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Background Basal forebrain cholinergic neurons are dependent on nerve growth factor (NGF) for growth and survival and these cells are among the first to degenerate in Alzheimer's disease (AD). Targeted delivery of NGF has been suggested as a potential therapy for AD. This hypothesis was tested in a clinical trial with encapsulated cell biodelivery of NGF (NGF-ECB) in AD patients. Three of six patients showed improved biomarkers for cognition by the end of the study. Here, we report on the effects of targeted delivery of NGF on human resting EEG. Materials and methods NGF-ECB implants were implanted bilaterally in the basal forebrain of six AD patients for 12 months. EEG recordings and quantitative analysis were performed at baseline, 3 and 12 months of NGF delivery, and analyzed for correlation with changes in Mini-mental state examination (MMSE) and levels of the cholinergic marker choline acetyltransferase (ChAT) in cerebrospinal fluid (CSF). Results We found significant correlations between the topographic variance of EEG spectral power at the three study points (baseline, 3 and 12 months) and changes in MMSE and CSF ChAT. This possible effect of NGF was identified in a narrow window of alpha frequency 10-11.5 Hz, where a stabilization in MMSE score during treatment was related to an increase in EEG alpha power. A similar relation was observed between the alpha power and ChAT. More theta power at 6.5 Hz was on the contrary associated with a decrease in CSF ChAT during the trial period. Conclusion In this exploratory study, there was a positive correlative pattern between physiological high-frequency alpha activity and stabilization in MMSE and increase in CSF ChAT in AD patients receiving targeted delivery of NGF to the cholinergic basal forebrain.

Typical cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is caused by mutations in the human NOTCH3 gene. Cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy is characterized by subcortical ischemic strokes due to severe arteriopathy and fibrotic thickening of small vessels. Blood regulating vascular smooth muscle cells (VSMCs) appear as the key target in CADASIL but the pathogenic mechanisms remain unclear. With the hypothesis that brain glucose metabolism is disrupted in VSMCs in CADASIL, we investigated post-mortem tissues and VSMCs derived from CADASIL patients to explore gene expression and protein immunoreactivity of glucose transporters (GLUTs), particularly GLUT4 and GLUT2 using quantitative RT-PCR and immunohistochemical techniques. In vitro cell model analysis indicated that both GLUT4 and -2 gene expression levels were down-regulated in VSMCs derived from CADASIL patients, compared to controls. In vitro studies further indicated that the down regulation of GLUT4 coincided with impaired glucose uptake in VSMCs, which could be partially rescued by insulin treatment. Our observations on reduction in GLUTs in VSMCs are consistent with previous findings of decreased cerebral blood flow and glucose uptake in CADASIL patients. That impaired ability of glucose uptake is rescued by insulin is also consistent with previously reported lower proliferation rates of VSMCs derived from CADASIL subjects. Overall, these observations are consistent with the development of severe cerebral arteriopathy in CADASIL, in which VSMCs are replaced by widespread fibrosis.

Additional file 1: Figure 1. Levels of CSF NFL, YKL-40, S100B and GFAP by CSF profile. Table 1. Univariable ROC analysis for distinguishing between CSF profile groups stratified by gender. Figure 2. Pearson’s correlations between levels of CSF NFL with neuropsychological tests reflecting verbal episodic memory by CSF profile. Figure 3. Pearson’s correlations between levels of CSF GFAP with neuropsychological tests reflecting processing speed and executive functions by CSF profile. Figure 4. Pearson’s correlations between CSF levels of NFL and T-tau with verbal episodic memory and GFAP with processing speed and executive functions, within the whole cohort and by CSF profile. Table 2. Pearson’s correlations between CSF markers, age, education and composite z-scores reflecting cognitive domains.

Figure S1. As can be seen, MAG:PLP1 correlated negatively with VEGF, although the relationship was relatively weak. Figure S2. ChAT concentration. There was no between-group difference in ChAT concentration in either BA18 (A) or BA19 (B). VH = visual hallucinations. Figure S3. ChAT activity. There was no significant between-group difference in ChAT activity in either brain area. Figure S4. Neither BChE activity nor concentration differed between the groups in either brain area. There was little relationship between either AChE or BChE activity and protein concentration, suggesting that some of the enzyme present was inactive. Figure S5. Examining the relationship between ChAT activity and the activity of cholinergic breakdown enzymes. The cholinergic index in A and B was calculated as ChAT activity/AChE activity + BChE activity. In C and D, the ration of ChAT activity to AChE activity alone is shown. Figure S6. Cholinergic markers and disease duration. ChAT activity (A and B), AChE activity (C and D) and BChE activity (E and F) activity did not change significantly with disease duration. Table S1. α-Synuclein results. Table S2. Comparison between diagnosis in life and the pathological diagnosis made post-mortem. The most common diagnosis listed in the other dementia column was unspecified “dementia” or “senile dementia”. Table S3. Further details on medical history for the individuals whose donated tissue was used in this study. The “other neurological diagnoses” included epilepsy late on in dementia (3 people), minor head injuries, vascular Parkinsonism (1 person) and possible SLE (1 person). It was apparent that some individuals were treated with antipsychotics to control distress at the end of their lives, rather than to treat psychotic symptoms. (DOCX 772 kb)