Petrucelli, Leonard

AbstractIntroductionWe created global rating scoring rules for the CDR® plus NACC FTLD to detect and track early frontotemporal lobar degeneration (FTLD) and to conduct clinical trials in FTLD.MethodsThe CDR plus NACC FTLD rating was applied to 970 sporadic and familial participants from the baseline visit of Advancing Research and Treatment in Frontotemporal Lobar Degeneration (ARTFL)/Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects (LEFFTDS). Each of the eight domains of the CDR plus NACC FTLD was equally weighed in determining the global score. An interrater reliability study was completed for 40 participants.ResultsThe CDR plus NACC FTLD showed very good interrater reliability. It was especially useful in detecting clinical features of mild non‐fluent/agrammatic variant primary progressive aphasia participants.DiscussionThe global CDR plus NACC FTLD score could be an attractive outcome measure for clinical trials in symptomatic FTLD, and may be useful in natural history studies and clinical trials in FTLD spectrum disorders.

AbstractObjectiveTo identify clinicopathological differences between frontotemporal lobar degeneration (FTLD) due to mutations in progranulin (FTLD‐GRN) and chromosome 9 open reading frame 72 (FTLD‐C9ORF72).MethodsWe performed quantitative neuropathologic comparison of 17 FTLD‐C9ORF72 and 15 FTLD‐GRN with a focus on microglia. For clinical comparisons, only cases with high quality medical documentation and concurring diagnoses by at least two neurologists were included (14 FTLD‐GRN and 13 FTLD‐C9ORF72). Neuropathological analyses were limited to TDP‐43 Type A to assure consistent assessment between the groups, acknowledging that Type A is a minority of C9ORF72 patients. Furthermore, only cases with sufficient tissue from all regions were studied (11 FTLD‐GRN and 11 FTLD‐C9ORF72). FTLD cases were also compared to age– and sex–matched normal controls. Immunohistochemistry was performed for pTDP‐43, IBA‐1, CD68, and GFAP. Morphological characterization of microglia was performed in sections of cortex blinded to clinical and genetic information.ResultsFTLD‐GRN patients had frequent asymmetric clinical features, including aphasia and apraxia, as well as more asymmetric cortical atrophy. Neuropathologically, FTLD‐C9ORF72 had greater hippocampal tau pathology and more TDP‐43 neuronal cytoplasmic inclusions. FTLD‐GRN had more neocortical microvacuolation, as well as more IBA‐1–positive ameboid microglia in superficial cortical layers and in subcortical white matter. FTLD‐GRN also had more microglia with nuclear condensation, possibly indicating apoptosis. Microglial morphology with CD68 immunohistochemistry in FTLD‐GRN and FTLD‐C9ORF72 differed from controls.InterpretationOur findings underscore differences in microglial response in FTLD‐C9ORF72 and FTLD‐GRN as shown by significant differences in ameboid microglia in gray and white matter. These results suggest the differential contribution of microglial dysfunction in FTLD‐GRN and FTLD‐C9ORF72 and suggest that clinical, neuroimaging and pathologic differences could in part be related to differences in microglia response.

How dipeptide repeats cause pathology A repeat expansion in the chromosome 9 open reading frame 72 ( C9orf72 ) gene is the most common known cause of two neurodegenerative diseases: frontotemporal dementia and amyotrophic lateral sclerosis. This expansion leads to the abnormal production of proteins of repeating dipeptides, but their contribution to disease pathogenesis remains unclear. Zhang et al. engineered a mouse model to study the consequences of one of these dipeptides—prolinearginine dipeptide repeat protein, poly(PR)—in the brain. They found that poly(PR) caused neuron loss as well as motor and memory impairments. These detrimental effects resulted from poly(PR)-induced perturbation of heterochromatin function, a tightly packed form of DNA that represses gene expression. Science , this issue p. eaav2606