Miroslaw Brys

Imaging and CSF Studies in the Preclinical Diagnosis of Alzheimer's Disease

Abstract:  It is widely believed that the path to early and effective treatment for Alzheimers disease (AD) requires the development of early diagnostic markers that are both sensitive and specific. To this aim, using longitudinal study designs, we and others have examined magnetic resonance imaging (MRI), 2‐fluoro‐2‐deoxy‐d‐glucose‐positron emission tomography (FDG/PET), and cerebrospinal fluid (CSF) biomarkers in cognitively normal elderly (NL) subjects and in patients with mild cognitive impairment (MCI). Such investigations have led to the often replicated findings that structural evidence of hippocampal atrophy as determined by MRI, as well as metabolic evidence from FDG‐PET scan of hippocampal damage, predicts the conversion from MCI to AD. In this article we present a growing body of evidence of even earlier diagnosis. Brain pathology can be detected in NL subjects and used to predict future transition to MCI. This prediction is enabled by examinations revealing reduced glucose metabolism in the hippocampal formation (hippocampus and entorhinal cortex [EC]) as well as by the rate of medial temporal lobe atrophy as determined by MRI. However, neither regional atrophy nor glucose metabolism reductions are specific for AD. These measures provide secondary not primary evidence for AD. Consequently, we will also summarize recent efforts to improve the diagnostic specificity by combining imaging with CSF biomarkers and most recently by evaluating amyloid imaging using PET. We conclude that the combined use of conventional imaging, that is MRI or FDG‐PET, with selected CSF biomarkers incrementally contributes to the early and specific diagnosis of AD. Moreover, selected combinations of imaging and CSF biomarkers measures are of importance in monitoring the course of AD and thus relevant to evaluating clinical trials.

Inflammation and Alzheimer's disease: possible role of periodontal diseases.

The molecular and cellular mechanisms responsible for the etiology and pathogenesis of Alzheimers disease (AD) have not been defined; however, inflammation within the brain is thought to play a pivotal role. Studies suggest that peripheral infection/inflammation might affect the inflammatory state of the central nervous system. Chronic periodontitis is a prevalent peripheral infection that is associated with gram‐negative anaerobic bacteria and the elevation of serum inflammatory markers including C‐reactive protein. Recently, chronic periodontitis has been associated with several systemic diseases including AD. In this article we review the pathogenesis of chronic periodontitis and the role of inflammation in AD. In addition, we propose several potential mechanisms through which chronic periodontitis can possibly contribute to the clinical onset and progression of AD. Because chronic periodontitis is a treatable infection, it might be a readily modifiable risk factor for AD.

Prediction and longitudinal study of CSF biomarkers in mild cognitive impairment

OBJECTIVES To longitudinally evaluate five cerebrospinal fluid (CSF) biomarkers in the transition from mild cognitive impairment (MCI) to Alzheimers disease (AD). METHODS A baseline and 2-year follow-up clinical and CSF study of 86 subjects, including 22 MCI patients that declined to AD (MCI-AD), 43 MCI that did not deteriorate (MCI-MCI) and 21 controls (NL-NL). All subjects were studied for total and phosphorylated tau (T-tau, P-tau(231)), amyloid beta (Abeta) Abeta(42)/Abeta(40) ratio, isoprostane (IP) as well as P-tau(231)/Abeta(42/40) and T-tau/Abeta(42/40) ratios. RESULTS At baseline and at follow-up MCI-AD showed higher levels P-tau(231), T-tau, IP, P-tau(231)/Abeta(42/40) and T-tau/Abeta(42/40) ratios and lower Abeta(42)/Abeta(40) than MCI-MCI or NL-NL. Baseline P-tau(231) best predicted MCI-AD (80%, p<0.001) followed in accuracy by P-tau(231)/Abeta(42/40) and T-tau/Abeta(42/40) ratios (both 75%, ps<0.001), T-tau (74%, p<0.001), Abeta(42)/Abeta(40) (69%, p<0.01), and IP (68%, p<0.01). Only IP showed longitudinal effects (p<0.05). CONCLUSIONS P-tau(231) is the strongest predictor of the decline from MCI to AD. IP levels uniquely show longitudinal progression effects. These results suggest the use of CSF biomarkers in secondary prevention trials.

