Conrad May

Cerebrospinal fluid production is reduced in healthy aging

In order to study age-related differences in cerebrospinal fluid (CSF) production in humans, we measured the rate of CSF production in 7 young (age 21 to 36 years) and 7 elderly (age 67 to 84 years) healthy volunteers, using a modified Masserman method. In addition, we evaluated CSF protein gradients by collecting CSF in serial fractions up to the 30th ml and assaying for total protein concentration. The mean rate of CSF production was significantly less in the elderly than in the young subjects. Mean CSF total protein concentrations were higher in the elderly than in the young, and significant rostrocaudal protein gradients with similar slopes were present in both groups. However, there was no correlation between CSF production and CSF total protein concentrations or protein gradient slopes. Age-related reductions in CSF production, together with the ventricular dilatation that occurs with aging, should presumably result in reduced CSF turnover and therefore influence measured concentrations of lumbar CSF constituents.

Cerebrospinal fluid concentrations of corticotropin‐releasing hormone (CRH) and corticotropin (ACTH) are reduced in patients with Alzheimer's disease

We examined corticotropin-releasing hormone-like immunoreactivity (CRH-LI) and corticotropin (ACTH) levels in the CSF of 33 patients with presumptive Alzheimers disease (AD) and 13 healthy, age-matched controls. The mean CRH-LI and ACTH levels of the AD patients were significantly less than controls. Despite these reductions, none of the patients had evidence of pituitary-adrenal dysfunction. A disorder of extrahypothalamic CRH may be involved in the pathophysiology of AD.

CSF and serum concentrations of albumin and IgG in Alzheimer's disease.

Cerebrospinal fluid (CSF) and serum concentrations of albumin and immunoglobulin G (IgG) were measured in 31 patients with presumptive Alzheimers disease (AD) and in 14 healthy control subjects. The albumin and IgG quotients, and IgG index were calculated to evaluate the permeability of the blood-brain barrier and the intrathecal production of immunoglobulins. X-ray computerized tomography (CT) of the head was performed to investigate the relation between cerebral atrophy and CSF protein concentrations. The albumin and IgG quotients, and the IgG index did not differ significantly between the AD and control groups. Cerebral atrophy, as measured by CSF volume, was not related to CSF protein concentrations in either group. The results do not support the hypothesized roles of blood-brain barrier disruption or of immunologically-mediated injury of the central nervous system in the pathogenesis of AD.

Galanin Immunoreactivity in Human CSF: Studies in Eating Disorders and Alzheimer’s Disease

Galanin is a peptide which stimulates feeding behavior in animals and is found within those basal forebrain cholinergic neurons which degenerate in Alzheimers disease. Galanin was measured in cerebrospinal fluid (CSF) by radioimmunoassay. The nature of the immunoreactivity was characterized chromatographically as authentic galanin. CSF galanin levels were determined in subjects with Alzheimers disease, involutional depression, anorexia nervosa and bulimia. No differences between any diagnostic group and age and sex-matched controls were found.

Quantitative analysis of polyols in human plasma and cerebrospinal fluid

We used gas chromatography in conjunction with flame ionization detection to quantitate nine polyols and aldo and keto sugars (as silyl derivatives) in human plasma and cerebrospinal fluid (CSF). Rhamnose, not found in CSF or plasma, was used as an internal standard with a lower limit of quantitation of 0.4 mg/l. CSF polyol and sugar concentrations (mean +/- S.D.) in fourteen healthy subjects (age range 27.1-85.9 years) were: anhydroglucitol, 19.9 +/- 5.3 mg/l; arabitol, 4.8 +/- 0.9 mg/l; erythritol, 2.4 +/- 0.5 mg/l; myoinositol, 28.6 +/- 8.3 mg/l; ribitol, 1.6 +/- 0.1 mg/l; fructose, 25.5 +/- 11.1 mg/l; glucose, 587 +/- 70 mg/l; glucitol, 7.7 +/- 1.5 mg/l; and mannose, 10.6 +/- 2.4 mg/l. The respective plasma concentrations were 30.6 +/- 11.5, less than 0.4, 0.4 +/- 0.2, 6.3 +/- 2.6, less than 0.4, 23.4 +/- 21.4, 897 +/- 214, less than 0.4 and 13.7 +/- 6.3 mg/l. Polyol CSF-to-plasma concentration ratios greater than 2 were observed for myoinositol, erythritol, arabitol, glucitol and ribitol, indicative of active accumulation or synthesis of these polyols within the central nervous system.

