Peter R. Bergethon

25-Hydroxyvitamin D, dementia, and cerebrovascular pathology in elders receiving home services

Background: Vitamin D deficiency has potential adverse effects on neurocognitive health and subcortical function. However, no studies have examined the association between vitamin D status, dementia, and cranial MRI indicators of cerebrovascular disease (CVD). Methods: Cross-sectional investigation of 25-hydroxyvitamin D [25(OH)D], dementia, and MRI measures of CVD in elders receiving home care (aged 65–99 years) from 2003 to 2007. Results: Among 318 participants, the mean age was 73.5 ± 8.1 years, 231 (72.6%) were women, and 109 (34.3%) were black. 25(OH)D concentrations were deficient (<10 ng/mL) in 14.5% and insufficient (10–20 ng/mL) in 44.3% of participants. There were 76 participants (23.9%) with dementia, 41 of which were classified as probable AD. Mean 25(OH)D concentrations were lower in subjects with dementia (16.8 vs 20.0 ng/mL, p < 0.01). There was a higher prevalence of dementia among participants with 25(OH)D insufficiency (≤20 ng/mL) (30.5% vs 14.5%, p < 0.01). 25(OH)D deficiency was associated with increased white matter hyperintensity volume (4.9 vs 2.9 mL, p < 0.01), grade (3.0 vs 2.2, p = 0.04), and prevalence of large vessel infarcts (10.1% vs 6.9%, p < 0.01). After adjustment for age, race, sex, body mass index, and education, 25(OH)D insufficiency (≤20 ng/mL) was associated with more than twice the odds of all-cause dementia (odds ratio [OR] = 2.3, 95% confidence interval [CI] 1.2–4.2), Alzheimer disease (OR = 2.5, 95% CI 1.1–6.1), and stroke (with and without dementia symptoms) (OR = 2.0, 95% CI 1.0–4.0). Conclusions: Vitamin D insufficiency and deficiency was associated with all-cause dementia, Alzheimer disease, stroke (with and without dementia symptoms), and MRI indicators of cerebrovascular disease. These findings suggest a potential vasculoprotective role of vitamin D.

Progression of ventricular wall thickening after liver transplantation for familial amyloidosis.

BACKGROUND Familial amyloidosis (FAP) is characterized by the progression of neurologic and cardiac impairment ultimately leading to death within 7 to 15 years after the onset of the disease. Liver transplantation represents the only definitive therapy for this disease and has been performed since 1990. METHODS To determine the effect of liver transplantation on disease progression, electrocardiography and Doppler echocardiography were performed and blindly analyzed on 11 patients with FAP who were followed 0.8 to 8.6 years before liver transplantation and 0.8 to 4.1 years after liver transplantation. RESULTS; After liver transplantation, five patients showed progression of left ventricular wall thickening with increased left ventricular mass, and three of these five showed a reduction in electrocardiographic voltage despite abolition of the mutant protein from the serum. Of the five patients showing progressive wall thickening, four had the transthyretin variant Glu 42 Gly and one patient had the Ala 36 Pro variant; none of the remaining six patients, all of whom possessed the Val 30 Met variant, showed echocardiographic changes. Although 9 of the 11 patients have shown symptomatic improvement in neurologic symptoms, 1 patient has developed heart failure and a second patient has suffered a sudden cardiac death. CONCLUSIONS After liver transplantation, patients with FAP should have regular clinical evaluations including electrocardiographic and echocardiographic examinations to look for continued deterioration in heart structure or function.

Effect of orthotopic liver transplantation on the progression of familial amyloidotic polyneuropathy.

BACKGROUND Familial amyloidotic polyneuropathy (FAP) is an autosomal dominant inherited disease associated with a mutant form of the protein transthyretin (TTR). It is characterized clinically by the systemic deposition of amyloid fibrils resulting in organ dysfunction and, ultimately, death. The majority of TTR is produced in the liver, and transplantation of the liver has been shown to ameliorate this source of mutant TTR, arresting the progression of this fatal disease. METHODS Thirteen patients with FAP have undergone successful liver transplant surgery at our center since 1992. The impact of liver transplantation on amyloid-related polyneuropathy, cardiovascular, and gastrointestinal dysfunction is reported in this study. Three patients who died before cardiovascular and neurological follow-up are excluded from the analysis. RESULTS Ten of 13 patients (77%) remain alive an average of 49 months (range, 17-64 months) after transplantation. Three patients suffered sudden death, with autopsy documentation of amyloid deposits involving the conduction system of the heart. Liver transplantation was performed more quickly, required less blood, and a shorter postoperative hospital stay in these patients, compared with patients with cirrhosis. Neurological and nutritional symptoms improved in the majority of affected patients. Those patients with echocardiographic evidence of ventricular wall and valve thickening before transplantation progressed postoperatively despite neurologic improvement. CONCLUSIONS Liver transplantation offers the only cure for the genetic defect causing FAP and appears to result in subjective and objective improvement in neurological dysfunction. Patients with preexisting cardiovascular abnormalities progress despite transplantation; therefore, consideration for combined heart-liver transplantation may be warranted in this subset of patients.

