Ronald J. Polinsky

Transmission and age‐at‐onset patterns in familial Alzheimer's disease Evidence for heterogeneity

We evaluated age at onset and lifetime risk for Alzheimers disease (AD) in 70 kindreds with familial AD (designated FAD) composed of 541 affected and 1,066 unaffected offspring of demented parents who were identified retrospectively. Using a survival analysis method which takes into account affected persons with unknown onset ages and unaffected persons with unknown censoring ages, we found lifetime risk of AD among at-risk offspring by age 87 to be 64%. Analysis of age at onset among kindreds showed evidence for a bimodal distribution: in this sample, families with a mean onset age of less than 58 years were designated as having early-onset, while late-onset families had a mean onset age greater than 58 years. At-risk offspring in early-onset families had an estimated lifetime risk for dementia of 53%, which is significantly less than the risk of 86% that was estimated for offspring in late-onset families. Men and women in early-onset families had equivalent risk of dementia. In late-onset families, the risk to female offspring was somewhat higher than to male offspring but this difference was marginally significant. Lifetime risk of dementia in early-onset FAD kindreds is consistent with an autosomal dominant inheritance model. Our results may suggest that late-onset FAD has at least 2 etiologies; AD in some families may be transmitted as a dominant trait, whereas a proportion of cases in these and other late-onset families may be caused by other genetic or shared environmental factors.

Contribution of plasma homovanillic acid (HVA) to urine and cerebrospinal gluid HVA in the monkey and its pharmacokinetic disposition

Abstract Homovanillic acid (HVA) labelled with two deuterium atoms (d2-HVA) was used to determine the contribution of HVA in the blood to HVA in the urine and CSF of monkeys. During and after a six-hour intravenous infusion of d2-HVA at a constant rate, the levels of both d2-HVA and endogenous HVA (d0-HVA) in plasma, urine, and CSF were determined by gas chromatography-mass spectrometry, and the relative enrichments of d2-HVA in each of these fluids calculated. Results indicate that HVA in the urine is derived exclusively from the blood, with no contribution from renal metabolism of dopamine (DA). Furthermore, less than one percent of HVA in either lumbar or ventricular CSF is derived from circulating HVA. The plasma elimination curve of d2-HVA was biexponential, with a terminal phase half-life ( t 1 2 ) of 44 minutes and an apparent volume of distribution of 0.8 liters/kg.

Electrophysiological tests of autonomic function in patients with idiopathic autonomic failure syndromes

Three electrophysiological tests of autonomic function were performed in patients with autonomic nervous system dysfunction to define test sensitivities and specificities. The skin sympathetic response, Valsalva ratio, and heart rate variation with deep breathing were studied in 10 patients with multiple system atrophy (MSA) and in 7 patients with pure (also called progressive or primary) autonomic failure (PAF); control subjects were 17 normal individuals of similar age. Thirteen patients had abnormal skin sympathetic responses, and 16 had abnormal Valsalva ratios. Fourteen patients had an abnormal variation of the heart rate with deep breathing. Taking the three tests together, binary logistic regression for distinguishing between patients and normal subjects correctly classified 91% of the 33 individuals for whom there were complete data with sensitivity of 88% and specificity of 94%. However, only 69% of the patients could be correctly classified by a logistic regression for discriminating between MSA and PAF. Electromyography (EMG) studies showed that 7 of 8 patients with MSA but only 2 of 7 patients with PAF (both multiparous women) had denervation of the rectal sphincter muscle. The EMG study is, therefore, valuable in men, but has a high false positive rate in women, probably because of pudendal nerve injury from parturition.

Familial Alzheimer disease: a large, multigeneration German kindred

Summary:A German family with 21 members affected by Alzheimer disease (AD) was studied clinically and genetically. The diagnosis was histologically verified in three affected family members. Ancestors were traced through seven generations to a couple residing in East-Westfalia during the middle of the 19th century. Dementia was often accompanied by extrapyramidal features and myoclonus. No cases of Down syndrome or hematologic malignancy occurred in this family. Clinical manifestations, temporal progression, neurological testing, and neuropathological features do not differ from the more common sporadic form of AD. The inheritance pattern is most consistent with autosomal-dominant transmission.

Hypersensitivity to DNA-Damaging Agents in Abiotrophies: A New Explanation for Degeneration of Neurons, Photoreceptors, and Muscle in Alzheimer, Parkinson and Huntington Diseases, Retinitis Pigmentosa, and Duchenne Muscular Dystrophy

Gowers (1902) introduced the term ‘abiotrophy’ to signify the premature death of neurons and skeletal muscle in primary neuronal degenerations and in muscular dystrophies respectively. Collins (1919) classified retinitis pigmentosa, with its premature degeneration of photoreceptors, as an abiotrophy. Abiotrophies share several characteristics in addition to the primary degeneration of excitable tissue which occurs in the absence of histopathologic evidence of the etiology (Gowers, 1902; Collins, 1919; Blackwood and Corsellis, 1976; Richardson and Adams, 1977). The abiotrophic degenerations: 1) become evident after the excitable tissue has attained a normal, mature development; 2) are relentlessly progressive; 3) selectively affect certain excitable tissues but not others; 4) have either a clear hereditary or a sporadic basis; and 5) may be variable in their clinical and pathological features and often overlap with one another. Examples of abiotrophies include xeroderma pigmentosum (XP), ataxia telangiectasia, Cockayne syndrome, Alzheimer disease, Parkinson disease, Huntington disease, Friedreich ataxia, Duchenne muscular dystrophy, and retinitis pigmentosa.

