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July 26, 2016; 87 (4) Article

Presymptomatic cognitive decline in familial frontotemporal dementia

A longitudinal study

Lize C. Jiskoot, Elise G.P. Dopper, Tom den Heijer, Reinier Timman, Rick van Minkelen, John C. van Swieten, Janne M. Papma
First published June 29, 2016, DOI: https://doi.org/10.1212/WNL.0000000000002895
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Abstract

Objective: In this prospective cohort study, we performed a 2-year follow-up study with neuropsychological assessment in the presymptomatic phase of familial frontotemporal dementia (FTD) due to GRN and MAPT mutations to explore the prognostic value of neuropsychological assessment in the earliest FTD disease stages.

Methods: Healthy, at-risk, first-degree relatives of patients with FTD who had a MAPT (n = 13) or GRN mutation (n = 30) and healthy controls (n = 39) underwent neuropsychological assessment at baseline and 2-year follow-up. We investigated baseline and longitudinal differences, as well as relationship with age and estimated years before symptom onset.

Results: At baseline, GRN mutation carriers showed lower scores on mental processing speed than healthy controls (p = 0.043). Two years later, MAPT mutation carriers showed a steeper decline than GRN mutation carriers on social cognition (p = 0.002). Older age was related to cognitive decline in visuoconstruction (p = 0.005) and social cognition (p = 0.026) in MAPT. Memory significantly declined from 8 to 6 years before estimated symptom onset in MAPT and GRN mutation carriers, respectively, and language and social cognition declined only in MAPT mutation carriers from 7 to 5 years before estimated symptom onset, respectively (p < 0.05).

Conclusions: Using longitudinal neuropsychological assessment, we detected gene-specific neuropsychological patterns of decline in, e.g., social cognition, memory, and visuoconstruction. Our results confirm the prognostic value of neuropsychological assessment as a potential clinical biomarker in the presymptomatic phase of familial FTD.

GLOSSARY

bvFTD=
behavioral variant frontotemporal dementia;
FTD=
frontotemporal dementia;
HC=
healthy control;
LDST=
Letter Digit Substitution Test;
RAVLT=
Rey Auditory Verbal Learning Test;
ToM=
theory of mind

Frontotemporal dementia (FTD) is a young-onset type of dementia, with a clinically heterogeneous presentation of either behavioral disturbances (behavioral variant [bvFTD]) and/or language deterioration.1 The neuropsychological profile is characterized by deficits in executive function, language, and social cognition, while memory and visuoconstruction are relatively spared.2,–,4

Because FTD has an autosomal dominant inheritance pattern in up to 40% (mutations in microtubule-associated protein tau [MAPT], progranulin [GRN], and chromosome 9 open reading frame 72 [C9orf72] genes),5 we can define mutation carriers in the presymptomatic phase.6 Studying this phase by means of longitudinal neuropsychological assessment could enable us to recognize cognitive patterns toward disease onset, which may serve as sensitive biomarkers for symptomatic onset in clinical practice and upcoming therapeutic trials.

Neuropsychological assessments in the presymptomatic stage of familial FTD are scarcely reported,7 with most studies being case8,–,10 or small family-based studies.7,11,–,16 A large multicenter cross-sectional study of presymptomatic FTD17 demonstrated the earliest neuropsychometric changes in mutation carriers around 5 years before expected symptom onset, showing naming and executive function decline.

In the present study, we explored the prognostic value of neuropsychological assessment in the presymptomatic phase of familial FTD due to GRN and MAPT mutations.18 We performed a 2-year follow-up study in which we investigated baseline and longitudinal differences, and the relationship with age (i.e., approaching symptom onset). By means of an exploratory analysis, we estimated how many years before symptom onset mutation carriers start to cognitively decline compared to controls.

METHODS

Participants.

