In the European FP7 IMI “PharmaCog” project (Grant Agreement n°115009, www.pharmacog.org), we evaluated whether cortical electroencephalographic (EEG) rhythms in quiet wakefulness reflected prodromal Alzheimer's disease (AD) in patients with amnesic mild cognitive impairment (aMCI). The research data (including human biological samples) were sourced and used in line with international ethical standards. Resting state eyes-closed EEG rhythms were recorded in 127 aMCI subjects along 24 months (i.e. baseline, 6-month, 12-month. 18-month, and 24-month follow ups). Cortical sources of those rhythms were estimated by eLORETA package (http://www.uzh.ch/keyinst/loreta.htm). Linear mixed models tested the hypothesis of characteristic EEG features of prodromal AD in aMCI condition. Compared with the aMCI sub-group showing “negativity” to Aβ1-42/phospho tau in the cerebrospinal fluid, the aMCI sub-group showing “positivity” (prodromal AD) exhibited higher delta (<4Hz) source activity in widespread cortical regions together with a lower posterior source activity in low-frequency alpha rhythms (8-10.5 Hz). Some of alpha sources were related to global cognitive status as revealed by ADAScog. The results of the PharmaCog project suggest that, in prodromal AD with aMCI, the reduction of on-going cortical alpha rhythms (8-12 Hz) may reflect cortical overexcitation and may be used as a promising endpoints of therapies aimed at mitigating that brain abnormality (e.g. adequate anti-epileptic drugs).

The apolipoprotein E (APOE) e4 allele and high beta-amyloid (Ab) are both strong risk factors for Alzheimer’s disease (AD) and linked to greater cognitive decline. The effect of these risk factors on cognitive impairment is less clear in individuals with Amnestic Mild Cognitive Impairment (aMCI). We examined cognitive function at baseline in individuals with aMCI who were Ab+ and Ab- as well as APOE ɛ4 carriers and non-carriers. We hypothesized that individuals who are Ab+ or APOE e4 carriers would perform worse on tests of memory and the impairments would be greater in individuals with both risk factors. 145 participants with aMCI were recruited from the European-ADNI study. Subjects were aged between 55-90, had a ≥1SD deficit in episodic memory and fulfilled a clinical diagnosis of aMCI. Individuals underwent computerised cognitive assessment using the CANTAB and lumbar punctures for CSF measurement of Abeta42. Individuals were divided into Ab+ (CSF-POS)(<550pg/ml)(n=55) and Ab- (CSF-NEG)(>550pg/ml)(n=90) based on CSF Abeta42 levels. aMCI Aβ+ individuals (compared to Aβ- individuals) performed worse on spatial recognition memory (SRM)(p=<0.01, EF=0.4) and working memory (i.e. delayed-matching-to-sample (DMS); p=<0.01; ES=0.6). APOE ɛ4 carriers (compared to non-carriers) performed worse on paired associate learning (PAL)(p=0.02; ES=0.4) and pattern recognition memory (PRM)(p=0.04; EF=0.4). In contrast, individuals with both risk factors (i.e. Aβ+/APOE ɛ4 carriers)(compared to Aβ-/APOE ɛ4 non-carriers) showed the greatest deficits on PAL (p=0.01; EF=0.6) and SRM (p<0.01; EF=0.8). In individual who were Aβ+, carriage of the APOE ɛ4 allele was also associated with worse performance on the PAL (p=0.01) and SRM (p=0.03). The presence of Aβ+ and at least one copy of the APOE e4 allele are related to greater cognitive impairment at baseline in individuals with aMCI. Aβ positivity was associated with greater fronto-striatal recognition and working memory deficits, while APOE carriage was associated with greater hippocampal dependent episodic memory deficits. Interestingly, the combined risk of Aβ+ and ɛ4 carriage were associated with the greatest impairments in both fronto-striatal and hippocampal dependent memory. These findings suggest that aMCI is associated with a diverse profile of memory impairment which are differentially moderated by Aβ and APOE ɛ4 status.

were other dementia.Mean age of subjects was 77.18 ± 7.0.10 subjects(90.9%)were female.Mean education years were 2.6 ± 3.2.There were no significant differences in MMSE-DS, GDS-K, DEX-K, and DCAP-IADL.But, there were significant improvements in NPI-K(pre-test=6.3 ± 6.9, post-test=1.6± 2.7, p=0.017,Wilcoxon signed ranks test) and caregiver burden(pre-test=21.1 ± 16.0, post-test=10.8± 12.0, p=0.033,Wilcoxon signed ranks test).Conclusions: Group therapy based on traditional play for dementia patients might be effective on reducing neuropsychiatric symptoms and caregiver burden.Further research will be required to confirm the effects of group therapy.

