-group differences were evaluated using the NP-C patients (p = 0.03), and amyloid-ß levels were sig- Welch t-test for normally distributed data, and the nificantly lower among eAD patients (p < 0.01) (Table 2). non-parametric Mann-Whitney test for non-normally distributed data. Raw scores from all neurocognitive Neurocognitive test results tests were transformed into normative percentile ranks Dementia screening indicated significantly greater over- stratified by age, gender and education, where cognitive all cognitive impairment among eAD patients compared Johnen et al. Orphanet Journal of Rare Diseases (2018) 13:91 Page 4 of 10 Table 1 Demographic and disease characteristics of patients with NP-C Demographics Clinical data Biochemical variables Patient No. Age (yrs) Gender Age at Symptom Duration of Primary clinical NP-C Plasma Plasma CSF Aβ CSF tau onset duration miglustat symptoms severity ChT C-triol (pg/mL) (pg/mL) (yrs) (yrs) therapy (mo) score (nmol/h/mL) (ng/mL) 1 35 F 28 7 10 Ataxia , dysarthria, mild VSGP 6 56 112 ND ND 2 31 M 17 14 26 Dysarthria , psychomotor 14 321 267 1337 807 agitation, dysphagia, ataxia, VSGP 3 45 F 34 11 18 Cataplexy , ataxia, dysarthria, 11 321 108 789 151 dystonia, mild VSGP 4 27 F 17 6 37 Cataplexy , mild ataxia 597 91 ND ND and dysarthria 5 54 F 42 12 28 Ataxia , dysarthria, VSGP, 9 367 302 ND ND mild dysphagia 6 33 F 25 8 3 Dysarthria , mild VSGP, 7 77 164 1282 313 mild ataxia 7 23 F 14 9 22 Ataxia , dystonia, mild 10 128 188 1267 354 dysarthria, VSGP, cataplexy, mild dysphagia a b Symptoms present at initial presentation; NP-C severity measured using the NP-C disability scale of Pineda et al [27], where escores ranged from 0 (best) to 24 (worst). Aβ, amyloid-beta protein; CSF cerebrospinal fluid, ChT chitotriosidase, C-triol cholestane-3β,5α,6β-triol, ND not determined. Analyte cut-off values: ChT < 100 nmol/h/mL; C-triol < 50 ng/mL; Aβ < 500 pg/mL; tau > 500 pg/mL with NP-C patients based on MMSE scores (p = 0.010). Overall, Chi-square analysis showed that impaired test While no statistical difference in frontal-executive im- parameters (i.e., those with performance scores PR < 10) pairment between NP-C and eAD patients was observed were significantly more frequent in the eAD group com- based on FAB screening (p = 0.245). pared with the NP-C group (p = 0.025). The largest dis- The frequencies of cognitive impairment in relation crepancies in the frequency of cognitive impairments to data from age-matched normative samples for between the NP-C and eAD groups were in terms of ver- both patient groups are summarised in Fig. 1.Over- bal memory deficits (all RAVLT parameters), which were all, patients with NP-C showed a cognitive profile of substantially more frequently observed in eAD patients. relatively preserved verbal episodic memory (RAVLT), Mean ± SD neurocognitive test raw scores are sum- but visuoconstruction and visual memory (RCFT re- marised in Table 3. In the majority of neurocognitive call [visual memory] and RCFT copy scores) were test parameters, significantly greater average impair- frequently impaired. Deficits in attention and execu- ment wasseenineAD compared with theNP-Cgroup. tive functions (i.e., processing speed [TMT-A], Significant between-group differences indicated greater set-shifting [TMT-B], and RWT word fluency) were degrees of impairment in eAD patients in most RAVLT also common. In contrast, patients with eAD gener- subscales (p-values from < 0.001 to 0.018), the RCFT ally showed a wider profile of cognitive impairment. copy subscale (p = 0.038) and the WMS digit span back- Deficits in verbal learning and memory (RAVLT), wards test (p = 0.037). Notably, the TMT-B score, which visuoconstruction and visual memory (RCFT), and has been highlighted as a particularly suggestive test for executive functions (TMT and verbal fluency scores) executive dysfunction in NP-C, was also significantly were similarly or more frequent than in the NP-C more impaired in the eAD group versus the NP-C group. group (p = 0.017). Table 2 Comparison of patient demographics and clinical characteristics in NP-C and eAD patients Parameter NP-C patients (n = 7) eAD patients (n = 15) Group difference p-value Age in years, mean ± SD 34.6 ± 12.2 55.1 ± 3.4 p < 0.01 Male: female, n (%): 2 (22): 7 (78) 6 (40): 9 (60) – Years in education, mean ± SD 11.6 ± 1.5 11.3 ± 1.5 p = 0.68 Amyloid-ß level (pg/ml) , mean ± SD 1168 ± 255 550 ± 148 p < 0.01 Total tau level (pg/ml) , mean ± SD 406 ± 281 860 ± 337 p = 0.03 Amyloid and tau based on N = 4 NP-C patients Johnen et al. Orphanet Journal of Rare Diseases (2018) 13:91 Page 5 of 10 Fig. 1 Neurocognitive profiles of patients with a NP-C and b eAD. Patients with eAD generally showed a wide profile of cognitive impairment with marked memory deficits, while patients with NP-C showed relatively preserved verbal memory (RAVLT), but frequent impairments in visuoconstruction, visual memory (RCFT recall [visual memory] and RCFT copy scores), and set-shifting and verbal fluency. RAVLT, Rey Auditory Verbal Learning Test; RCFT, Rey Complex Figure Test and Recognition Trial; RWT, Regensburger verbal fluency test; TMT, Trail-Making Tests A and B; WMS Wechsler Memory Scale No other cognitive tests showed significant Importantly, there did not appear to be any influence between-group differences. However, NP-C patients of neurological deficits (e.g., speech or manipulation im- showed a marginally (albeit non-significantly) worse aver- pairment) on patients’ performance of neurocognitive age performance on the RWT phonematic word fluency tests. Subscores for these domains on the NP-C disabil- (letter S) test compared with eAD patients (p =0.225). ity scale assessments showed only slight to moderate Among all of the neurocognitive tests we applied, the impairements: all subscores were ≤ 3 for all patients. greatest difference between the NP-C and eAD groups in terms of deficit frequency was in RAVLT7 (delayed Discussion verbal recall) scores. This parameter also showed the This is the first study to directly compare the neurocogni- greatest between-group effect size in terms of raw tive symptom profile of patients with NP-C with that seen scores. ROC analysis showed that this parameter dis- in a ‘reference’ group of patients with deficits due to eAD criminated well between patients with NP-C and those – the most common primary neurodegenerative dementia with eAD, with an area under the curve (AUC) of 0.981 syndrome before the age of 65 years. The detailed battery demonstrating both high sensitivity (85.7%) and high of neurocognitive tests applied in this study identified specificity (93.3%) using a cut-off of 6/15 recalled words specific, statistically significant differences between the after 30 min. Other neurocognitive tests, including those NP-C and eAD groups, which may aid in the differential previously suggested as effective in detecting mild NP-C, diagnosis of patients with early cognitive impairment and showed insufficient discriminative power (all AUC values further neurological deficits (i.e., dementia-plus syndrome) < 0.7) (Fig. 2). suggestive of possible NP-C. Johnen et al. Orphanet Journal