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ABSTRACT: Genome-wide association studies have pointed to clusterin (apolipoprotein J) as being linked to the occurrence of Alzheimer's disease (AD); studies have identified the protein as a possible biomarker. The association between clusterin and senile plaques in AD brain is well known and clusterin levels in AD brain are 40% higher than in control subjects. The present study investigates, immunohistochemically, the association between clusterin and Aβ peptides in AD and control cortex. A unique and specific association between clusterin and Aβ40 was observed in plaques in the cerebral cortex from AD subjects in that only plaques that contained Aβ40 showed clusterin immunoreactivity while the many plaques with Aβ42 alone lacked clusterin labelling. Cerebrovascular Aβ in AD brain generally lacked Aβ42 but was positively labelled by both the Aβ40 and clusterin antibodies. In control subjects, however, Aβ40 was absent from plaques although very occasional plaques were found to be labelled by both the Aβ42 and clusterin antibodies. Overall, in AD, but not aged control brain, clusterin was associated specifically with the Aβ40 form of Aβ in the brain. The lack of clusterin in association with Aβ42 may be a significant feature in neuronal loss and neurodegeneration in the disease state.
Brain Pathology 03/2013; · 3.99 Impact Factor
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ABSTRACT: The cannabinoid system seems to play an important role in various neurodegenerative diseases including Alzheimer's disease (AD). The relationship of cannabinoid receptors (CB(1)R and CB(2)R) to cognitive function and neuropathological markers in AD remains unclear. In the present study, postmortem cortical brain tissues (Brodmann area 10) from a cohort of neuropathologically confirmed AD patients and age-matched controls were used to measure CB(1)R and CB(2)R by immunoblotting. Correlational analyses were performed for the neurochemical and cognitive data. CB(1)R expression was significantly decreased in AD. Levels of CB(1)R correlated with hypophagia, but not with any AD molecular marker or cognitive status (Mini Mental State Examination score). The level of CB(2)R was significantly higher (40%) in AD. Increases in the expression of the glial marker glial fibrillar acidic protein were also found. CB(2)R expression did not correlate with cognitive status. Interestingly, expression levels of CB(2)R correlated with two relevant AD molecular markers, Aβ(42) levels and senile plaque score. These results may constitute the basis of CB(2)R-based therapies and/or diagnostic approaches.
Neurobiology of aging 07/2012; · 5.94 Impact Factor
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ABSTRACT: A dysfunctional ubiquitin proteasome system may be a mediating factor of disease progression in Lewy body dementia (LBD). The effects of proteasome inhibition using lactacystin and epoxomicin in primary neuronal culture were studied to assess the validity of this model to reflect the cortical pathology of LBD. Treatment of primary cortical neurons with 5 μM lactacystin for 24 h led to a 38 % reduction in the levels of β-III-tubulin (p < 0.05), a 48 % reduction in the levels of synaptophysin (p < 0.05) and a 74 % reduction in the levels of drebrin (p < 0.01), when compared to controls. Results for epoxomicin were similar. The loss of neuronal protein occurred prior to any loss of mitochondrial activity or cell death. The results are reflective of the loss of synapses and the synaptic changes observed in LBD, which may be an early event in the neurodegeneration of LBD. The similarities with the pathological changes in LBD highlight the possibility that this model can potentially provide a platform to test novel treatments.
Acta Neurovegetativa 05/2012; · 2.73 Impact Factor
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ABSTRACT: Agitation and aggressive behavior are common symptoms of Alzheimer's disease (AD), and tangle density in frontal cortex is a possible regional substrate of these behaviors. To investigate this further, 16 AD patients, 8 patients with non-AD dementia, and 13 age-matched control subjects for frontal cortex and, respectively, 21, 7, and 6 patients for parietal cortex were analyzed for tau and phospho-tau by enzyme-linked immunosorbent assay (ELISA). Agitation/aggression was determined by the Present Behavioural Examination. In a subset of cases, glycogen synthase kinase-3β (GSK-3β) phosphorylation and protein phosphatase 2A (PP2A) expression were measured. Phospho-tau and the phospho-tau/total tau ratio were elevated in AD in both cortical regions. In keeping with our hypothesis, the phospho-tau/total tau ratio was elevated in the frontal cortex of those patients with agitation/aggression during life, and there was a significant correlation (p = 0.024) between these behaviors and the phospho-tau/total tau ratio in the cortex. PP2A expression was lower (p < 0.01) in the frontal cortex of patients with high tau phosphorylation. This study confirms a link between tau phosphorylation and agitation/aggression and suggests that reducing tau phosphorylation may provide symptomatic relief.