We recruited 84 healthy, 50% at-risk family members from Dutch pathologically confirmed genetic FTD families (either GRN or MAPT) for our prospective cohort study between December 2009 and March 2011, as previously described.18 Because the C9orf72 repeat expansion was not yet discovered at the start of our study, we did not include families with this mutation in this report. All participants underwent standardized neuropsychological assessment at baseline and 2-year follow-up. The majority of the participants (>75%) came to the study visits with a knowledgeable informant (e.g., siblings, spouses); they were interviewed on possible cognitive and/or behavioral changes. We defined participants as presymptomatic when established criteria for FTD were not fulfilled,2 i.e., no cognitive disorders (≥2 SDs below normative data mean) on neuropsychological testing and no progressive behavior deterioration or functional decline. We excluded participants with a history of other neurologic or severe psychiatric illness. We excluded 2 non–mutation carriers from 2 GRN families, as they had cognitive disorders (≥2 SD below mean) on multiple domains. We defined the expected symptom onset for each participant as the mean onset age per family. We then calculated years from estimated symptom onset by subtracting the estimated onset age from the actual age per participant.

Standard protocol approvals, registrations, and patient consents.

We obtained written informed consent from all participants. The study has been approved by the Medical and Ethical Review Committee of the Erasmus Medical Center. All clinical investigators and participants were blinded to the participants' genetic status.

DNA sequencing.

We performed venipunction for DNA sequencing at baseline. We sequenced DNA of both strands of exon 2–13 of GRN (NM_002087.2) and strands of exons 2 and 11–15 of MAPT (NM_005910.3). We assigned participants either to the mutation carrier (n = 43; 13 MAPT, 30 GRN) or healthy control (HC) group (n = 39; 9 MAPT, 30 GRN).14 See table e-1 on the Neurology® Web site at Neurology.org for specific MAPT and GRN mutations, sample size, carriers' age, and mean family onset per mutation.

Neuropsychological assessment.

We selected neuropsychological tests to assess global cognitive functioning, as well as 6 cognitive domains: (1) language, (2) attention and mental processing speed, (3) executive functioning, (4) social cognition, (5) memory, and (6) visuoconstruction. We assessed global cognitive functioning by means of the Mini-Mental State Examination.e1 We assessed language by means of the 60-item Boston Naming Test,e2 verbal Semantic Association Test,e3 categorical (animals) and letter fluency,e4 and ScreeLing phonology.e5 We rated attention and mental processing speed with the Trail Making Test Part A,e6 Stroop Color–Word Test I and II,e7 and the Letter Digit Substitution Test (LDST).e8 We assessed executive functioning using Trail Making Test Part B,e6 Stroop Color–Word Test III,e7 and modified Wisconsin Card Sorting Test concepts.e9 We evaluated memory using the Dutch Rey Auditory Verbal Learning Test (RAVLT),e10 short Visual Association Test,e11 and Wechsler Adult Intelligence Scale–III Digit Span.e12 Clock drawing (Royall)e13 and Wechsler Adult Intelligence Scale–III Block Designe12 measured visuoconstruction. We evaluated social cognition by means of Happé cartoons (theory of mind [ToM], non–theory of mind [non-ToM])e14 and Ekman Faces.e15 We rated depressive symptoms using Beck Depression Inventory.e16 At follow-up, we assessed behavioral symptoms using the Neuropsychiatric Inventory Questionnairee17 and Cambridge Behavioural Inventory–Revised.e18 Alternate test forms were used at follow-up, when applicable (letter fluency, RAVLT, Visual Association Test). An experienced neuropsychologist administered and scored all tests.

Statistical analysis.

Statistical analyses were performed using SPSS Statistics 21.0 (IBM Corp., Armonk, NY). We set the significance level at p < 0.05 (2-tailed) across all comparisons, uncorrected for multiple comparisons because of the explorative nature of our study. For ease of interpretation, we standardized all raw neuropsychological test scores by converting them into z scores (i.e., individual test score minus the mean of HCs, divided by the SD of HCs). We calculated composite z scores for the respective 6 cognitive domains by averaging the z scores of the individual tests per time point. We considered the composite z score missing if more than half of the test scores in that domain were missing. We compared demographic data and cross-sectional baseline and follow-up z scores between groups by means of one-way analyses of covariance. We analyzed differences in sex between GRN mutation carriers, MAPT mutation carriers, and HCs using Pearson χ2 tests. We performed longitudinal comparisons by means of repeated-measures analysis of covariance, with z scores at baseline and follow-up as within-subject variable and carriership and gene as between-subject variables. We used age, sex, and education level as covariates in both cross-sectional and longitudinal comparisons. We calculated correlations per gene in order to relate cognitive decline per domain or individual test performance (Δ baseline minus follow-up z score) with age at baseline; a positive correlation therefore represented cognitive decline with older age. We used multilevel linear regression modeling to calculate how many years before estimated symptom-onset domain and individual test performance deteriorated significantly between baseline and follow-up. We excluded the 2 converters from this model (see Results). We postulated separate models per gene and each outcome. There were 2 levels in the models: the participants constituted the upper level, their repeated measures the lower level. We entered time (Δ baseline minus follow-up), mutation status, estimated years to symptom onset, and (first- and second-order) interactions as covariates. We used contrasts at various levels of the years before estimated symptom onset for the time × mutation status × years to onset interaction to determine when the time difference became significant.

