Spinal Arteriolosclerosis Is Common in Older Adults and Associated With Parkinsonism.

BACKGROUND AND PURPOSE: There are few studies of spinal microvascular pathologies in older adults. We characterized spinal cord microvascular pathologies and examined their associations with other spinal and brain postmortem indices and parkinsonism in older adults. METHODS: We documented 3 features of microvascular pathologies in spinal cord and brain specimens from 165 deceased older participants. We also measured spinal white matter pallor. Parkinsonian signs were assessed with a modified version of the motor section of the Unified Parkinson's Disease Rating Scale. We examined the associations of spinal arteriolosclerosis with other spinal and brain postmortem indices and parkinsonism proximate to death using regression models which controlled for age and sex. RESULTS: Microinfarcts and cerebral amyloid angiopathy were not observed within the spinal cord parenchyma. Spinal arteriolosclerosis was observed at all spinal levels (C7, T7, L4, S4) examined and was more severe posteriorly than anteriorly (posterior: 4.3, SD=0.72 versus anterior: 3.9, SD=0.74; t=14.58; P<0.001). Arteriolosclerosis was more severe in the spinal cord than in the brain (cord: 4.10, SD=0.70; brain: 3.5, SD=0.98; t=10.39; P<0.001). The severity of spinal arteriolosclerosis was associated with spinal white matter pallor (r=0.47; P<0.001). Spinal arteriolosclerosis accounted for ≈3% of the variation in parkinsonism in models controlling for age, sex, brain arteriolosclerosis, and cerebrovascular disease pathologies. Further models showed that the association of spinal arteriolosclerosis and parkinsonism was not mediated via spinal white matter pallor. CONCLUSIONS: Although the regional distribution of microvascular pathologies varies within the central nervous system, spinal arteriolosclerosis is common and may contribute to the severity of spinal white matter pallor and parkinsonism in older adults.

Locus coeruleus neuron density and parkinsonism in older adults without Parkinson's disease.

Previous work has showed that nigral neuron density is related to the severity of parkinsonism proximate to death in older persons without a clinical diagnosis of Parkinson's disease (PD). We tested the hypothesis that neuron density in other brain stem aminergic nuclei is also related to the severity of parkinsonism. We studied brain autopsies from 125 deceased older adults without PD enrolled in the Memory and Aging Project, a clinicopathologic investigation. Parkinsonism was assessed with a modified version of the Unified Parkinson's Disease Rating Scale (UPDRS). We measured neuron density in the substantia nigra, ventral tegmental area, locus coeruleus, and dorsal raphe, along with postmortem indices of Lewy body disease, Alzheimer's disease and cerebrovascular pathologies. Mean age at death was 88.0 years, and global parkinsonism was 14.8 (SD, 9.50). In a series of regression models that controlled for demographics and neuron density in the substantia nigra, neuron density in the locus coeruleus (estimate, -0.261; SE, 0.117; P = .028) but not in the ventral tegmental area or dorsal raphe was associated with severity of global parkinsonism proximate to death. These findings were unchanged in models that controlled for postmortem interval, whole-brain weight, and other common neuropathologies including Alzheimer's disease and Lewy body pathology and cerebrovascular vascular pathologies. In older adults without a clinical diagnosis of PD, neuron density in locus coeruleus nuclei is associated with the severity of parkinsonism and may contribute to late-life motor impairments.

Spinal motor neurons and motor function in older adults.

This study examined the relation between lumbar spinal motor neuron (SMN) indices and motor function proximate to death in community-dwelling older adults. Older adults (N = 145) participating in the Rush Memory and Aging Project underwent structured clinical testing proximate to death and brain and spinal cord autopsy at time of death. Ten motor performances were summarized by a composite global motor score. Choline acetyltransferase immunostaining was used to identify spinal motor neurons of the L4/5 segment. SMN counts and area and ventral horn area were collected. Linear regression modeling showed that the association of SMN counts and density with global motor scores proximate to death varied with sex. Separate models in men and women showed that this significant interaction was due to the association of higher SMN counts and density with higher global motor scores proximate to death in men but not women. These associations were unchanged when we controlled for indices of brain pathologies or chronic health conditions. In 38 cases with counts of activated microglia available, higher counts of activated microglia were associated with lower SMN counts. Activated spinal microglia and loss of spinal motor neurons may contribute to motor impairments in older men.