Neurobiology of aging 02/2012; 33(12):2798-806. · 5.94 Impact Factor
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Marisa Hanney,
Vee Prasher,
Nicola Williams,
Emma L Jones,
Dag Aarsland,
Anne Corbett,
Dale Lawrence,
Ly-Mee Yu,
Stephen Tyrer, Paul T Francis,
Tony Johnson,
Roger Bullock,
Clive Ballard
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ABSTRACT: Prevalence of Alzheimer's disease in people with Down's syndrome is very high, and many such individuals who are older than 40 years have pathological changes characteristic of Alzheimer's disease. Evidence to support treatment with Alzheimer's drugs is inadequate, although memantine is beneficial in transgenic mice. We aimed to assess safety and efficacy of memantine on cognition and function in individuals with Down's syndrome.
In our prospective randomised double-blind trial, we enrolled adults (>40 years) with karyotypic or clinically diagnosed Down's syndrome, with and without dementia, at four learning disability centres in the UK and Norway. We randomly allocated participants (1:1) to receive memantine or placebo for 52 weeks by use of a computer-generated sequence and a minimisation algorithm to ensure balanced allocation for five prognostic factors (sex, dementia, age group, total Down's syndrome attention, memory, and executive function scales [DAMES] score, and centre). The primary outcome was change in cognition and function, measured with DAMES scores and the adaptive behaviour scale (ABS) parts I and II. We analysed differences in DAMES and ABS scores between groups with analyses of covariance or quantile regression in all patients who completed the 52 week assessment and had available follow-up data. This study is registered, number ISRCTN47562898.
We randomly allocated 88 patients to receive memantine (72 [82%] had DAMES data and 75 [85%] had ABS data at 52 weeks) and 85 to receive placebo (74 [87%] and 73 [86%]). Both groups declined in cognition and function but rates did not differ between groups for any outcomes. After adjustment for baseline score, there were non-significant differences between groups of -4·1 (95% CI -13·1 to 4·8) in DAMES scores, -8·5 (-20·1 to 3·1) in ABS I scores, and 2·0 (-7·2 to 11·3) in ABS II scores, all in favour of controls. 10 (11%) of 88 participants in the memantine group and six (7%) of 85 controls had serious adverse events (p=0·33). Five participants in the memantine group and four controls died from serious adverse events (p=0·77).
There is a striking absence of evidence about pharmacological treatment of cognitive impairment and dementia in people older than 40 years with Down's syndrome. Despite promising indications, memantine is not an effective treatment. Therapies that are effective for Alzheimer's disease are not necessarily effective in this group of patients.
Lundbeck.
The Lancet 02/2012; 379(9815):528-36. · 38.28 Impact Factor
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ABSTRACT: Dietary factors may play a role in Alzheimer's disease (AD) pathogenesis. In an effort to recapitulate some of the synaptic protein changes observed in the disease, AD transgenic and wild-type mice were fed either a normal or pro-oxidant diet for 3 months from three months of age. Pro-oxidant diet treatment resulted in altered expression of vesicular glutamate transporter-1 and glutamine synthetase, suggesting changes in glutamatergic synaptic function, and increased expression of urokinase plasminogen activator receptor, possibly reflecting oxidative stress.
Acta Neurovegetativa 11/2011; 119(4):493-6. · 2.73 Impact Factor
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Journal of Neurochemistry 10/2011; · 4.06 Impact Factor
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Evert-Jan Kooi,
Marloes Prins,
Natasha Bajic,
Jeroen A M Beliën,
Wouter H Gerritsen,
Jack van Horssen,
Eleonora Aronica,
Anne-Marie van Dam,
Jeroen J M Hoozemans, Paul T Francis,
Paul van der Valk,
Jeroen J G Geurts
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ABSTRACT: Hippocampal pathology was shown to be extensive in multiple sclerosis (MS) and is associated with memory impairment. In this post-mortem study, we investigated hippocampal tissue from MS and Alzheimer's disease (AD) patients and compared these to non-neurological controls. By means of biochemical assessment, (immuno)histochemistry and western blot analyses, we detected substantial alterations in the cholinergic neurotransmitter system in the MS hippocampus, which were different from those in AD hippocampus. In MS hippocampus, activity and protein expression of choline acetyltransferase (ChAT), the acetylcholine synthesizing enzyme, was decreased, while the activity and protein expression of acetylcholinesterase (AChE), the acetylcholine degrading enzyme, was found to be unaltered. In contrast, in AD hippocampus both ChAT and AChE enzyme activity and protein expression was decreased. Our findings reveal an MS-specific cholinergic imbalance in the hippocampus, which may be instrumental in terms of future treatment options for memory problems in this disease.
