Progressive, age-dependent remodeling of motor cortex somatotopic remodeling is demonstrated in 5XFAD mice, characterized by early expansion of specific simple movement cortical sites followed by deterioration of both complex and simple motor cortical maps as disease advances.
The basal ganglia are characterized by somatotopic representation and are organized in parallel, functionally segregated corticostriatal circuits, but the impact of Parkinson’s disease (PD) on this architecture is unknown. We mapped task-evoked dopamine release using [11C]raclopride positron emission tomography/magnetic resonance in 13 early PD and 15 healthy control (HC) subjects during the performance of motor, cognitive, and reward tasks. In PD, motor tasks elicited decreased relative dopamine release in dorsal putamen but increased in less affected caudate and ventral striatum compared to HC. HC showed distinct dopaminergic topographies for upper versus lower limb activation; this somatotopy was absent in PD. HC exhibited segregated patterns of dopamine release across all tasks, but both anatomical and functional segregation were lost in PD. Compensatory effects of altered dopamine release topography may help to maintain function in patients with PD, but loss of segregation may contribute to challenges in discrete selection of movement and in multitasking.
Dongning Su, J. Hanania, Alexandra Pavel et al.· Science Advances· 0 citations
Recent studies suggest that cortical hyperexcitability in Alzheimer's disease (AD) may accelerate disease progression. However, the field lacks validated non-invasive methods to assay excitability in humans. In this study we used transcranial magnetic stimulation with electromyography to investigate mechanisms of motor cortical excitability in 63 biomarker-positive early-AD (ranging from mild cognitive impairment to mild dementia) participants and 72 cognitively unimpaired age-matched adults (CU). Single-pulse stimulation was applied to motor cortex to record resting motor thresholds (rMT) and motor-evoked potentials. An Input-Output curve was generated by delivering 10 pulses each at eight different intensities of maximum stimulator output (%MSO). Linear models or equivalent non-parametric tests 1) compared excitability metrics between groups, 2) tested correlations with cognition (mini-mental state exam, MMSE; Alzheimer's disease assessment scale-cognitive, ADAS-Cog), and 3) tested the impact of APOE4. Results show that early-AD participants have increased motor cortical excitability than CU, with lower rMT (p < 0.001), lower Input-Output curve Inflection Point (p = 0.007), and higher Dynamic Range (p = 0.035). An analysis of the Input-Output curve adjusting for rMT showed larger responses in AD specifically in the 135-150% rMT range (p = 0.023). In AD, higher excitability was related to worse cognition (rMT: MMSE p = 0.008, Inflection Point: MMSE p = 0.030 and ADAS-Cog p = 0.041). There was no relationship between APOE4 and excitability. In conclusion, AD participants have increased motor cortical excitability, related to cognition. This is evident both at lower and higher stimulation intensities. TMS may provide a useful measure of target engagement for therapies aimed at preserving cognition or slowing decline in early-AD.
Julia H. Cho, Brice Passera, Giacomo Bertazzoli et al.· Neurobiology of Aging· 0 citations
Abstract Background and objectives: Posterior Cortical Atrophy (PCA) is a focal variant of Alzheimer's Disease (AD) characterized by disproportionate and early visuospatial deficits with relative sparing of other cognitive abilities. PCA commonly arises before age 65, consistent with early onset AD (EOAD). Because studies of PCA pathology in patients with detailed cognitive assessment are rare, relationships between severity and distribution of neurofibrillary tangle (NFT) density and visuospatial deficits in PCA are not fully known. Our objectives were to: (1) determine if ratio of NFT density in occipital cortex (OC) versus hippocampus (HC) is higher in PCA than typical EOAD and (2) determine if this ratio correlates with severity of visuospatial deficits in EOAD generally. Methods: We determined density of tau NFT pathology in primary visual cortex (OC), midfrontal cortex (MF), and HC and calculated ratios of these densities for EOAD patients with PCA (n = 12) or non-PCA (n = 33) clinical phenotypes. Groups were compared using linear regression that adjusted for age at death and sex. Correlation between NFT density and visuospatial and other cognitive domain scores were examined using linear regression that adjusted for age at cognitive testing, education, sex and test-death interval. Analyses were repeated with the non-PCA EOAD patients grouped into those with mild (EOAD-Typical, n = 21) or severe (EOAD-Visual, n = 12) visuospatial impairment. Results: PCA patients had lower HC (β = –11.7 ± 5.7, p = 0.045) and a trend toward higher OC (β = 6.9 ± 3.7, p = 0.07) NFT density, and higher OC/HC (β = 0.30 ± 0.14, p = 0.04) and OC/MF (β = 0.56 ± 0.16, p = 0.001) ratios, than typical non-PCA EOAD patients. The EOAD-Visual had higher OC/HC NFT ratios (β = 0.38 ± 0.13, p = 0.008) than the EOAD-Typical non-PCA patients even though they did not meet clinical criteria for PCA. Correlations between OC/HC NFT ratios and visuospatial domain scores were strong (β = –1.29 ± 0.45, p = 0.008) and remained significant when limited to the non-PCA EOAD group (β = –1.22 ± 0.43, p = 0.008). Discussion: PCA is associated with a distribution of NFT pathology (i.e., high OC/HC NFT ratio) that coincides with early predominant visuospatial impairment. Non-PCA EOAD with a memory-predominant presentation and concomitant visuospatial impairment has an NFT distribution profile similar to PCA. NFT pathology in occipital cortex may moderate degree of visuospatial impairment in EOAD regardless of clinical syndrome.