of Rare Diseases (2018) 13:91 Page 6 of 10 Table 3 Dementia screening and neurocognitive test parameter scores in patients with NP-C and patients with eAD Test n NP-C patients (n = 7) n eAD patients (n = 15) Mean group Cohen’s d p-value difference effect-size Mean ± SD Mean ± SD Dementia screenings MMSE 4 27.0 ± 2.16 13 21.9 ± 1.9 5.1 2.5 p = 0.010 FAB 5 14.4 ± 3.3 5 11.8 ± 3.3 2.6 0.8 p = 0.245 Neurocognitive test parameters RAVLT1 (verbal span) 7 7.0 ± 3.1 15 3.3 ± 1.6 3.7 1.5 p = 0.018 RAVLT5 (verbal learning) 7 12.9 ± 3.1 15 6.7 ± 2.7 5.6 1.9 p = 0.002 RAVLT1–5 (total learning) 7 51.0 ± 14.6 15 28.6 ± 8.7 22.4 1.9 p = 0.006 RAVLT6 (recall after interference) 7 10.1 ± 4.4 15 3.3 ± 2.5 6.9 1.9 p = 0.005 RAVLT5–6 (forgetting after interference) 7 2.1 ± 1.8 15 3.5 ± 1.9 −1.3 − 0.7 p = 0.141 RAVLT7 (delayed verbal recall) 7 10.7 ± 3.5 15 1.9 ± 2.1 8.8 3.0 p < 0.001 RAVLT5–7 (forgetting after delay) 7 1.6 ± 1.1 15 4.8 ± 2.1 −3.2 −1.9 p < 0.001 RAVLT8 (recognition) 7 13.7 ± 1.9 14 11.3 ± 3.9 2.4 0.5 p = 0.058 RCFT copy (visuoconstructional ability) 5 29.8 ± 4.1 13 20.7 ± 12.9 9.1 0.9 p = 0.038 RCFT time to copy (seconds) 5 233.4 ± 95.9 8 306.5 ± 123.5 − 73.1 −0.7 p = 0.259 RCFT recall (visual memory) 5 12.3 ± 8.0 13 4.8 ± 4.8 7.5 1.1 p = 0.107 TMT-A (processing speed; seconds) 7 61.6 ± 40.7 14 93.1 ± 81.5 −31.5 −0.3 p = 0.252 TMT-B (set shifting; seconds) 7 119.0 ± 54.4 10 226.7 ± 101.9 − 107.7 −1.3 p = 0.017 RWT word fluency (1 min animals) 7 17.3 ± 5.1 13 14.8 ± 5.4 2.4 0.5 p = 0.335 RWT word fluency (1 min letter S) 7 8.4 ± 3.1 14 11.4 ± 7.8 −3.0 −0.5 p = 0.225 WMS digit span (forwards) 6 7.0 ± 2.4 14 5.9 ± 1.4 1.1 0.6 p = 0.353 WMS digit span (backwards) 6 5.7 ± 1.5 14 3.8 ± 1.9 1.9 1.1 p = 0.037 a b Effect sizes calculated according to methodology for Cohen’s d statistic for paired t-tests; p-values specified based on the Welch t-test, unless otherwise specified; p-values based on the Mann-Whitney test; For TMT-A, TMT-B, RCFT time to copy, RAVLT5–6, and RAVLT5–7 subscales, lower scores indicate better performance. Higher raw scores signify better performance for all other neurocognitive test parameters. For dementia screening scores, higher scores represent less impairment on the MMSE and the FAB. FAB Frontal Assessment Battery, MMSE Mini-Mental Status Evaluation, RAVLT Rey Auditory Verbal Learning Test, RCFT Rey Complex Figure Test and Recognition Trial, RWT Regensburger verbal fluency test, TMT Trail-Making Tests A and B, WMS Wechsler Memory Scales NP-C and AD share a number of pathophysiological specifically, positron emission tomography (PET) studies similarities such as increased levels of brain tau protein, in adult NP-C patients have indicated that frontal-lobe amyloid deposition, the presence of neurofibrillary tan- hypometabolism may contribute to frontal-executive gles, and the influence of apolipoprotein E ε4 genotype deficits [44, 45]. [6–9, 35]. Other neurological commonalities include Overall, taking patient age, gender, and education into basal forebrain cholinergic system alterations and account, eAD patients showed wider, more generalised chronic neuroinflammation [36–38]. However, there are impairments in affected cognitive domains compared distinct differences in the localisation of neuropathology with the profile seen in NP-C patients in the current between the two conditions. Purkinje cells in the cere- study. Deficits were also more frequent and greater in bellum are the most affected neurons in NP-C, with magnitude in eAD on most of the neurocognitive tests NFTs mainly found in subcortical structures, while le- that we employed. Bergeron et al. reported that in con- sions in AD are mainly seen in the neocortical and med- trast to NP-C, the general cognitive profile in AD is ial temporal lobes [6, 15, 39, 40]. It therefore follows characterized predominantly by memory dysfunction that certain clinical neurocognitive differences exist be- [15]. In the current study, the key neurocognitive differ- tween NP-C and eAD patients [16, 17]. ence between NP-C and eAD was also observed in terms MRI and diffusion tensor imaging (DTI) studies in of verbal memory performance, as measured by the NP-C patients have suggested that cerebral atrophy in RAVLT. Most RAVLT subscores (excluding forgetfulness key deep grey matter regions including the hippocam- after interference) were statistically significantly more pus, thalamus, cerebellum, and striatum, as well as impaired in eAD patients. In particular, the RAVLT7 major white-matter tracts, may account for global im- subscale (delayed verbal recall), an indicator of verbal pairments in cognitive function in NP-C [41–43]. More memory that has been shown to correlate with Johnen et al. Orphanet Journal of Rare Diseases (2018) 13:91 Page 7 of 10 Fig. 2 Receiver operating curves (ROC) analyses of key neurocognitive test raw scores in eAD and NP-C patients. A high AUC for the RAVLT-7 but low to moderate AUCs for the TMT-A, TMT-B, RWT letter fluency (S-words) and RWT semantic fluency (animals) were observed. Area-under-curve values: a 0.981 for RAVLT-7; b 0.362 for TMT-A; c 0.143 for TMT-B; d 0.444 for RWT letter fluency (S-words); e 0.665 for RWT semantic fluency (animals). ROC, Receiver operating characteristics curve analysis; RAVLT, Rey Auditory Verbal Learning Test; RWT, Regensburger Word Fluency Test; TMT, Trail Making Test hippocampal pathology [46, 47], showed the greatest ef- Alzheimer’s disease (CERAD) word list recall test also fect size between the two groups. Our ROC analyses addresses this neurocognitive domain through delayed suggested that delayed verbal recall also showed good recall of a learned word list and is faster to apply than sensitivity and specificity in distinguishing between the RAVLT. However, the disadvantage of this test is NP-C and eAD patients. Relatively preserved verbal that it is geared toward dementia patients of higher age, memory has recently also been reported in a French co- and normative data for younger patients are not avail- hort of 21 patients with mild adult NP-C [16]. able [17]. The Free and Cued Selective Reminding Test With regard to alternative tests for verbal episodic (FCSRT) is an alternative verbal memory test that, simi- memory, the Consortium to Establish a Registry for lar to the RAVLT, provides normative data versus Johnen et al. Orphanet Journal of Rare Diseases (2018) 13:91 Page 8 of 10 younger adults, and might therefore also be suited to developmental disorder, poor school performance, and cognitive assessments in NP-C [16]. learning disabilities [4, 15, 48]. One difficulty in this re- A number of previous studies in patients with NP-C spect is that not all neurocognitive tests are similarly ap- have described impaired executive functions (e.g. plicable in different age-groups, particularly in patients set-shifting and word fluency) and attention as the pri- with the juvenile-onset or early adolescent-onset forms: mary neurocognitive deficit in NP-C [5, 15–17, 19]. Our this constitutes a problem. For instance, Klarner et al. used findings are in line with previous published evidence, in the CERAD battery to determine the cognitive profile of