Parkinson's Disease and Other Alzheimer's Disease and Related Dementia Pathologies and the Progression of Parkinsonism in Older Adults.

Background: The interrelationship of parkinsonism, Parkinson's disease (PD) and other Alzheimer's disease (AD) and Alzheimer's disease and related dementias (ADRD) pathologies is unclear.

Objective: We examined the progression of parkinsonian signs in adults with and without parkinsonism, and their underlying brain pathologies.

Methods: Annual parkinsonian signs were based on a modified Unified Parkinson's Disease Rating Scale.

Alzheimer's Disease Pathology Outside of the Cerebrum Is Related to a Higher Odds of Dementia.

Background: Assessments of Alzheimer's disease pathology do not routinely include lower brainstem, olfactory bulb, and spinal cord.

Objective: Test if amyloid-β (Aβ) and paired helical filament (PHF) tau-tangles outside the cerebrum are associated with the odds of dementia.

Methods: Autopsies were obtained in decedents with cognitive testing (n = 300).

Contrasting walking styles map to discrete neural substrates in the mouse brainstem.

Walking is a slow gait which is particularly adaptable to meet internal or external needs and is prone to maladaptive alterations that lead to gait disorders. Alterations can affect speed, but also style (the way one walks). While slowed speed may signify the presence of a problem, style represents the hallmark essential for clinical classification of gait disorders.

Stereotaxic Surgical Approach to Microinject the Caudal Brainstem and Upper Cervical Spinal Cord via the Cisterna Magna in Mice.

Stereotaxic surgery to target brain sites in mice is commonly guided by skull landmarks. Access is then obtained via burr holes drilled through the skull. This standard approach can be challenging for targets in the caudal brainstem and upper cervical cord due to specific anatomical challenges as these sites are remote from skull landmarks, leading to imprecision.

Brain β-Amyloid Links the Association of Change in Body Mass Index With Cognitive Decline in Community-Dwelling Older Adults.

Background: We tested the hypothesis that indices of Alzheimer's disease and related dementia (ADRD) pathologies may explain associations between change in body mass index (BMI) and cognitive decline in old age.

Method: We used data from 436 older decedents participating in a prospective longitudinal cohort study who had undergone annual cognitive and BMI assessments and postmortem collection of indices of 12 brain pathologies. We identified ADRD brain pathologies associated with BMI range, a previously published metric of change in BMI.

Shifts in Gait Signatures Mark the End of Lifespan in Mice, With Sex Differences in Timing.

Reduced walking speed is a hallmark of functional decline in aging across species. An age-related change in walking style may represent an additional key marker signifying deterioration of the nervous system. Due to the speed dependence of gait metrics combined with slowing of gait during aging, it has been challenging to determine whether changes in gait metrics represent a change in style.

Multitarget Transcranial Electrical Stimulation for Freezing of Gait: A Randomized Controlled Trial.

Background: Treatments of freezing of gait (FOG) in Parkinson's disease are suboptimal.

Objective: The aim of this study was to evaluate the effects of multiple sessions of transcranial direct current stimulation (tDCS) targeting the left dorsolateral prefrontal cortex and primary motor cortex (M1) on FOG.

Methods: Seventy-seven individuals with Parkinson's disease and FOG were enrolled in a double-blinded randomized trial.

Neocortical Lewy bodies are associated with impaired odor identification in community-dwelling elders without clinical PD.

Background: The association of Lewy bodies (LBs) with olfactory dysfunction was investigated in community-dwelling elders without clinical Parkinson's disease (PD) using the 12-item Brief Smell Identification Test (BSIT), a standard measure of odor identification.

Methods: 280 participants in the Rush Memory and Aging Project completed the BSIT annually. Lewy bodies were detected in 13 brain regions by immunohistochemistry and were assigned to the Braak PD stages 1-6.

Non-Crh Glutamatergic Neurons in Barrington's Nucleus Control Micturition via Glutamatergic Afferents from the Midbrain and Hypothalamus.

Lower urinary tract symptoms (LUTS) are exceptionally common and debilitating, and they are likely caused or exacerbated by dysfunction of neural circuits controlling bladder function. An incomplete understanding of neural control of bladder function limits our ability to clinically address LUTS. Barrington's nucleus (Bar) provides descending control of bladder and sphincter function, and its glutamatergic neurons expressing corticotropin releasing hormone (Bar) are implicated in bladder control.

Translational methods to detect asymmetries in temporal and spatial walking metrics in parkinsonian mouse models and human subjects with Parkinson's disease.

Clinical signs in Parkinson's disease (PD), including parkinsonian gait, are often asymmetric, but mechanisms underlying gait asymmetries in PD remain poorly understood. A translational toolkit, a set of standardized measures to capture gait asymmetries in relevant mouse models and patients, would greatly facilitate research efforts. We validated approaches to quantify asymmetries in placement and timing of limbs in mouse models of parkinsonism and human PD subjects at speeds that are relevant for human walking.

