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CSF Cholinergic Index, a New Biomeasure of Treatment Effect in Patients With Alzheimer's Disease.

ABSTRACT: Alzheimer's disease (AD) is a progressive disease with early degeneration of the central cholinergic neurons. Currently, three of four AD drugs act by inhibiting the acetylcholine (ACh) degrading enzyme, acetylcholinesterase (AChE). Efficacy of these drugs depends on available amount of ACh, which is biosynthesized by choline acetyltransferase (ChAT). We investigated whether treatment with a cholinesterase-inhibitor, galantamine, alters the relative levels of AChE to ChAT in cerebrospinal fluid (CSF) and whether levels of these CSF biomarkers correlate with in vivo AChE activity and nicotinic binding sites in the brain assessed by positron emission tomography (PET). Protein concentrations and activities of ChAT and AChE were measured in CSF of 18 patients with mild AD prior to and after 3 months of treatment with galantamine (n = 12) or placebo (n = 6), followed by nine additional months of galantamine treatment in all patients. A Cholinergic index was defined as the ratio of ChAT to AChE in CSF and was evaluated in relation to the in vivo AChE activity, the nicotinic binding sites and different measures of cognition. Besides an expected inhibition of AChE activity, galantamine treatment was accompanied by a mild increase in CSF ChAT activity. Thereby, the Cholinergic index was significantly increased in the Galantamine group (60% ± 14) after 3 months compared to baseline (p < 0.0023) or (p < 0.0004). This index remained high in the Galantamine group compared to baseline (54% ± 11) at 12 months follow-up, while it showed an increase in the Placebo group when they switched to active galantamine treatment (44% ± 14 vs. baseline, 61% ± 14 vs. 3 months, all p-values < 0.05). Furthermore, the in vivo brain AChE activity (assessed by PET) correlated with the CSF Cholinergic index at 12 months (r = 0.98, p < 0.001). The CSF Cholinergic index also correlated with ADAS-Cog and some other neuropsychological tests at 12 months. This is the first study assessing a CSF Cholinergic index in relation to treatment with a cholinesterase inhibitor. The treatment-specific increase in CSF ChAT activity suggests that cholinesterase-inhibitors may also increase the ACh-biosynthesis capacity in the patients. Additional studies are warranted to evaluate the utility of the CSF Cholinergic index as a biomeasure of therapeutic effect in AD.

SUBMITTER: Karami A

PROVIDER: S-EPMC6798072 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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CSF Cholinergic Index, a New Biomeasure of Treatment Effect in Patients With Alzheimer's Disease.

Karami Azadeh A Eriksdotter Maria M Kadir Ahmadul A Almkvist Ove O Nordberg Agneta A Darreh-Shori Taher T

Frontiers in molecular neuroscience 20191011

Alzheimer's disease (AD) is a progressive disease with early degeneration of the central cholinergic neurons. Currently, three of four AD drugs act by inhibiting the acetylcholine (ACh) degrading enzyme, acetylcholinesterase (AChE). Efficacy of these drugs depends on available amount of ACh, which is biosynthesized by choline acetyltransferase (ChAT). We investigated whether treatment with a cholinesterase-inhibitor, galantamine, alters the relative levels of AChE to ChAT in cerebrospinal fluid ...[more]