that executive functions as measured by the TMT-A/B patients with NP-C [17]. However, this test battery is not and word fluency as measured by the RWT, were the associated with normative data for patients aged < 50 years most frequently impaired domains in NP-C patients and frequently produces ceiling effects in younger pa- [17]. However, the frequency and magnitude of these im- tients. In contrast, the RCFT, RAVLT, TMT, RWT and pairments were actually lower among NP-C patients on WMS-digit span tests included in the current study all the majority of neurocognitive tests assessing attention provide normative data for both children, as well as older and executive functions versus eAD. As a result, these age groups. The current test battery may therefore be tests cannot be expected to function as differential cog- more suited for use in NP-C than classical senile dementia nitive markers on their own. test batteries like the CERAD or dementia screenings. Interestingly, the RWT word fluency (letters) task was Finally, structural neuroimaging data to investigate po- the only neurocognitive measure on which NP-C patients tential links between memory scores and medial temporal were more impaired than eAD patients at the raw score lobe atrophy in eAD versus NP-C, and the possible rela- level. However, the NP-C versus eAD effect-size seen with tionship between frontal executive functions and frontal/ this parameter was small and non-significant, and the fre- subcortical atrophy with executive dysfunction, are a sub- quency of impaired cases (compared with age-matched ject for potential, future studies. In addition, more specific normative data) on this test was similar in both groups. cognitive and behavioural functions associated with While global dementia screening tools such as the frontal lobe integrity (e.g., social cognition tests, abnormal MMSE, or more specific tools such as the FAB may not behaviour) may also function as differential markers for be powerful enough to distinguish specific neurocogni- NP-C. However, these aspects have not yet been tested in tive deficits between NP-C and eAD, the majority of detail in this rare patient group. NP-C patients in our study presented with impaired per- formance on both of these scales. In particular, FAB may Conclusion prove useful for this purpose in clinical practice as it ef- In conclusion, based on our findings, we recommend that fectively assesses executive dysfunctions in a general dementia screening assessments (e.g., MMSE, time-economic way. Overall, due to lack of specificity FAB) should not be used in isolation to evaluate cognitive and the lack of normative age-matched control data in performance in patients with suspected NP-C, as these pa- younger patients, these screening tests cannot substitute tients may present with milder cognitive deficits than pa- an extensive neurocognitive assessment, particularly in tients with eAD. Such screening studies may therefore addressing memory and executive function. prevent the detection of important differences in the neu- The small sample size, particularly of the NP-C group rocognitive profiles between eAD and NP-C. Detailed, yet is a weakness of this study. However, this is due to the easy-to-apply neurocognitive tests such as the RAVLT extreme rarity of NP-C and the single-centre nature of assessing verbal episodic memory, the TMT-B assessing this study. The between-group differences in age in the set-shifting and a verbal letter fluency task, with normative NP-C and eAD patients introduces a further degree of data available for age-groups typically associated with uncertainty, with patient age acting as a potential con- NP-C, appear more appropriate. Further studies in larger founding factor in our statistical analyses. Age has an numbers of patients are warranted. Parallel studies of such important influence on the range and severity of cogni- neurocognitive scales alongside imaging parameters (e.g., tive, neurological, visceral and psychiatric symptoms in based on MRI volumetry or DTI) would allow further NP-C [1, 2, 15]. It is notable that patients with eAD in insight through the assessment of underlying neuroana- this study were significantly older than those with NP-C. tomical correlates of cognitive dysfunction in NP-C. While this could be considered as a study limitation, it Abbreviations should also be noted that, in general, cognitive impair- AUC: Area under the curve; DTI: Diffusion tensor imaging; eAD: Early ment in NP-C has a lower age at onset compared with Alzheimer’s disease; EOCD: Early-onset cognitive decline; FAB: Frontal eAD. While cognitive deterioration is observed in most Assessment Battery; FAB: Frontal assessment battery; FCSRT: Free and Cued Selective Reminding Test; FTD: Frontotemporal dementia; MMSE: Mini-mental patients with adolescent/adult-onset NP-C [1, 2, 15], status examination; MRI: Magnetic resonance imaging; NP-C: Niemann-Pick EOCD is most usually recognized among patients with disease type C; PET: Positron emission tomography; PR: Percentile rank; childhood-onset NP-C in the form of intellectual RAVLT: Rey Auditory Verbal Learning Test; RCFT: Rey Complex Figure Test Johnen et al. Orphanet Journal of Rare Diseases (2018) 13:91 Page 9 of 10 and Recognition Trial; ROC: Receiver operating characteristics; 12. Schicks J, Muller Vom Hagen J, Bauer P, Beck-Wodl S, Biskup S, Krägeloh- RWT: Regensburger verbal fluency test; TMT-A/TMT-B: Trail Making tests A & Mann I, et al. Niemann-Pick type C is frequent in adult ataxia with cognitive B; WMS: Wechsler Memory Scale decline and vertical gaze palsy. Neurology. 2013;80:1169–70. 13. Bauer P, Balding DJ, Klünemann HH, Linden DE, Ory DS, Pineda M, et al. Acknowledgements Genetic screening for Niemann-Pick disease type C in adults with Matthew Reilly PhD at InTouch Medical Ltd. provided medical writing neurological and psychiatric symptoms: findings from the ZOOM study. support in the preparation of this manuscript, paid for by the University Hum Mol Genet. 2013;22:4349–56. Hospital of Münster, Münster, Germany. 14. Maubert A, Hanon C, Sedel F. Psychiatric disorders in adult form of Niemann-Pick disease type C. L’Encephale. 2016;42:208–13. Availability of data and materials 15. Bergeron D, Poulin S, Laforce R Jr. Cognition and anatomy of adult The datasets used and/or analysed during the current study are available Niemann-Pick disease type C: insights for the Alzheimer field. Cogn from the corresponding author on reasonable request. Neuropsychol. 2017;35:1–14. https://www.tandfonline.com/doi/full/10.1080/ 02643294.2017.1340264. Authors’ contributions 16. Heitz C, Epelbaum S, Nadjar Y. Cognitive impairment profile in adult All authors had roles in the conception and design of the study, analysis and patients with Niemann Pick type C disease. Orphanet J Rare Dis. 2017; interpretation of the clinical data, and drafting the article content or [accepted October 2017] providing critical review. All authors provided approval of the final 17. Klarner B, Klünemann HH, Lurding R, Aslanidis C, Rupprecht R. manuscript for submission. 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Distinguishing neurocognitive deficits in adult patients with NP-C from early onset Alzheimer’s dementia