Accumulation of beta amyloid (Abeta) in the brain and carriage of the apolipoprotein E (APOE) ɛ4 allele have both been reported to independently and interactively linked with greater neurodegeneration, cognitive decline and incipient Alzheimer's disease (AD). However, as most studies have observed these effects over 18-months or more, the effect of Abeta and e4 on cognitive decline over 12-months remains unknown. Detection and monitoring of subtle cognitive decline over shorter time periods is critical for diagnosis of patients at risk for dementia and monitoring the therapeutic effects of symptomatic and disease modifying treatments. In this study we examined the effects of Abeta and e4 on rates of cognitive change assessed using the CANTAB over 12-months in aMCI patients. We hypothesized that Abeta+ individuals would show a greater decline in episodic memory and this would be increased in APOE ɛ4 carriers. 145 participants with aMCI were recruited from the European-ADNI study. They were aged between 55-90, had a ≥1SD deficit in episodic memory and fulfilled a clinical diagnosis of aMCI. Participants underwent cognitive assessment using the CANTAB at baseline, 6 and 12 months and lumbar punctures for CSF measurement of Abeta42. Individuals were divided into Abeta+ (<550pg/ml) (n=55) and Abeta- (>550pg/ml) (n=90). Abeta+ aMCI individuals (relative to Abeta-) showed faster decline in paired associates learning (PAL) (p=0.02, ES=0.4) over 12 months. Abeta+ aMCI individuals who were APOE e4 carriers (compared to non- carriers) had a greater decline in PAL (p<0.01, ES=0.6). No other cognitive domain including attention and executive function were affected by Abeta positivity and/or APOE e4 carriage. Abeta+ individuals with aMCI declined at a faster rate over 12-months on the CANTAB-PAL task of episodic memory (i.e. learning of an association between object and location). The decline in memory in Abeta+ individuals with aMCI was exacerbated by the presence of the APOE ɛ4 allele. Other cognitive domains including psychomotor speed, sustained attention, working memory and executive function were not affected Abeta positivity and/or APOE e4 carriage. These findings suggest a memory decline in Abeta+ individuals with aMCI can be detected as early as 12 months using sensitive computerised tests of episodic memory.

Mild cognitive impairment (MCI) subjects were previously characterized by abnormal auditory oddball event-related potentials (AO-ERPs) but it is unclear the specificity of this result with reference to Alzheimer's disease (AD). To address this issue, IMI PharmaCoG project (Grant Agreement n°115009, www.pharmacog.org) evaluated whether cortical sources of AO-ERPs are related to cerebrospinal fluid (CSF) β amyloid (Aβ) level in amnesic MCI subjects. The research data (including human biological samples) were sourced ethically and their research use was in accord with the terms of the international ethical standards. Artifact free AO-ERPs (19 electrodes) were recorded in 79 MCI subjects in the framework of WP5 planning the enrolment of 147 individuals (analysis of additional individual EEG datasets is in progress, so the present results are just preliminary). Individual data sets were broken down into those with high CSF Aβ level (50 MCI NEG, CSF Aβ > 550 pg/ml) and those with low CSF Aβ level (29 MCI POS, CSF Aβ < 550 pg/ml). Cortical sources of late positive frontal (P3a; novelty of rare targets) and posterior (P3b; attention and reaction to rare targets) peak components of AO-ERPs were estimated by sLORETA package.T test of sLORETA package compared these sources between the two MCI groups (p<0.05, corrected). We observed a statistically greater magnitude of prefrontal P3a cortical sources following oddball target stimuli in the MCI POS compared to the MCI NEG (Figure 1).

Mild cognitive impairment (MCI) subjects were previously characterized by abnormal cortical sources of resting state electroencephalographic (EEG) rhythms but it is unclear the specificity of this result with reference to Alzheimer's disease (AD). To address this issue, IMI PharmaCoG project (Grant Agreement n°115009, www.pharmacog.org) evaluated whether cortical sources of these rhythms are correlated to cerebrospinal fluid (CSF) β amyloid (Aβ) level in amnesic MCI subjects. The research data (including human biological samples) were sourced ethically and their research use was in accord with the terms of the international ethical standards. Artifact free resting state eyes-closed EEG rhythms (19 electrodes) were recorded in the context of WP5 planning the enrolment of 147 individuals (analysis of additional individual EEG datasets is in progress, so the present results are just preliminary). Individual data sets were broken down into those with high CSF Aβ level (57 MCI NEG, CSF Aβ > 550 pg/ml) and those with low CSF Aβ level (38 MCI POS, CSF Aβ < 550 pg/ml). Cortical sources of EEG rhythms at frequency bands of interest (delta <4 Hz, low-frequency alpha 8-10.5 Hz) were estimated by LORETA package. ANOVA compared these sources between the two MCI groups (p<0.05, corrected). Furthermore, these sources were correlated to CSF Aβ level across all MCI subjects as a whole group (Pearson test, p<0.05). We observed no statistically significant difference of these cortical sources between the two groups (p>0.05). In contrast, there was a statistically significant negative correlation between global delta sources and CSF Aβ level (r= -0.28; p=0.007) across all MCI subjects (Figure 1).