Reduced hippocampal insulin-degrading enzyme in late-onset Alzheimer's disease is associated with the apolipoprotein E-epsilon4 allele

Abeta is the major component of amyloid plaques characterizing Alzheimer's disease (AD). Abeta accumulation can be affected by numerous factors including increased rates of production and/or impaired clearance. Insulin-degrading enzyme (IDE) has been implicated as a candidate enzyme responsible for the degradation and clearance of Abeta in the brain. We have previously shown that AD patients exhibit abnormalities in insulin metabolism that are associated with apoliprotein E (APOE) status. The possible association of IDE with AD, as well as the link between APOE status and insulin metabolism, led us to examine the expression of IDE in AD. We report that hippocampal IDE protein is reduced by approximately 50% in epsilon4+ AD patients compared to epsilon4- patients and controls. The allele-specific decrease of IDE in epsilon4+ AD patients is not associated with neuronal loss since neuron-specific enolase levels were comparable between the AD groups, regardless of APOE status. Hippocampal IDE mRNA levels were also reduced in AD patients with the epsilon4 allele compared to AD and normal subjects without the epsilon4 allele. These findings show that reduced IDE expression is associated with a significant risk factor for AD and suggest that IDE may interact with APOE status to affect Abeta metabolism.     

Partial loss-of-function mutations in insulin-degrading enzyme that induce diabetes also impair degradation of amyloid beta-protein

The causes of cerebral accumulation of amyloid beta-protein (Abeta) in most cases of Alzheimer's disease (AD) remain unknown. We recently found that homozygous deletion of the insulin-degrading enzyme (IDE) gene in mice results in an early and marked elevation of cerebral Abeta. Both genetic linkage and allelic association in the IDE region of chromosome 10 have been reported in families with late-onset AD. For IDE to remain a valid candidate gene for late-onset AD on functional grounds, it must be shown that partial loss of function of IDE can still alter Abeta degradation, but without causing early, severe elevation of brain Abeta. Here, we show that naturally occurring IDE missense mutations in a well-characterized rat model of type 2 diabetes mellitus (DM2) result in decreased catalytic efficiency and a significant approximately 15 to 30% deficit in the degradation of both insulin and Abeta. Endogenously secreted Abeta(40) and Abeta(42) are significantly elevated in primary neuronal cultures from animals with the IDE mutations, but there is no increase in steady-state levels of rodent Abeta in the brain up to age 14 months. We conclude that naturally occurring, partial loss-of-function mutations in IDE sufficient to cause DM2 also impair neuronal regulation of Abeta levels, but the brain can apparently compensate for the partial deficit during the life span of the rat. Our findings have relevance for the emerging genetic evidence suggesting that IDE may be a late-onset AD-risk gene, and for the epidemiological relationships among hyperinsulinemia, DM2, and AD.     

17β-Estradiol regulates insulin-degrading enzyme expression via an ERβ/PI3-K pathway in hippocampus: Relevance to Alzheimer's prevention

Insulin-degrading enzyme (IDE), an enzyme that primarily degrades insulin, has recently been demonstrated to play a significant role in the catabolism of amyloid β (Aβ) protein in the brain. Reduced IDE expression and/or activity have been associated with the etiology and development of Alzheimer's disease (AD). Using three model systems, the present investigation provides the first documentation indicating that estrogen robustly regulates the expression of IDE in normal, menopausal and early-stage AD brains. In vitro analyses in primary cultures of rat hippocampal neurons revealed that 17β-estradiol (17β-E2) increased IDE in both mRNA and protein levels in a time-dependent manner. Further pharmacological analyses indicated that 17β-E2-induced IDE expression was dependent upon estrogen receptor (ER) β and required activation of phosphatidylinositol 3-kinase (PI3-K). In vivo analyses in adult female rats revealed a brain region-specific responsive profile. Ovariectomy (OVX) induced a significant decline in IDE expression in the hippocampus, which was prevented by 17β-E2. Neither OVX nor 17β-E2 affected IDE expression in the cerebellum. In vivo analyses in triple transgenic AD (3xTg-AD) female mice revealed an inverse correlation between the age-related increase in Aβ load and the decrease in IDE expression in the hippocampal formation. Treatment with 17β-E2 attenuated Aβ accumulation/plaque formation and elevated hippocampal IDE expression in 12-month-old 3xTg-AD OVX mice. Collectively, these findings indicate that 17β-E2 regulates IDE expression in a brain region-specific manner and such a regulatory role in the hippocampus, mediated by an ERβ/PI3-K pathway, could serve as a direct mechanism underlying estrogen-mediated preventative effect against AD when initiated at the onset of menopause.     