RESULTS

Demographics.

Demographic data for the mutation carriers and HCs are shown in table 1. MAPT mutation carriers were younger than GRN mutation carriers (p = 0.024). The mean onset age of families carrying GRN mutations was higher than those with MAPT mutations (p < 0.001). There were no significant differences in follow-up duration or behavioral measures between mutation carriers and HCs.

View this table:
Table 1

Demographic data

Converters.

Two presymptomatic mutation carriers (1 MAPT and 1 GRN) converted to symptomatic bvFTD between baseline and follow-up, based on follow-up neuropsychological assessment and MRI scanning of the brain. Together with an in-depth interview with knowledgeable informants regarding functional and behavioral decline and confirmation of the presence of the pathogenic mutation, formal diagnostic criteria for bvFTD with definite frontotemporal lobar degeneration pathology were met.2 The MAPT (P301L) converter presented with disinhibition and the GRN (S82 fs) converter with apathy and loss of initiative. The MAPT converter declined significantly on tests for divided attention, emotion recognition (all ≥2 SDs below group mean), executive function, ToM, and fluency (all ≥1 SD). The GRN converter showed a significant decline concerning tests for divided attention, executive function, emotion recognition (all ≥2 SDs), fluency, and perceptual organization (all ≥1 SD) (tables e-2 and e-3).

Baseline neuropsychological assessment.

Table 2 shows the baseline and follow-up z scores of neuropsychological test performance in GRN and MAPT mutation carriers—HCs have been left out as they had means of zero and SD of one by definition. None of the presymptomatic participants performed at disorder level at baseline or follow-up (i.e., ≥2 SDs below normative data mean). GRN mutation carriers showed lower scores on the LDST than HCs. There were no significant differences between MAPT mutation carriers and HCs, and between GRN and MAPT mutation carriers, regarding any of the neuropsychological tests. See tables e-4 and e-5 for baseline neuropsychological test performance per specific MAPT and GRN mutation.

View this table:
Table 2

Neuropsychological baseline and follow-up data (z scores) of MAPT and GRN carriers

Longitudinal neuropsychological assessment.

From baseline to follow-up, MAPT mutation carriers significantly worsened regarding the LDST, categorical fluency, and Happé non-ToM compared to HCs (table 2), whereas no significant deterioration over time was found in GRN mutation carriers compared to HCs. MAPT mutation carriers showed a steeper decline in social cognition than GRN mutation carriers (domain score, p = 0.046; Happé non-ToM, p = 0.002). Furthermore, MAPT mutation carriers worsened regarding categorical fluency in comparison to GRN mutation carriers (p = 0.011). By excluding the converter with the MAPT mutation, Happé non-ToM remained significant (p = 0.039 compared to HCs and p = 0.032 compared to GRN mutation carriers), whereas LDST and categorical fluency were no longer significant (p = 0.082 and p = 0.098, respectively). See tables e-4 and e-5 for follow-up neuropsychological test performance per specific MAPT and GRN mutation.

Cognitive decline in relationship to age.

In MAPT mutation carriers, older age was significantly correlated with cognitive decline in the domains visuoconstruction and social cognition, and on the following individual tests: RAVLT-recall, clock drawing, and Happé non-ToM (table 3). In GRN mutation carriers, older age related to decline in RAVLT-recognition, Wisconsin Card Sorting Test, and Happé non-ToM (table 3). By excluding the MAPT converter, the correlations regarding the visuoconstruction domain as well as all individual test results remained significant. The social cognition domain was no longer significant (r = 0.586, p = 0.058). Excluding the GRN converter did not alter the significance of age correlations with domain and individual test scores. No relationship between age and cognitive decline was found in HCs (table 3).

