%0 Journal Article %J J Alzheimers Dis %D 2018 %T Neuropsychiatric Symptoms Complicating the Diagnosis of Alzheimer's Disease: A Case Report. %A Eikelboom, Willem S %A van Rooij, Jeroen G J %A van den Berg, Esther %A Coesmans, Michiel %A Jiskoot, Lize C %A Singleton, Ellen %A Ossenkoppele, Rik %A van Swieten, John C %A Seelaar, Harro %A Papma, Janne M %X

Neuropsychiatric symptoms (NPS) are increasingly recognized as a core element of Alzheimer's disease (AD); however, clinicians still consider AD primarily as a cognitive disorder. We describe a case in which the underrecognition of NPS as part of AD resulted in substantial delay of an AD diagnosis, a wrong psychiatric diagnosis, and the organization of inappropriate care. The aim of this paper is to acknowledge NPS as an (early) manifestation of AD and to suggest features that may point toward underlying AD in older adults with late-life behavioral changes.

%B J Alzheimers Dis %V 66 %P 1363-1369 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/30412494?dopt=Abstract %R 10.3233/JAD-180700 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Single Subject Classification of Alzheimer's Disease and Behavioral Variant Frontotemporal Dementia Using Anatomical, Diffusion Tensor, and Resting-State Functional Magnetic Resonance Imaging. %A Bouts, Mark J R J %A Möller, Christiane %A Hafkemeijer, Anne %A van Swieten, John C %A Dopper, Elise %A van der Flier, Wiesje M %A Vrenken, Hugo %A Wink, Alle Meije %A Pijnenburg, Yolande A L %A Scheltens, Philip %A Barkhof, Frederik %A Schouten, Tijn M %A de Vos, Frank %A Feis, Rogier A %A van der Grond, Jeroen %A de Rooij, Mark %A Rombouts, Serge A R B %X

BACKGROUND/OBJECTIVE: Overlapping clinical symptoms often complicate differential diagnosis between patients with Alzheimer's disease (AD) and behavioral variant frontotemporal dementia (bvFTD). Magnetic resonance imaging (MRI) reveals disease specific structural and functional differences that aid in differentiating AD from bvFTD patients. However, the benefit of combining structural and functional connectivity measures to-on a subject-basis-differentiate these dementia-types is not yet known.

METHODS: Anatomical, diffusion tensor (DTI), and resting-state functional MRI (rs-fMRI) of 30 patients with early stage AD, 23 with bvFTD, and 35 control subjects were collected and used to calculate measures of structural and functional tissue status. All measures were used separately or selectively combined as predictors for training an elastic net regression classifier. Each classifier's ability to accurately distinguish dementia-types was quantified by calculating the area under the receiver operating characteristic curves (AUC).

RESULTS: Highest AUC values for AD and bvFTD discrimination were obtained when mean diffusivity, full correlations between rs-fMRI-derived independent components, and fractional anisotropy (FA) were combined (0.811). Similarly, combining gray matter density (GMD), FA, and rs-fMRI correlations resulted in highest AUC of 0.922 for control and bvFTD classifications. This, however, was not observed for control and AD differentiations. Classifications with GMD (0.940) and a GMD and DTI combination (0.941) resulted in similar AUC values (p = 0.41).

CONCLUSION: Combining functional and structural connectivity measures improve dementia-type differentiations and may contribute to more accurate and substantiated differential diagnosis of AD and bvFTD patients. Imaging protocols for differential diagnosis may benefit from also including DTI and rs-fMRI.

%B J Alzheimers Dis %V 62 %P 1827-1839 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29614652?dopt=Abstract %R 10.3233/JAD-170893 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Three VCP Mutations in Patients with Frontotemporal Dementia. %A Wong, Tsz Hang %A Pottier, Cyril %A Hondius, David C %A Meeter, Lieke H H %A van Rooij, Jeroen G J %A Melhem, Shami %A van Minkelen, Rick %A van Duijn, Cornelia M %A Rozemuller, Annemieke J M %A Seelaar, Harro %A Rademakers, Rosa %A van Swieten, John C %X

Valosin-containing protein (VCP) is involved in multiple cellular activities. Mutations in VCP lead to heterogeneous clinical presentations including inclusion body myopathy with Paget's disease of the bone, frontotemporal dementia and amyotrophic lateral sclerosis, even in patients carrying the same mutation. We screened a cohort of 48 patients with familial frontotemporal dementia (FTD) negative for MAPT, GRN, and C9orf72 mutations for other known FTD genes by using whole exome sequencing. In addition, we carried out targeted sequencing of a cohort of 37 patients with frontotemporal lobar degeneration with Transactive response DNA-binding protein 43 (TDP-43) subtype from the Netherlands Brain bank. Two novel (p.Thr262Ser and p.Arg159Ser) and one reported (p.Met158Val) VCP mutations in three patients with a clinical diagnosis of FTD were identified, and were absence in population-match controls. All three patients presented with behavioral changes, with additional semantic deficits in one. No signs of Paget or muscle disease were observed. Pathological examination of the patient with VCP p.Arg159Ser mutation showed numerous TDP-43 immunoreactive (IR) neuronal intranuclear inclusions (NII) and dystrophic neurites (DN), while a lower number of NII and DN were observed in the patient with the VCP p.Thr262Ser mutation. Pathological findings of both patients were consistent with FTLD-TDP subtype D. Furthermore, only rare VCP-IR NII was observed in both cases. Our study expands the clinical heterogeneity of VCP mutations carriers, and indicates that other additional factors, such as genetic modifiers, may determine the clinical phenotype.

