William W. Pendlebury

Skeletal Muscle and Cardiovascular Adaptations to Exercise Conditioning in Older Coronary Patients

BACKGROUND Older coronary patients suffer from a low functional capacity and high rates of disability. Supervised exercise programs improve aerobic capacity in middle-aged coronary patients by improving both cardiac output and peripheral extraction of oxygen. Physiological adaptations to aerobic conditioning, however, have not been well studied in older coronary patients. METHODS AND RESULTS The effect of a 3-month and a 1-year program of intense aerobic exercise was studied in 60 older coronary patients (mean age, 68 +/- 5 years) beginning 8 +/- 5 weeks after myocardial infarction or coronary bypass surgery. Outcome measures included peak aerobic capacity, cardiac output, arterio-venous oxygen difference, hyperemic calf blood flow, and skeletal muscle fiber morphometry, oxidative enzyme activity, and capillarity. Training results were compared with a sedentary, age- and diagnosis-matched control group (n = 10). Peak aerobic capacity increased in the intervention group at 3 months and at 1 year by 16% and 20%, respectively (both P < .01). Peak exercise cardiac output, hyperemic calf blood flow, and vascular conductance were unaffected by the conditioning protocol. At 3 and 12 months, arteriovenous oxygen difference at peak exercise was increased in the exercise group but not in control subjects. Histochemical analysis of skeletal muscle documented a 34% increase in capillary density and a 23% increase in succinate dehydrogenase activity after 3 months of conditioning (both P < .02). At 12 months, individual fiber area increased by 29% compared with baseline (P < .01). CONCLUSIONS Older coronary patients successfully improve peak aerobic capacity after 3 and 12 months of supervised aerobic conditioning compared with control subjects. The mechanism of the increase in peak aerobic capacity is associated almost exclusively with peripheral skeletal muscle adaptations, with no discernible improvements in cardiac output or calf blood flow.

Aluminum-induced neurofibrillary degeneration affects a subset of neurons in rabbit cerebral cortex, basal forebrain and upper brainstem.

Neurofibrillary tangles in Alzheimers disease show a predilection for cortical pyramidal and subcortical projection neurons. The antigenic composition, neuronal specificity and distribution of aluminum-induced neurofibrillary degeneration were examined in regions of rabbit brain analogous to those that develop neurofibrillary tangles in Alzheimers disease. Neurofibrillary degeneration was induced by intraventricular instillation of aluminum chloride. In aluminum-treated rabbits, intensely immunoreactive filamentous aggregates were seen in affected neuronal perikarya after staining with an antiphosphorylated neurofilament antibody (SMI 31), while in controls immunoreactivity was confined to axon-like elements. Monoclonal antibodies against Microtubule-associated protein 2 and tau, which stain human neurofibrillary tangles, did not stain aluminum-induced neurofibrillary degeneration. Pyramidal neurons exhibiting neurofibrillary degeneration formed a discrete linear pattern in layers III and V of cortex. Cortical somatostatin and nicotinamide adenine dinucleotide phosphate diaphorase-reactive neurons identified in double-stained sections were unaffected. Large perikarya in the vicinity of the globus pallidus, some of which contained acetylcholinesterase, were frequently SMI 31-immunoreactive. Among the cell groups affected in the upper brainstem were the nucleus raphe dorsalis and locus coeruleus. These findings show that aluminum-induced neurofibrillary degeneration differs antigenically from neurofibrillary tangles in Alzheimers disease. Nevertheless, many neuronal subsets that are particularly susceptible to Alzheimers disease, including cortical pyramidal neurons, basal forebrain cholinergic neurons and upper brainstem catecholaminergic neurons, are also affected by aluminum-induced neurofibrillary degeneration.

Disruption of classical conditioning in patients with Alzheimer's disease

One of the primary features of Alzheimers disease (AD) is a disorder of memory. Although considerable effort has been devoted to characterizing this memory disorder, simple forms of memory such as classical (Pavlovian) conditioning have not been studied. The prevailing view has been that these simple forms of memory are not affected in AD. These forms of memory, however, may be of particular interest because they are beginning to be well understood at the neurobiological level. Because of this, when memory disorders are detected, it may be possible to specify their neurobiological substrate. We now report that classical conditioning of the eyeblink response is disrupted in AD patients compared to age-matched controls. This deficit in conditioning is not due to nonassociative factors such as changes in sensitivity to stimuli or disruption of the motor response. The results are considered in terms of using simple forms of memory to help generate hypotheses regarding the neurobiology of age-related memory disorders.