The normal equilibrium between CSF and plasma amyloid beta levels is disrupted in Alzheimer's disease

Amyloid-beta (Abeta) with 40 (Abeta40) and 42 (Abeta42) amino acids, the main components of amyloid plaques in the Alzheimer's disease (AD) brain, can be measured in human cerebrospinal fluid (CSF) and plasma. Whereas CSF Abeta42 is decreased in AD, some studies have reported changed plasma Abeta levels in AD and in subjects with mild cognitive impairment (MCI). To this date it is unclear if and how CSF and plasma levels of Abeta correlate with each other in healthy individuals, albeit earlier studies on AD patients found no correlation between CSF and plasma Abeta. We have measured Abeta40 and Abeta42 in paired CSF and plasma samples from patients with AD (n=39), MCI (n=29) and healthy control subjects (n=18). We observed a clear correlation between CSF and plasma levels for both Abeta40 and Abeta42 in healthy individuals, whereas no such correlation could be seen for AD or MCI cases. Similarly to other studies we also found low levels of Abeta42 in AD CSF, whereas there were no significant differences in plasma Abeta levels between the diagnostic groups. Our findings suggest that the normal equilibrium between CSF and plasma Abeta may be disrupted with the initiation of amyloid deposition in the brain.     

Regulation of beta-amyloid levels in the brain of cholesterol-fed rabbit, a model system for sporadic Alzheimer's disease

Accumulation of beta-amyloid (Abeta) peptide in the brain is a major hallmark of Alzheimer's disease (AD). Hypercholesterolemia is a risk factor for AD and has been shown by laboratory studies to cause Abeta accumulation. Abeta levels in the brain are governed by its generation from amyloid precursor protein by beta-secretase (BACE1), degradation by the insulin degrading enzyme (IDE), clearance from the brain by the low density lipoprotein receptor-related protein (LRP-1), and transport from circulation into the brain by receptor for advanced glycation end products (RAGE). However, the mechanisms by which hypercholesterolemia causes Abeta accumulation in the brain and contributes to the pathogenesis of AD are still to be determined. In the present study, we determined the extent to which hypercholesterolemia-induced Abeta accumulation is associated with alterations in BACE1, IDE, LRP-1, and RAGE expression levels. We show that hypercholesterolemia increases Abeta production, an effect that is associated with increased levels of BACE1 and RAGE and reduced levels of IDE and LRP-1. These results suggest that reducing Abeta accumulation in the brain may require strategies that combine reduction of generation and transport of Abeta in addition to acceleration of degradation and clearance of this peptide.     

Non-Aβ Component of Alzheimer’s Disease Amyloid (NAC) Revisited : NAC and α-Synuclein Are Not Associated with Aβ Amyloid