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Abstract

Background: Niemann-Pick disease type C (NP-C) is a rare, progressive neurodegenerative disease caused by mutations in the NPC1 or the NPC2 gene. Neurocognitive deficits are common in NP-C, particularly in patients with the adolescent/adult-onset form. As a disease-specific therapy is available, it is important to distinguish clinically between the cognitive profiles in NP-C and primary dementia (e.g., early Alzheimer’s disease; eAD). Methods: In a prospective observational study, we directly compared the neurocognitive profiles of patients with confirmed NP-C (n =7) and eAD (n = 15). All patients underwent neurocognitive assessment using dementia screening tests (mini-mental status examination [MMSE] and frontal assessment battery [FAB]) and an extensive battery of tests assessing verbal memory, visuoconstructive abilities, visual memory, executive functions and verbal fluency. Results: Overall cognitive impairment (MMSE) was significantly greater in eAD vs. NP-C (p = 0.010). The frequency of patients classified as cognitively ‘impaired’ was also significantly greater in eAD vs. NP-C (p = 0.025). Patients with NP-C showed relatively preserved verbal memory, but frequent impairment in visual memory, visuoconstruction, executive functions and in particular, verbal fluency. In the eAD group, a wider profile of more frequent and more severe neurocognitive deficits was seen, primarily featuring severe verbal and visual memory deficits along with major executive impairment. Delayed verbal memory recall was a particularly strong distinguishing factor between the two groups. Conclusion: A combination of detailed yet easy-to-apply neurocognitive tests assessing verbal memory, executive functions and verbal fluency may help distinguish NP-C cases from those with primary dementia due to eAD. Keywords: Niemann-Pick disease type C, Alzheimer’s disease, Dementia, Cognitive function Background > 65 years, there is a much wider range of differential Niemann-Pick disease type C (NP-C) is a rare, progres- diagnoses, including underlying inherited neurodegener- sive neurodegenerative disease caused by mutations in ative aetiologies such as NP-C. the NPC1 or the NPC2 gene, which lead to impaired NP-C shares a number of clinical and neuropatho- cholesterol metabolism [1, 2]. Neurocognitive and logical features in common with AD and other demen- neuropsychiatric deficits are commonly reported in pa- tias, including eAD, frontotemporal dementia (FTD), tients NP-C, particularly among patients with the ado- and Lewy body dementia [6–10]. Patients with EOCD lescent/adult-onset form [1, 3–5]. Early-onset cognitive and eAD have therefore been suggested as a potential decline (EOCD) is characterised by presentation of cog- clinical niche for the identification of new, as yet un- nitive impairment before the age of 65 years, and clinical detected cases of NP-C [11]. In particular, patients with diagnoses of EOCD are increasingly being reported. dementia-plus syndromes featuring concomitant psychi- Most cases are related to early Alzheimer’s disease atric symptoms, movement disorders such as degenera- (eAD). However, compared to dementia in patients aged tive ataxia and/or vertical supranuclear saccade palsy (VSSP) are also considered to have an increased likeli- hood of having NP-C [11–13]. * Correspondence: Andreas.Johnen@ukmuenster.de Department of Neurology, University Hospital of Münster, Albert-Schweitzer-Campus 1, Building A1, 48149 Münster, Germany © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Johnen et al. Orphanet Journal of Rare Diseases (2018) 13:91 Page 2 of 10 Although the burden of clinical symptoms of adult The recognition of NP-C as early as possible in the NP-C patients impacts on activities of daily living, cere- disease course is important as a current treatment bral magnetic resonance imaging (MRI) findings are (miglustat) is available in Europe and many other usually normal or show non-specific minor cerebral at- countries that may help stabilise the progression of rophy [2, 5]. Thus, cognitive deterioration among pa- neurological and neurocognitive symptoms. Intrathecal tients with adolescent/adult-onset NP-C can easily be hydroxypropyl-beta-cyclodextrin is a promising future mistaken for primary psychiatric disorders or other neu- alternative treatment that is currently undergoing clin- rodegenerative dementias [12–14]. It is therefore import- ical trials. Encouraging data with this agent were re- ant to be able to distinguish at the initial clinical level ported by Ory et al. in 2017, and further studies are between the cognitive profile of patients with NP-C and ongoing [14, 16, 22–25]. those with common dementia subtypes such as eAD. The advent of biochemical laboratory markers and the However, there are few published studies on valid neuro- increasing availability of next-generation gene sequen- cognitive tests that could be used to distinguish adult cing methods are major advances for the identification NP-C patients from those with other neurodegenerative of new cases of NP-C. However, these methods are only dementia aetiologies [15]. applied in patients or patient groups considered at high A wide range of neurocognitive symptoms are encoun- risk of NP-C. Clinical methods of defining the level of tered among NP-C patients, but published data on the risk or suspicion of NP-C are necessary to direct such specific neurocognitive profile of NP-C are based on further diagnostic investigations. The characterization studies adopting a range of methodologies, resulting in and delineation of the neurocognitive profile of NP-C inconsistent or incomplete findings [12, 16–19]. Early may help clinicians to achieve earlier diagnoses, particu- signs of cognitive impairment have been reported to larly when combined with approaches that help distin- comprise reduced executive function, processing speed, guish potential cases from another primary degenerative and verbal memory due to frontal-subcortical neural disease such as eAD. dysfunction [3, 17, 19]. Continued disease progression In this study, we used a detailed neurocognitive test leads to further general cognitive decline, progressive de- battery to assess whether there is a recognizable, specific terioration in abilities to perform daily tasks, highly dimin- profile of deficits in adult patients with genetically ished memory, and behavioural impairment [5, 17, 20, 21]. proven NP-C. We were particularly interested in Based on findings from a pilot study in 10 patients whether neurocognitive tests from attentional and ex- with NP-C, Klarner et al. [17] reported impairments in ecutive domains identified by previous studies as useful fine motor skills, language, attention, working memory, in the detection of NP-C (e.g., TMT-A and B, verbal flu- and visuospatial functions. A number of deficits similar ency tests) were able to differentiate NP-C from eAD. to those seen in eAD were observed, including verbal Importantly and in contrast to previous studies [17], the