View this table:
Table 3

Correlations between age and cognitive decline in MAPT carriers, GRN carriers, and HCs

Cognitive decline in relationship to years from estimated symptom onset.

In MAPT mutation carriers, the domains language, social cognition, and memory significantly started to decline (negative Δ) from 7, 5, and 6 years before estimated symptom onset, respectively (figure, A, D, and E) when compared with HC. Visuoconstruction showed positive z scores and therefore improvement in MAPT mutation carriers until 13 years before estimated onset, with a tendency toward decline with approaching estimated onset from then onward (figure, F). Regarding individual tests, decline between assessments was found in RAVLT immediate and delayed recall (immediate recall from 3 years before estimated onset; delayed recall from 4 years before), Ekman faces (1 year before), Boston Naming Test (from 3 years before), and categorical fluency (from 6 years before). In addition, LDST declined in MAPT mutation carriers from 7 years before estimated symptom onset. In GRN mutation carriers, the memory domain declined from 8 years before estimated symptom onset (figure, E). Regarding individual tests, Happé non-ToM declined from 5 years before estimated symptom onset.

Figure
Figure Cognitive decline in relationship to years from estimated symptom onset

Multilevel linear regression model displaying how many years before estimated symptom onset composite domain scores decline significantly between baseline and follow-up assessments in MAPT mutation carriers (dark blue), GRN mutation carriers (light blue), and healthy controls (green). Models are displayed for each cognitive domain: (A) language, (B) attention and mental processing speed, (C) executive function, (D) social cognition, (E) memory, and (F) visuoconstruction. A negative delta represents a decline in performance; a positive delta represents better performance. Brackets with p < 0.05 represent the years before estimated symptom onset in which there is a significant decline in mutation carriers compared to healthy controls. GRN = progranulin; MAPT = microtubule-associated protein tau.

DISCUSSION

This study examined a large cohort of at-risk participants from GRN and MAPT families by means of longitudinal neuropsychological assessment. We demonstrated a significant decline over time in social cognition, and a relationship between older age and decline in social cognition and memory in mutation carriers. Our exploratory model furthermore suggests cognitive decline in mutation carriers up to 8 years before estimated symptom onset. These data confirm the prognostic value of neuropsychological assessment as potential clinical biomarker in the presymptomatic phase of familial FTD.

Mutation carriers demonstrated gene-specific cognitive decline, with lower language and mental processing speed scores in MAPT mutation carriers and a steeper decline on social cognition tests in MAPT than in GRN mutation carriers. This is in line with a previous study, in which MAPT mutation carriers showed lower scores on these tests 3 decades before predicted symptom onset.12 In contrast, presymptomatic GRN mutation carriers demonstrated lower scores in attention, mental flexibility, and naming,13 visuospatial function, and working memory.14 These findings could be explained by partly overlapping but also distinct frontal and temporal atrophy patterns in MAPT and GRN mutations, resulting in different clinical presentations.19 Lower visuoconstruction scores before symptom onset in our MAPT mutation carriers are unexpected, given evidence of early parietal involvement due to GRN but not MAPT mutations.3 However, visuospatial dysfunction was also found in Pick disease, another FTD-tauopathy, later in the disease course20—follow-up studies of our cohort of presymptomatic carriers will enable us to determine the robustness of this finding. The unexpected trajectories in other domains did not reach significance, but are probably to be explained by task-familiarity at follow-up. Early executive dysfunction is widely recognized in MAPT mutations.19 Although we did not find longitudinal differences in executive function tests, we have found significant decline in categorical fluency in MAPT compared to GRN mutation carriers and HCs. One could argue the underlying construct of such language tasks, as they are verbally mediated but also require executive functions as self-monitoring and cognitive flexibility.21 With the temporal cortex mediating category fluency,21 predominant temporal lobe atrophy in MAPT mutations19 could provide a well-grounded explanation for the verbal fluency decline in our cohort.