alpha-Synuclein (alphaSN), also termed the precursor of the non-Abeta component of Alzheimer's disease (AD) amyloid (NACP), is a major component of Lewy bodies and Lewy neurites pathognomonic of Parkinson's disease (PD) and dementia with Lewy bodies (DLB). A fragment of alphaSN termed the non-Abeta component of AD amyloid (NAC) had previously been identified as a constituent of AD amyloid plaques. To clarify the relationship of NAC and alphaSN with Abeta plaques, antibodies were raised to three domains of alphaSN. All antibodies produced punctate labeling of human cortex and strong labeling of Lewy bodies. Using antibodies to alphaSN(75-91) to label cortical and hippocampal sections of pathologically proven AD cases, we found no evidence for NAC in Abeta amyloid plaques. Double labeling of tissue sections in mixed DLB/AD cases revealed alphaSN in dystrophic neuritic processes, some of which were in close association with Abeta plaques restricted to the CA1 hippocampal region. In brain homogenates alphaSN was predominantly recovered in the cytosolic fraction as a 16-kd protein on Western analysis; however, significant amounts of aggregated and alphaSN fragments were also found in urea extracts of SDS-insoluble material from DLB and PD cases. NAC antibodies identified an endogenous fragment of 6 kd in the cytosolic and urea-soluble brain fractions. This fragment may be produced as a consequence of alphaSN aggregation or alternatively may accelerate aggregation of the full-length alphaSN.     

Age- and region-dependent alterations in Abeta-degrading enzymes: implications for Abeta-induced disorders

Accumulation of amyloid beta-protein (Abeta) is a fundamental feature of certain human brain disorders such as Alzheimer's disease (AD) and Down syndrome and also of the skeletal muscle disorder inclusion body myositis (IBM). Emerging evidence suggests that the steady-state levels of Abeta are determined by the balance between production and degradation. Although the proteolytic processes leading to Abeta formation have been extensively studied, less is known about the proteases that degrade Abeta, which include insulin-degrading enzyme (IDE) and neprilysin (NEP). Here we measured the steady-state levels of these proteases as a function of age and brain/muscle region in mice and humans. In the hippocampus, which is vulnerable to AD pathology, IDE and NEP steady-state levels diminish as function of age. By contrast, in the cerebellum, a brain region not marked by significant Abeta accumulation, NEP and IDE levels either increase or remain unaltered during aging. Moreover, the steady-state levels of IDE and NEP are significantly higher in the cerebellum compared to the cortex and hippocampus. We further show that IDE is more oxidized in the hippocampus compared to the cerebellum of AD patients. In muscle, we find differential levels of IDE and NEP in fast versus slow twitch muscle fibers that varies with aging. These findings suggest that age- and region-specific changes in the proteolytic clearance of Abeta represent a critical pathogenic mechanism that may account for the susceptibility of particular brain or muscle regions in AD and IBM.     

Evaluation of plasma Abeta(40) and Abeta(42) as predictors of conversion to Alzheimer's disease in patients with mild cognitive impairment

Numerous studies have shown a marked decrease of beta-amyloid(42) (Abeta(42)) in the cerebrospinal fluid (CSF) of patients with incipient Alzheimer's disease (AD). However, studies on Abeta in plasma are contradictory, and show very marginal differences between patients and controls. Here, we analyzed plasma samples using a new multiplex immunoassay for simultaneous analysis of Abeta(1-40), Abeta(n-40), Abeta(1-42), and Abeta(n-42). The plasma samples were obtained at baseline from two independent cohorts of patients with mild cognitive impairment (MCI) and age-matched controls. In the first cohort, 41% of the 117 MCI cases converted to AD during a clinical follow-up period of 4-7 years. In the second cohort, 14% of the 110 MCI subjects developed AD during a clinical follow-up period of 2-4 years. None of the plasma Abeta isoforms differed between MCI patients that subsequently developed AD and healthy controls or stable MCI patients. The Cox proportional hazards model did not reveal any differences in the probability of progression from MCI to AD related to plasma Abeta levels. In contrast, low levels of Abeta(1-42) in CSF were strongly associated with increased risk of future AD. The absence of a change in plasma Abeta in incipient AD, despite the marked change in CSF, may be explained by the lack of a correlation between the levels of Abeta(1-42) in CSF and plasma. In conclusion, the results show that CSF biomarkers are better predictors of progression to AD than plasma Abeta isoforms.     