Acta Neuropathologica 06/2011; 122(3):313-22. · 9.32 Impact Factor
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Annika Ohrfelt,
Henrik Zetterberg,
Kerstin Andersson,
Rita Persson,
Dzemila Secic,
Gunnar Brinkmalm,
Anders Wallin,
Ezra Mulugeta, Paul T Francis,
Eugeen Vanmechelen,
Dag Aarsland,
Clive Ballard,
Kaj Blennow,
Ann Westman-Brinkmalm
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ABSTRACT: Parkinson's disease (PD) and Dementia with Lewy bodies (DLB) are neurodegenerative diseases that are characterized by intra-neuronal inclusions of Lewy bodies in distinct brain regions. These inclusions consist mainly of aggregated α-synuclein (α-syn) protein. The present study used immunoprecipitation combined with nanoflow liquid chromatography (LC) coupled to high resolution electrospray ionization Fourier transform ion cyclotron resonance tandem mass spectrometry (ESI-FTICR-MS/MS) to determine known and novel isoforms of α-syn in brain tissue homogenates. N-terminally acetylated full-length α-syn (Ac-α-syn₁₋₁₄₀) and two N-terminally acetylated C-terminally truncated forms of α-syn (Ac-α-syn₁₋₁₃₉ and Ac-α-syn₁₋₁₀₃) were found. The different forms of α-syn were further studied by Western blotting in brain tissue homogenates from the temporal cortex Brodmann area 36 (BA36) and the dorsolateral prefrontal cortex BA9 derived from controls, patients with DLB and PD with dementia (PDD). Quantification of α-syn in each brain tissue fraction was performed using a novel enzyme-linked immunosorbent assay (ELISA).
Neurochemical Research 06/2011; 36(11):2029-42. · 2.24 Impact Factor
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ABSTRACT: Alterations in plasma and in lumbar cerebrospinal fluid amyloid-B peptide (Aβ) levels have been reported in Alzheimer's disease. Studies have also suggested similar changes in depressed patients. No information is available on the impact of psychotropic drugs on this in patients with depression. We therefore quantified Aβ in ventricular cerebrospinal fluid (CSF) in a population of patients with treatment-resistant depression, with and without antipsychotic medication.
A cross-sectional study of 32 patients undergoing subcaudate tractotomy for major (unipolar) depressive disorder. Ventricular CSF concentrations of Aβ peptide 1-40 and 1-42, also p-tau and total tau were determined by Western blotting or enzyme-linked immunosorbent assay.
Patients taking antipsychotic medication in the 2 weeks prior to surgery demonstrated significantly higher levels of Aβ 1-40 (mean ± SD: 727.3 ± 382.3 vs. 440.9 ± 337.2 pg/ml; p = 0.032, Student's t-test) but unaltered Aβ 1-42 (mean 72.1 ± 67.5 vs. 60.0 ± 56.7 pg/ml; p = 0.587) compared to a matched sample not treated with antipsychotic drugs. The same group demonstrated elevated total tau (mean 945.0 ± 422.2 vs. 534.3 ± 388.3 pg/ml; p = 0.010) but not p-tau (mean 98.6 ± 71.5 vs. 88.1 ± 70.5 pg/ml; p = 0.694). No similar effect was found with lithium, antidepressants, carbamazepine or benzodiazepines.
This preliminary study suggests antipsychotic drugs, widely used in patients with severe depression across all age ranges, may be associated with alteration of Aβ 1-40 and total tau, indices strongly linked with progressive organic brain disease. Further confirmatory work is needed.