Improvement in the polyneuropathy associated with familial amyloid polyneuropathy after liver transplantation

Objective: To study, following liver transplantation, the neurologic progression or regression of the polyneuropathy in a cohort of patients with familial amyloidotic polyneuropathy (FAP). Background: FAP is characterized by the relentless progression of neurologic and cardiac impairment, leading to death within 7 to 15 years after disease onset. No effective treatment to slow or halt the progression of this disease has been found to date. Design/Methods: Over the past 3 years, our FAP patients were offered liver transplantation as treatment. We report on nine patients who were followed longitudinally with serial neurologic examinations since transplantation. Results: Clinically, all patients evaluated for neurologic progression reported significant improvement in general well being. No patient showed any progression in neurologic disease since receiving a liver transplant. Improvements are documented in symptomatic, autonomic, and sensorimotor neurologic disease in all patients. Conclusion: Our experience suggests that liver transplantation may offer hope for arrest of progression and neurologic improvement in patients with FAP. NEUROLOGY 1996;47: 944-951

Diffusion Tensor Imaging, White Matter Lesions, the Corpus Callosum, and Gait in the Elderly

Background and Purpose— Gait impairment is common in the elderly, especially those with stroke and white matter hyperintensities on conventional brain MRI. Diffusion tensor imaging (DTI) is more sensitive to white matter damage than conventional MRI. The relationship between DTI measures and gait has not been previously evaluated. Our purpose was to investigate the relationship between the integrity of white matter in the corpus callosum as determined by DTI and quantitative measures of gait in the elderly. Methods— One hundred seventy-three participants of a community-dwelling elderly cohort had neurological and neuropsychological examinations and brain MRI. Gait function was measured by Tinetti gait (0 to 12), balance (0 to 16) and total (0 to 28) scores. DTI assessed fractional anisotropy in the genu and splenium of the corpus callosum. Conventional MRI was used to evaluate for brain infarcts and white matter hyperintensity volume. Results— Participants with abnormal gait had low fractional anisotropy in the genu of the corpus callosum but not the splenium. Multiple regressions analyses showed an independent association between these genu abnormalities and all 3 Tinetti scores (P<0.001). This association remained significant after adding MRI infarcts and white matter hyperintensity volume to the analysis. Conclusions— The independent association between quantitative measures of gait function and DTI findings shows that white matter integrity in the genu of corpus callosum is an important marker of gait in the elderly. DTI analyses of white matter tracts in the brain and spinal cord may improve knowledge about the pathophysiology of gait impairment and help target clinical interventions.

Levetiracetam for seizures after liver transplantation.

Seizures may occur after orthotopic liver transplantation. Antiepileptic drugs (AEDs) are used to treat these seizures, but the immunosuppressant regimen also may be altered. Levetiracetam is an attractive treatment because of its efficacy, lack of hepatic enzyme induction, and its rapid attainment of serum levels. Treatment with levetiracetam is efficacious, and levetiracetam-treated patients require significantly lower doses of immunosuppressant medications to achieve an equivalent antirejection effect.

Low-Frequency Spontaneous Oscillations of Cerebral Hemodynamics Investigated With Near-Infrared Spectroscopy: A Review

Hemodynamic low-frequency oscillations (LFOs), in the range 0.01-0.1 Hz, are intriguing, yet elusive phenomena, which occur spontaneously in the vascular system. More than 150 years have passed since their discovery, but the cellular mechanisms at their origin and their physiological implications have yet to be unraveled. The study of LF hemodynamic oscillations is considered to be relevant in areas of brain research such as cerebral autoregulation, functional and effective connectivity, and their related pathologies. These research areas have been traditionally investigated by transcranial Doppler (autoregulation) and functional MRI [functional connectivity (FC)]. The purpose of this paper is to review the work that has been done in this area using near-infrared spectroscopy (NIRS), which is a noninvasive technique used for monitoring and imaging tissue hemodynamics. NIRS has the advantage of being sensitive to both oxy- and deoxyhemoglobin concentration changes. Therefore, not only can it be used in autoregulation and FC studies (for broader populations of subjects), it can also help understand the local interplay between vascular and metabolic parameters. Finally, we present a novel approach to the study of LFOs and to the physiological interpretation of the amplitude and relative phase of oscillatory components of oxy- and deoxyhemoglobin concentrations.

