Hippocampal glutamate NMDA receptor loss tracks progression in Alzheimer's disease: quantitative autoradiography in postmortem human brain.

Early Alzheimer's disease (AD) is characterized by memory loss and hippocampal atrophy with relative sparing of basal ganglia. Activation of glutamate NMDA receptors in the hippocampus is an important step in memory formation. We measured the density of NMDA receptors in samples of hippocampus, entorhinal cortex and basal ganglia obtained from subjects who died with pathologically confirmed AD and age- and sex- matched non-demented controls. We found significant decreases in NMDA receptor density in the hippocampus and entorhinal cortex but not in the basal ganglia. Loss of NMDA receptors was significantly correlated with neuropathological progression as assessed by Braak staging postmortem. The same samples were probed for neuroinflammation by measuring the density and gene expression of translocator protein 18 kDA (TSPO), an established marker of microglial activation. Unlike NMDA receptor loss, increased densities of TSPO were found in all of the brain regions sampled. However hippocampal, but not striatal TSPO density and gene expression were inversely correlated with NMDA receptor density and positively correlated with Braak stage, suggesting NMDA receptors exacerbate neuroniflammatory damage. The high correlation between hippocampal NMDA receptor loss and disease progression supports the use of non invasive imaging with NMDA receptor tracers and positron emission tomography as a superior method for diagnosis, staging and treatment monitoring of AD in vivo

Cognitive Decline and Dementia in the Oldest-Old

The oldest-old are the fastest growing segment of the Western population. Over half of the oldest-old will have dementia, but the etiology is yet unknown. Age is the only risk factor consistently associated with dementia in the oldest-old. Many of the risk and protective factors for dementia in the young elderly, such as ApoE genotype, physical activity, and healthy lifestyle, are not relevant for the oldest-old. Neuropathology is abundant in the oldest-old brains, but specific pathologies of Alzheimer’s disease (AD) or vascular dementia are not necessarily correlated with cognition, as in younger persons. It has been suggested that accumulation of both AD-like and vascular pathologies, loss of synaptic proteins, and neuronal loss contribute to the cognitive decline observed in the oldest-old. Several characteristics of the oldest-old may confound the diagnosis of dementia in this age group. A gradual age-related cognitive decline, particularly in executive function and mental speed, is evident even in non-demented oldest-old. Hearing and vision losses, which are also prevalent in the oldest-old and found in some cases to precede/predict cognitive decline, may mechanically interfere in neuropsychological evaluations. Difficulties in carrying out everyday activities, observed in the majority of the oldest-old, may be the result of motor or physical dysfunction and of neurodegenerative processes. The oldest-old appear to be a select population, who escapes major illnesses or delays their onset and duration toward the end of life. Dementia in the oldest-old may be manifested when a substantial amount of pathology is accumulated, or with a composition of a variety of pathologies. Investigating the clinical and pathological features of dementia in the oldest-old is of great importance in order to develop therapeutic strategies and to provide the most elderly of our population with good quality of life

Regional TSPO mRNA gene expression in relation to AD pathology and ApoE genotype.

<div><p>A. TSPO gene expression by region and disease state. TSPO mRNA gene expression was measured by RT-PCR and expressed as fold change over expression in the reference sample. **p<0.005.</p> <p>B. TSPO gene expression as a function of Braak stage in hippocampus (left) and striatum (right).</p> <p>*p<0.05 relative to Braak stages 0-II, one way ANOVA followed by Fisher’s PLSD posthoc test.</p> <p>C. Effect of genotype on TSPO gene expression in hippocampus (left) and striatum (right).</p> <p>*p<0.05, students t-test 2 tailed.</p></div

Regional neuroinflammation in AD subjects and controls measured with [³H]PK11195 autoradiography.

<div><p>A. Representative autoradiographic and anatomical images. </p> <p>Top –Hippocampal anatomy is shown on the left followed by a representative pseudocolored TSPO autoradiogram from hippocampus of a control subject and a representative autoradiogram from hippocampus of a subject with AD. The bottom row depicts striatal anatomy on the left followed by a representative TSPO autoradiogram from a control striatum and a representative autoradiogram from a subject with AD. </p> <p>Autoradiograms were pseudocolored using the rainbow spectrum (bar on the right).</p> <p>B. Quantitative autoradiographic measurements of regional TSPO density (expressed as specific binding of [3H]PK11195 in nCi/mg tissue).</p> <p>Abbreviations: CA1-4 cornu ammoni fields of the hippocampus, DG=gentate gyrus, SubP=subpyramidal layers of CA1, Sub=subiculum, ECx=entorhinal cortex, Str=striatum. </p> <p>*p<0.05, **p<0.005 AD relative to control; ANOVA followed by Fisher’s PLSD posthoc test. </p> <p>C. TSPO density in CA1 pyramidal cell body layer as a function of Braak stage (left) and genotype (right). </p> <p>*p<0.05 relative to Braak stages 0-II, one way ANOVA followed by Fisher’s PLSD posthoc test.</p> <p>**p<0.005, student’s t test. </p></div

Regional NMDA receptor density in AD and control subjects measured with [³H]MK801 autoradiography.

<div><p>A. Representative autoradiographic and anatomical images. </p> <p>Top –Hippocampal anatomy is shown on the left followed by a representative pseudocolored NMDAR autoradiogram from hippocampus of a control subject and a representative autoradiogram from hippocampus of a subject with AD. The bottom row depicts striatal anatomy on the left followed by a representative NMDAR autoradiogram from a control striatum and a representative autoradiogram from a subject with AD. Autoradiograms were pseudocolored using the rainbow spectrum (bar on the right).</p> <p>B. Quantitative autoradiographic measurements of regional NMDAR density (expressed as specific binding of [³H]MK801 in nCi/mg tissue).</p> <p>Abbreviations: CA1-4 cornu ammoni fields of the hippocampus, DG=gentate gyrus, SubP=subpyramidal layers of CA1(including stratum radiatum, lacunosum, and moleculare),, Sub=subiculum, ECx=entorhinal cortex, Str=striatum. </p> <p>*p<0.05, **p<0.005 AD relative to control; ANOVA followed by Fisher’s PLSD posthoc test. </p> <p>C. NMDAR density in the CA1 pyramidal layer as a function of Braak stage (left) and genotype (right). </p> <p>*p<0.05 relative to Braak stages 0-II, one way ANOVA followed by Fisher’s PLSD posthoc test.</p> <p>**p<0.005, student’s t test. </p></div

Region dependent correlation between TSPO and NMDAR density.

<div><p>Quantitative analyses of [³H]MK801 binding to NMDAR and [³H]PK11195 binding to TSPO were performed by autoradiography. The correlation between NMDAR and TSPO density was negative in the CA1 hippocampal field (left, <i>n</i> = 38, Spearman’s <i>p</i> < 0.001) and positive in the striatum (right, <i>n</i> = 37, Spearman’s <i>p</i> < 0.001).</p> <p>SB=specific binding.</p></div