Analysis of the prion protein gene in thalamic dementia

Thalamic degenerations or dementias are poorly understood conditions. The familial forms are (1) selective thalamic degenerations and (2) thalamic degenerations associated with multiple system atrophy. Selective thalamic degenerations share clinical and pathologic features with fatal familial insomnia, an autosomal dominant disease linked to a mutation at codon 178 of the prion protein (PrP) gene that causes the substitution of asparagine for aspartic acid (178Asn mutation). We amplified the carboxyl terminal coding region of the PrP gene from subjects with selective thalamic dementia or thalamic dementia associated with multiple system atrophy. Three of the four kindreds with selective thalamic dementia and none of the three kindreds with thalamic dementia associated with multiple system atrophy had the PrP 178Asn mutation. Thus, analysis of the PrP gene may be useful in diagnosing the subtypes of thalamic dementia. Moreover, since selective thalamic dementia with the PrP 178Asn mutation and fatal familial insomnia share clinical and histopathologic features, we propose that they are the same disease.

Multiple microabscesses in the central nervous system: a clinicopathologic study

We reviewed 2, 107 consecutive autopsies with neuropathologic examination at the Medical Center Hospital of Vermont, and identified 92 cases with significant pathologic evidence for infection involving the central nervous system (CNS). Of these, 35 took the form of multiple microabscesses. There were 19 men and 16 women, mean age 56. All patients were chronically ill, usually with an associated impaired immunity. The lung was the most frequent site of primary infection, and sepsis was often present. The most commonly identified causative organisms were Staphylococcus aureus and Candida albicans. Patients with CNS microabscesses developed a progressive encephalopathy associated with waxing and waning signs and symptoms. Laboratory and neuroradiologic studies were not helpful in elucidating the problem. We conclude that multiple microabscesses are a frequent, usually unrecognized, manifestation of CNS infection, and should be considered in the differential diagnosis of encephalopathy in hospitalized patients with chronic disease, immunosuppression and sepsis.

Immunoglobulin derived depositions in the nervous system: novel mass spectrometry application for protein characterization in formalin-fixed tissues

Proteinaceous deposits are occasionally encountered in surgically obtained biopsies of the nervous system. Some of these are amyloidomas, although the precise nature of other cases remains uncertain. We studied 13 cases of proteinaceous aggregates in clinical specimens of the nervous system. Proteins contained within laser microdissected areas of interest were identified from tryptic peptide sequences by liquid chromatography–electrospray tandem mass spectrometry (LC-MS/MS). Immunohistochemical studies for immunoglobulin heavy and light chains and amyloidogenic proteins were performed in all cases. Histologically, the cases were classified into three groups: ‘proteinaceous deposit not otherwise specified’ (PDNOS) (n=6), amyloidoma (n=5), or ‘intracellular crystals’ (n=2). LC-MS/MS demonstrated the presence of λ, but not κ, light chain as well as serum amyloid P in all amyloidomas. λ-Light-chain immunostaining was noted in amyloid (n=5), although demonstrable monotypic lymphoplasmacytic cells were seen in only one case. Conversely, in PDNOS κ, but not λ, was evident in five cases, both light chains being present in a single case. In three cases of PDNOS, a low-grade B-cell lymphoma consistent with marginal zone lymphoma was present in the brain specimen (n=2) or spleen (n=1). Lastly, in the ‘intracellular crystals’ group, the crystals were present within CD68+ macrophages in one case wherein κ-light chain was found by LC-MS/MS only; the pathology was consistent with crystal-storing histiocytosis. In the second case, the crystals contained immunoglobulin G within CD138+ plasma cells. Our results show that proteinaceous deposits in the nervous system contain immunoglobulin components and LC-MS/MS accurately identifies the content of these deposits in clinical biopsy specimens. LC-MS/MS represents a novel application for characterization of these deposits and is of diagnostic utility in addition to standard immunohistochemical analyses.

An immunocytochemical comparison of cytoskeletal proteins in aluminum-induced and Alzheimer-type neurofibrillary tangles.