Cerebrospinal fluid monoamine markers are decreased in dementia of the Alzheimer type with extrapyramidal features

We measured monoamine metabolites and biopterin in the CSF of 37 patients with dementia of the Alzheimer type (DAT), with or without extrapyramidal signs, and in 14 age-matched healthy controls. Compared with concentrations in DAT and controls, the concentrations of homovanillic acid (HVA) and biopterin were significantly decreased in DAT with extrapyramidal signs (EDAT). CSF 3-methoxy-4-hydroxy-phenethyleneglycol and 5-hydroxyindoleacetic acid did not differ significantly among these groups. Age at onset of dementia was positively correlated with CSF HVA (r = 0.49, p < 0.05). The two dementia groups did not differ significantly in the extent of ventricular dilation as measured by quantitative CT, but EDAT patients had lower Mini-Mental State Examination scores than did DAT patients. When patients were matched for age and dementia severity, CSF HVA and biopterin concentrations remained significantly lower in EDAT than in DAT patients. These results indicate that EDAT patients form a distinct subgroup of DAT with evidence of central monoamine dysfunction.

CSF α‐MSH in dementia of the Alzheimer type

We measured CSF α-melanocyte stimulating hormone-like immunoreactivity (α-MSH-LI) in 35 patients with dementia of the Alzheimer type (DAT) and in 27 healthy control subjects. Mean α-MSH-LI concentration was significantly decreased in DAT patients as compared with age-matched controls. However, when the DAT patients were analyzed according to age at onset of dementia or presence of extrapyramidal signs, α-MSH-LI concentrations remained significantly lower than in controls only in DAT patients with late onset of dementia (>65 years of age). No correlation was found between α-MSH levels and degree of mental impairment. A significant negative correlation was found between CSF concentrations of α-MSH and homovanillic acid in the group of all DAT patients (p < 0.001). These results suggest that hypothalamic neurons which produce pro-opiomelanocortin-related peptides may be involved in Alzheimers disease.

Cerebral metabolism, anatomy, and cognition in monozygotic twins discordant for dementia of the Alzheimer type.

One pair of monozygotic twins discordant for dementia of the Alzheimer type (DAT) was studied using neuropsychological testing, quantitative x-ray computed tomography (QCT) and magnetic resonance imaging (MRI) of the brain. Cerebral glucose metabolism was measured using positron emission tomography (PET) and 2-[18-F]fluoro-2-deoxy-D-glucose (FDG). The affected twin had a seven year history of progressive cognitive impairment and was severely demented. Neuropsychological testing of the affected twin demonstrated marked deficits in all areas of cognitive function. The asymptomatic twin showed some impairment on tests of perceptual organisation and delayed recall. The affected twin had loss of gray matter and ventricular enlargement on QCT and MRI compared with healthy controls (p less than 0.05). He also had frontal and parietal lobe hypometabolism and increased asymmetry of metabolism on PET compared to both his twin and healthy age-matched controls (p less than 0.05). PET, QCT, and MRI distinguished changes in the twin with DAT compared with his brother and healthy controls. Although the subtle neuropsychological abnormalities of the asymptomatic twin may be signs of early DAT, they were not accompanied by any changes in regional cerebral metabolism or brain structure.

Alzheimer's disease Low levels of peptide a‐amidation activity in brain and CSF

Carboxyl terminal a-amidation confers biologic activity to many neuropeptides. Levels of a-amidating activity, peptidyl-glycine α-amidating monooxygenase (PAM), were reduced in the CSF of patients with dementia of the Alzheimer type (DAT) compared with healthy, age-matched controls. Repeat lumbar puncture data revealed a decline in CSF PAM activity of approximately 16% per year in DAT patients. Of the cerebral cortical regions examined, only the temporal pole showed reduced PAM activity in patients with Alzheimers disease (AD) compared with controls. These studies may indicate selective dysfunction of neurons which normally synthesize biologically active, a-amidated peptides in the CNS of AD patients.

Cerebrospinal fluid gradients of acetylcholinesterase and butyrylcholinesterase activity in healthy aging.

Acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) activities were measured in 13 sequential 2 ml aliquots of cerebrospinal fluid (CSF) obtained by lumbar puncture from 7 young and 7 elderly healthy normal subjects. The slopes of the rostrocaudal gradients of AChE and BChE were calculated and compared to those of total protein concentration and the major dopaminergic metabolite homovanillic acid (HVA), for which a pronounced rostrocaudal gradient (with highest concentrations of HVA in more rostral CSF) is consistent with HVA originating primarily from the brain. AChE activity was higher in more caudal fractions of young, but not elderly subjects and there was a significant difference between the mean AChE gradient slopes in the young and old groups. These results suggest that the spinal cord makes an important contribution to AChE activity in lumbar CSF. Furthermore, the absence of a negative AChE gradient in elderly subjects may be the result of a greater rate of entry of cerebral AChE into CSF, possibly as a consequence of an increased ventricular surface area and shorter diffusion distances in atrophic elderly brains. In contrast to AChE, BChE activity and total protein concentrations were higher in more caudal CSF fractions of not only young but also old subjects. In addition, there was a significant correlation between the gradient slopes of BChE activity and total protein concentrations, suggesting that the majority of BChE activity in lumbar CSF derives from the same source as the majority of total protein, namely plasma. The diffuse (i.e. brain and spinal cord) origin of AChE in lumbar CSF would explain the relatively modest changes in lumbar CSF AChE activity in diseases involving certain central cholinergic systems, most notably Alzheimers disease.