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.

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).

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.

A translational approach to capture gait signatures of neurological disorders in mice and humans.

A method for capturing gait signatures in neurological conditions that allows comparison of human gait with animal models would be of great value in translational research. However, the velocity dependence of gait parameters and differences between quadruped and biped gait have made this comparison challenging. Here we present an approach that accounts for changes in velocity during walking and allows for translation across species.

A novel approach for assigning levels to monkey and human lumbosacral spinal cord based on ventral horn morphology.

Proper identification of spinal cord levels is crucial for clinical-pathological and imaging studies in humans, but can be a challenge given technical limitations. We have previously demonstrated in non-primate models that the contours of the spinal ventral horn are determined by the position of motoneuron pools. These positions are preserved within and among individuals and can be used to identify lumbosacral spinal levels.

Barrington's nucleus: Neuroanatomic landscape of the mouse "pontine micturition center".

Barrington's nucleus (Bar) is thought to contain neurons that trigger voiding and thereby function as the "pontine micturition center." Lacking detailed information on this region in mice, we examined gene and protein markers to characterize Bar and the neurons surrounding it. Like rats and cats, mice have an ovoid core of medium-sized Bar neurons located medial to the locus coeruleus (LC).

Urinary Incontinence, Incident Parkinsonism, and Parkinson's Disease Pathology in Older Adults.

Objective: To test the hypothesis that urinary incontinence (UI) is associated with incident parkinsonism in older adults.

Methods: We used data from 2,617 older persons without dementia. Assessment included baseline self-report UI and annual structured exam which assessed parkinsonian signs, motor performances, cognitive function, and self-report disabilities.

Clinical Impact of 123I-Ioflupane SPECT (DaTscan) in a Movement Disorder Center.

Background/aims: The clinical diagnosis of degenerative forms of parkinsonism is imperfect, with past studies reporting a high rate of misdiagnosis by neurologists and movement disorder specialists, particularly early in the disease course. 123I-ioflupane SPECT (DaTscan) is a diagnostic neuroimaging tool used to distinguish essential tremor from tremor due to degenerative parkinsonisms. The present study expands upon prior studies of the clinical impact of DaTscan imaging in movement disorder centers by assessing quantitative estimates of diagnostic certainty, the impact on subsequent clinical decisions, and the degree to which the asymmetry in the results corresponds to laterality by clinical history and examination.

Post-mortem brain pathology is related to declining respiratory function in community-dwelling older adults.

Damage to brain structures which constitute the distributed neural network that integrates respiratory muscle and pulmonary functions, can impair adequate ventilation and its volitional control. We tested the hypothesis that the level of brain pathology in older adults is associated with declining respiratory function measured during life. 1,409 older adults had annual testing with spirometry (SPI) and respiratory muscle strength (RMS) based on maximal inspiratory and maximal expiratory pressures (MEPs).

α-Synuclein pathology accumulates in sacral spinal visceral sensory pathways.

Urinary urgency and frequency are common in α-synucleinopathies such as Parkinson disease, Lewy body dementia, and multiple system atrophy. These symptoms cannot be managed with dopamine therapy, and their underlying pathophysiology is unclear. We show that in individuals with Parkinson disease, Lewy body dementia, or multiple system atrophy, α-synuclein pathology accumulates in the lateral collateral pathway, a region of the sacral spinal dorsal horn important for the relay of pelvic visceral afferents.

Respiratory-related outputs of glutamatergic, hypercapnia-responsive parabrachial neurons in mice.

In patients with obstructive sleep apnea, airway obstruction during sleep produces hypercapnia, which in turn activates respiratory muscles that pump air into the lungs (e.g., the diaphragm) and that dilate and stabilize the upper airway (e.

Associations between quantitative mobility measures derived from components of conventional mobility testing and Parkinsonian gait in older adults.

Objective: To provide objective measures which characterize mobility in older adults assessed in the community setting and to examine the extent to which these measures are associated with parkinsonian gait.

Methods: During conventional mobility testing in the community-setting, 351 ambulatory non-demented Memory and Aging Project participants wore a belt with a whole body sensor that recorded both acceleration and angular velocity in 3 directions. We used measures derived from these recordings to quantify 5 subtasks including a) walking, b) transition from sit to stand, c) transition from stand to sit, d) turning and e) standing posture.

Lack of tryptophan hydroxylase-1 in mice results in gait abnormalities.

The role of peripheral serotonin in nervous system development is poorly understood. Tryptophan hydroxylase-1 (TPH1) is expressed by non-neuronal cells including enterochromaffin cells of the gut, mast cells and the pineal gland and is the rate-limiting enzyme involved in the biosynthesis of peripheral serotonin. Serotonin released into circulation is taken up by platelets via the serotonin transporter and stored in dense granules.

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.