Sexual Dimorphism in Post-Stroke Cognitive Trajectories: Dissecting Domain-Specific MoCA Index Variations and Neurobiological Mechanisms in Rehabilitation

Abstract

Post-stroke cognitive impairment (PSCI) represents a major clinical bottleneck in neurorehabilitation, severely limiting functional independence and quality of life. While functional deficits following acute cerebrovascular events are well characterized, biological sex significantly modifies cognitive recovery trajectories across distinct cognitive domain profiles. This article explores the neurobiological mechanisms underlying sex-dimorphic outcomes evaluated via Montreal Cognitive Assessment (MoCA) domain index scores. Sexual dimorphism in PSCI is driven by differential neurovascular unit (NVU) dynamics, estrogen and androgen receptor activation, microglial inflammatory phenotypes, and synaptic plasticity mechanisms. Clinical evidence demonstrates that female post-stroke trajectories exhibit distinct patterns in visuospatial/executive function, memory, and language processing compared to male cohorts. Estrogen receptor alpha (ERα) and G-protein coupled estrogen receptor 1 (GPER1) signaling confer neuroprotection by suppressing excitotoxicity and endoplasmic reticulum stress, whereas age-related reductions in endogenous 17β-estradiol alter microglial reactivity. Integrating sex-and-gender-based analysis (SGBA) into post-stroke rehabilitative paradigms enables precision stratification, allowing targeted cognitive protocols and neuroprotective therapeutics tailored to sex-specific physiological phenotypes.

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Introduction & Cellular Mechanisms

Stroke triggers a destructive biochemical cascade characterized by acute energy failure, localized hypoxia, microvascular breakdown, and widespread neurodegeneration. In the post-stroke phase, secondary neurodegeneration extends beyond the primary infarct zone, disrupting distant functional networks and leading to post-stroke cognitive impairment (PSCI). Understanding the subcellular drivers of this cognitive decline is fundamental to developing targeted neurorehabilitative protocols.

At the cellular level, cerebral ischemia induces massive depolarizations and uncontrolled release of glutamate into the synaptic cleft. Overactivation of N-methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors triggers a rapid, pathological influx of intracellular calcium ($\text{Ca}^{2+}$). This cytosolic calcium overload targets organelles directly:

1. Mitochondrial Dysfunction and Oxidative Stress: Excessive calcium uptake by the mitochondrial calcium uniporter (MCU) dissipates the mitochondrial membrane potential ($\Delta\Psi_m$), opening mitochondrial permeability transition pores (mPTPs). This releases cytochrome *c* and apoptosis-inducing factor (AIF) into the cytosol, activating caspase-dependent and caspase-independent apoptotic pathways. Additionally, dysregulation of mitochondrial fission/fusion dynamics—mediated by dynamin-related protein 1 (Drp1) upregulation—leads to mitochondrial fragmentation, generating massive amounts of reactive oxygen species (ROS) that oxidize lipid membranes, structural proteins, and nucleic acids.

2. Endoplasmic Reticulum (ER) Stress: Calcium depletion within the ER lumen disrupts protein folding machinery, activating the unfolded protein response (UPR) via three primary transmembrane sensors: PERK, IRE1α, and ATF6. Prolonged UPR activation upregulates the pro-apoptotic transcription factor CHOP, driving neuronal death in vulnerable regions such as the CA1 field of the hippocampus and the prefrontal cortex, both critical nodes for executive function and memory consolidation.

3. Neuroinflammation and Microglial Polarization: Ischemic cell damage exposes damage-associated molecular patterns (DAMPs), which activate resident microglia via Toll-like receptors (TLR2/4). Microglia shift toward a pro-inflammatory phenotype, releasing elevated levels of tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), and interleukin-6 (IL-6). This neuroinflammatory environment degrades matrix metalloproteinases (e.g., MMP-9), compromising blood-brain barrier (BBB) integrity and exacerbating neurovascular unit (NVU) decoupling.

4. Neurotrophic Deprivation: Ischemic injury downregulates brain-derived neurotrophic factor (BDNF) and impedes its signaling through the tropomyosin receptor kinase B (TrkB) receptor, blunting downstream ERK/MAPK and PI3K/Akt survival pathways. This impairment reduces synaptic density, alters dendritic spine morphogenesis, and impedes long-term potentiation (LTP), directly underlying domain-specific cognitive deficits measured in rehabilitation settings.

```
Ischemic Event ──> Glutamate Excitotoxicity ──> Ca²⁺ Overload
│
┌────────────────────────────────────────────┼────────────────────────────────────────────┐
▼ ▼ ▼
Mitochondrial mPTP Opening ER Stress (UPR Pathways) Microglial Activation
├─ ROS Generation ├─ PERK / IRE1α / ATF6 ├─ Pro-inflammatory Cytokines
└─ Cytochrome c Release └─ CHOP Upregulation └─ Matrix Metalloproteinase (MMP-9)
│ │ │
└────────────────────────────────────────────┼────────────────────────────────────────────┘
▼
Loss of NVU Integrity & LTP
│
▼
Domain-Specific Cognitive Impairment
```