episodic memory impairment. Appropriate neurocogni- neurocognitive test battery used here was geared to- tive tests incorporating disease staging were recom- wards the typical age span of patients with adult NP-C mended to detect NP-C: the Trail Making tests (TMT) and eAD instead of senile dementia, in which ceiling ef- A & B and verbal fluency tests were judged as most use- fects must be expected. Thus, we conducted the first dir- ful in patients with mild disease, and The Mini-Mental ect comparison of the observed NP-C neurocognitive Status Examination (MMSE), Corsi Block-tapping, Find profile with a reference group of adults with confirmed Similarities, and Clock Drawing Tests were considered eAD, the most frequent aetiology of EOCD. more appropriate in patients with more advanced dis- ease. Other, separate studies have reported frontal im- Methods pairments and decreases in executive functions and Study design attention [5, 16]. A systematic literature review of case This was a prospective observational cohort study includ- reports based on 23 separate patients has also reported ing consecutive patients encountered at the Memory executive dysfunction as the most frequent cognitive Disorder Unit at the Department of Neurology, University deficit in adult NP-C [15], possibly due to neuropathol- Hospital Münster, Germany between 2012 and 2016. All ogy in cerebellar regions and deep grey matter nuclei participants had confirmed pathogenic NPC1 genotypes. (e.g., the thalamus and striatum). Overall, the current lit- Included patients underwent neurological and psychi- erature points towards attentional and executive dys- atric examination by a physician trained in the assess- functions as the hallmark of neurocognitive impairment ment of patients suffering from dementia. Lumbar in patients with NP-C. However, it remains unclear puncture, electroencephalography, event-related poten- whether the previously recommended tests assessing tials (P300), 3.0 Tesla brain MRI, and comprehensive these cognitive domains could help distinguish NP-C pa- neurocognitive testing were also performed. Within the tients from other dementia subtypes such as eAD. eAD group, all patients were classified as having Johnen et al. Orphanet Journal of Rare Diseases (2018) 13:91 Page 3 of 10 probable eAD according to McKhann criteria [26], with ‘impairment’ was defined when patients scored below the at least intermediate pathophysiological evidence of AD 10th percentile rank (PR) of the respective normative sam- based on cerebrospinal fluid biomarker profile and MRI ple detailed in the professional manuals for each test. The brain atrophy pattern. All patients underwent follow-up proportions of patients categorized as ‘impaired’ based on visits for ≥12 months. Functional disability was evaluated their neurocognitive profiles were compared between the in NP-C patients using a well-established and validated NP-C and eAD groups using the Chi-square test. For all disease-specific disability scale for NP-C [27], which as- between-group comparisons, statistical significance was sesses six key domains (ambulation, manipulation, lan- concluded at the p < 0.05 level. guage, swallowing, ocular movements, and epilepsy) on Cohen’s d effect-sizes for between-group differences, a composite scale with scores ranging from 0 (best) to taking into account the within-group variance and 24 (worst). homogeneity of scores, were derived for each test par- Subjects with a history of neurological disorders other ameter. Based on this analysis, receiver operating char- than eAD or NP-C such as other dementia subtypes, other acteristics (ROC) curves were used to calculate the neurodegenerative disorders (e.g., Huntington’s disease, sensitivity and specificity of the parameter with the lar- multiple system atrophy, motor neuron disease), stroke, gest effect-size for differential diagnosis between NP-C hydrocephalus, epilepsy, brain tumour, traumatic brain in- and eAD, and in test parameters previously suggested to jury, major psychiatric illness not related to dementia (e.g., be useful in detecting mild NP-C [17]. drug or alcohol abuse), and other systemic diseases known to interfere with cognitive function were excluded. Results Patients Assessments A total of nine patients with NP-C were selected for inclu- Demographic data and clinical parameters were col- sion in the study, all of whom had confirmed diagnoses lected for all patients. An extensive battery of neurocog- based on molecular genetic testing. Two NP-C patients nitive tests was applied, which assessed all major who were initially selected for the study were excluded from cognitive domains. The test battery included: the the data analysis because they were not testable due to the German equivalent of the Rey Auditory Verbal Learning severity of their motor dysfunction. Individual patient Test (RAVLT) [28] for verbal span, verbal learning effi- demographics, disease characteristics, biochemical variables ciency, verbal short-term retrieval, verbal long-term re- and disability scores of the seven included NP-C patients trieval, and verbal recognition; the Rey Complex Figure are presented in Table 1. All seven patients had been symp- Test and Recognition Trial (RCFT) [29] for visuocon- tomatic (symptom duration 6–14 years) and were on on- structive abilities and visual short-term retrieval; TMT-A going miglustat treatment for a range of 3–14 months. and -B for processing speed, and set-shifting speed, re- Ataxia was the most common symptom at initial presenta- spectively [30]; the Regensburger verbal fluency test tion (three patients), followed by cataplexy and dysarthria (RWT) [31] for lexical and semantic word fluency; and (in two patients each). None of the patients in this cohort the forwards and backwards digit span tests from the showed more than mild dementia, and no patients pre- Wechsler Memory Scale (WMS) [32] for attention and sented with epileptic seizures or psychotic symptoms. Dis- working memory capacity. Among these neurocognitive ability scores indicated relatively mild disease severity [27]. parameters, lower raw scores indicate better perform- Table 2 shows a comparison of NP-C and eAD patient ance on the TMT-A, TMT-B, RCFT time to copy, the group characteristics. The mean ± SD age of the adult/ RAVLT5–6, and RAVLT5–7 scores. Higher raw scores adolescent onset NP-C patients in this cohort (34.6 ± signify better performance for all other parameters. 