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Atypical frontal, dysexecutive\/behavioural variants and early-onset variants of Alzheimer\u2019s disease have been previously reported, but no diagnostic criteria exist for a progressive dysexecutive syndrome. In this retrospective review, we report on 55 participants diagnosed with a clinically defined progressive dysexecutive syndrome with 18F-fluorodeoxyglucose-positron emission tomography and Alzheimer\u2019s disease biomarkers available. Sixty-two per cent of participants were female with a mean of 15.2\u2009years of education. The mean age of reported symptom onset was 53.8\u2009years while the mean age at diagnosis was 57.2\u2009years. Participants and informants commonly referred to initial cognitive symptoms as \u2018memory problems\u2019 but upon further inquiry described problems with core executive functions of working memory, cognitive flexibility and cognitive inhibitory control. Multi-domain cognitive impairment was evident in neuropsychological testing with executive dysfunction most consistently affected. The frontal and parietal regions which overlap with working memory networks consistently demonstrated hypometabolism on positron emission tomography. Genetic testing for autosomal dominant genes was negative in all eight participants tested and at least one APOE \u03b54 allele was present in 14\/26 participants tested. EEG was abnormal in 14\/17 cases with 13 described as diffuse slowing. Furthermore, CSF or neuroimaging biomarkers were consistent with Alzheimer\u2019s disease pathophysiology, although CSF p-tau was normal in 24% of cases. Fifteen of the executive predominate participants enrolled in research neuroimaging protocols and were compared to amnestic (n\u2009=\u2009110), visual (n\u2009=\u200918) and language (n\u2009=\u20097) predominate clinical phenotypes of Alzheimer\u2019s disease. This revealed a consistent pattern of hypometabolism in parieto-frontal brain regions supporting executive functions with relative sparing of the medial temporal lobe (versus amnestic phenotype), occipital (versus visual phenotype) and left temporal (versus language phenotype). We propose that this progressive dysexecutive syndrome should be recognized as a distinct clinical phenotype disambiguated from behavioural presentations and not linked specifically to the frontal lobe or a particular anatomic substrate without further study. This clinical presentation can be due to Alzheimer\u2019s disease but is likely not specific for any single aetiology. Diagnostic criteria are proposed to facilitate additional research into this understudied clinical presentation.<\/jats:p>","DOI":"10.1093\/braincomms\/fcaa068","type":"journal-article","created":{"date-parts":[[2020,5,27]],"date-time":"2020-05-27T05:10:05Z","timestamp":1590556205000},"source":"Crossref","is-referenced-by-count":140,"title":["Progressive dysexecutive syndrome due to Alzheimer\u2019s disease: a description of 55 cases and comparison to other phenotypes"],"prefix":"10.1093","volume":"2","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3566-3969","authenticated-orcid":false,"given":"Ryan A","family":"Townley","sequence":"first","affiliation":[{"name":"Department of Neurology Mayo Clinic, Rochester, MN 55902, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2770-0691","authenticated-orcid":false,"given":"Jonathan","family":"Graff-Radford","sequence":"additional","affiliation":[{"name":"Department of Neurology Mayo Clinic, Rochester, MN 55902, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William G","family":"Mantyh","sequence":"additional","affiliation":[{"name":"Department of Neurology Mayo Clinic, Rochester, MN 55902, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4390-685X","authenticated-orcid":false,"given":"Hugo","family":"Botha","sequence":"additional","affiliation":[{"name":"Department of Neurology Mayo Clinic, Rochester, MN 55902, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angelina J","family":"Polsinelli","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN 55902, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Scott A","family":"Przybelski","sequence":"additional","affiliation":[{"name":"Department of Biomedical Statistics, Mayo Clinic, Rochester, MN 55902, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mary M","family":"Machulda","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN 55902, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8068-522X","authenticated-orcid":false,"given":"Ahmed T","family":"Makhlouf","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN 55902, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew L","family":"Senjem","sequence":"additional","affiliation":[{"name":"Department of Diagnostic Radiology, Mayo Clinic, Rochester, MN 55902, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melissa E","family":"Murray","sequence":"additional","affiliation":[{"name":"Department of Molecular Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ross R","family":"Reichard","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55902, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rodolfo","family":"Savica","sequence":"additional","affiliation":[{"name":"Department of Neurology Mayo Clinic, Rochester, MN 55902, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bradley F","family":"Boeve","sequence":"additional","affiliation":[{"name":"Department of Neurology Mayo Clinic, Rochester, MN 55902, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel A","family":"Drubach","sequence":"additional","affiliation":[{"name":"Department of Neurology Mayo Clinic, Rochester, MN 55902, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keith A","family":"Josephs","sequence":"additional","affiliation":[{"name":"Department of Neurology Mayo Clinic, Rochester, MN 55902, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David S","family":"Knopman","sequence":"additional","affiliation":[{"name":"Department of Neurology Mayo Clinic, Rochester, MN 55902, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Val J","family":"Lowe","sequence":"additional","affiliation":[{"name":"Department of Diagnostic Radiology, Mayo Clinic, Rochester, MN 55902, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"suffix":"Jr","given":"Clifford R","family":"Jack","sequence":"additional","affiliation":[{"name":"Department of Diagnostic Radiology, Mayo Clinic, Rochester, MN 55902, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ronald C","family":"Petersen","sequence":"additional","affiliation":[{"name":"Department of Neurology Mayo Clinic, Rochester, MN 55902, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David 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