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BACKGROUND: There are currently no disease-targeted treatments for cognitive or behavioral symptoms in patients with behavioral variant frontotemporal dementia (bvFTD). OBJECTIVE: To determine the effect of tolcapone, a specific inhibitor of Catechol-O-Methyltransferase (COMT), in patients with bvFTD. METHODS: In this randomized, double-blind, placebo-controlled, cross-over study at two study sites, we examined the effect of tolcapone on 28 adult outpatients with bvFTD. The primary outcome was reaction time on the N-back cognitive test. As an imaging outcome, we examined differences in the resting blood oxygen level dependent (BOLD) functional magnetic resonance imaging (fMRI) signal intensity between subjects on placebo versus tolcapone performing the N-back test. Secondary outcomes included measures of cognitive performance and behavioral disturbance using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), Neuropsychiatric Inventory-Questionnaire (NPI-Q), and Clinical Global Impressions scale (CGI). RESULTS: Tolcapone was well tolerated and no patients dropped out. The most frequent treatment-related adverse event during tolcapone treatment was elevated liver enzymes (21%). There were no significant differences between tolcapone treatment and placebo in the primary or imaging outcomes. However, there were significant differences between RBANS total scores (p < 0.01), NPI-Q total scores (p = 0.04), and CGI total scores (p = 0.035) between treatment conditions which were driven by differences between baseline and tolcapone conditions. Further, there was a trend toward significance between tolcapone and placebo on the CGI (p = 0.078). CONCLUSIONS: Further study of COMT inhibition and related approaches with longer duration of treatment and larger sample sizes in frontotemporal lobar degeneration-spectrum disorders may be warranted.

Background Anticholinergic challenge can induce odor identification impairment that indicates Alzheimer's disease (AD) pathology, and short-term change in odor identification impairment with cholinesterase inhibitor (CheI) treatment may predict longer term cognitive outcomes. Objective In patients with mild cognitive impairment (MCI) treated prospectively with donepezil, a CheI, for 52 weeks, to determine if 1) acute decline in odor identification ability with anticholinergic challenge can predict cognitive improvement, and 2) change in odor identification over 8 weeks can predict cognitive improvement. Methods MCI was diagnosed clinically without AD biomarkers. At baseline, the University of Pennsylvania Smell identification Test (UPSIT) was administered before and after an anticholinergic atropine nasal spray challenge. Donepezil was started at 5 mg daily, increased to 10 mg daily if tolerated, and this dose was maintained for 52 weeks. Main outcomes were ADAS-Cog total score and Selective Reminding Test (SRT) total immediate recall score measured at baseline, 26 and 52 weeks. Results In 100 study participants, mean age 70.14 (SD 9.35) years, atropine-induced decrease in UPSIT score at baseline was not associated with change in ADAS-Cog or SRT scores over 52 weeks. Change in UPSIT score from 0 to 8 weeks did not show a significant association with change in the ADAS-Cog or SRT measures over 52 weeks. Conclusion These negative findings in a relatively large sample of patients with MCI did not replicate results in much smaller samples. Change in odor identification with anticholinergic challenge, and over 8 weeks, may not be useful predictors of cognitive improvement with CheI in patients with MCI.

BACKGROUND Anticholinergic challenge can induce odor identification impairment that indicates Alzheimer's disease pathology. OBJECTIVE To determine if decline in odor identification ability with anticholinergic challenge can predict improvement with donepezil, a cholinesterase inhibitor (ChEI), in patients with mild cognitive impairment (MCI). METHODS At baseline, the University of Pennsylvania Smell identification Test (UPSIT) was administered before and after an anticholinergic atropine nasal spray challenge. Donepezil was started at 5 mg daily, increased to 10 mg daily if tolerated, and then the dose was kept constant for 52 weeks. Main outcomes were change in Selective Reminding Test (SRT) total immediate recall and ADAS-Cog total score from baseline to 26 and 52 weeks. RESULTS In 37 participants, mean age 70.4 (SD 9.8) y, greater atropine-induced decrease in UPSIT score at baseline was associated with greater improvement in SRT total recall score from baseline to 26 and 52 weeks (p

Background Apathy is a common and problematic symptom of several neurodegenerative illnesses, but its neuroanatomical bases are not understood. Objective To determine the regions associated with apathy in subjects with mild Alzheimer's disease (AD) using a method that accounts for the significant co-linearity of regional atrophy and neuropsychiatric symptoms. Methods We identified 57 subjects with mild AD (CDR = 1) and neuropsychiatric symptoms in the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. We performed a multivariate multiple regression with LASSO regularization on all symptom subscales of the Neuropsychiatric Inventory and the whole-brain ROI volumes calculated from their baseline MRIs with FreeSurfer. We compared our results to those from a previous study using the same method in patients with frontotemporal dementia (FTD) and corticobasal syndrome (CBS). Results Of neuropsychiatric symptoms, apathy showed the most robust neuroanatomical associations in the AD subjects. Atrophy of the following regions were independently associated with apathy: the ventromedial prefrontal cortex; ventrolateral prefrontal cortex; posterior cingulate cortex and adjacent lateral cortex; and the bank of the superior temporal sulcus. These results replicate previous studies using FTD and CBS patients, mostly agree with the previous literature on apathy in AD, and correspond to the Medial and Orbital Prefrontal Cortex networks identified in non-human primates. Conclusion The current study, previous studies from our laboratory, and the previous literature suggest that impairment of the same brain networks involved in arousal, threat response, and reward processing are associated with apathy in AD and FTD.

The study's objective was to compare demographics, APOE genotypes, and rate of rise over time in functional impair- ment in neuropsychologically defined language, typical, and memory subgroups of clinical Alzheimer's disease (AD). 1,368 participants from the National Alzheimer's Coordinating Center database with a diagnosis of probable AD (CDR 0.5-1.0) were included. A language subgroup (n = 229) was defined as having language performance >1 SD worse than memory performance. A memory subgroup (n = 213) was defined as having memory performance >1 SD worse than language performance. A typ- ical subgroup (n = 926) was defined as having a difference in language and memory performance of