Cerebrospinal Fluid Concentrations of Functionally Important Amino Acids and Metabolic Compounds in Patients with Mild Cognitive Impairment and Alzheimer’s Disease

Kaiser, Elmar; Schoenknecht, Peter; Kassner, Stefan; Hildebrandt, Wulf; Kinscherf, Ralf; Schröeder, Johannes

doi:10.1159/000287953

Cited by 50 publications

(34 citation statements)

References 83 publications

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“…This effect can lead to glutamate dyshomeostasis and/or glutamate excitotoxicity. This phenomenon has been suggested in AD because AD patients have increasing glutamate levels in their cerebral spinal fluid as dementia progresses (Jimenez-Jimenez et al, 1998;Kaiser et al, 2010).…”

Section: Discussionmentioning

confidence: 98%

Ceftriaxone ameliorates tau pathology and cognitive decline via restoration of glial glutamate transporter in a mouse model of Alzheimer's disease

Zumkehr

Rodriguez‐Ortiz

Cheng

et al. 2015

Neurobiology of Aging

134

106

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TauAmyloid b a b s t r a c t Glial glutamate transporter, GLT-1, is the major Na þ -driven glutamate transporter to control glutamate levels in synapses and prevent glutamate-induced excitotoxicity implicated in neurodegenerative disorders including Alzheimer's disease (AD). Significant functional loss of GLT-1 has been reported to correlate well with synaptic degeneration and severity of cognitive impairment among AD patients, yet the underlying molecular mechanism and its pathological consequence in AD are not well understood.Here, we find the temporal decrease in GLT-1 levels in the hippocampus of the 3xTg-AD mouse model and that the pharmacological upregulation of GLT-1 significantly ameliorates the age-dependent pathological tau accumulation, restores synaptic proteins, and rescues cognitive decline with minimal effects on Ab pathology. In primary neuron and astrocyte coculture, naturally secreted Ab species significantly downregulate GLT-1 steady-state and expression levels. Taken together, our data strongly suggest that GLT-1 restoration is neuroprotective and Ab-induced astrocyte dysfunction represented by a functional loss of GLT-1 may serve as one of the major pathological links between Ab and tau pathology.

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Section: Discussionmentioning

confidence: 98%

Ceftriaxone ameliorates tau pathology and cognitive decline via restoration of glial glutamate transporter in a mouse model of Alzheimer's disease

Zumkehr

Rodriguez‐Ortiz

Cheng

et al. 2015

Neurobiology of Aging

134

106

View full text Add to dashboard Cite

show abstract

“…Notably, two analyses have reported alterations in CSF metabolome of AD. One study has showed the increase of the concentrations of eight amino acids in AD versus MCI [111]. Another larger examination, after measuring 343 analytes has also led to detect eight molecules with statistical significance; interestingly, one of these markers, cortisol, correlated with the advancement of the disease [112].…”

Section: Upcoming Candidate Biomarkersmentioning

confidence: 99%

Perspective on future role of biological markers in clinical therapy trials of Alzheimer's disease: A long-range point of view beyond 2020

Hampel

Lista

Teipel

et al. 2014

Biochemical Pharmacology

105

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Recent advances in understanding the molecular mechanisms underlying various paths toward the pathogenesis of Alzheimer's disease (AD) has begun to provide new insight for interventions to modify disease progression. The evolving knowledge gained from multidisciplinary basic research has begun to identify new concepts for treatments and distinct classes of therapeutic targets; as well as putative disease-modifying compounds that are now being tested in clinical trials. There is a mounting consensus that such disease modifying compounds and/or interventions are more likely to be effectively administered as early as possible in the cascade of pathogenic processes preceding and underlying the clinical expression of AD. The budding sentiment is that "treatments" need to be applied before various molecular mechanisms converge into an irreversible pathway leading to morphological, metabolic and functional alterations that characterize the pathophysiology of AD. In light of this, biological indicators of pathophysiological mechanisms are desired to chart and detect AD throughout the asymptomatic early molecular stages into the prodromal and early dementia phase. A major conceptual development in the clinical AD research field was the recent proposal of new diagnostic criteria, which specifically incorporate the use of biomarkers as defining criteria for preclinical stages of AD. This paradigm shift in AD definition, conceptualization, operationalization, detection and diagnosis represents novel fundamental opportunities for the modification of interventional trial designs. This perspective summarizes not only present knowledge regarding biological markers but also unresolved questions on the status of surrogate indicators for detection of the disease in asymptomatic people and diagnosis of AD

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“…As progressive failure of neuronal networks and neurotransmitter systems is one of the prominent features of AD, it is not surprising that in the CSF of AD patients abnormal concentrations of neurotransmitters and their metabolites have been found. Hence, many studies tried to assess the diagnostic potential of CSF neurotransmitters (110,111). However, the results on CSF monoamine metabolites in AD patients are conflicting (112,113).…”

Section: Novel Csf Biomarkersmentioning

confidence: 99%

Update on the core and developing cerebrospinal fluid biomarkers for Alzheimer disease

et al. 2014

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Alzheimer disease (AD) is a complex neurodegenerative disorder, whose prevalence will dramatically rise by 2050. Despite numerous clinical trials investigating this disease, there is still no effective treatment. Many trials showed negative or inconclusive results, possibly because they recruited only patients with severe disease, who had not undergone disease-modifying therapies in preclinical stages of AD before severe degeneration occurred. Detection of AD in asymptomatic at risk individuals (and a few presymptomatic individuals who carry an autosomal dominant monogenic AD mutation) remains impractical in many of clinical situations and is possible only with reliable biomarkers. In addition to early diagnosis of AD, biomarkers should serve for monitoring disease progression and response to therapy. To date, the most promising biomarkers are cerebrospinal fluid (CSF) and neuroimaging biomarkers. Core CSF biomarkers (amyloid β1-42, total tau, and phosphorylated tau) showed a high diagnostic accuracy but were still unreliable for preclinical detection of AD. Hence, there is an urgent need for detection and validation of novel CSF biomarkers that would enable early diagnosis of AD in asymptomatic individuals. This article reviews recent research advances on biomarkers for AD, focusing mainly on the CSF biomarkers. In addition to core CSF biomarkers, the potential usefulness of novel CSF biomarkers is discussed.

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Cerebrospinal Fluid Concentrations of Functionally Important Amino Acids and Metabolic Compounds in Patients with Mild Cognitive Impairment and Alzheimer’s Disease

Cited by 50 publications

References 83 publications

Ceftriaxone ameliorates tau pathology and cognitive decline via restoration of glial glutamate transporter in a mouse model of Alzheimer's disease

Ceftriaxone ameliorates tau pathology and cognitive decline via restoration of glial glutamate transporter in a mouse model of Alzheimer's disease

Perspective on future role of biological markers in clinical therapy trials of Alzheimer's disease: A long-range point of view beyond 2020

Update on the core and developing cerebrospinal fluid biomarkers for Alzheimer disease

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