Spinal Lewy body pathology in older adults without an antemortem diagnosis of Parkinson's disease.

To test the hypothesis that Lewy body pathology (LBs) is present in the spinal cord of older community-dwelling adults without a clinical diagnosis of Parkinson's disease (PD). We studied 162 prospective autopsies from older adults with PD (N = 6) and without PD (N = 156). We documented the presence of LBs in cerebrum and brainstem structures from each of the six regions used for Braak PD staging and four spinal cord levels (C5/6, T7, L4/5 and S4/5). Parkinsonism proximate to death was based on a previously validated measure present if two or more of the four signs of parkinsonism were present based on a modified version of the Unified Parkinson's Disease Rating Scale (UPDRS). Fifty-three of 156 individuals without PD (34%) had LBs in a least one site within the CNS. About half of cases with LBs in the cerebrum or brainstem, (25/53, 47%) also had spinal LBs. Almost 90% (22/25, 88%) of cases with spinal LBs had LBs in the cerebrum (Braak stages 4-6) and about 10% (3/25, 12%) had only brainstem LBs (Braak stages 1-3). Four of six cases with PD showed LBs in cerebrum, brainstem and spinal cord. Individuals with LBs in the spinal cord were more likely to have clinical parkinsonism proximate to death compared to individuals with LBs in brainstem and cerebrum alone (52% vs. 32%; Chi-Square x2 = 5.368, d.f. = 1, P = 0.0.021) and more severe nigral neuronal loss (48% vs. 11%; Chi-Square x2 = 9.049, d.f. = 1, P = 0.003). These findings were unchanged when we included cases with a history of PD. Older community-dwelling adults without a clinical diagnosis of PD have evidence of LBs throughout the CNS including the spinal cord which is associated with parkinsonism and more severe nigral neuronal loss.

The organization of the brainstem and spinal cord of the mouse: relationships between monoaminergic, cholinergic, and spinal projection systems.

Information regarding the organization of the CNS in terms of neurotransmitter systems and spinal connections in the mouse is sparse, especially at the level of the brainstem. An overview is presented of monoaminergic and cholinergic systems in the brainstem and spinal cord that were visualized immunohistochemically in inbred C57BL/6 and outbred CD-1 mice. This information is complemented with data on spinal cord-projecting systems that were characterized using retrograde tracing, spinal hemisections, and double labeling techniques. Attention is given to differences in these systems related to spinal levels. The data are discussed with reference to studies in the rat, and to standardized information as provided in the atlas of the mouse brain. Although the overall organization of these systems in the mouse is largely similar to those in the rat, species differences are present in relative location, size and/or connectivity of cell groups. For example, catecholaminergic neurons in the (ventro)lateral pons (A5 and A7 cell groups) in the mouse project to the spinal cord mainly via contralateral, and not ipsilateral, pathways. The data further supplement information as provided in standardized brainstem sections of the C57BL/6 mouse [Paxinos, G., Franklin, K.B.J., 2001. The mouse brain in stereotaxic coordinates. Academic Press, San Diego], especially with respect to the size and/or location of the catecholaminergic retrorubral field (A8 group), A5, A1, and C1 cell groups, and the serotonergic B4 group, reticulotegmental nucleus (B9 group), lateral paragigantocellular nucleus and raphe magnus nucleus (B3 group). Altogether this study provides a comprehensive overview of the spatial relationships of neurochemically and anatomically defined neuronal systems in the mouse brainstem and spinal cord.

Nucleus retroambiguus-spinal pathway in the mouse: Localization, gender differences, and effects of estrogen treatment.