Hypometabolism and Altered Cerebrospinal Fluid Markers in Normal Apolipoprotein E E4 Carriers with Subjective Memory Complaints

BACKGROUND We examined whether cerebral metabolic rates for glucose (CMRglc) on 2-[(18)F]fluoro-2-deoxy-D-glucose (FDG)-positron emission tomography (PET) and cerebrospinal fluid (CSF) markers of Alzheimers disease (AD) are altered in cognitively normal apolipoprotein E (ApoE) E4 carriers with subjective memory complaints (SMC). METHODS Twenty-eight middle-aged normal subjects (NL) were examined, including 13 E4 carriers (E4+; 6 with SMC [SMC+] and 7 without SMC [SMC-]) and 15 noncarriers (E4-; 7 SMC+ and 8 SMC-). Subjects received an FDG-PET scan and a lumbar puncture to measure CSF total (T-Tau) and hyperphosphorylated tau(231) (P-Tau), 40 and 42 amino acid forms of beta-amyloid (Abeta40 and Abeta42), and F(2)-isoprostane (IP). RESULTS As compared with E4-, E4+ subjects showed decreased CMRglc in AD-related brain regions and associated higher CSF IP, P-Tau, T-Tau, and P-Tau/Abeta42 levels (ps < .05). As compared with SMC-, SMC+ subjects showed reduced parietotemporal and parahippocampal gyrus (PHG) CMRglc. A significant ApoE by SMC status interaction was found, with the E4+/SMC+ showing the lowest PHG CMRglc and the highest CSF IP, P-Tau, and P-Tau/Abeta42 levels as compared with all other subgroups (ps < or = .05). The combination of CSF and CMRglc measures significantly improved the accuracy of either measures alone in discriminating ApoE groups (86% accuracy, odds ratio [OR] = 4.1, p < .001) and E4+/SMC+ from all other subgroups (86% accuracy, OR = 3.7, p = .005). Parahippocampal gyrus CMRglc was the most accurate discriminator of SMC groups (75% accuracy, OR = 2.4, p < .001). CONCLUSIONS Normal E4 carriers with SMC show altered AD-related CSF and FDG-PET measures. Longitudinal studies are needed to assess whether these brain abnormalities foreshadow clinical decline.

Enzyme replacement therapy improves function of C-, Aδ-, and Aβ-nerve fibers in Fabry neuropathy

Background: Peripheral neuropathy in Fabry disease predominantly involves small nerve fibers. Recently, enzyme replacement therapy (ERT) with recombinant human α-galactosidase A has become available. Objective: To evaluate whether ERT improves Fabry neuropathy. Methods: In 22 Fabry patients (age 27.9 ± 8.0 years) undergoing ERT with recombinant human α-galactosidase A (agalsidase beta) for 18 (n = 11) or 23 (n = 11) months and in 25 control subjects (age 29.0 ± 10.4 years), the authors performed quantitative sensory testing using the 4, 2, and 1 stepping algorithm (CASE IV™). Detection thresholds of vibration (VDT) on the first toe were assessed; cold detection thresholds (CDT), heat-pain onset (HP 0.5), and intermediate heat-pain (HP 5.0) assessments were made on the dorsum of the feet. Patient values above mean + 2.5 SD of control values were considered abnormal. Results: Before ERT, VDT, CDT, HP 0.5, and HP 5.0 were higher in patients than control subjects (p < 0.05). Following ERT, patients developed lower thresholds than prior to ERT for VDT (15.5 ± 3.5 vs 14.3 ± 4.1; p < 0.05), HP 0.5 (22.3 ± 6.7 vs 19.4 ± 1.3; p < 0.01), and HP 5.0 (27.3 ± 5.6 vs 22.5 ± 2.3; p < 0.01). Moreover, fewer patients had abnormal results of VDT (2 vs 4), CDT (7 vs 12), HP 0.5 (0 vs 9), and HP 5.0 (4 vs 20) after than before ERT. Conclusions: ERT therapy with agalsidase beta significantly improves function of C-, Aδ-, and Aβ-nerve fibers and intradermal vibration receptors in Fabry neuropathy. Lack of recovery in some patients with abnormal cold or heat-pain perception suggests the need for early ERT, prior to irreversible nerve fiber loss.

Early detection of Alzheimer's disease using neuroimaging.

Neuroimaging is being increasingly used to complement clinical assessments in the early detection of Alzheimers disease (AD). Structural magnetic resonance imaging (MRI) and metabolic positron emission tomography (FDG-PET) are the most clinically used and promising modalities to detect brain abnormalities in individuals who might be at risk for AD but who have not yet developed symptoms. The knowledge of established risk factors for AD enabled investigators to develop enrichment strategies for longitudinal imaging studies to reduce the sample sizes and study duration. The present review focuses on the results obtained by MRI and FDG-PET studies that examined the preclinical AD stages in several at risk populations: (1) individuals from families with autosomal dominant early-onset AD (FAD), (2) patients with mild cognitive impairment (MCI), particularly in memory, who are at very high risk for declining to AD with an estimated decline rate of 10-30% per year, (3) normal young and middle-age subjects carriers of known susceptibility genes for late-onset AD such as the Apolipoprotein E (ApoE) E4 allele, and (4) as age is the main risk factor for AD, normal elderly individuals followed to the onset of MCI and AD. Overall, these studies show that the use of imaging for the early detection of AD is successful even in the earlier stages of disease when clinical symptoms are not fully expressed and the regional brain damage may be limited.