Denis S. Smirnov, Sophie M. Dickinson, Melanie F Estrella et al.· Free neuropathology· 0 citations
Alzheimer's disease and related dementias are typically described at two levels: the accumulation of molecular pathology and the emergence of cognitive impairment. Understanding the relationship between pathology, often studied in animal models, and human cognition will require measurements spanning intermediate scales, including single neurons, neuronal populations, and distributed networks. Here we combine longitudinal measurements of behavior and neuronal population activity with fluid and histological biomarkers in a macaque model of early-stage disease. We find in two animals that visually guided behavior becomes increasingly disorganized, with less consistent and more variable patterns of exploration, despite preserved performance on simple tasks. In parallel, coordinated activity within and between neuronal populations in visual and parietal cortex declines, even as single-neuron tuning and basic feature encoding remain stable. The magnitude of these physiological changes was broadly consistent with biomarker progression. These changes arise when pathology is largely confined to regions providing feedback to visual cortex, indicating that functional disruption extends beyond sites of prominent pathology. Together, these results show that early disease progression is not marked by the loss of individual functions at any single level, but by a selective disruption of coordination across levels, from neuronal populations to behavior. This disorganized state is measurable and modifiable: methylphenidate administration was associated with a transient restoration of behavioral organization. These findings identify disruption of neuronal population organization as a defining feature of early-stage Alzheimer's disease and establish coordinated population activity as a candidate target for therapeutic intervention.
Douglas A. Ruff, Drew E. G. Sheets, Ramanujan Srinath et al.· Proceedings of the National...· 0 citations
Dysfunction of the primary motor cortex (M1) has long been implicated in the pathophysiology of Parkinson’s disease (PD), mostly as a link by which abnormal basal ganglia and thalamic activities are translated into motor symptoms. However, emerging evidence suggests that M1 neurons also exhibit maladaptive changes in advanced parkinsonism. Here, using a progressive mouse model of nigrostriatal neurodegeneration (i.e., the MitoPark mice, MP), we found that M1 neurons develop age- and striatal dopamine-dependent synaptic and cellular adaptations as parkinsonism progresses. The optogenetic, electrophysiological, pharmacological, and CRISPR-mediated genetic studies demonstrated that impaired α5-GABAA receptor-mediated inhibition and excessive activation of NMDA receptors of M1 pyramidal neurons are key microcircu it mechanisms underlying cortical circuit remodeling during progressive striatal dopamine (DA) loss. Furthermore, we found that treatment with L-DOPA at early or late stages of parkinsonism can prevent or rescue, respectively, the synaptic and cellular adaptations in M1. Together, the present study demonstrates the time course and the underlying molecular and microcircuit mechanisms of cortical network dysfunction during the development of parkinsonism.
Liqiang Chen, Hiba Douja Chehade, S. Somavarapu et al.· bioRxiv· 0 citations
Introduction Alzheimer’s disease (AD), a neurodegenerative disorder associated with amyloid beta (Aβ) plaque deposition, leads to cognitive decline in affected individuals. Vision changes are among the reported symptoms in AD with studies showing both decline in functions performed by the visual system as well as associations between vision loss and cognitive impairment in AD patients. Due to the increasing number of individuals diagnosed with AD and its early impact on vision, we sought to provide an in-depth analysis of how Aβ, a primary pathology typically preceding many other AD-associated pathologies, affects visual regions of the brain and how microglia, key immune regulators of the brain’s environment, respond to this AD-like pathology. Methods Amyloid pathology was examined in histological sections containing the dorsolateral geniculate nucleus (dLGN), and the primary visual cortex (V1), suprachiasmatic nucleus (SCN), and superior colliculus (SC) of 5xFAD mice using thioflavin-S and anti-amyloid staining. Microglia morphology was analyzed in Iba1 antibody-stained sections and phagocytic activity was evaluated with CD68 co-staining. Results We found that in the pathway for image-forming vision, including the dLGN and V1, there was significant Aβ pathology, shifts in microglial morphology to an amoeboid state, localization of microglia around plaques, and increased Iba1/CD68 co-labeling. However, in non-image-forming visual brain regions such as the SC and SCN, there was minimal Aβ pathology, ramified microglial morphology, and minimal phagocytic activity. Conclusion Overall, Aβ plaque deposition was related to brain-region-specific differences in microglial responses, indicating that visual brain regions are differentially affected by AD pathology in the 5xFAD mouse model of amyloidosis.
Shaylah McCool, A. Jain, Jennie C. Smith et al.· Frontiers in Aging Neuroscie...· 0 citations