Resistance to Alzheimer's pathology is associated with nuclear hypertrophy in neurons

This study focuses on the morphometric changes of neurons in asymptomatic Alzheimer's disease (AD), a state characterized by the presence of AD lesions in subjects without cognitive impairment. In autopsy brains, we used stereological methods to compare the cell body and nuclear volumes of anterior cingulate gyrus (ACG) and CA1 hippocampal neurons in asymptomatic AD subjects (n=9), subjects with AD dementia (AD, n=8), mild cognitive impairment (MCI, n=9), and age-matched controls (controls, n=9). In ACG, we observed a significant decrease in the neuronal volume of MCI and AD compared to controls; by contrast, no atrophy was present in asymptomatic AD. Moreover, we found a significant increase in nuclear volume in asymptomatic AD compared to controls (P<0.001), MCI (P<0.01) and AD (P<0.001) brains. Similar results were found in the CA1 region of the hippocampus. This nuclear hypertrophy may represent an early neuronal reaction to Abeta or Tau, or a compensatory mechanism which forestalls the progression of AD and allows the brain to resist the development of dementia.     

Insulin, insulin-degrading enzyme and amyloid-beta peptide in Alzheimer's disease: review and hypothesis

Clinical and epidemiological studies have found that type 2 diabetes, and hyperinsulinaemia, increased the risk of developing Alzheimer's disease (AD) in the elderly. The link between hyperinsulinaemia and AD may be insulin-degrading enzyme (IDE). This enzyme degrades both insulin and amylin, peptides related to the pathology of type 2 diabetes, along with amyloid-beta peptide (Abeta), a short peptide found in excess in the AD brain. We review the current evidence, which suggests that hyperinsulinaemia may elevate Abeta through insulin's competition with Abeta for IDE. Genetic studies have also shown that IDE gene variations are associated with the clinical symptoms of AD as well as the risk of type 2 diabetes. The deficiency of IDE can be caused by genetic variation or by the diversion of IDE from the metabolism of Abeta to the metabolism of insulin. It is intriguing to notice that both hyperinsulinaemia and IDE gene variations are related to the risk of AD when the Apolipoprotein E4 (ApoE4) allele, the major risk factor of late-onset AD, is not present. Further studies of the role of IDE in the pathogenesis of AD, which may uncover potential treatment target, are much needed.     

Decreased phosphatidylethanolamine binding protein expression correlates with Abeta accumulation in the Tg2576 mouse model of Alzheimer's disease

Phosphatidylethanolamine binding protein (PEBP) is a multifunctional protein, with proposed roles as the precursor protein of hippocampal cholinergic neurostimulating peptide (HCNP), and as the Raf kinase inhibitor protein (RKIP). Previous studies have demonstrated a decrease in PEBP mRNA in CA1 region of AD hippocampus. The current study demonstrates that PEBP is decreased in the hippocampus of 11 month Tg2576 mice, in the absence of change in mRNA levels compared to non-transgenic littermates. The level of PEBP in transgenic mouse hippocampus significantly decreases at 11 months (a time point when Abeta begins accumulating) and 15 months (when Abeta plaques have formed). There was a significant correlation between decreased PEBP expression and accumulation of Abeta. Immunohistochemical studies on Tg2576 and AD brain sections demonstrate that PEBP immunoreactivities are present at the periphery of dense multicore Abeta plaques, and in selective astrocytes, primarily surrounding plaques. These findings suggest that PEBP expression may be influenced by accumulation of Abeta. Down-regulation of PEBP may result in lower levels of HCNP or altered coordination of signal transduction pathways that may contribute to neuronal dysfunction and pathogenesis in AD.     

Abeta-degrading enzymes in Alzheimer's disease.