A Photodependent Switch of Liposome Stability and Permeability

Liposomes offer a method to encapsulate high concentrations of a drug, protecting the therapeutic upon in vivo administration. With an appropriate mechanism to manipulate lipid bilayer permeability, liposomes have the potential to deliver encapsulated drugs in a spatially and temporally controlled manner. In this investigation, the photosensitizer aluminum phthalocyanine disulfonic acid (AlPcS(2)) is identified as a modulator of the colloidal properties of liposomes. AlPcS(2) adsorption to liposomes stabilizes lipid bilayers and reduces permeability. Spectroscopic data suggests that AlPcS(2) interacts with the phospholipid to increase lipid bilayer stability. In the presence of AlPcS(2), the liposome permeability was five times lower than that without the photosensitizer. This results in more stable liposome systems that contain higher doses of the encapsulated material for longer. Then, upon irradiation of the AlPcS(2)-liposome system with tissue penetrating red light, lipid bilayer permeability increases 10-fold over the baseline. The release is shown to be a singlet oxygen mediated process, due to the type II photodynamic action of AlPcS(2). It is concluded that this activity provides a novel photorelease mechanism for liposome mediated drug delivery.

Phase-amplitude investigation of spontaneous low-frequency oscillations of cerebral hemodynamics with near-infrared spectroscopy: A sleep study in human subjects

We have investigated the amplitude and phase of spontaneous low-frequency oscillations (LFOs) of the cerebral deoxy- and oxy-hemoglobin concentrations ([Hb] and [HbO]) in a human sleep study using near-infrared spectroscopy (NIRS). Amplitude and phase analysis was based on the analytic signal method, and phasor algebra was used to decompose measured [Hb] and [HbO] oscillations into cerebral blood volume (CBV) and flow velocity (CBFV) oscillations. We have found a greater phase lead of [Hb] vs. [HbO] LFOs during non-REM sleep with respect to the awake and REM sleep states (maximum increase in [Hb] phase lead: ~π/2). Furthermore, during non-REM sleep, the amplitudes of [Hb] and [HbO] LFOs are suppressed with respect to the awake and REM sleep states (maximum amplitude decrease: 87%). The associated cerebral blood volume and flow velocity oscillations are found to maintain their relative phase difference during sleep, whereas their amplitudes are attenuated during non-REM sleep. These results show the potential of phase-amplitude analysis of [Hb] and [HbO] oscillations measured by NIRS in the investigation of hemodynamics associated with cerebral physiology, activation, and pathological conditions.

Oxidation of peptidyl lysine by copper complexes of pyrroloquinoline quinone and other quinones. A model for oxidative pathochemistry

Various o- and p-quinones were assessed as oxidants of peptidyl lysine in elastin and collagen substrates in the presence and absence of divalent copper as paradigms of protein-lysine 6-oxidase (lysyl oxidase) which contains both quinone and copper cofactors. Pyrroloquinoline quinone was among the most active in the absence and the most active of the o- and p-quinones tested in the presence of copper. The optimal rate of elastin oxidation occurred at a 2:1 PQQ/Cu(II) ratio while Cu(II) itself oxidized elastin relatively slightly. Elastin oxidation by 2:1 PQQ/Cu(II) required aerobic conditions consistent with oxygen-dependent turnover of this catalytic pair. Dimethylsulfoxide and catalase individually or in combination inhibited elastin oxidation by PQQ/Cu(II) by approx. 50%, suggesting that oxygen free radical species participate in the reaction. Amino-acid analysis of elastin and collagen substrates oxidized by 2:1 PQQ/Cu and then reduced with borohydride revealed that alpha-aminoadipic-delta-semialdehyde and lesser amounts of covalent cross-linkages were generated by this oxidant. In contrast, lysine oxidase produced aldehydes and significantly greater quantities of cross-linkage products, consistent with the known specificity of the enzyme. These data, thus, indicate the potential for free quinones, such as PQQ, particularly when stimulated by appropriate metal ions, to act as adventitious oxidants of lysine side-chains in proteins.