12.2 years) was significantly lower than that in the reference Overall cognitive function was screened using the group of eAD patients (55.1 ± 3.4 years; p = 0.004). Patients MMSE [33], where higher scores represent less impair- in both groups had a similar level of education. ment. Frontal-executive impairment was screened using Disease biomarker levels in the eAD group confirmed the Frontal Assessment Battery (FAB), where higher that all eAD patients had notable/substantial AD path- scores also indicate less impairment [34]. ology. Amyloid-ß and total tau levels were measured in four NP-C patients. Mean total tau concentration was Data analysis significantly higher in the eAD group compared with Between-group differences were evaluated using the NP-C patients (p = 0.03), and amyloid-ß levels were sig- Welch t-test for normally distributed data, and the nificantly lower among eAD patients (p < 0.01) (Table 2). non-parametric Mann-Whitney test for non-normally distributed data. Raw scores from all neurocognitive Neurocognitive test results tests were transformed into normative percentile ranks Dementia screening indicated significantly greater over- stratified by age, gender and education, where cognitive all cognitive impairment among eAD patients compared Johnen et al. Orphanet Journal of Rare Diseases (2018) 13:91 Page 4 of 10 Table 1 Demographic and disease characteristics of patients with NP-C Demographics Clinical data Biochemical variables Patient No. Age (yrs) Gender Age at Symptom Duration of Primary clinical NP-C Plasma Plasma CSF Aβ CSF tau onset duration miglustat symptoms severity ChT C-triol (pg/mL) (pg/mL) (yrs) (yrs) therapy (mo) score (nmol/h/mL) (ng/mL) 1 35 F 28 7 10 Ataxia , dysarthria, mild VSGP 6 56 112 ND ND 2 31 M 17 14 26 Dysarthria , psychomotor 14 321 267 1337 807 agitation, dysphagia, ataxia, VSGP 3 45 F 34 11 18 Cataplexy , ataxia, dysarthria, 11 321 108 789 151 dystonia, mild VSGP 4 27 F 17 6 37 Cataplexy , mild ataxia 597 91 ND ND and dysarthria 5 54 F 42 12 28 Ataxia , dysarthria, VSGP, 9 367 302 ND ND mild dysphagia 6 33 F 25 8 3 Dysarthria , mild VSGP, 7 77 164 1282 313 mild ataxia 7 23 F 14 9 22 Ataxia , dystonia, mild 10 128 188 1267 354 dysarthria, VSGP, cataplexy, mild dysphagia a b Symptoms present at initial presentation; NP-C severity measured using the NP-C disability scale of Pineda et al [27], where escores ranged from 0 (best) to 24 (worst). Aβ, amyloid-beta protein; CSF cerebrospinal fluid, ChT chitotriosidase, C-triol cholestane-3β,5α,6β-triol, ND not determined. Analyte cut-off values: ChT < 100 nmol/h/mL; C-triol < 50 ng/mL; Aβ < 500 pg/mL; tau > 500 pg/mL with NP-C patients based on MMSE scores (p = 0.010). Overall, Chi-square analysis showed that impaired test While no statistical difference in frontal-executive im- parameters (i.e., those with performance scores PR < 10) pairment between NP-C and eAD patients was observed were significantly more frequent in the eAD group com- based on FAB screening (p = 0.245). pared with the NP-C group (p = 0.025). The largest dis- The frequencies of cognitive impairment in relation crepancies in the frequency of cognitive impairments to data from age-matched normative samples for between the NP-C and eAD groups were in terms of ver- both patient groups are summarised in Fig. 1.Over- bal memory deficits (all RAVLT parameters), which were all, patients with NP-C showed a cognitive profile of substantially more frequently observed in eAD patients. relatively preserved verbal episodic memory (RAVLT), Mean ± SD neurocognitive test raw scores are sum- but visuoconstruction and visual memory (RCFT re- marised in Table 3. In the majority of neurocognitive call [visual memory] and RCFT copy scores) were test parameters, significantly greater average impair- frequently impaired. Deficits in attention and execu- ment wasseenineAD compared with theNP-Cgroup. tive functions (i.e., processing speed [TMT-A], Significant between-group differences indicated greater set-shifting [TMT-B], and RWT word fluency) were degrees of impairment in eAD patients in most RAVLT also common. In contrast, patients with eAD gener- subscales (p-values from < 0.001 to 0.018), the RCFT ally showed a wider profile of cognitive impairment. copy subscale (p = 0.038) and the WMS digit span back- Deficits in verbal learning and memory (RAVLT), wards test (p = 0.037). Notably, the TMT-B score, which visuoconstruction and visual memory (RCFT), and has been highlighted as a particularly suggestive test for executive functions (TMT and verbal fluency scores) executive dysfunction in NP-C, was also significantly were similarly or more frequent than in the NP-C more impaired in the eAD group versus the NP-C group. group (p = 0.017). Table 2 Comparison of patient demographics and clinical characteristics in NP-C and eAD patients Parameter NP-C patients (n = 7) eAD patients (n = 15) Group difference p-value Age in years, mean ± SD 34.6 ± 12.2 55.1 ± 3.4 p < 0.01 Male: female, n (%): 2 (22): 7 (78) 6 (40): 9 (60) – Years in education, mean ± SD 11.6 ± 1.5 11.3 ± 1.5 p = 0.68 Amyloid-ß level (pg/ml) , mean ± SD 1168 ± 255 550 ± 148 p < 0.01 Total tau level (pg/ml) , mean ± SD 406 ± 281 860 ± 337 p = 0.03 Amyloid and tau based on N = 4 NP-C patients Johnen et al. Orphanet Journal of Rare Diseases (2018) 13:91 Page 5 of 10 Fig. 1 Neurocognitive profiles of patients with a NP-C and b eAD. Patients with eAD generally showed a wide profile of cognitive impairment with marked memory deficits, while patients with NP-C showed relatively preserved verbal memory (RAVLT), but frequent impairments in visuoconstruction, visual memory (RCFT recall [visual memory] and RCFT copy scores), and set-shifting and verbal fluency. RAVLT, Rey Auditory Verbal Learning Test; RCFT, Rey Complex Figure Test and Recognition Trial; RWT, Regensburger verbal fluency test; TMT, Trail-Making Tests A and B; WMS Wechsler Memory Scale No other cognitive tests showed significant Importantly, there did not appear to be any influence between-group differences. However, NP-C patients of neurological deficits (e.g., speech or manipulation im- showed a marginally (albeit non-significantly) worse aver- pairment) on patients’ performance of neurocognitive age performance on the RWT phonematic word fluency tests. Subscores for these domains on the NP-C disabil- (letter S) test compared with eAD patients (p =0.225). ity scale assessments showed only slight to moderate Among all of the neurocognitive tests we applied, the impairements: all subscores were ≤ 3 for all patients. greatest difference between the NP-C and eAD groups in terms of deficit frequency was in RAVLT7 (delayed Discussion verbal recall) scores. This parameter also showed the This is the first study to directly compare the neurocogni- greatest between-group effect size in terms of raw tive symptom profile of patients with NP-C with that seen scores. ROC analysis showed that this parameter dis- in a ‘reference’ group of patients with deficits due to eAD criminated well between patients with NP-C and those – the most common primary neurodegenerative dementia with eAD, with an area under the curve (AUC) of 0.981 syndrome before the age of 65 years. The detailed battery demonstrating both high sensitivity (85.7%) and high of neurocognitive tests applied in this study identified specificity (93.3%) using a cut-off of 6/15 recalled words specific, statistically significant differences between the after 30 min. Other neurocognitive tests, including those NP-C and eAD groups, which may aid in the differential previously suggested as effective in detecting mild NP-C, diagnosis of patients with early cognitive impairment and showed insufficient discriminative power (all AUC values further neurological deficits (i.e., dementia-plus syndrome) < 0.7) (Fig. 2). suggestive of possible NP-C. Johnen et