SummaryExposure of the central nervous system (CNS) of rabbits to aluminum salts produces a progressive encephalopathy. Examination of CNS strucres discloses widespread perikaryal neurofibrillary tangle (NFTs) formation. The aluminum-induced NFTs consist of collections of normal neurofilaments, and differ ultrastructurally and in their solubility characteristics from Alzheimer-type NFTs, the latter being composed of largely insoluble paired helical filaments. The present study compares NFTs found in the rabbit to those of Alzheimers disease, using monoclonal antibodies (SMI 31, SMI 32) that recognize phosphorylated and non-phosphorylated determinants respectively in normal neurofilaments, and an antiserum raised against purified microtubules. Paraffin-embedded sections were stained by the avidin-biotin immunocytochemical method. Intense staining of aluminum-induced NFTs was found after processing with SMI 31 and SMI 32, while no staining of non-tangled perikarya of control rabbits or of Alzheimer-type NFTs was seen. Antimicrotubule antiserum gave weak, nonfocal staining in the aluminum-treated and control rabbits, while Alzheimer-type NFTs were stained intensely. These results show that phosphorylated and non-phosphorylated neurofilaments accumulate in aluminum-induced NFTs, thus complementing the previously demonstrated specific slowing of the axonal transport of neurofilaments in aluminum intoxication. Further, they suggest that the presence of microtubular proteins may be necessary for altered neurofilaments to take on a paired helical configuration.

Chronic inflammatory demyelinating polyradiculoneuropathy in diabetic patients.

This retrospective analysis was undertaken to determine whether a subset of diabetic patients with demyelinating polyneuropathy were similar to patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). Ten patients meeting the clinical criteria for idiopathic CIDP were compared to nine patients with diabetes and demyelinating polyneuropathy. The diabetic patients with demyelinating polyneuropathy displayed clinical, electrophysiologic, and histologic features that were similar to those in CIDP patients. All six patients with diabetes and demyelinating polyneuropathy who were treated with immunomodulatory therapy showed a favorable response. Our study highlights the importance of investigating diabetic patients with polyneuropathy in an attempt to identify patients with demyelinating polyneuropathy, because of the likelihood of benefit in these patients from immunomodulatory treatment. Muscle Nerve 27: 465–470, 2003

Frontal lobe atrophy due to a mutation in the cholesterol binding protein HE1/NPC2

This is the first description of slowly progressive Niemann–Pick disease type C (NPC) without the typical lysosomal storage in bone marrow and viscera in two descendants of a group of 17th century French‐Canadians. The index patient was a married 43‐year‐old woman with onset of dementia in her thirties, later followed by the development of ataxia and athetoid movements. Her autopsy disclosed frontal lobe atrophy, neurolysosomal storage with oligolamellar inclusion and tau‐positive neurofibrillary tangles. Of the 119 family members screened, only a married 42‐year‐old sister displayed symptoms of a dementia. Both women displayed vertical supranuclear ophthalmoplegia; expressive aphasia; concrete, stimulus‐bound, perseverative behavior; and impaired conceptualization and planning. Cultured fibroblasts showed decreased cholesterol esterification and positive filipin staining, but no mutation was detected in coding or promoter regions of the NPC1 gene using conformation sensitive gel electrophoresis and sequencing. Sequencing showed a homozygous gene mutation that is predicted to result in an amino acid substitution, V39M, in the cholesterol binding protein HE1 (NPC2). Adult‐onset NPC2 with lysosomal storage virtually restricted to neurons represents a novel phenotypic and genotypic variant with diffuse cognitive impairment and focal frontal involvement described for the first time. Ann Neurol 2002;52:000–000

Age-related disruption of classical conditioning: a model systems approach to memory disorders.

The model systems approach to the neurobiology of memory involves studying a well characterized learned response in a relatively simple and well controlled preparation. The best characterized mammalian model system is classical conditioning of the rabbits eyeblink response. Using this preparation, significant progress has been made toward understanding the neurobiological systems and mechanisms involved in elaboration of the conditioned response. Using a well characterized model system such as classical eyeblink conditioning, it should be possible to both characterize the changes in learning and memory that accompany aging and to investigate their neural substrates. Our strategy for using the conditioned eyeblink preparation for studying age-related memory deficits is four-fold and includes investigating conditioning deficits in: (1) humans across the life span, (2) rabbits across the life span, (3) Alzheimers disease patients, and (4) rabbits with aluminum-induced neurofibrillary degeneration. In this paper, we present exemplary data from each of these lines of research. If similar deficits occur in each of these groups, it may be possible to begin to form hypotheses about the neurobiology of age-related memory disorders.