In Alzheimer's disease (AD) Abeta accumulates because of imbalance between the production of Abeta and its removal from the brain. There is increasing evidence that in most sporadic forms of AD, the accumulation of Abeta is partly, if not in some cases solely, because of defects in its removal--mediated through a combination of diffusion along perivascular extracellular matrix, transport across vessel walls into the blood stream and enzymatic degradation. Multiple enzymes within the central nervous system (CNS) are capable of degrading Abeta. Most are produced by neurons or glia, but some are expressed in the cerebral vasculature, where reduced Abeta-degrading activity may contribute to the development of cerebral amyloid angiopathy (CAA). Neprilysin and insulin-degrading enzyme (IDE), which have been most extensively studied, are expressed both neuronally and within the vasculature. The levels of both of these enzymes are reduced in AD although the correlation with enzyme activity is still not entirely clear. Other enzymes shown capable of degrading Abetain vitro or in animal studies include plasmin; endothelin-converting enzymes ECE-1 and -2; matrix metalloproteinases MMP-2, -3 and -9; and angiotensin-converting enzyme (ACE). The levels of plasmin and plasminogen activators (uPA and tPA) and ECE-2 are reported to be reduced in AD. Reductions in neprilysin, IDE and plasmin in AD have been associated with possession of APOEepsilon4. We found no change in the level or activity of MMP-2, -3 or -9 in AD. The level and activity of ACE are increased, the level being directly related to Abeta plaque load. Up-regulation of some Abeta-degrading enzymes may initially compensate for declining activity of others, but as age, genetic factors and diseases such as hypertension and diabetes diminish the effectiveness of other Abeta-clearance pathways, reductions in the activity of particular Abeta-degrading enzymes may become critical, leading to the development of AD and CAA.     

Toward prevention of Alzheimers disease--potential nutraceutical strategies for suppressing the production of amyloid beta peptides

Alzheimers disease (AD) can be viewed as a vicious cycle in which excess production and deposition of amyloid beta (Abeta) peptides promote microglial activation, and the resultant production of inflammatory mediators further boosts Abeta production while inducing death and dysfunction of neurons. Abeta production is mediated by beta- and gamma-secretase activities; it is prevented by alpha-secretase activity, and insulin-degrading enzyme (IDE) catabolizes Abeta. High cellular cholesterol content increases Abeta synthesis by boosting beta-secretase activity; inhibition of cholesterol syntheses and/or stimulation of cholesterol export thus diminishes Abeta production. PPARgamma activity decreases Abeta production by promoting harmless catabolism of amyloid precursor protein while blocking the up-regulatory impact of cytokines on beta-secretase expression. Nitric oxide produced by the healthy cerebral microvasculature can suppress Abeta production by boosting expression of alpha-secretase while suppressing that of beta-secretase; conversely, cerebral ischemia provokes increased APP expression. Good insulin sensitivity and efficient brain insulin function protect by inhibiting gamma-secretase activity and increasing expression of IDE. The DHA provided by fish oil diminishes cerebral Abeta deposition in rodent AD models, for unclear reasons. Various measures which oppose microglial activation can inhibit up-regulation of beta-secretase and gamma-secretase by oxidants and cytokines, respectively. These considerations suggest that a number of nutraceutical or lifestyle measures may have potential for preventing or slowing AD: policosanol; 9-cis-beta-carotene; isomerized hops extract; DHA; measures which promote efficient endothelial NO generation, such as low-salt/potassium-rich diets, exercise training, high-dose folate, and flavanol-rich cocoa; chromium picolinate and cinnamon extract as aids for insulin sensitivity; and various agents which can oppose microglial activation, including vitamin D, genistein, and sesamin. The impact of these measures on Abeta production in rodent models of AD should be evaluated, with the intent of defining practical strategies for AD prevention.     