al. Orphanet Journal of Rare Diseases (2018) 13:91 Page 6 of 10 Table 3 Dementia screening and neurocognitive test parameter scores in patients with NP-C and patients with eAD Test n NP-C patients (n = 7) n eAD patients (n = 15) Mean group Cohen’s d p-value difference effect-size Mean ± SD Mean ± SD Dementia screenings MMSE 4 27.0 ± 2.16 13 21.9 ± 1.9 5.1 2.5 p = 0.010 FAB 5 14.4 ± 3.3 5 11.8 ± 3.3 2.6 0.8 p = 0.245 Neurocognitive test parameters RAVLT1 (verbal span) 7 7.0 ± 3.1 15 3.3 ± 1.6 3.7 1.5 p = 0.018 RAVLT5 (verbal learning) 7 12.9 ± 3.1 15 6.7 ± 2.7 5.6 1.9 p = 0.002 RAVLT1–5 (total learning) 7 51.0 ± 14.6 15 28.6 ± 8.7 22.4 1.9 p = 0.006 RAVLT6 (recall after interference) 7 10.1 ± 4.4 15 3.3 ± 2.5 6.9 1.9 p = 0.005 RAVLT5–6 (forgetting after interference) 7 2.1 ± 1.8 15 3.5 ± 1.9 −1.3 − 0.7 p = 0.141 RAVLT7 (delayed verbal recall) 7 10.7 ± 3.5 15 1.9 ± 2.1 8.8 3.0 p < 0.001 RAVLT5–7 (forgetting after delay) 7 1.6 ± 1.1 15 4.8 ± 2.1 −3.2 −1.9 p < 0.001 RAVLT8 (recognition) 7 13.7 ± 1.9 14 11.3 ± 3.9 2.4 0.5 p = 0.058 RCFT copy (visuoconstructional ability) 5 29.8 ± 4.1 13 20.7 ± 12.9 9.1 0.9 p = 0.038 RCFT time to copy (seconds) 5 233.4 ± 95.9 8 306.5 ± 123.5 − 73.1 −0.7 p = 0.259 RCFT recall (visual memory) 5 12.3 ± 8.0 13 4.8 ± 4.8 7.5 1.1 p = 0.107 TMT-A (processing speed; seconds) 7 61.6 ± 40.7 14 93.1 ± 81.5 −31.5 −0.3 p = 0.252 TMT-B (set shifting; seconds) 7 119.0 ± 54.4 10 226.7 ± 101.9 − 107.7 −1.3 p = 0.017 RWT word fluency (1 min animals) 7 17.3 ± 5.1 13 14.8 ± 5.4 2.4 0.5 p = 0.335 RWT word fluency (1 min letter S) 7 8.4 ± 3.1 14 11.4 ± 7.8 −3.0 −0.5 p = 0.225 WMS digit span (forwards) 6 7.0 ± 2.4 14 5.9 ± 1.4 1.1 0.6 p = 0.353 WMS digit span (backwards) 6 5.7 ± 1.5 14 3.8 ± 1.9 1.9 1.1 p = 0.037 a b Effect sizes calculated according to methodology for Cohen’s d statistic for paired t-tests; p-values specified based on the Welch t-test, unless otherwise specified; p-values based on the Mann-Whitney test; For TMT-A, TMT-B, RCFT time to copy, RAVLT5–6, and RAVLT5–7 subscales, lower scores indicate better performance. Higher raw scores signify better performance for all other neurocognitive test parameters. For dementia screening scores, higher scores represent less impairment on the MMSE and the FAB. FAB Frontal Assessment Battery, MMSE Mini-Mental Status Evaluation, RAVLT Rey Auditory Verbal Learning Test, RCFT Rey Complex Figure Test and Recognition Trial, RWT Regensburger verbal fluency test, TMT Trail-Making Tests A and B, WMS Wechsler Memory Scales NP-C and AD share a number of pathophysiological specifically, positron emission tomography (PET) studies similarities such as increased levels of brain tau protein, in adult NP-C patients have indicated that frontal-lobe amyloid deposition, the presence of neurofibrillary tan- hypometabolism may contribute to frontal-executive gles, and the influence of apolipoprotein E ε4 genotype deficits [44, 45]. [6–9, 35]. Other neurological commonalities include Overall, taking patient age, gender, and education into basal forebrain cholinergic system alterations and account, eAD patients showed wider, more generalised chronic neuroinflammation [36–38]. However, there are impairments in affected cognitive domains compared distinct differences in the localisation of neuropathology with the profile seen in NP-C patients in the current between the two conditions. Purkinje cells in the cere- study. Deficits were also more frequent and greater in bellum are the most affected neurons in NP-C, with magnitude in eAD on most of the neurocognitive tests NFTs mainly found in subcortical structures, while le- that we employed. Bergeron et al. reported that in con- sions in AD are mainly seen in the neocortical and med- trast to NP-C, the general cognitive profile in AD is ial temporal lobes [6, 15, 39, 40]. It therefore follows characterized predominantly by memory dysfunction that certain clinical neurocognitive differences exist be- [15]. In the current study, the key neurocognitive differ- tween NP-C and eAD patients [16, 17]. ence between NP-C and eAD was also observed in terms MRI and diffusion tensor imaging (DTI) studies in of verbal memory performance, as measured by the NP-C patients have suggested that cerebral atrophy in RAVLT. Most RAVLT subscores (excluding forgetfulness key deep grey matter regions including the hippocam- after interference) were statistically significantly more pus, thalamus, cerebellum, and striatum, as well as impaired in eAD patients. In particular, the RAVLT7 major white-matter tracts, may account for global im- subscale (delayed verbal recall), an indicator of verbal pairments in cognitive function in NP-C [41–43]. More memory that has been shown to correlate with Johnen et al. Orphanet Journal of Rare Diseases (2018) 13:91 Page 7 of 10 Fig. 2 Receiver operating curves (ROC) analyses of key neurocognitive test raw scores in eAD and NP-C patients. A high AUC for the RAVLT-7 but low to moderate AUCs for the TMT-A, TMT-B, RWT letter fluency (S-words) and RWT semantic fluency (animals) were observed. Area-under-curve values: a 0.981 for RAVLT-7; b 0.362 for TMT-A; c 0.143 for TMT-B; d 0.444 for RWT letter fluency (S-words); e 0.665 for RWT semantic fluency (animals). ROC, Receiver operating characteristics curve analysis; RAVLT, Rey Auditory Verbal Learning Test; RWT, Regensburger Word Fluency Test; TMT, Trail Making Test hippocampal pathology [46, 47], showed the greatest ef- Alzheimer’s disease (CERAD) word list recall test also fect size between the two groups. Our ROC analyses addresses this neurocognitive domain through delayed suggested that delayed verbal recall also showed good recall of a learned word list and is faster to apply than sensitivity and specificity in distinguishing between the RAVLT. However, the disadvantage of this test is NP-C and eAD patients. Relatively preserved verbal that it is geared toward dementia patients of higher age, memory has recently also been reported in a French co- and normative data for younger patients are not avail- hort of 21 patients with mild adult NP-C [16]. able [17]. The Free and Cued Selective Reminding Test With regard to alternative tests for verbal episodic (FCSRT) is an alternative verbal memory test that, simi- memory, the Consortium to Establish a Registry for lar to the RAVLT, provides normative data versus Johnen et al. Orphanet Journal of Rare Diseases (2018) 13:91 Page 8 of 10 younger adults, and might therefore also be suited to developmental disorder, poor school performance, and cognitive assessments in NP-C [16]. learning disabilities [4, 15, 48]. One difficulty in this re- A number of previous studies in patients with NP-C spect is that not all neurocognitive tests are similarly ap- have described impaired executive functions (e.g. plicable in different age-groups, particularly in patients set-shifting and word fluency) and attention as the pri- with the juvenile-onset or early adolescent-onset forms: mary neurocognitive deficit in NP-C [5, 15–17, 19]. Our this constitutes a problem. For instance, Klarner et al. used findings are in line with previous published evidence, in the CERAD battery to determine the cognitive