PMID: 31680850

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Project description:Cholinergic synapses are ubiquitous in the human central nervous system. Their high density in the thalamus, striatum, limbic system, and neocortex suggest that cholinergic transmission is likely to be critically important for memory, learning, attention and other higher brain functions. Several lines of research suggest additional roles for cholinergic systems in overall brain homeostasis and plasticity. As such, the brain's cholinergic system occupies a central role in ongoing research related to normal cognition and age-related cognitive decline, including dementias such as Alzheimer's disease. The cholinergic hypothesis of Alzheimer's disease centres on the progressive loss of limbic and neocortical cholinergic innervation. Neurofibrillary degeneration in the basal forebrain is believed to be the primary cause for the dysfunction and death of forebrain cholinergic neurons, giving rise to a widespread presynaptic cholinergic denervation. Cholinesterase inhibitors increase the availability of acetylcholine at synapses in the brain and are one of the few drug therapies that have been proven clinically useful in the treatment of Alzheimer's disease dementia, thus validating the cholinergic system as an important therapeutic target in the disease. This review includes an overview of the role of the cholinergic system in cognition and an updated understanding of how cholinergic deficits in Alzheimer's disease interact with other aspects of disease pathophysiology, including plaques composed of amyloid-β proteins. This review also documents the benefits of cholinergic therapies at various stages of Alzheimer's disease and during long-term follow-up as visualized in novel imaging studies. The weight of the evidence supports the continued value of cholinergic drugs as a standard, cornerstone pharmacological approach in Alzheimer's disease, particularly as we look ahead to future combination therapies that address symptoms as well as disease progression.

Project description:AimsCholinesterase inhibitors (CEIs) have been shown to improve cognitive functioning in Alzheimer's disease (AD) patients, but are associated with multiple side effects and only 20-40% of the patients clinically improve. In this study, we aimed to investigate the acute pharmacodynamic (PD) effects of administration of a single dose of galantamine on central nervous system (CNS) functioning in mild to moderate AD patients and its potential to predict long-term treatment response.MethodsThis study consisted of a challenge and treatment phase. In the challenge phase, a single dose of 16 mg galantamine was administered to 50 mild to moderate AD patients in a double-blind, placebo-controlled cross-over fashion. Acute PD effects were monitored up to 5 hours after administration with use of the NeuroCart CNS test battery and safety and pharmacokinetics were assessed. In the treatment phase, patients were treated with open-label galantamine according to regular clinical care. After 6 months of galantamine treatment, patients were categorized as either responder or as non-responder based on their minimental state examination (MMSE), neuropsychiatric inventory (NPI) and disability assessment in dementia (DAD) scores. An analysis of covariance was performed to study the difference in acute PD effects during the challenge phase between responders and non-responders.ResultsA single dose of galantamine significantly reduced saccadic reaction time (-0.0099; 95% CI = -0.0195, -0.0003; P = .0430), absolute frontal EEG parameters in alpha (-14.9; 95% CI = -21.0, -8.3; P = .0002), beta (-12.6; 95% CI = -19.4, -5.3; P = .0019) and theta (-17.9; 95% CI = -25.0, -10.0; P = .0001) frequencies. Relative frontal (-1.669; 95% CI = -2.999, -0.339; P = .0156) and occipital (-1.856; 95% CI = -3.339, -0.372; P = .0166) EEG power in theta frequency and relative occipital EEG power in the gamma frequency (1.316; 95% CI = 0.158, 2.475; P = .0273) also increased significantly compared to placebo. Acute decreases of absolute frontal alpha (-20.4; 95% CI = -31.6, -7.47; P = .0046), beta (-15.7; 95% CI = -28.3, -0.93; P = .0390) and theta (-25.9; 95% CI = -38.4, -10.9; P = .0024) EEG parameters and of relative frontal theta power (-3.27%; 95% CI = -5.96, -0.58; P = .0187) on EEG significantly distinguished responders (n = 11) from non-responders (n = 32) after 6 months.ConclusionsThis study demonstrates that acute PD effects after single dose of galantamine are correlated with long-term treatment effects and that patients who demonstrate a reduction in EEG power in the alpha and theta frequency after a single administration of galantamine 16 mg will most likely respond to treatment.