Our finding of marked decline of ToM corresponds to the changes in social cognition and behavior characteristic for the symptomatic stage of bvFTD.4 Neuroimaging studies investigating its neural basis suggest a distributed brain network mediating different aspects of ToM processing, including the prefrontal cortex, temporal poles, and amygdala—areas particularly known for early FTD pathology.4 Consistent with this, the baseline MRI study of our cohort demonstrated lower integrity of the right uncinate fasciculus and lower prefrontal cortex connectivity in presymptomatic carriers.18 Overall, our results underline the importance of a systematic use of ToM tasks during diagnostic assessment in early FTD,4 and constitute a strong argument to implement social cognition measurements in the standard diagnostic workup.

Apparent episodic memory decline over time in relation to age and estimated symptom onset is an important finding, as marked memory deficits have been considered an exclusion criterion for FTD.2 Increasing evidence, however, suggests that memory deficits can be seen in FTD22 and neuroimaging studies have shown the contributing role of prefrontal atrophy.22 Within this line of reasoning, it is suggested that patients with FTD do not display a “true” amnesia, but memory dysfunction results from defective, frontal lobe–dependent, retrieval strategies.23 Of note, we found different profiles of memory decline in GRN and MAPT mutation carriers, with deficits in RAVLT-recall in GRN and recognition deficits in MAPT mutation carriers. It is possible that the multifactorial nature of this test places different demands on prefrontal vs medial temporal lobe functioning22—i.e., the clinical presentation of episodic memory deficits in FTD depends on the mutation involved.9,22

Estimated age at symptom onset has been used in several studies in dementia, as individual age at symptom onset is often strongly associated with parental and family onset age in autosomal dominant AD and FTD.17,24 The use of estimated age at symptom onset in FTD-GRN may be a matter of debate, as this varies between 45 and 76 years in our families with GRN mutations24—whereas the variability is smaller for MAPT mutations.17 Both converters in our cohort developed symptoms close to their predicted age at onset. Within our whole cohort, we have found a rather comparable pattern of cognitive decline in estimated age at symptom onset to the analyses with current age. Furthermore, a previous study using mean age at onset within FTD families17 has demonstrated that the carriers' age at symptom onset significantly correlates with both median and mean age at onset within the family, and that age at symptom onset of symptomatic carriers does not significantly differ from mean family onset age. Although estimated age at symptom onset has limitations, in our view, its use in an exploratory analysis is justified. With the conversion of more presymptomatic carriers to the symptomatic stage within our long-term follow-up, we will obtain more robust information about the level of congruence between estimated and actual symptom onset age.

Key strengths of our study are the large number of at-risk participants—allowing not only gene-specific analyses, but also the use of a well-defined and matched control group of family members. Moreover, the comparison of baseline and follow-up neuropsychological assessments reflects a true longitudinal study, whereas previous studies were cross-sectional in nature. Exploring our findings with and without the 2 converters has confirmed the existence of a “pure” presymptomatic cognitive profile, as results were not merely driven by cognitive decline due to clinical onset. The addition of social cognition tasks lastly adds great value to our neuropsychological battery, detecting deficits in the ToM domain that would otherwise be largely unrecognized.4 Although we applied a well-validated test protocol, it is possible that the cognitive changes may be so subtle in the presymptomatic phase that the tests used lack adequate sensitivity to small magnitudes of change or are not robust to practice effects—aspects that could have negatively influenced our results. Our large neuropsychological protocol might have increased the family-wise error rate in our data—however, we emphasize the exploratory nature of our study and therefore lack of correction for multiple comparisons. In retrospect, in light of conversion to the symptomatic phase, it would have been informative to monitor functional changes in addition to cognitive decline.

This exploratory study investigates longitudinal cognitive performance in a large cohort of individuals at risk of FTD. We provide evidence that in the absence of apparent cognitive disorders, follow-up neuropsychological assessment is able to identify gene-specific decline with approaching symptom onset in GRN and MAPT mutation carriers. These results underline the potential value of neuropsychometric testing as biomarker for monitoring FTD disease progression in clinical practice as well as endpoints in future disease-modifying medication trials. Longer follow-up as part of our longitudinal study, in which more presymptomatic mutation carriers will convert to the clinical stage, should allow us to explore the possibility of cognitive and functional prediction models.