Conversion from cognitive health to mild cognitive impairment and Alzheimer's disease: prediction by plasma amyloid beta 42, medial temporal lobe atrophy and homocysteine

The changes of plasma amyloid beta (Abeta42) protein, homocysteine and medial temporal lobe atrophy (MTA) were studied by the transition from cognitive health to mild cognitive impairment (MCI) and to Alzheimer's disease (AD) in a prospective cohort of individuals aged 75 years. MTA but not plasma Abeta42 measured at baseline predicted which persons remained cognitively healthy (CH) and who developed AD 2.5 years later. The increase of plasma Abeta42 over time significantly distinguished between persons who remained CH on the one hand and MCI converters and AD converters out of cognitive health on the other (CH-to-MCI and CH-to-AD converters). Although both groups showed similar increase of Abeta42 levels, CH-to-AD converters had a higher increase of homocysteine compared to CH-to-MCI converters or to persons remaining CH. In comparison to all cognitive subgroups, the AD converters from MCI at baseline showed the smallest increase of Abeta42 levels and rather no increase of homocysteine. In logistic regression analysis, the increase of plasma Abeta42 but not change of MTA significantly predicted the conversion from CH to MCI, and changes of MTA and homocysteine but not of plasma Abeta42 predicted the conversion from CH to AD. The increase of plasma Abeta42 correctly allocated CH-to-MCI and CH-to-AD converters with low (63%) specificity (for both) and low (60%) sensitivity (54% for AD group). These results indicate that (1) plasma Abeta42 alone is not suitable as a biomarker for AD, (2) in the course of cognitive deterioration of the AD-type the increase of plasma Abeta42 seems to be an initial event, (3) similar to cerebrospinal fluid, changes of plasma Abeta42 may reflect the transition from cognitive health to AD, and (4) whether persons with MCI develop AD may depend on an accumulation of further toxic metabolites such as homocysteine.     

阿尔茨海默病患者海马结构的断层影像学研究

目的观察阿尔茨海默病(AD)发病进程中海马结构在断层影像上的形态学改变。方法依据AD发病进程,分别采集正常对照(NC)组、轻度认知损害(MCI)组、AD组各34例共102例受试者脑核磁共振图像,每组男、女各17例。观测海马面积、横径、矢径和颞叶钩回间距、颞角宽度等。分析组间各测量值变化趋势,以及海马面积等相关测量值与各神经评定量表评分的相关性。结果各组海马面积侧别均无统计学差异。各组间测量值比较,AD组海马面积小于NC组及MCI组(P均<0.05);AD组海马横径小于NC组及MCI组,MCI组海马横径小于NC组(P均<0.01);AD组颞叶钩回间距大于NC组及MCI组(P均<0.01),MCI组颞叶钩回间距大于NC组(P<0.05)。海马面积、海马横径与临床痴呆分级量表(CDR)及汉密尔顿抑郁量表(HAMD)评分均呈负相关,与蒙特利尔认知评估量表(MoCA)评分均呈正相关;颞叶钩回间距与神经心理量表评分相关性同海马面积、海马横径相反。结论海马面积与海马横径随AD病情进展逐渐缩小,颞叶钩回间距随AD病情进展逐渐增大;海马结构的改变可损伤其认知功能。     

Intraneuronal Abeta accumulation precedes plaque formation in beta-amyloid precursor protein and presenilin-1 double-transgenic mice

beta-Amyloid peptides are key molecules that are involved in the pathology of Alzheimer's disease (AD). The source and place of the neurotoxic action of Abeta, however, is still a matter of controversial debates. In the present report, we studied the neuropathological events in a transgenic mouse model expressing human mutant beta-amyloid precursor protein and human mutant presenilin-1 in neurons. Western blot and immunohistochemical analysis revealed that intracellular Abeta staining preceded plaque deposition, which started in the hippocampal formation. At later stages, many neuritic Abeta positive plaques were found in all cortical, hippocampal and many other brain areas. Interestingly, intraneuronal Abeta staining was no longer detected in the brain of aged double-transgenic mice, which correlates with the typical neuropathology in the brain of chronic AD patients.     