International Journal of Geriatric Psychiatry 02/2011; 26(12):1283-91. · 2.42 Impact Factor
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ABSTRACT: Previous studies have shown extensive serotonergic deficits in the hippocampus of Alzheimer's disease (AD) patients. However, it is unclear whether such deficits play a role in non-cognitive, neuropsychiatric behaviors that occur frequently in AD and cause significant caregiver distress.
In this study, we aimed to correlate serotonergic markers in the AD hippocampus with neuropsychiatric behaviors.
Using postmortem hippocampal homogenates from aged controls as well as a cohort of longitudinally assessed AD patients, measurements of 5-HT(1A) receptors, 5-HT(2A) receptors, and serotonin re-uptake (5-HTT) sites were performed by binding with (3)H-labeled 8-OH-DPAT, ketanserin, and citalopram, respectively.
Alterations of 5-HT(1A) receptors and 5-HTT were found to be differentially involved in neuropsychiatric behaviors, with loss of 5-HT(1A) receptors specifically correlated with depressive symptoms, while 5-HTT sites were preserved or up-regulated in patients with aggressive behaviors.
Our data suggest that neuropsychiatric behaviors in AD share certain neurochemical features with psychiatric disorders like major depression and that serotonergic drugs used in psychiatric disorders may also be efficacious against behavioral symptoms in AD.
Psychopharmacologia 02/2011; 213(2-3):431-9. · 4.08 Impact Factor
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ABSTRACT: A novel class of 2-amido-3-hydroxypyridin-4-one iron chelators is described. These compounds have been designed to behave as suitable molecular probes which will improve our knowledge of the role of iron in neurodegenerative conditions. Neurodegenerative disorders, such as Alzheimer's disease (AD) and Parkinson disease (PD), can be considered as diverse pathological conditions sharing critical metabolic processes such as protein aggregation and oxidative stress. Interestingly, both these metabolic alterations seem to be associated with the involvement of metal ions, including iron. Iron chelation is therefore a potential therapeutic approach. The physico-chemical (pK(a), pFe(3+) and logP) and biological properties (inhibition of iron-containing enzymes) of these chelators have been investigated in order to obtain a suitable profile for the treatment of neurodegenerative conditions. Studies with neuronal cell cultures confirm that the new iron chelators are neuroprotective against β-amyloid-induced toxicity.
Bioorganic & medicinal chemistry 02/2011; 19(3):1285-97. · 2.82 Impact Factor
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ABSTRACT: Genetic risk factors have not been clearly established for vascular dementias (VaD) related to stroke and cerebrovascular disease.
Samples were genotyped for APOE, MTHFR and ICAM. Aβ levels and choline acetyltransferase (ChAT) activities were assayed in controls and individuals with VaD.
Associations were found between the APOE-ε4 allele and mixed dementia, infarct/stroke dementia and subcortical ischemic vascular dementia (SIVD), and higher Aβ1-42 levels and decreased ChAT activity. MTHFR was more associated with SIVD, mixed dementia, and lower ChAT activity.
The study demonstrates important differences in the genetic associations of VaD and begins to clarify the genetic basis of key pathological substrates.
Dementia and Geriatric Cognitive Disorders 01/2011; 31(4):247-53. · 2.14 Impact Factor
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ABSTRACT: Oxidative stress is implicated in the pathogenesis of Alzheimer's disease (AD) causing neurodegeneration and decreased monoamine neurotransmitters. We investigated the effect of administration of a pro-oxidant diet on the levels of monoamines and metabolites in the brains of wildtype and transgenic mice expressing mutant APP and PS-1 (TASTPM mice). Three-month-old TASTPM and wildtype (C57BL6/J) mice were fed either normal or pro-oxidant diet for 3 months. The neocortex, cerebellum, hippocampus and striatum were assayed for their monoamine and monoamine metabolite content using HPLC with electrochemical detection. Striatal tyrosine hydroxylase (TOH) levels were analysed by Western blotting. In the striatum, female TASTPM mice had higher levels of DOPAC and male TASTPM mice had higher levels of 5-HIAA compared to wildtype mice. Administration of pro-oxidant diet increased striatal MHPG, turnover of NA and 5-HT levels in female TASTPM mice compared to TASTPM mice fed control diet. The pro-oxidant diet also decreased DOPAC levels in female TASTPM mice compared to those fed control diet. Striatal TOH did not depend on diet, gender or genotype. In the neocortex, the TASTPM genotype increased levels of 5-HIAA in male mice fed control diet compared to wildtype mice. In the cerebellum, the TASTPM genotype led to decreased levels of HVA (male mice only) and also decreased turnover of DA (female mice only) compared to wildtype mice. These data suggest a sparing of monoaminergic neurones in the cortex, striatum and hippocampus of TASTPM mice fed pro-oxidant diet and could be indicative of increased activity in corticostriatal circuits. The decreased cerebellar levels of HVA and turnover of DA in TASTPM mice hint at possible axonal degeneration within this subregion.
