Kaolin-induced chronic hydrocephalus accelerates amyloid deposition and vascular disease in transgenic rats expressing high levels of human APP.

BACKGROUND: Normal pressure hydrocephalus (NPH) is most common in the elderly and has a high co-morbidity with Alzheimer's disease (AD) and cerebrovascular disease (CVD). To understand the relationship between NPH, AD and CVD, we investigated how chronic hydrocephalus impacts brain amyloid-beta peptide (Aß) accumulation and vascular pathology in an AD transgenic rodent model. Previously we showed that the altered CSF physiology produced by kaolin-hydrocephalus in older wild-type Sprague-Dawley rats increased Aß and hyperphosphorylated Tau (Silverberg et. al. Brain Res. 2010, 1317:286-296). We postulated that hydrocephalus would similarly affect an AD rat model. METHODS: Thirty-five transgenic rats (tgAPP21) that express high levels of human APP and naturally overproduce Aß40 were used. Six- (n = 7) and twelve-month-old (n = 9) rats had hydrocephalus induced by cisternal kaolin injection. We analyzed Aß burden (Aß40, Aß42 and oligomeric Aß) and vascular integrity (Masson trichrome and Verhoeff-Van Gieson) by immunohistochemistry and chemical staining at 10 weeks (n = 8) and 6 months (n = 5) post hydrocephalus induction. We also analyzed whether the vascular pathology seen in tgAPP21 rats, which develop amyloid angiopathy, was accelerated by hydrocephalus. Age-matched naïve and sham-operated tgAPP21 rats served as controls (n = 19). RESULTS: In hydrocephalic tgAPP21 rats, compared to naïve and sham-operated controls, there was increased Aß 40 and oligomeric Aß in hippocampal and cortical neurons at 10 weeks and 6 months post-hydrocephalus induction. No dense-core amyloid plaques were seen, but diffuse Aß immunoreactivity was evident in neurons. Vascular pathology was accelerated by the induction of hydrocephalus compared to controls. In the six-month-old rats, subtle degenerative changes were noted in vessel walls at 10 weeks post-kaolin, whereas at six months post-kaolin and in the 12-month-old hydrocephalic rats more pronounced amyloid angiopathic changes were seen, with frequent large areas of infarction noted. CONCLUSIONS: Kaolin-hydrocephalus can accelerate intraneuronal Aß40 accumulation and vascular pathology in tgAPP21 rats. In addition, disrupted CSF production and reduced CSF turnover results in impaired Aß clearance and accelerated vascular pathology in chronic hydrocephalus. The high co-morbidity seen in NPH, AD and CVD is likely not to be an age-related coincidence, but rather a convergence of pathologies related to diminished CSF clearance.

Minimally invasive laminectomy in spondylolisthetic lumbar stenosis.

BACKGROUND: Degenerative lumbar stenosis associated with spondylolisthesis is common in elderly patients. The most common symptoms are those of neurogenic claudication with leg pain. Surgery is indicated for those who fail conservative management. The generally accepted recommendation is to perform a laminectomy and a fusion at the involved level. METHODS: We reviewed our results for minimally invasive single-level decompression without fusion performed by the senior author in patients with symptomatic lumbar stenosis with spondylolisthesis with no dynamic instability from 2008 to 2011 at a single institution. Outcomes were measured using the visual analog scale (VAS), Prolo Economic Functional Rating Scale, and revised Oswestry Disability Index (ODI) at initial presentation and at 3-month, 6-month, and 1-year follow-up time points. RESULTS: Records for 28 patients (19 males, 9 females) were reviewed. The success rate, defined as improvement in pain and functional outcome without the need for surgical fusion, was 86%. VAS scores decreased by 6.3 points, Prolo scores increased by 3.5 points, and the ODI decreased by 31% at 1 year. All changes were statistically significant. CONCLUSION: Minimally invasive decompression alone can be a reasonable alternative to decompression and fusion for patients with spondylolisthetic lumbar stenosis and neurogenic claudication with leg pain. Decompression without fusion should be considered for older patients and for patients who are not ideal fusion candidates.

Temporal course of cerebrospinal fluid dynamics and amyloid accumulation in the aging rat brain from three to thirty months.