AUTHOR CONTRIBUTIONS

Lize C. Jiskoot was involved in data collection, data analysis, and writing of the manuscript. Elise G.P. Dopper was involved in data collection and the writing process. Tom den Heijer contributed to the design of the study and the writing process. Reinier Timman contributed to the data analysis and the writing process. Rick van Minkelen was involved in data collection regarding genetic status and the writing process. John C. van Swieten contributed to the design of the study, data collection and interpretation, and writing of the manuscript. Janne M. Papma contributed to the design of the study, data interpretation, and writing of the manuscript.

STUDY FUNDING

This work was supported by Dioraphte Foundation grant 09-02-03-00, the Association for Frontotemporal Dementias research grant 2009, The Netherlands Organization for Scientific Research (NWO) grant HCMI 056-13-018, and Netherlands Alzheimer Foundation.

DISCLOSURE

The authors report no disclosures relevant to the manuscript. Go to Neurology.org for full disclosures.

ACKNOWLEDGMENT

The authors thank all the participants and their families for taking part in the study.

Footnotes

  • ↵* These authors contributed equally to this work.

  • Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.

  • Supplemental data at Neurology.org

  • Received December 9, 2015.
  • Accepted in final form April 14, 2016.

REFERENCES

  1. 1.↵
    1. Snowden JS,
    2. Pickering-Brown SM,
    3. Mackenzie IR, et al.
    Progranulin gene mutations associated with frontotemporal dementia and progressive non-fluent aphasia. Brain 2006;129:3091–3102.
    OpenUrlAbstract/FREE Full Text
  2. 2.↵
    1. Rascovsky K,
    2. Hodges JR,
    3. Knopman D, et al.
    Sensitivity of revised diagnostic criteria for the behavioural variant of frontotemporal dementia. Brain 2011;134:2456–2477.
    OpenUrlAbstract/FREE Full Text
  3. 3.↵
    1. Seelaar H,
    2. Rohrer JD,
    3. Pijnenburg Y,
    4. Fox NC,
    5. van Swieten JC
    . Clinical, genetic and pathological heterogeneity of frontotemporal dementia: a review. J Neurol Neurosurg Psychiatry 2011;82:476–486.
    OpenUrlAbstract/FREE Full Text
  4. 4.↵
    1. Adenzato M,
    2. Cavallo M,
    3. Enrici I
    . Theory of mind ability in the behavioural variant of frontotemporal dementia: an analysis of the neural, cognitive, and social levels. Neuropsychologia 2010;48:2–12.
    OpenUrlCrossRefPubMed
  5. 5.↵
    1. Warren JD,
    2. Rohrer JD,
    3. Rossor MN
    . Clinical review: frontotemporal dementia. BMJ 2013;347:f4827.
    OpenUrlFREE Full Text
  6. 6.↵
    1. Rabinovici GD,
    2. Boeve BF
    . Imaging prodromal FTD: seeing the future through PET crystals. Neurology 2013;81:1282–1283.
    OpenUrlAbstract/FREE Full Text
  7. 7.↵
    1. Hallam BJ,
    2. Jacova C,
    3. Hsiung GY, et al.
    Early neuropsychological characteristics of progranulin mutation carriers. J Int Neuropsychol Soc 2014;20:694–703.
    OpenUrlPubMed
  8. 8.↵
    1. Janssen JC,
    2. Schott JM,
    3. Cipolotti L, et al.
    Mapping the onset and progression of atrophy in familial frontotemporal lobar degeneration. J Neurol Neurosurg Psychiatry 2005;76:162–168.
    OpenUrlAbstract/FREE Full Text
  9. 9.↵
    1. Rohrer JD,
    2. Warren JD,
    3. Barnes J, et al.
    Mapping the progression of progranulin-associated frontotemporal lobar degeneration. Nat Clin Pract Neurol 2008;4:455–460.
    OpenUrlCrossRefPubMed
  10. 10.↵
    1. Spina S,
    2. Farlow MR,
    3. Unverzagt FW, et al.
    The tauopathy associated with mutation +3 in intron 10 of tau: characterization of the MSTD family. Brain 2008;131:72–89.