Alpha‐adrenergic receptors in orthostatic hypotension syndromes

Alpha-adrenergic receptor function was measured in platelets from patients with orthostatic hypotension and normotensive controls. Patients with idiopathic orthostatic hypotension (IOH) or multiple system atrophy (MSA) had more α-receptors than controls. Patients with IOH, but not MSA, produced less prostaglandin E1 (PGE1)-stimulated cyclic AMP (cAMP) than controls. Patients with sympathotonic orthostatic hypotension (SOH) were similar to controls in receptor number and cAMP production. The percent norepinephrine (NE) inhibition of PGE1-stimulated cAMP production was similar in patients and controls. An increase in α-receptor number may result from decreased peripheral NE secretion in IOH and MSA. Increased α-receptor number and decreased cAMP production, which accompany essential hypertension, may contribute to the supine hypertension of IOH, and an increase in α-receptor number may contribute to the supine hypertension of MSA. SOH patients appear to have no abnormalities of α-receptor function.

Relationship between urinary excretion of homovanillic acid and norepinephrine metabolites in normal subjects and patients with orthostatic hypotension

Patients with neurogenic orthostatic hypotension due to multiple system atrophy (MSA) or pure autonomic failure (PAF) excrete lower amounts of homovanillic acid (HVA) than do normal subjects. There is a highly significant correlation between the rates of excretion of HVA and norepinephrine metabolites. The regression line relating excretion of the dopamine and norepinephrine metabolites suggests that about one third of dopamine formed in noradrenergic neurons is converted to norepinephrine and the remainder metabolized, mainly to HVA. About one fourth of urinary HVA appears to be derived from a source independent of norepinephrine; this source is probably brain dopaminergic neurons.

Cerebrospinal fluid microglial antibodies: Potential diagnostic markers for immune mechanisms in Alzheimer's disease

Hallmark lesions of Alzheimers disease (AD) are filled with reactive immunocompetent microglia, suggesting that immunological aberrations may participate in the pathophysiology of this disorder. Microglia may participate in the initial stages of neurodegeneration before the onset of dementia. If immune mediated processes are closely linked to neuronal breakdown it would be of importance to have a reliable means to detect these processes. Serum and cerebrospinal fluid (CSF) antibodies are discussed as such potential sources. The serendipitous use of the developing rat central nervous system (CNS) to screen CSF antibrain antibodies produced some unexpected findings. Firstly, CSF antibodies of AD and other dementia patients recognized distinctly different neuronal structures in the developing rat brain. Secondly, some AD CSF recognized fiber networks whereas others recognized amoeboid microglial cells. The same AD CSF which recognized amoeboid microglia cells also specifically marked activated microglia and neural macrophages in experimentally induced lesions. AD CSF microglial antibodies appear to be significant in view of the increasing association between microglia and neurogenerative processes in AD. In addition, CSF microglial antibodies are present in numerous at-risk descendants of familial AD patients. Some have subsequently developed the disorder. These findings together with the fact that microglial antibodies are usually found in the early stages of AD suggest that AD CSF microglial antibodies could be of value in detecting neurodegenerative processes before the onset of dementia. These findings add further support to the concept that inflammation and similar immune mechanisms may contribute to AD pathogenesis.

Chronic autonomic failure: CSF and plasma 3-methoxy-4-hydroxyphenylglycol.

We measured CSF and plasma levels of 3-methoxy-4-hydroxyphenylglycol (MHPG) in patients with orthostatic hypotension. Total CSF MHPG levels were significantly lower than normal in patients with either multiple system atrophy (MSA) or idiopathic orthostatic hypotension (IOH). Only IOH patients had low plasma levels of MHPG. Correction of CSF MHPG levels for the contribution from plasma free MHPG provides an index of central norepinephrine metabolism. In MSA, abnormal function of central noradrenergic pathways seems to cause the low CSF MHPG levels. In IOH, the decreased CSF MHPG results from the diminished plasma MHPG levels.

Beta‐receptor sensitivity in autonomic failure

We examined the cardiovascular, plasma norepinephrine (NE), and plasma renin (PRA) responses to isoproterenol infusion in patients with autonomic failure and in normal subjects. Slopes of the blood pressure response/dose relationships were more negative in patients with multiple system atrophy and pure autonomic failure (PAF) than in normal subjects, consistent with impaired baroreflex modulation. A shift to the left in patients with PAF suggests β-adrenergic receptor supersensitivity. In normal subjects, the increase in plasma NE and PRA was proportional to the log of the plasma isoproterenol level. Isoproterenol infusion did not increase plasma NE or PRA in either patient group despite a reduction in mean blood pressure. Reflexive cardiovascular and renal mechanisms appear to play a role in eliciting the plasma NE and PRA responses to isoproterenol infusion in normal subjects.