Medial septal beta-amyloid 1-40 injections alter septo-hippocampal anatomy and function

Degeneration of septal neurons in Alzheimer's disease (AD) results in abnormal information processing at cortical circuits and consequent brain dysfunction. The septum modulates the activity of hippocampal and cortical circuits and is crucial to the initiation and occurrence of oscillatory activities such as the hippocampal theta rhythm. Previous studies suggest that amyloid beta peptide (Abeta) accumulation may trigger degeneration in AD. This study evaluates the effects of single injections of Abeta 1-40 into the medial septum. Immunohistochemistry revealed a decrease in septal cholinergic (57%) and glutamatergic (53%) neurons in Abeta 1-40 treated tissue. Additionally, glutamatergic terminals were significantly less in Abeta treated tissue. In contrast, septal GABAergic neurons were spared. Unitary recordings from septal neurons and hippocampal field potentials revealed an approximately 50% increase in firing rates of slow firing septal neurons during theta rhythm and large irregular amplitude (LIA) hippocampal activities and a significantly reduced hippocampal theta rhythm power (49%) in Abeta 1-40 treated tissue. Abeta also markedly reduced the proportion of slow firing septal neurons correlated to the hippocampal theta rhythm by 96%. These results confirm that Abeta alters the anatomy and physiology of the medial septum contributing to septo-hippocampal dysfunction. The Abeta induced injury of septal cholinergic and glutamatergic networks may contribute to an altered hippocampal theta rhythm which may underlie the memory loss typically observed in AD patients.     

Hippocampal Proton MR Spectroscopy in Early Alzheimer��s Disease and Mild Cognitive Impairment

Proton magnetic resonance spectroscopy ((1)H-MRS) studies have previously reported reduced brain N-acetyl aspartate (NAA) and increased myo-inositol (mI) in people with established Alzheimer's disease (AD). The earliest structure affected by AD is the hippocampus but relatively few studies have examined its neuronal integrity by MRS in AD and fewer still in people with amnestic mild cognitive impairment (MCI). We measured the hippocampal concentration of NAA, mI, choline (Cho) and creatine?+?phosphocreatine (Cr?+?PCr) in 39 patients with AD, 21 subjects with MCI and 38 age matched healthy elderly controls. Patients with AD had a significantly lower hippocampal [NAA] than controls, with subjects with MCI intermediate between the other two groups. [NAA] was positively correlated with memory in the impaired groups. Using mean hippocampal [NAA] and [Cr?+?PCr] we correctly classified 72% of people with AD, and 75% of controls. Reductions in [NAA] can be detected in the hippocampi of subjects with MCI and hippocampal [NAA] and [Cr?+?PCr] can distinguish between mild AD and normal elderly controls.     

Longitudinal CSF and MRI biomarkers improve the diagnosis of mild cognitive impairment

The diagnosis of Alzheimer's disease (AD) in patients with mild cognitive impairment (MCI) is limited because it is based on non-specific behavioral and neuroimaging findings. The lesions of Alzheimer's disease: amyloid beta (Abeta) deposits, tau pathology and cellular oxidative damage, affect the hippocampus in the earlier stages causing memory impairment. In a 2-year longitudinal study of MCI patients and normal controls, we examined the hypothesis that cerebrospinal fluid (CSF) markers for these pathological features improve the diagnostic accuracy over memory and magnetic resonance imaging (MRI)-hippocampal volume evaluations. Relative to control, MCI patients showed decreased memory and hippocampal volumes and elevated CSF levels of hyperphosphorylated tau and isoprostane. These two CSF measures consistently improved the diagnostic accuracy over the memory measures and the isoprostane measure incremented the accuracy of the hippocampal volume achieving overall diagnostic accuracies of about 90%. Among MCI patients, over 2 years, longitudinal hippocampal volume losses were closely associated with increasing hyperphosphorylated tau and decreasing amyloid beta-42 levels. These results demonstrate that CSF biomarkers for AD contribute to the characterization of MCI.