Neurochemistry International 11/2010; 57(5):504-11. · 2.86 Impact Factor
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ABSTRACT: The cannabinoid CB1 receptor has gained much attention as a potential pharmacotherapeutic target in various neurodegenerative diseases including Alzheimer's disease (AD). However, the relation of CB1 receptors to cognitive function in AD is at present unclear. In this study, postmortem brain tissues from a cohort of prospectively assessed, neuropathologically confirmed AD patients and aged controls were used to measure CB1 receptors by immunoblotting, and a subset of subjects also had [(3)H]SR141716A binding. Correlational analyses were then performed for the neurochemical and cognitive data. We found that CB1 receptor levels in were unchanged AD in the brain regions assessed (frontal cortex, anterior cingulate gyrus, hippocampus, caudate nucleus). Within the AD group, frontal cortical CB1 immunoreactivity correlated with cognitive scores assessed within a year of death. Our study suggests that CB1 receptors are intact in AD and may play a role in preserving cognitive function. Therefore, CB1 receptors should be further assessed as a potential therapeutic target in AD.
Neurochemistry International 10/2010; 57(8):985-9. · 2.86 Impact Factor
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ABSTRACT: The etiology of Alzheimer's disease (AD) is complex with oxidative stress being a possible contributory factor to pathogenesis and disease progression. TASTPM transgenic mice expressing familial AD-associated amyloid precursor protein (APPswe) and presenilin transgenes (PS1M146V) show increased brain amyloid beta (Aβ) levels and Aβ plaques from 3 months. We tested if enhancing oxidative stress through diet would accelerate Aβ-related pathology. TASTPM were fed a pro-oxidant diet for 3 months resulting in increased brain levels of protein carbonyls, increased Nrf2, and elevated concentrations of glutathione (GSH). The diet increased both amyloid precursor protein (APP) and Aβ in the cortex of TASTPM but did not alter Aβ plaque load, presenilin 1, or β-secretase (BACE1) expression. TASTPM cortical neurons were cultured under similar pro-oxidant conditions resulting in increased levels of APP and Aβ likely as a result of enhanced β/γ secretase processing of APP. Thus, pro-oxidant conditions increase APP levels and enhance BACE1-mediated APP processing and in doing so might contribute to pathogenesis in AD.
Neurobiology of aging 08/2010; 33(5):960-8. · 5.94 Impact Factor
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Madhav Thambisetty,
Andrew Simmons,
Latha Velayudhan,
Abdul Hye,
James Campbell,
Yi Zhang,
Lars-Olof Wahlund,
Eric Westman,
Anna Kinsey,
Andreas Güntert, [......],
Jill C Richardson,
Susan M Resnick,
Luigi Ferrucci,
Dean F Wong,
Yun Zhou,
Sebastian Muehlboeck,
Alan Evans, Paul T Francis,
Christian Spenger,
Simon Lovestone
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ABSTRACT: Blood-based analytes may be indicators of pathological processes in Alzheimer disease (AD).
To identify plasma proteins associated with AD pathology using a combined proteomic and neuroimaging approach.
Discovery-phase proteomics to identify plasma proteins associated with correlates of AD pathology. Confirmation and validation using immunodetection in a replication set and an animal model.
A multicenter European study (AddNeuroMed) and the Baltimore Longitudinal Study of Aging.
Patients with AD, subjects with mild cognitive impairment, and healthy controls with standardized clinical assessments and structural neuroimaging.
Association of plasma proteins with brain atrophy, disease severity, and rate of clinical progression. Extension studies in humans and transgenic mice tested the association between plasma proteins and brain amyloid.