    OpenUrlAbstract/FREE Full Text
  11. 11.↵
    1. Ferman TJ,
    2. McRae CA,
    3. Arvanitakis Z,
    4. Tsuboi Y,
    5. Vo A,
    6. Wszolek ZK
    . Early and pre-symptomatic neuropsychological dysfunction in the PPND family with the N279K tau mutation. Parkinsonism Relat Disord 2003;9:265–270.
    OpenUrlPubMed
  12. 12.↵
    1. Geschwind DH,
    2. Robidoux J,
    3. Alarcón M, et al.
    Dementia and neurodevelopmental predisposition: cognitive dysfunction in presymptomatic subjects precedes dementia by decades in frontotemporal dementia. Ann Neurol 2001;50:741–746.
    OpenUrlCrossRefPubMed
  13. 13.↵
    1. Barandiaran M,
    2. Estanga A,
    3. Moreno F, et al.
    Neuropsychological features of asymptomatic c.709-1G>A progranulin mutation carriers. J Int Neuropsychol Soc 2012;18:1086–1090.
    OpenUrlPubMed
  14. 14.↵
    1. Pievani M,
    2. Paternico D,
    3. Benussi L, et al.
    Pattern of structural and functional brain abnormalities in asymptomatic granulin mutation carriers. Alzheimers Dement 2014;10(suppl 5):S354–S363.e1.
    OpenUrlPubMed
  15. 15.↵
    1. Borroni B,
    2. Alberici A,
    3. Premi E, et al.
    Brain magnetic resonance imaging structural changes in a pedigree of asymptomatic progranulin mutation carriers. Rejuvenation Res 2008;11:585–595.
    OpenUrlCrossRefPubMed
  16. 16.↵
    1. Borroni B,
    2. Alberici A,
    3. Cercignani M, et al.
    Granulin mutation drives brain damage and reorganization from preclinical to symptomatic FTLD. Neurobiol Aging 2012;33:2506–2520.
    OpenUrlCrossRefPubMed
  17. 17.↵
    1. Rohrer JD,
    2. Nicholas JM,
    3. Cash DM, et al.
    Presymptomatic cognitive and neuroanatomical changes in genetic frontotemporal dementia in the Genetic Frontotemporal Dementia Initiative (GENFI) Study: a cross-sectional analysis. Lancet Neurol 2015;14:253–262.
    OpenUrlCrossRefPubMed
  18. 18.↵
    1. Dopper EG,
    2. Rombouts SA,
    3. Jiskoot LC, et al.
    Structural and functional brain connectivity in presymptomatic familial frontotemporal dementia. Neurology 2014;83:e19–e26.
    OpenUrlAbstract/FREE Full Text
  19. 19.↵
    1. Rohrer JD,
    2. Ridgway GR,
    3. Modat M, et al.
    Distinct profiles of brain atrophy in frontotemporal lobar degeneration caused by progranulin and tau mutations. Neuroimage 2010;53:1070–1076.
    OpenUrlCrossRefPubMed
  20. 20.↵
    1. Irwin DJ,
    2. Brettschneider J,
    3. McMillan CT, et al.
    Deep clinical and neuropathological phenotyping of Pick disease. Ann Neurol 2016;79:272–287.
    OpenUrlPubMed
  21. 21.↵
    1. Baldo JV,
    2. Schwartz S,
    3. Wilkins D,
    4. Dronkers NF
    . Role of frontal versus temporal cortex in verbal fluency as revealed by voxel-based lesion symptom mapping. J Int Neuropsychol Soc 2006;12:896–900.
    OpenUrlCrossRefPubMed
  22. 22.↵
    1. Hornberger M,
    2. Piguet O
    . Episodic memory in frontotemporal dementia: a critical review. Brain 2012;135:678–692.
    OpenUrlAbstract/FREE Full Text
  23. 23.↵
    1. Collette F,
    2. Van der Linden M,
    3. Salmon E
    . Dissociation between controlled and automatic processes in the behavioral variant of fronto-temporal dementia. J Alzheimers Dis 2010;22:897–907.
    OpenUrlPubMed
  24. 24.↵
    1. van Swieten JC,
    2. Heutink P
    . Mutations in progranulin (GRN) within the spectrum of clinical and pathological phenotypes of frontotemporal dementia. Lancet Neurol 2008;7:965–974.
    OpenUrlCrossRefPubMed
  25. 25.
    1. Verhage F
    Intelligence and Age: Study with Dutch People Aged 12–77. Assen: Van Gorcum; 1964.

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