%B J Alzheimers Dis %V 65 %P 1139-1146 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/30103325?dopt=Abstract %R 10.3233/JAD-180301 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Differential Hemispheric Predilection of Microstructural White Matter and Functional Connectivity Abnormalities between Respectively Semantic and Behavioral Variant Frontotemporal Dementia. %A Meijboom, Rozanna %A Steketee, Rebecca M E %A Ham, Leontine S %A van der Lugt, Aad %A van Swieten, John C %A Smits, Marion %X

Semantic dementia (SD) and behavioral variant frontotemporal dementia (bvFTD), subtypes of frontotemporal dementia, are characterized by distinct clinical symptoms and neuroimaging features, with predominant left temporal grey matter (GM) atrophy in SD and bilateral or right frontal GM atrophy in bvFTD. Such differential hemispheric predilection may also be reflected by other neuroimaging features, such as brain connectivity. This study investigated white matter (WM) microstructure and functional connectivity differences between SD and bvFTD, focusing on the hemispheric predilection of these differences. Eight SD and 12 bvFTD patients, and 17 controls underwent diffusion tensor imaging and resting state functional MRI at 3T. Whole-brain WM microstructure was assessed to determine distinct WM tracts affected in SD and bvFTD. For these tracts, diffusivity measures and lateralization indices were calculated. Functional connectivity was established for GM regions affected in early stage SD or bvFTD. Results of a direct comparison between SD and bvFTD are reported. Whole-brain WM microstructure abnormalities were more pronounced in the left hemisphere in SD and bilaterally- with a slight predilection for the right- in bvFTD. Lateralization of tract-specific abnormalities was seen in SD only, toward the left hemisphere. Functional connectivity of disease-specific regions was mainly decreased bilaterally in SD and in the right hemisphere in bvFTD. SD and bvFTD show WM microstructure and functional connectivity abnormalities in different regions, that are respectively more pronounced in the left hemisphere in SD and in the right hemisphere in bvFTD. This indicates differential hemispheric predilection of brain connectivity abnormalities between SD and bvFTD.

%B J Alzheimers Dis %V 56 %P 789-804 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28059782?dopt=Abstract %R 10.3233/JAD-160564 %0 Journal Article %J J Alzheimers Dis %D 2017 %T A Longitudinal Study on Resting State Functional Connectivity in Behavioral Variant Frontotemporal Dementia and Alzheimer's Disease. %A Hafkemeijer, Anne %A Möller, Christiane %A Dopper, Elise G P %A Jiskoot, Lize C %A van den Berg-Huysmans, Annette A %A van Swieten, John C %A van der Flier, Wiesje M %A Vrenken, Hugo %A Pijnenburg, Yolande A L %A Barkhof, Frederik %A Scheltens, Philip %A van der Grond, Jeroen %A Rombouts, Serge A R B %X

BACKGROUND/OBJECTIVE: Alzheimer's disease (AD) and behavioral variant frontotemporal dementia (bvFTD) are the most common types of early-onset dementia. We applied longitudinal resting state functional magnetic resonance imaging (fMRI) to delineate functional brain connections relevant for disease progression and diagnostic accuracy.

METHODS: We used two-center resting state fMRI data of 20 AD patients (65.1±8.0 years), 12 bvFTD patients (64.7±5.4 years), and 22 control subjects (63.8±5.0 years) at baseline and 1.8-year follow-up. We used whole-network and voxel-based network-to-region analyses to study group differences in functional connectivity at baseline and follow-up, and longitudinal changes in connectivity within and between groups.

RESULTS: At baseline, connectivity between paracingulate gyrus and executive control network, between cuneal cortex and medial visual network, and between paracingulate gyrus and salience network was higher in AD compared with controls. These differences were also present after 1.8 years. At follow-up, connectivity between angular gyrus and right frontoparietal network, and between paracingulate gyrus and default mode network was lower in bvFTD compared with controls, and lower compared with AD between anterior cingulate gyrus and executive control network, and between lateral occipital cortex and medial visual network. Over time, connectivity decreased in AD between precuneus and right frontoparietal network and in bvFTD between inferior frontal gyrus and left frontoparietal network. Longitudinal changes in connectivity between supramarginal gyrus and right frontoparietal network differ between both patient groups and controls.

CONCLUSION: We found disease-specific brain regions with longitudinal connectivity changes. This suggests the potential of longitudinal resting state fMRI to delineate regions relevant for disease progression and for diagnostic accuracy, although no group differences in longitudinal changes in the direct comparison of AD and bvFTD were found.