Clusterin/apolipoprotein J was associated with atrophy of the entorhinal cortex, baseline disease severity, and rapid clinical progression in AD. Increased plasma concentration of clusterin was predictive of greater fibrillar amyloid-beta burden in the medial temporal lobe. Subjects with AD had increased clusterin messenger RNA in blood, but there was no effect of single-nucleotide polymorphisms in the gene encoding clusterin with gene or protein expression. APP/PS1 transgenic mice showed increased plasma clusterin, age-dependent increase in brain clusterin, as well as amyloid and clusterin colocalization in plaques.
These results demonstrate an important role of clusterin in the pathogenesis of AD and suggest that alterations in amyloid chaperone proteins may be a biologically relevant peripheral signature of AD.
Archives of general psychiatry 07/2010; 67(7):739-48. · 12.26 Impact Factor
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ABSTRACT: Neuron and synapse loss together with neurotransmitter dysfunction have, along with Abeta deposition and neurofibrillary tangles, been recognized as hallmarks of Alzheimer's disease (AD). Furthermore, clinical and preclinical studies point to neuronal loss and associated neurochemical alterations of several transmitter systems as a main factor underlying both cognitive and neuropsychiatric symptoms. Treatment for the cognitive decline in AD, based on early findings of a cholinergic deficit, has been in the clinic for more than a decade but provides only modest benefit in most patients. Therefore there is still considerable scope for new treatments that demonstrate greater efficacy against cognitive dysfunction in spite of the fact that the mainstays of current treatments, the cholinesterase inhibitors Aricept, Exelon and Reminyl (Razadyne) will become generic over the next few years. However, the most important area for drug development is for the treatment of behavioural disturbance in AD since many existing treatments have limited efficacy and have potentially life-threatening side effects. This review examines the neurochemical underpinning of both cognitive and neuropsychiatric symptoms in dementia and provides some basis for rational drug development.
Neuropharmacology 02/2010; 59(4-5):221-9. · 4.81 Impact Factor
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ABSTRACT: Neurotransmitter system dysfunction and synapse loss have been recognized as hallmarks of Alzheimer's disease (AD). Our hypothesis is that specific neurochemical populations of neurons might be more vulnerable to degeneration in AD due to particular deficits in synaptic plasticity. We have studied, in postmortem brain tissue, the relationship between levels of synaptic markers (NCAM and BDNF), neurochemical measurements (cholinacetyltransferase activity, serotonin, dopamine, GABA, and glutamate levels), and clinical data (cognitive status measured as MMSE score). NCAM levels in frontal and temporal cortex from AD patients were significantly lower than control patients. Interestingly, these reductions in NCAM levels were associated to an ApoE4 genotype. Levels of BDNF were also significantly reduced in both frontal and temporal regions in AD patients. The ratio between plasticity markers and neurochemical measurements was used to study which of the neurochemical populations was particularly associated to plasticity changes. In both the frontal and temporal cortex, there was a significant reduction in the ChAT/NCAM ratio in AD samples compared to controls. None of the ratios to BDNF were different between control and AD samples. Furthermore, Pearson's product moment showed a significant positive correlation between MMSE score and the ChAT/NCAM ratio in frontal cortex (n=19; r=0.526*; p=0.037) as well as in temporal cortex (n=19; r=0.601*; p=0.018) in AD patients. Altogether, these data suggest a potential involvement of NCAM expressing neurons in the cognitive deficits in AD.
Journal of Alzheimer's disease: JAD 02/2010; 20(2):659-68. · 3.74 Impact Factor
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ABSTRACT: Hyperphagia and associated eating changes occur frequently in Alzheimer's disease (AD) and lead to considerable morbidity. However, the neurochemical basis for these neuropsychiatric behaviours is at present unclear. In this study, we measured serotonin transporters, 5-HT(1A), 5-HT(2A), and 5-HT(4) receptors using radioligand binding assays in the postmortem temporal cortex of a cohort of controls and AD patients longitudinally assessed for hyperphagia. We found significant decreases in 5-HT(4) receptor densities in the hyperphagic, but not normophagic, AD group. Our data suggest that 5-HT(4) receptor deficits may be a specific neurochemical correlate of hyperphagia, and point to the potential pharmacotherapeutic utility of 5-HT(4) agonists for these behaviours in AD.
Journal of the neurological sciences 10/2009; 288(1-2):151-5. · 2.32 Impact Factor
