Synaptic proteins predict cognitive decline in Alzheimer's disease and Lewy body dementia

Bereczki, Erika; Francis, Paul T.; Howlett, David; Pereira, Joana B.; Höglund, Kina; Bogstedt, Anna; Cedazo-Mı́nguez, Ángel; Baek, Jean-Ha; Hortobágyi, Tibor; Attems, Johannes; Ballard, Clive; Aarsland, Dag

doi:10.1016/j.jalz.2016.04.005

Cited by 143 publications

(120 citation statements)

References 46 publications

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“…Of note, several other proteins implicated in PD — in particular, PINK1, Parkin, leucine-rich repeat serine/threonine-protein kinase 2 (LRRK2) and DJ1 — are also involved in synaptic regulation. We have found that reduced neocortical levels of ZnT3, a marker of synaptic plasticity, and two key synaptic proteins, neurogranin and SNAP25 (REFS 31,32), are associated with cognition in PD. These findings suggest that cortical synaptic changes lead to cognitive decline in PD, consistent with imaging findings (see below), and preliminary work indicates that synaptic changes are also reflected in the cerebrospinal fluid (CSF).…”

Section: Mechanismsmentioning

confidence: 99%

Cognitive decline in Parkinson disease

et al. 2017

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Dementia is a frequent problem encountered in advanced stages of Parkinson disease (PD). In recent years, research has focused on the pre-dementia stages of cognitive impairment in PD, including mild cognitive impairment (MCI). Several longitudinal studies have shown that MCI is a harbinger of dementia in PD, although the course is variable, and stabilization of cognition — or even reversal to normal cognition — is not uncommon. In addition to limbic and cortical spread of Lewy pathology, several other mechanisms are likely to contribute to cognitive decline in PD, and a variety of biomarker studies, some using novel structural and functional imaging techniques, have documented in vivo brain changes associated with cognitive impairment. The evidence consistently suggests that low cerebrospinal fluid levels of amyloid-β42, a marker of comorbid Alzheimer disease (AD), predict future cognitive decline and dementia in PD. Emerging genetic evidence indicates that in addition to the APOE*ε4 allele (an established risk factor for AD), GBA mutations and SCNA mutations and triplications are associated with cognitive decline in PD, whereas the findings are mixed for MAPT polymorphisms. Cognitive enhancing medications have some effect in PD dementia, but no convincing evidence that progression from MCI to dementia can be delayed or prevented is available, although cognitive training has shown promising results.

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Section: Mechanismsmentioning

confidence: 99%

Cognitive decline in Parkinson disease

et al. 2017

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“…Several studies associate this hypometabolism with cognitive impairment, suggesting that hypometabolism in PD primarily reflects cognitive deterioration 27, 28. Though a very recent postmortem study suggests that loss of synaptic markers predicts cognitive decline in Lewy body diseases,29 to the best of our knowledge, no direct links have been established between reduced glucose metabolism in PD and independent synaptic markers.…”

Section: Introductionmentioning

confidence: 99%

Impaired synaptic function is linked to cognition in Parkinson's disease

Selnes

Stav

Johansen

et al. 2017

Ann Clin Transl Neurol

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ObjectiveCognitive impairment is frequent in Parkinson's disease, but the underlying mechanisms are insufficiently understood. Because cortical metabolism is reduced in Parkinson's disease and closely associated with cognitive impairment, and CSF amyloid‐β species are reduced and correlate with neuropsychological performance in Parkinson's disease, and amyloid‐β release to interstitial fluid may be related to synaptic activity; we hypothesize that synapse dysfunction links cortical hypometabolism, reduced CSF amyloid‐β, and presynaptic deposits of α‐synuclein. We expect a correlation between hypometabolism, CSF amyloid‐β, and the synapse related‐markers CSF neurogranin and α‐synuclein.MethodsThirty patients with mild‐to‐moderate Parkinson's disease and 26 healthy controls underwent a clinical assessment, lumbar puncture, MRI, 18F‐fludeoxyglucose‐PET, and a neuropsychological test battery (repeated for the patients after 2 years).ResultsAll subjects had CSF amyloid‐β 1‐42 within normal range. In Parkinson's disease, we found strong significant correlations between cortical glucose metabolism, CSF Aβ, α‐synuclein, and neurogranin. All PET CSF biomarker‐based cortical clusters correlated strongly with cognitive parameters. CSF neurogranin levels were significantly lower in mild‐to‐moderate Parkinson's disease compared to controls, correlated with amyloid‐β and α‐synuclein, and with motor stage. There was little change in cognition after 2 years, but the cognitive tests that were significantly different, were also significantly associated with cortical metabolism. No such correlations were found in the control group.Interpretation CSF Aβ, α‐synuclein, and neurogranin concentrations are related to cortical metabolism and cognitive decline. Synaptic dysfunction due to Aβ and α‐synuclein dysmetabolism may be central in the evolution of cognitive impairment in Parkinson's disease.