%B J Alzheimers Dis %V 55 %P 521-537 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27662284?dopt=Abstract %R 10.3233/JAD-150695 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Rare Genetic Variant in SORL1 May Increase Penetrance of Alzheimer's Disease in a Family with Several Generations of APOE-ɛ4 Homozygosity. %A Louwersheimer, Eva %A Cohn-Hokke, Petra E %A Pijnenburg, Yolande A L %A Weiss, Marjan M %A Sistermans, Erik A %A Rozemuller, Annemieke J %A Hulsman, Marc %A van Swieten, John C %A van Duijn, Cock M %A Barkhof, Frederik %A Koene, Teddy %A Scheltens, Philip %A van der Flier, Wiesje M %A Holstege, Henne %X

BACKGROUND: The major genetic risk factor for late onset Alzheimer's disease (AD) is the APOE-ɛ4 allele. However, APOE-ɛ4 homozygosity is not fully penetrant, suggesting co-occurrence of additional genetic variants.

OBJECTIVE: To identify genetic factors that, next to APOE-ɛ4 homozygosity, contribute to the development of AD.

METHODS: We identified a family with nine AD patients spanning four generations, with an inheritance pattern suggestive of autosomal dominant AD, with no variants in PSEN1, PSEN2, or APP. We collected DNA from four affected and seven unaffected family members and performed exome sequencing on DNA from three affected and one unaffected family members.

RESULTS: All affected family members were homozygous for the APOE-ɛ4 allele. Statistical analysis revealed that AD onset in this family was significantly earlier than could be expected based on APOE genotype and gender. Next to APOE-ɛ4 homozygosity, we found that all four affected family members carried a rare variant in the VPS10 domain of the SORL1 gene, associated with AβPP processing and AD risk. Furthermore, three of four affected family members carried a rare variant in the TSHZ3 gene, also associated with AβPP processing. Affected family members presented between 61 and 74 years, with variable presence of microbleeds/cerebral amyloid angiopathy and electroencephalographic abnormalities.

CONCLUSION: We hypothesize that next to APOE-ɛ4 homozygosity, impaired SORL1 protein function, and possibly impaired TSHZ3 function, further disturbed Aβ processing. The convergence of these genetic factors over several generations might clarify the increased AD penetrance and the autosomal dominant-like inheritance pattern of AD as observed in this family.

%B J Alzheimers Dis %V 56 %P 63-74 %G eng %N 1 %R 10.3233/JAD-160091 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Heterogeneous Language Profiles in Patients with Primary Progressive Aphasia due to Alzheimer's Disease. %A Louwersheimer, Eva %A Keulen, M Antoinette %A Steenwijk, Martijn D %A Wattjes, Mike P %A Jiskoot, Lize C %A Vrenken, Hugo %A Teunissen, Charlotte E %A van Berckel, Bart N M %A van der Flier, Wiesje M %A Scheltens, Philip %A van Swieten, John C %A Pijnenburg, Yolande A L %K Aged %K Alzheimer Disease %K Aphasia, Primary Progressive %K Atrophy %K Biomarkers %K Brain %K Female %K Humans %K Language %K Language Tests %K Magnetic Resonance Imaging %K Male %K Mental Status Schedule %K Organ Size %K Positron-Emission Tomography %K Retrospective Studies %X

BACKGROUND: The logopenic variant of Primary Progressive Aphasia (lvPPA) is associated with underlying Alzheimer's disease (AD) pathology and characterized by impaired single word retrieval and repetition of phrases and sentences.

OBJECTIVE: We set out to study whether logopenic aphasia is indeed the prototypic language profile in PPA patients with biomarker evidence of underlying AD pathology and to correlate language profiles with cortical atrophy patterns on MRI.

METHODS: Inclusion criteria: (I) clinical diagnosis of PPA; (II) CSF profile and/or PiB-PET scan indicative for amyloid pathology; (III) availability of expert language evaluation. Based on language evaluation, patients were classified as lvPPA (fulfilling lvPPA core criteria), lvPPA extended (fulfilling core criteria plus other language disturbances), or PPA unclassifiable (not fulfilling lvPPA core criteria). Cortical atrophy patterns on MRI were visually rated and quantitative measurements of cortical thickness were performed using FreeSurfer.

RESULTS: We included 22 patients (age 67±7 years, 50% female, MMSE 21±6). 41% were classified as lvPPA, 36% as lvPPA extended with additional deficits in language comprehension and/or confrontation naming, and 23% as PPA unclassifiable. By both qualitative and quantitative measurements, patients with lvPPA showed mild global cortical atrophy on MRI, whereas patients with lvPPA extended showed more focal cortical atrophy, predominantly at the left tempo-parietal side. For PPA unclassifiable, qualitative measurements revealed a heterogeneous atrophy pattern.

CONCLUSION: Although most patients fulfilled the lvPPA criteria, we found that their language profiles were heterogeneous. The clinical and radiological spectrum of PPA due to underlying AD pathology is broader than pure lvPPA.

%B J Alzheimers Dis %V 51 %P 581-90 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26890751?dopt=Abstract %R 10.3233/JAD-150812