BACKGROUND: Amyloid accumulation in the brain parenchyma is a hallmark of Alzheimer's disease (AD) and is seen in normal aging. Alterations in cerebrospinal fluid (CSF) dynamics are also associated with normal aging and AD. This study analyzed CSF volume, production and turnover rate in relation to amyloid-beta peptide (Aß) accumulation in the aging rat brain. METHODS: Aging Fischer 344/Brown-Norway hybrid rats at 3, 12, 20, and 30 months were studied. CSF production was measured by ventriculo-cisternal perfusion with blue dextran in artificial CSF; CSF volume by MRI; and CSF turnover rate by dividing the CSF production rate by the volume of the CSF space. Aß40 and Aß42 concentrations in the cortex and hippocampus were measured by ELISA. RESULTS: There was a significant linear increase in total cranial CSF volume with age: 3-20 months (p < 0.01); 3-30 months (p < 0.001). CSF production rate increased from 3-12 months (p < 0.01) and decreased from 12-30 months (p < 0.05). CSF turnover showed an initial increase from 3 months (9.40 day-1) to 12 months (11.30 day-1) and then a decrease to 20 months (10.23 day-1) and 30 months (6.62 day-1). Aß40 and Aß42 concentrations in brain increased from 3-30 months (p < 0.001). Both Aß42 and Aß40 concentrations approached a steady state level by 30 months. CONCLUSIONS: In young rats there is no correlation between CSF turnover and Aß brain concentrations. After 12 months, CSF turnover decreases as brain Aß continues to accumulate. This decrease in CSF turnover rate may be one of several clearance pathway alterations that influence age-related accumulation of brain amyloid.

Amyloid-beta transporter expression at the blood-CSF barrier is age-dependent.

BACKGROUND: Age is the major risk factor for many neurodegenerative diseases, including Alzheimer's disease (AD). There is an accumulation of amyloid-beta peptides (Aß) in both the AD brain and the normal aging brain. Clearance of Aß from the brain occurs via active transport at the blood-brain barrier (BBB) and blood-cerebrospinal fluid barrier (BCSFB). With increasing age, the expression of the Aß efflux transporters is decreased and the Aß influx transporter expression is increased at the BBB, adding to the amyloid burden in the brain. Expression of the Aß transporters at the choroid plexus (CP) epithelium as a function of aging was the subject of this study. METHODS: This project investigated the changes in expression of the Aß transporters, the low density lipoprotein receptor-related protein-1 (LRP-1), P-glycoprotein (P-gp), LRP-2 (megalin) and the receptor for advanced glycation end-products (RAGE) at the BCSFB in Brown-Norway/Fischer rats at ages 3, 6, 9, 12, 20, 30 and 36 months, using real time RT-PCR to measure transporter mRNA expression, and immunohistochemistry (IHC) to measure transporter protein in isolated rat CP. RESULTS: There was an increase in the transcription of the Aß efflux transporters, LRP-1 and P-gp, no change in RAGE expression and a decrease in LRP-2, the CP epithelium influx transporter, at the BCSFB with aging. Decreased Aß42 concentration in the CP, as measured by quantitative IHC, was associated with these Aß transporter alterations. CONCLUSIONS: Age-dependent alterations in the CP Aß transporters are associated with a decrease in Aß42 accumulation in the CP, and are reciprocal to the changes seen in these transporters at the BBB, suggesting a possible compensatory role for the BCSFB in Aß clearance in aging.

Amyloid and Tau accumulate in the brains of aged hydrocephalic rats.

AD pathology is often seen in cortical biopsies of NPH patients. It remains unclear whether these findings are coincidental or causally related. In an aged animal model of NPH, we quantify Abeta and pTau accumulation and describe its temporal and spatial distribution. One-year-old male Sprague-Dawley rats had hydrocephalus induced by cisternal kaolin injection. Immunohistochemistry (IMHC) for AbetaPP, Abeta40, Abeta42 and pTau (epitope pT231) and ELISA for Abeta40, Abeta42 and pT231 were performed on controls and after 2, 6 and 10 weeks of hydrocephalus. Rats had double-label fluorescence IMHC for localization of Abeta42 and pT231. IMHC showed no change in neuronal AbetaPP expression following hydrocephalus. Abeta42 appeared earliest in CSF clearance pathways, p<0.05, and also showed significant rises in perivascular spaces and in cortical parenchyma. Mean ELISA values for Abeta40 and Abeta42 increased three- to four-fold in hydrocephalic rats at 6 and 10 weeks. Abeta40 increased between 2 and 6 weeks (p=0.0001), and remained stable at 10 (p=0.0002); whereas Abeta42 was elevated at 2 weeks (p<0.04) and remained at 6 (p=0.015). PTau at 6 and 10 weeks showed AD-like increased neuronal somatic staining and loss of dendritic staining. ELISA demonstrated increased pT231 in hydrocephalic rats at 10 weeks (p<0.0002). Double-label fluorescence for Abeta42 and pT231 revealed intraneuronal co-localization. Hydrocephalus in the elderly rat, therefore, can induce both Abeta and pTau accumulation. As distinct from brain injury models, no increase in AbetaPP expression was demonstrated. Rather, altered CSF dynamics appears to impair Abeta clearance in this NPH model.