Nucleus retroambiguus (NRA)-motoneuronal projections are species-specific and serve expiration, Valsalva maneuvers, vocalization, and sexual behavior. In cat and monkey, estrogen induces sprouting of NRA-spinal axons. This pathway may thus serve as a model to study mechanisms through which estrogen induces neuronal plasticity. In this study, NRA-spinal projections are described in adult mice by using anterograde and retrograde tracing techniques, with attention to gender, strain (CD-1 and C57BL/6), and estrogen-induced changes (in ovariectomized females). Labeled NRA-spinal neurons at the level of the decussation of the corticospinal tract were most numerous after tracer injections into the thoracic and upper lumbar cord. They were medium-sized and had axons that descended through the contralateral cord. A group of small neurons was labeled in the NRA immediately rostral to the decussation of the corticospinal tract after cervical and thoracic, but not after lumbar injections. This group projected mainly via an ipsilateral pathway. The main projections from the caudal NRA involved motoneurons in the thoracic and upper-lumbar cord that supply abdominal wall and cremaster muscles. Pelvic floor motoneurons did not receive substantial input. NRA-spinal projections, especially those involving the upper lumbar cord, were sexually dimorphic, being more extensive in males than in females. Moreover, they were more distinct in estrogen-treated females than in control females. Strain differences were not observed. The unique features of the caudal NRA-spinal pathway in the mouse are discussed in the framework of possible functions of this system, such as mating behavior and related social behaviors, parturition, thermoregulation, and control of balance.

Estrogen receptor-alpha and -beta immunoreactive neurons in the brainstem and spinal cord of male and female mice: relationships to monoaminergic, cholinergic, and spinal projection systems.

For many populations of estrogen-sensitive neurons it remains unknown how they are associated with central nervous system circuitries that mediate estrogen-induced modulation of behavioral components. With the use of double-labeling immunohistochemistry and tracing techniques, the relationships of estrogen receptor (ER)-alpha- and ER-beta-immunoreactive (IR) neurons in the mouse brainstem and spinal cord to monoaminergic, cholinergic, and spinal projection systems are explored. Similar distributions of ER-IR neurons were present in females and males, with differences in labeling intensity of ER-alpha immunoreactivity among males and estrogen-, and oil-treated females. Barrington's nucleus, the ventrolateral medulla, and the nucleus of the solitary tract contained spinal-projecting ER-alpha-IR neurons, whereas ER-alpha-IR neurons in the periaqueductal gray, parabrachial nucleus, and catecholaminergic A1 cell group received spinal input. Numerous tyrosine hydroxylase (TH)-IR ER-alpha-IR neurons were present in the ventral periaqueductal gray, nucleus of the solitary tract, A1 cell group, and lumbosacral cord. The dorsal raphe nucleus contained ER-alpha-IR and ER-beta-IR neurons that colocalized with serotonin (5HT), and the reticulotegmental nucleus contained 5HT-IR ER-alpha-IR neurons. Fibers IR for vesicular acetylcholine transporter (VAChT), TH, and 5HT were located among ER-alpha-IR neurons in the dorsal horn and spinal autonomic regions. Robust staining for TH and VAChT, but not 5HT, was present among ER-alpha-IR neurons in the lumbosacral lateral collateral pathway. Possible modulatory actions of estrogen on each of these ER-IR populations are discussed in the context of their specific function, including micturition, sexual behavior, ejaculation, cardiovascular and respiratory control, tactile and nociceptive sensory processing, anti-nociception, endocrine regulation, and feeding.

Axonal sprouting of a brainstem-spinal pathway after estrogen administration in the adult female rhesus monkey.

The nucleus retroambiguus (NRA) is located in the caudal medulla oblongata and contains premotor neurons that project to motoneuronal cell groups in the brainstem and spinal cord. NRA projections to the lumbosacral cord are species specific and might be involved in mating behavior. In the female cat, this behavior is estrogen dependent, and estrogen induces axonal sprouting in the NRA-lumbosacral pathway. Because female receptive behavior in primates is not fully dependent on estrogen, the question arises as to whether the capacity of estrogen-induced sprouting is preserved in primates. The effect of estrogen was studied on the NRA-lumbosacral projection with the use of wheat germ agglutinin conjugated to horseradish peroxidase as a tracer in six adult ovariectomized rhesus monkeys with or without estrogen priming (three controls and three treated with 20 microg/day of estradiol benzoate subcutaneously for 14 days). Light microscopy showed that the density of arborizing labeled NRA axons in the lumbosacral cord was greater in estrogen-treated than in control animals. Ultrastructurally, labeled NRA terminal profiles were quantified in motoneuron pools that supply muscles of the abdominal wall, axial, and pelvic floor. After estrogen treatment, the average number of labeled terminal profiles per area of the abdominal wall, axial, and pelvic floor motoneuron pool increased 1.5-, 3.3-, and 2.8-fold, respectively. In the estrogen-treated cases, 8.9% of labeled terminal profiles showed characteristics of growth cones. In controls, such profiles were rarely observed. The results showed that estrogen induces axonal sprouting in a brainstem-spinal pathway in the adult female rhesus monkey. These findings supported the concept that the NRA-lumbosacral pathway may be involved in sexual behavior. Moreover, they demonstrated that a long descending brainstem-spinal tract in adult nonhuman primates retains the capacity for axonal sprouting.