profile of that executive functions as measured by the TMT-A/B patients with NP-C [17]. However, this test battery is not and word fluency as measured by the RWT, were the associated with normative data for patients aged < 50 years most frequently impaired domains in NP-C patients and frequently produces ceiling effects in younger pa- [17]. However, the frequency and magnitude of these im- tients. In contrast, the RCFT, RAVLT, TMT, RWT and pairments were actually lower among NP-C patients on WMS-digit span tests included in the current study all the majority of neurocognitive tests assessing attention provide normative data for both children, as well as older and executive functions versus eAD. As a result, these age groups. The current test battery may therefore be tests cannot be expected to function as differential cog- more suited for use in NP-C than classical senile dementia nitive markers on their own. test batteries like the CERAD or dementia screenings. Interestingly, the RWT word fluency (letters) task was Finally, structural neuroimaging data to investigate po- the only neurocognitive measure on which NP-C patients tential links between memory scores and medial temporal were more impaired than eAD patients at the raw score lobe atrophy in eAD versus NP-C, and the possible rela- level. However, the NP-C versus eAD effect-size seen with tionship between frontal executive functions and frontal/ this parameter was small and non-significant, and the fre- subcortical atrophy with executive dysfunction, are a sub- quency of impaired cases (compared with age-matched ject for potential, future studies. In addition, more specific normative data) on this test was similar in both groups. cognitive and behavioural functions associated with While global dementia screening tools such as the frontal lobe integrity (e.g., social cognition tests, abnormal MMSE, or more specific tools such as the FAB may not behaviour) may also function as differential markers for be powerful enough to distinguish specific neurocogni- NP-C. However, these aspects have not yet been tested in tive deficits between NP-C and eAD, the majority of detail in this rare patient group. NP-C patients in our study presented with impaired per- formance on both of these scales. In particular, FAB may Conclusion prove useful for this purpose in clinical practice as it ef- In conclusion, based on our findings, we recommend that fectively assesses executive dysfunctions in a general dementia screening assessments (e.g., MMSE, time-economic way. Overall, due to lack of specificity FAB) should not be used in isolation to evaluate cognitive and the lack of normative age-matched control data in performance in patients with suspected NP-C, as these pa- younger patients, these screening tests cannot substitute tients may present with milder cognitive deficits than pa- an extensive neurocognitive assessment, particularly in tients with eAD. Such screening studies may therefore addressing memory and executive function. prevent the detection of important differences in the neu- The small sample size, particularly of the NP-C group rocognitive profiles between eAD and NP-C. Detailed, yet is a weakness of this study. However, this is due to the easy-to-apply neurocognitive tests such as the RAVLT extreme rarity of NP-C and the single-centre nature of assessing verbal episodic memory, the TMT-B assessing this study. The between-group differences in age in the set-shifting and a verbal letter fluency task, with normative NP-C and eAD patients introduces a further degree of data available for age-groups typically associated with uncertainty, with patient age acting as a potential con- NP-C, appear more appropriate. Further studies in larger founding factor in our statistical analyses. Age has an numbers of patients are warranted. Parallel studies of such important influence on the range and severity of cogni- neurocognitive scales alongside imaging parameters (e.g., tive, neurological, visceral and psychiatric symptoms in based on MRI volumetry or DTI) would allow further NP-C [1, 2, 15]. It is notable that patients with eAD in insight through the assessment of underlying neuroana- this study were significantly older than those with NP-C. tomical correlates of cognitive dysfunction in NP-C. While this could be considered as a study limitation, it Abbreviations should also be noted that, in general, cognitive impair- AUC: Area under the curve; DTI: Diffusion tensor imaging; eAD: Early ment in NP-C has a lower age at onset compared with Alzheimer’s disease; EOCD: Early-onset cognitive decline; FAB: Frontal eAD. While cognitive deterioration is observed in most Assessment Battery; FAB: Frontal assessment battery; FCSRT: Free and Cued Selective Reminding Test; FTD: Frontotemporal dementia; MMSE: Mini-mental patients with adolescent/adult-onset NP-C [1, 2, 15], status examination; MRI: Magnetic resonance imaging; NP-C: Niemann-Pick EOCD is most usually recognized among patients with disease type C; PET: Positron emission tomography; PR: Percentile rank; childhood-onset NP-C in the form of intellectual RAVLT: Rey Auditory Verbal Learning Test; RCFT: Rey Complex Figure Test Johnen et al. Orphanet Journal of Rare Diseases (2018) 13:91 Page 9 of 10 and Recognition Trial; ROC: Receiver operating characteristics; 12. Schicks J, Muller Vom Hagen J, Bauer P, Beck-Wodl S, Biskup S, Krägeloh- RWT: Regensburger verbal fluency test; TMT-A/TMT-B: Trail Making tests A & Mann I, et al. Niemann-Pick type C is frequent in adult ataxia with cognitive B; WMS: Wechsler Memory Scale decline and vertical gaze palsy. Neurology. 2013;80:1169–70. 13. Bauer P, Balding DJ, Klünemann HH, Linden DE, Ory DS, Pineda M, et al. Acknowledgements Genetic screening for Niemann-Pick disease type C in adults with Matthew Reilly PhD at InTouch Medical Ltd. provided medical writing neurological and psychiatric symptoms: findings from the ZOOM study. support in the preparation of this manuscript, paid for by the University Hum Mol Genet. 2013;22:4349–56. Hospital of Münster, Münster, Germany. 14. Maubert A, Hanon C, Sedel F. Psychiatric disorders in adult form of Niemann-Pick disease type C. L’Encephale. 2016;42:208–13. Availability of data and materials 15. Bergeron D, Poulin S, Laforce R Jr. Cognition and anatomy of adult The datasets used and/or analysed during the current study are available Niemann-Pick disease type C: insights for the Alzheimer field. Cogn from the corresponding author on reasonable request. Neuropsychol. 2017;35:1–14. https://www.tandfonline.com/doi/full/10.1080/ 02643294.2017.1340264. Authors’ contributions 16. Heitz C, Epelbaum S, Nadjar Y. Cognitive impairment profile in adult All authors had roles in the conception and design of the study, analysis and patients with Niemann Pick type C disease. Orphanet J Rare Dis. 2017; interpretation of the clinical data, and drafting the article content or [accepted October 2017] providing critical review. All authors provided approval of the final 17. Klarner B, Klünemann HH, Lurding R, Aslanidis C, Rupprecht R. manuscript for submission. 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