Subjective Memory Complaints: Presence, Severity and Future Outcome in Normal Older Subjects

Background/Aims: Subjective memory complaint (SMC) in normal individuals may predict future cognitive decline. The goal of this study was to examine whether the probability of decline increases with growing intensity of complaint. Methods: Normal subjects over the age of 50 years were included in a longitudinal retrospective study (mean follow-up time = 8 years). All subjects (n = 230) underwent cognitive and medical examination at baseline. The presence of SMC was determined based on Global Deterioration Scale staging. A subgroup of 83 participants also received baseline assessment for the intensity of SMC. Logistic regression was used to predict outcome from baseline variables. Three outcome groups were established at the final visit: nondeclining, declining and diagnostically unstable (i.e. the diagnosis changed over time: from normal to mild cognitive impairment, then back to normal). Results: The presence of SMC was a predictor of future decline but also increased the likelihood of the unstable diagnosis. Increasing intensity of SMC did not further raise the risk for decline. High intensity of complaints and more pronounced affective symptoms predicted the unstable clinical diagnosis. Conclusions: The presence of SMC contributes to the risk of future decline, however, the increasing intensity of the perceived impairment does not further enhance the risk.

TNF-α and antibodies to periodontal bacteria discriminate between Alzheimer’s disease patients and normal subjects

The associations of inflammation/immune responses with clinical presentations of Alzheimers disease (AD) remain unclear. We hypothesized that TNF-alpha and elevated antibodies to periodontal bacteria would be greater in AD compared to normal controls (NL) and their combination would aid clinical diagnosis of AD. Plasma TNF-alpha and antibodies against periodontal bacteria were elevated in AD patients compared with NL and independently associated with AD. The number of positive IgG to periodontal bacteria incremented the TNF-alpha classification of clinical AD and NL. This study shows that TNF-alpha and elevated numbers of antibodies against periodontal bacteria associate with AD and contribute to the AD diagnosis.

Reduced cerebral blood flow velocity and impaired cerebral autoregulation in patients with Fabry disease

Abstract.In Fabry disease, there is glycosphingolipid storage in vascular endothelial and smooth muscle cells and neurons of the autonomic nervous system. Vascular or autonomic dysfunction is likely to compromise cerebral blood flow velocities and cerebral autoregulation. This study was performed to evaluate cerebral blood flow velocities and cerebral autoregulation in Fabry patients. In 22 Fabry patients and 24 controls, we monitored resting respiratory frequency, electrocardiographic RR-intervals, blood pressure, and cerebral blood flow velocities (CBFV) in the middle cerebral artery using transcranial Doppler sonography. We assessed the Resistance Index, Pulsatility Index, Cerebrovascular Resistance, and spectral powers of oscillations in RR-intervals, mean blood pressure and mean CBFV in the high (0.15–0.5 Hz) and sympathetically mediated low frequency (0.04–0.15 Hz) ranges using autoregressive analysis. Cerebral autoregulation was determined from the transfer function gain between the low frequency oscillations in mean blood pressure and mean CBFV. Mean CBFV (P < 0.05) and the powers of mean blood pressure (P < 0.01) and mean CBFV oscillations (P < 0.05) in the low frequency range were lower,while RR-intervals, Resistance Index (P < 0.01), Pulsatility Index, Cerebrovascular Resistance (P < 0.05), and the transfer function gain between low frequency oscillations in mean blood pressure and mean CBFV (P < 0.01) were higher in patients than in controls. Mean blood pressure, respiratory frequency and spectral powers of RR-intervals did not differ between the two groups (P > 0.05). The decrease of CBFV might result from downstream stenoses of resistance vessels and dilatation of the insonated segment of the middle cerebral artery due to reduced sympathetic tone and vessel wall pathology with decreased elasticity. The augmented gain between blood pressure and CBFV oscillations indicates inability to dampen blood pressure fluctuations by cerebral autoregulation. Both, reduced CBFV and impaired cerebral autoregulation, are likely to be involved in the increased risk of stroke in patients with Fabry disease.

The effects of normal aging and ApoE genotype on the levels of CSF biomarkers for Alzheimer's disease.

While cerebrospinal fluid (CSF) biomarkers are of use in the prediction and diagnosis of Alzheimers disease our understanding of the background effects of age and the ApoE genotype is limited. Seventy-eight community-based normal volunteers (mean age 60+/-10 years, range 36-86) were examined to determine the relationships between CSF measures of total tau (T-tau), hyperphosphorylated tau (P-tau 231), amyloid beta (Abeta42/Abeta40 ratio), and isoprostane (IP) with age and ApoE genotype. The results showed that age by epsilon4 genotype interactions were found for P-tau231 (beta=1.82; p<0.05) and IP (beta=1.6; p<0.05). T-tau CSF concentration increased with age. The increasing CSF concentrations of P-tau and IP in epsilon4 carriers suggest that early tauopathy and oxidative stress may be related to the increased risk for AD. The data also suggest that T-tau changes are more age dependent than Abeta changes. The evidence that P-tau231 and IP are the earliest markers for the neuronal damage related to AD awaits longitudinal study.