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“…In the brains of patients with DLB and PDD, most α‐synuclein aggregates are located in the presynaptic terminals and cause synaptic dysfunction via significant reduction of pre‐ and postsynaptic proteins, such as synaptophysin and drebrin . To quantitatively evaluate the effects of abnormal α‐synuclein accumulation on synaptic proteins in the frontal cortex and hippocampus, we assessed synaptophysin and synapsin I levels as presynaptic markers and drebrin and PSD‐95 levels as postsynaptic markers using capillary western blot.…”

Section: Resultsmentioning

confidence: 99%

T‐495, a novel low cooperative M₁ receptor positive allosteric modulator, improves memory deficits associated with cholinergic dysfunction and is characterized by low gastrointestinal side effect risk

Mandai

Sako

Kurimoto

et al. 2020

Pharmacology Res & Perspec

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M1 muscarinic acetylcholine receptor (M1R) activation can be a new therapeutic approach for the treatment of cognitive deficits associated with cholinergic hypofunction. However, M1R activation causes gastrointestinal (GI) side effects in animals. We previously found that an M1R positive allosteric modulator (PAM) with lower cooperativity (α‐value) has a limited impact on ileum contraction and can produce a wider margin between cognitive improvement and GI side effects. In fact, TAK‐071, a novel M1R PAM with low cooperativity (α‐value of 199), improved scopolamine‐induced cognitive deficits with a wider margin against GI side effects than a high cooperative M1R PAM, T‐662 (α‐value of 1786), in rats. Here, we describe the pharmacological characteristics of a novel low cooperative M1R PAM T‐495 (α‐value of 170), using the clinically tested higher cooperative M1R PAM MK‐7622 (α‐value of 511) as a control. In rats, T‐495 caused diarrhea at a 100‐fold higher dose than that required for the improvement of scopolamine‐induced memory deficits. Contrastingly, MK‐7622 showed memory improvement and induction of diarrhea at an equal dose. Combination of T‐495, but not of MK‐7622, and donepezil at each sub‐effective dose improved scopolamine‐induced memory deficits. Additionally, in mice with reduced acetylcholine levels in the forebrain via overexpression of A53T α‐synuclein (ie, a mouse model of dementia with Lewy bodies and Parkinson's disease with dementia), T‐495, like donepezil, reversed the memory deficits in the contextual fear conditioning test and Y‐maze task. Thus, low cooperative M1R PAMs are promising agents for the treatment of memory deficits associated with cholinergic dysfunction.

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Synaptic proteins predict cognitive decline in Alzheimer's disease and Lewy body dementia

Cited by 143 publications

References 46 publications

Cognitive decline in Parkinson disease

Cognitive decline in Parkinson disease

Impaired synaptic function is linked to cognition in Parkinson's disease

T‐495, a novel low cooperative M₁ receptor positive allosteric modulator, improves memory deficits associated with cholinergic dysfunction and is characterized by low gastrointestinal side effect risk

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Synaptic proteins predict cognitive decline in Alzheimer's disease and Lewy body dementia

Cited by 143 publications

References 46 publications

Cognitive decline in Parkinson disease

Cognitive decline in Parkinson disease

Impaired synaptic function is linked to cognition in Parkinson's disease

T‐495, a novel low cooperative M1 receptor positive allosteric modulator, improves memory deficits associated with cholinergic dysfunction and is characterized by low gastrointestinal side effect risk

Contact Info

Product

Resources

About

T‐495, a novel low cooperative M₁ receptor positive allosteric modulator, improves memory deficits associated with cholinergic dysfunction and is characterized by low gastrointestinal side effect risk