Estrogen receptor-alpha immunoreactive neurons in the ventrolateral periaqueductal gray receive monosynaptic input from the lumbosacral cord in the rhesus monkey.

Estrogen affects female sexual behavior, analgesia, and micturition in mammals. One of the possible sites at which estrogen might exert its effect on these functions is the periaqueductal gray (PAG). The PAG is involved in each of these functions, it receives sensory input relevant to these functions from the lumbosacral cord, and contains estrogen receptor-alpha immunoreactive (ER-alpha IR) neurons. The present light (LM) and electron microscopic (EM) study seeks to determine whether there are monosynaptic projections from the lumbosacral cord to ER-alpha IR neurons in the PAG of the female rhesus monkey. Tracer was injected into the lumbosacral cord to visualize the lumbosacral-PAG projection, and the distribution of ER-alpha IR neurons in the PAG was studied immunohistochemically. The medial part of the ventrolateral caudal PAG received the densest projection from the lumbosacral cord. Another prominent projection was found in the lateral PAG at the intercollicular level. Although ER-alpha IR neurons were widely distributed throughout the PAG, approximately 40% of ER-alpha IR PAG neurons were located as a distinct cluster in the medial portion of the ventrolateral, caudal PAG. Double labeling experiments showed that the location of this cluster precisely overlapped with the densest lumbosacral-PAG projection. EM revealed that axons from the lumbosacral cord made asymmetrical synaptic contacts with unlabeled dendrites and ER-alpha IR neuronal somata in the ventrolateral PAG. It is concluded that there exists a specific, monosynaptic pathway from lumbosacral neurons to ER-alpha expressing PAG neurons in the rhesus monkey. This pathway might be involved in the mechanisms of analgesia, blood pressure, mating behavior, and micturition.

Spinal projections of the A5, A6 (locus coeruleus), and A7 noradrenergic cell groups in rats.

The pontine noradrenergic cell groups, A5, A6 (locus coeruleus), and A7, provide the only noradrenergic innervation of the spinal cord, but the individual contribution of each of these populations to the regional innervation of the spinal cord remains controversial. We used an adeno-associated viral (AAV) vector encoding green fluorescent protein under an artificial dopamine beta-hydroxylase (PRSx8) promoter to trace the spinal projections from the A5, A6, and A7 groups. Projections from all three groups travel through the spinal cord in both the lateral and ventral funiculi and in the dorsal surface of the dorsal horn, but A6 axons take predominantly the dorsal and ventral routes, whereas A5 axons take mainly a lateral and A7 axons a ventral route. The A6 group provides the densest innervation at all levels, and includes all parts of the spinal gray matter, but it is particularly dense in the dorsal horn. The A7 group provides the next most dense innervation, again including all parts of the spinal cord, but is it denser in the ventral horn. The A5 group supplies only sparse innervation to the dorsal and ventral horns and to the cervical and lumbosacral levels, but provides the densest innervation to the thoracic intermediolateral cell column, and in particular to the sympathetic preganglionic neurons. Thus, the pontine noradrenergic cell groups project in a roughly topographic and complementary fashion onto the spinal cord. The pattern of spinal projections observed suggests that the locus coeruleus might have the greatest effect on somatosensory transmission, the A7 group on motor function, and the A5 group on sympathetic function.