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.     

CSF biomarkers for Alzheimer's disease: current utility and potential future use

Over the past 15 years, cerebrospinal fluid (CSF) biomarkers have been shown to be useful for both the diagnosis as well as the prognosis in Alzheimer's disease. It has been shown the CSF levels of amyloid-β (Aβ)(42) are a very good marker for the presence of amyloid deposition in the brain regardless of clinical status and that total tau and phosphorylated forms of tau are useful in detection of neurodegeneration. When combined together, these CSF markers are useful not only in differential diagnosis but also in predicting conversion and rate of progression from mild cognitive impairment/very mild dementia to more severe impairment. The markers are also useful in predicting conversion from cognitive normalcy to very mild dementia. This field is briefly reviewed and recommendations for future studies in this area are provided.     

The interaction between sleep-disordered breathing and apolipoprotein E genotype on cerebrospinal fluid biomarkers for Alzheimer's disease in cognitively normal elderly individuals

Previous studies have suggested a link between sleep disordered breathing (SDB) and dementia risk. In the present study, we analyzed the relationship between SDB severity, cerebrospinal fluid (CSF) Alzheimer's disease-biomarkers, and the ApoE alleles. A total of 95 cognitively normal elderly participants were analyzed for SDB severity, CSF measures of phosphorylated-tau (p-tau), total-tau (t-tau), and amyloid beta 42 (Aβ-42), as well as ApoE allele status. In ApoE3+ subjects, significant differences were found between sleep groups for p-tau (F[df2] = 4.3, p = 0.017), and t-tau (F[df2] = 3.3, p = 0.043). Additionally, among ApoE3+ subjects, the apnea and/or hypopnea with 4% O₂-desaturation index was positively correlated with p-tau (r = 0.30, p = 0.023), t-tau (r = 0.31, p = 0.021), and Aβ-42 (r = 0.31, p = 0.021). In ApoE2+ subjects, the apnea and/or hypopnea with 4% O₂-desaturation index was correlated with lower levels of CSF Aβ-42 (r = −0.71, p = 0.004), similarly to ApoE4+ subjects where there was also a trend toward lower CSF Aβ-42 levels. Our observations suggest that there is an association between SDB and CSF Alzheimer's disease-biomarkers in cognitively normal elderly individuals. Existing therapies for SDB such as continuous positive airway pressure could delay the onset to mild cognitive impairment or dementia in normal elderly individuals.     

Using CSF biomarkers to replicate genetic associations in Alzheimer's disease

Defining cases and controls on the basis of biomarkers rather than clinical diagnosis may reduce sample sizes required for genetic studies. The aim of this study was to assess whether characterizing case/control status on the basis of cerebrospinal fluid (CSF) profile would increase power to replicate known genetic associations for Alzheimer's disease (AD). Independent of clinical diagnosis, Alzheimer's Disease Neuroimaging Initiative (ADNI) subjects with 2 CSF biomarkers for AD (Aβ1-42 < 192 pg/mL and tau phosphorylated at threonine 181 (p-tau) > 23 pg/mL, "CSF-positive") were compared with those without CSF evidence for AD (Aβ1-42 > 192 pg/mL and 181-phosphorylated tau < 23 pg/mL, "CSF-negative"). Minor allele frequency (MAF) and odds ratios (ORs) between these 2 groups were calculated for 7 single-nucleotide polymorphisms (SNPs) of interest. Two hundred thirty-two individuals were CSF-positive and 94 CSF-negative. There were no differences in age (74.7 ± 7.2 vs. 75.0 ± 6.5 years, p = 0.7), but significant differences in Mini Mental State Examination (MMSE) (25.9 ± 2.6 vs. 28.2 ± 1.7, p < 0.001) between the CSF-positive and CSF-negative groups. Significant differences in MAF (p < 0.05, uncorrected) were seen for CR1 (rs1408077; OR, 1.59; 95% confidence interval [CI], 1.01-2.49), PICALM (rs541458; OR, 0.68, 95% CI, 0.47-0.98), TOMM40 (rs2075650; OR, 4.30; 95% CI, 2.61-7.06); and possession of 1 or more APOE ε4 alleles (OR, 9.84; 95% CI, 5.48-17.67). These results suggest that using biomarkers of AD pathology to define case and control status may increase power in genetic association studies.     

Attentional networks in normal aging and Alzheimer's disease

By combining a flanker task and a cuing task into a single paradigm, the authors assessed the effects of orienting and alerting on conflict resolution and explored how normal aging and Alzheimer's disease (AD) modulate these attentional functions. Orienting failed to enhance conflict resolution; alerting was most beneficial for trials without conflict, as if acting on response criterion rather than on information processing. Alerting cues were most effective in the older groups--healthy aging and AD. Conflict resolution was impaired only in AD. Orienting remained unchanged across groups. These findings provide evidence of different life span developmental and clinical trajectories for each attentional network.     