Project description:IntroductionAlzheimer's disease (AD) is the most prevalent form of dementia with symptoms of deteriorating cognitive functions and memory loss, partially as a result of a decrease in cholinergic neurotransmission. The disease is incurable and treatment with cholinesterase inhibitors (ChEIs) is symptomatic. Choline acetyltransferase (ChAT), the enzyme that synthesizes acetylcholine (ACh), has been proven recently to be present in both cerebrospinal fluid (CSF) and plasma. As ChAT plays a role in regulating the extracellular ACh levels, it may have an impact on prognosis and cognitive performance in AD patients.ObjectivesTo measure ChAT activity and its protein concentration in CSF and plasma from patients with AD, mild cognitive impairment (MCI), or Subjective cognitive impairment (SCI).MethodsPlasma and CSF samples were obtained from 21 AD, 32 MCI, and 30 SCI patients. The activity and protein levels of ChAT and acetylcholinesterase (AChE), the enzyme catalyzing the hydrolysis of ACh, were analyzed using an integrated activity and protein concentration ELISA-like assay. A Cholinergic Index was calculated as the ratio of ChAT to AChE activities in CSF. The data were analyzed in relation to dementia biomarkers and cognitive performance of the patients.ResultsThe CSF ChAT activity was significantly higher (55-67%) in MCI patients compared to AD and SCI cases. The CSF Cholinergic Index was 41 and 22% lower in AD patients than in MCI and SCI subjects, respectively. This index correlated positively with the Aβ42/p-tau ratio in CSF in SCI but negatively with that in AD and MCI. The ChAT activity and protein levels in plasma exhibited significant differences with the pattern of AD>>M C I>SCI.ConclusionThis is the first study investigating soluble levels of the key cholinergic enzyme, ChAT, in both plasma and CSF of individuals at different clinical stages of dementia. Although further validation is needed, the overall pattern of the results suggests that in the continuum of AD, the cholinergic signaling exhibits an inverse U-shape dynamic of changes in the brain that greatly differs from the changes observed in the plasma compartment.

Project description:IntroductionInflammatory markers have long been observed in the brain, cerebrospinal fluid (CSF), and plasma of Alzheimer's disease (AD) patients, suggesting that inflammation contributes to AD and might be a therapeutic target. However, non-steroidal anti-inflammatory drug trials in AD and mild cognitive impairment (MCI) failed to show benefit. Our previous work seeking to understand why people with the inflammatory disease rheumatoid arthritis are protected from AD found that short-term treatment of transgenic AD mice with the pro-inflammatory cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF) led to an increase in activated microglia, a 50% reduction in amyloid load, an increase in synaptic area, and improvement in spatial memory to normal. These results called into question the consensus view that inflammation is solely detrimental in AD. Here, we tested our hypothesis that modulation of the innate immune system might similarly be used to treat AD in humans by investigating the ability of GM-CSF/sargramostim to safely ameliorate AD symptoms/pathology.MethodsA randomized, double-blind, placebo-controlled trial was conducted in mild-to-moderate AD participants (NCT01409915). Treatments (20 participants/group) occurred 5 days/week for 3 weeks plus two follow-up (FU) visits (FU1 at 45 days and FU2 at 90 days) with neurological, neuropsychological, blood biomarker, and imaging assessments.ResultsSargramostim treatment expectedly changed innate immune system markers, with no drug-related serious adverse events or amyloid-related imaging abnormalities. At end of treatment (EOT), the Mini-Mental State Examination score of the sargramostim group increased compared to baseline (P = .0074) and compared to placebo (P = .0370); the treatment effect persisted at FU1 (P = .0272). Plasma markers of amyloid beta (Aβ40 [decreased in AD]) increased 10% (P = .0105); plasma markers of neurodegeneration (total tau and UCH-L1) decreased 24% (P = .0174) and 42% (P = .0019), respectively, after sargramostim treatment compared to placebo.DiscussionThe innate immune system is a viable target for therapeutic intervention in AD. An extended treatment trial testing the long-term safety and efficacy of GM-CSF/sargramostim in AD is warranted.

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CSF Cholinergic Index, a New Biomeasure of Treatment Effect in Patients With Alzheimer's Disease.

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CSF Cholinergic Index, a New Biomeasure of Treatment Effect in Patients With Alzheimer's Disease.

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