Insulin effects on CSF norepinephrine and cognition in Alzheimer's disease

We assessed the effects of induced hyperinsulinemia on plasma and cerebrospinal fluid (CSF) levels of norepinephrine (NE) and on cognition for patients with Alzheimer's disease (AD) and normal older adults. For normal adults, insulin increased plasma and CSF NE levels; also, recall for paraphrased details of a story improved as CSF NE levels increased. Mental control was positively correlated with CSF levels of NE for patients. These findings demonstrate that raising peripheral insulin levels can modulate CNS NE levels and suggest that insulin-stimulated increases in NE may modulate cognitive functions.     

Seasonal effects on cortisol secretion in normal aging, mild cognitive impairment and Alzheimer's disease

Previous studies found higher cortisol levels in Alzheimer's disease (AD) compared to normal elderly controls (NCs). However, studies on individuals with mild cognitive impairment (MCI), who are at risk to progress to AD, are contentious. In this study, we examined whether seasonal variations in cortisol secretion in NCs, MCI individuals and AD patients might mask group differences in cortisol secretion. We found significant seasonal differences in salivary cortisol levels in all three groups. Moreover, by testing everyone in the same seasons, we found lower salivary cortisol levels in NCs compared to MCI individuals and AD patients. This suggests that controlling for the season of sampling may help elucidate subtle effects of normal and pathological aging on basal cortisol secretion.     

Odor identification in normal aging and early Alzheimer's disease: effects of retrieval support

Odor sensitivity and identification were examined in normal aging and early Alzheimer's disease (AD). The aims were to investigate AD as associated with lower odor sensitivity, odor identification as a function of retrieval support, and the relationship between global cognitive functioning (Mini-Mental State Exam [MMSE]; M. F. Folstein, S. E. Folstein, & P. R. McHugh, 1975) and olfactory performance. Results indicated intact odor sensitivity but deficient odor identification in AD. Both groups benefited from cues in identification, and the size of the gains was equally large in AD patients and controls. The finding of no selective benefit from retrieval support in AD suggests that a degradation of olfactory knowledge contributes to the odor identification deficits in these patients. MMSE and identification were positively related, whereas MMSE and olfactory sensitivity were unrelated. These findings suggest that the AD-related olfactory impairment stems from lesions in cortical rather than peripheral structures.     

Imaging and biomarkers for Alzheimer's disease

The development of acetyl-cholinesterase inhibitors, and the prospect of future therapies to prevent, or modify, the course of Alzheimer's disease necessitates greater accuracy in diagnosis of this heterogeneous disease. Current diagnosis is based on clinical criteria and neuropathology. This is not always sufficient, and the development of sensitive and specific biomarkers would enable earlier and more accurate diagnosis. Genetic markers, such as Apolipoprotein E4, and cerebrospinal fluid markers such as β-amyloid and tau, support a diagnosis of Alzheimer's disease. The latter can also predict conversion from mild cognitive impairment to dementia. Imaging markers improve diagnostic accuracy by reflecting brain function or aspects of in vivo pathological changes. In order for such biomarkers to become clinically useful, however, effective treatments need to become available, and long-term follow-up studies are necessary to evaluate the relevance of cross-sectional biomarker changes for the longitudinal natural history of the disease.     

Interactions between phasic alerting and spatial orienting: effects of normal aging and Alzheimer's disease

The effects of aging and Alzheimer's disease (AD) on phasic alerting and exogenous spatial orienting were examined within a single precuing task. Phasic alerting decreased with normal aging and was completely eliminated with AD. AD patients also demonstrated an increased spatial orienting effect, attributable to an increased benefit from spatial orienting that was associated with a decreased benefit from nonselective alerting. These results suggest that performance within the precuing paradigm reflects the product of an interaction between nonselective alerting processes and spatially selective orienting processes. The results also highlight the importance of simultaneously assessing alerting and orienting within the same task, because changes attributable to alerting may otherwise be attributed incorrectly to changes in 1 or more processes associated with spatial orienting.     

Specificity of inhibitory deficits in normal aging and Alzheimer's disease

Deficits of suppression abilities are frequently observed in normal aging and Alzheimer's disease. However, few studies have explored these deficits in the two populations simultaneously using a large battery of tasks. The aim of the present study was to explore if the pattern of performance presented by elderly subjects and AD patients is in agreement with theoretical frameworks [Wilson, S.P., Harnishfeger, K.K., 1998. The development of efficient inhibition: Evidence from directed forgetting tasks. Dev. Rev. 18, 86-123; see also Nigg J.T., 2000. On inhibition/disinhibition in developmental psychopathology: views from cognitive and personality psychology and a working inhibition taxonomy. Psychol. Bull. 126, 220-246], distinguishing between the concepts of inhibition (a voluntary suppression of irrelevant information) and interference (an automatic suppression process occurring prior to conscious awareness). The results obtained demonstrated that (1) there is an alteration of the inhibitory process in normal elderly subjects; (2) inhibitory and interference resolution processes are quantitately less efficient in AD, since these patients present a correct performance only for information which leaves weak traces in memory.     

Combined rCBF and CSF biomarkers predict progression from mild cognitive impairment to Alzheimer's disease

This study aimed to identify preclinical Alzheimer's disease (AD) in patients with mild cognitive impairment (MCI) using measurements of both regional cerebral blood flow (rCBF) and cerebrospinal fluid (CSF) biomarkers. Baseline rCBF assessments ((133)Xe method) were performed in 70 patients with MCI who were cognitively stable for 4-6 years, 69 patients with MCI who subsequently developed AD, and 33 healthy individuals. CSF was collected at baseline and analyzed for beta-amyloid(1-42), total tau and phophorylated tau. In contrast to patients with stable MCI, those who subsequently developed AD had decreased rCBF in the temporo-parietal cortex already at baseline. The relative risk of future progression to AD was particularly increased in MCI patients with decreased rCBF in parietal cortex (hazard ratio 3.1, P<0.0001). Subjects with pathological levels of both CSF tau and beta-amyloid(1-42) were also at high risk of developing AD (hazard ratio 13.4, P<0.0001). The MCI patients with a combination of decreased parietal rCBF and pathological CSF biomarkers at baseline had a substantially increased risk of future development of AD, with a hazard ratio of 24.3 (P<0.0001), when compared to those with normal CSF biomarkers. Moreover, decreased parietal rCBF (but not CSF biomarkers) was associated with a more rapid progression to AD. In conclusion, the combination of rCBF and CSF biomarkers improves the risk assessment of progression to AD in patients with MCI.     

Brain levels of sex steroid hormones in men and women during normal aging and in Alzheimer's disease

We examined the relationships between normal aging, Alzheimer's disease (AD), and brain levels of sex steroid hormones in men and women. In postmortem brain tissue from neuropathologically normal, postmenopausal women, we found no age-related changes in brain levels of either androgens or estrogens. In comparing women with and without AD at different ages, brain levels of estrogens and androgens were lower in AD cases aged 80 years and older but not significantly different in the 60-79 year age range. In male brains, we observed that normal aging was associated with significant decreases in androgens but not estrogens. Further, in men aged 60-79 years, brain levels of testosterone but not estrogens were lower in cases with mild neuropathological changes as well as those with advanced AD neuropathology. In male cases over age 80, brain levels hormones did not significantly vary by neuropathological status. To begin investigating the relationships between hormone levels and indices of AD neuropathology, we measured brain levels of soluble β-amyloid (Aβ). In male cases with mild neuropathological changes, we found an inverse relationship between brain levels of testosterone and soluble Aβ. Collectively, these findings demonstrate sex-specific relationships between normal, age-related depletion of androgens and estrogens in men and women, which may be relevant to development of AD.     

Processing of semantic relations in normal aging and Alzheimer's disease.

The decline in semantic memory observed in Alzheimer's disease is presumed to result from progressive loss of the attributes underlying category representation. Here, we explored the possibility that semantic deterioration would affect attributes differently, depending on the type of semantic relationship connecting the subject and the object of the attribution. We compared the performance of 50 patients with probable Alzheimer's disease (APs) to that of 30 elderly controls in two semantic tasks: a verbal sentence verification task and a visual test of analogical relations, both including several types of semantic relations. On the sentence verification task, the performance of APs was comparable to that of elderly controls when statements were true, but deteriorated significantly when statements were false. This result was interpreted as a failure of controlled processes to successfully search semantic space when statements were incongruent or false. In addition, all participants found some semantic relations more difficult to process than others, with relative difficulty being consistent across tasks. Taxonomic semantic relations were the most difficult, while part/whole relations were the easiest, but also the ones to deteriorate most rapidly. In contrast, functional attributes were comparatively preserved as the disease progressed. These results emphasize the role of attention and semantic context in jointly determining access to relevant attributes and categories. Furthermore, they suggest that semantic memory impairments in Alzheimer's are affected by the type of processing and semantic relationship required by the task.