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Sex-Dimorphic Regulation & Translational Implications

Sex-and-gender-based analysis (SGBA) reveals that male and female brains process ischemic insult and subsequent neurorehabilitative inputs differently. These dimorphisms stem from organizational organizational and activational effects of sex hormones, expression patterns of X-chromosome-linked genes, and intrinsic cellular resilience mechanisms. Dissecting these differences via domain-specific assessment tools, such as the Montreal Cognitive Assessment (MoCA) index scores (evaluating Executive, Visuospatial, Memory, Language, and Attention domains), is essential for advancing precision medicine.

1. Hormonal Modulation & Receptor Dynamics

Sex steroids significantly modulate neuroprotective cascades and synaptic remodeling post-stroke:

Estrogen Signaling: 17β-estradiol (E2) acts through nuclear receptors (ERα, ERβ) and the membrane-bound G-protein coupled estrogen receptor 1 (GPER1). ERα activation drives neuroprotective signaling by upregulating anti-apoptotic Bcl-2 and enhancing PI3K/Akt pathway activation, which mitigates ischemic excitotoxicity. Furthermore, GPER1 stimulation rapidly enhances actin polymerization via LIM kinase activation, supporting dendritic spine restructuring in the hippocampus and cortex. However, post-menopausal reductions in systemic E2 levels attenuate these endogenous protective pathways, leaving older female patients vulnerable to accelerated post-stroke neurodegeneration.

Androgen Dynamics: Testosterone and dihydrotestosterone (DHT) signal via androgen receptors (AR) to modulate local oxidative stress and synaptic density. While physiological androgen levels foster axonal regeneration, severe ischemic depletion or excessive local conversions can promote neuroinflammation, contributing to sexually dimorphic recovery trajectories in spatial orientation and executive control domains.

2. Microglial Heterogeneity and Neurovascular Coupling

Biological sex heavily influences immune cell phenotypes and vascular reactivity following stroke:

Immune Cell Epigenetics: X-chromosome inactivation escapees, such as *KDM6A* (a histone demethylase) and *TLR7*, endow female microglia with a distinct transcriptional profile. While pre-menopausal females exhibit a predominant pro-resolving inflammatory profile, post-menopausal females undergo an exaggerated inflammatory shift post-stroke, displaying prolonged elevation of microglial TNF-α and IL-1β relative to age-matched males.

Neurovascular Unit (NVU) Maintenance: Females exhibit higher baseline expression of tight-junction proteins (claudin-5, occludin) maintained by estrogenic pathways. Ischemia-induced loss of estrogenic signaling causes pronounced vascular leakage in elderly females, altering regional cerebral blood flow during cognitive rehabilitative tasks.

3. MoCA Domain Profiling & Translational Stratification

Translating sex-dimorphic cellular mechanisms into clinical neurorehabilitation requires precise cognitive phenotyping using MoCA subdomain indices:
1. Visuospatial / Executive Index: Male cohorts frequently exhibit distinct baseline trajectories in parieto-frontal visuospatial networks, influenced by androgenic structural organization. Conversely, females show heightened vulnerability in executive subdomains post-stroke when estrogenic support of prefrontal cortex signaling is depleted, necessitating early, targeted executive training.
2. Memory and Delayed Recall Index: Estrogen receptor distribution in the CA1/CA3 hippocampal subfields directly correlates with delayed recall recovery. Post-stroke female cohorts demonstrate distinct responsiveness to cognitive training regimens when paired with therapies that mitigate local hippocampal neuroinflammation.
3. Language and Abstraction Indices: Sex-dimorphic functional connectivity and hemispheric lateralization contribute to variations in linguistic recovery. Females typically demonstrate broader bilateral network engagement during language processing tasks, promoting faster recovery in naming and fluency subdomains under appropriate multi-modal rehabilitative stimulation.

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Conclusions & Clinical Outlook

Deciphering the molecular pathways of post-stroke cognitive decline through a sex-and-gender-based lens transforms our understanding of neurorehabilitation. The interplay between neurovascular unit breakdown, excitotoxic organelle stress, and sex-dimorphic hormonal/immune signaling highlights the inadequacy of "one-size-fits-all" rehabilitation protocols.

Future directions in translational research must focus on:

Precision Biomarker Panels: Combining domain-specific MoCA index scoring with circulating sex-specific biomarkers (e.g., plasma Neurofilament Light Chain [NfL], sex-steroid ratios, and microRNA profiles such as miR-124/miR-29) to monitor real-time neuroinflammation and synaptic repair.

Targeted Pharmacological Adjuvants: Developing selective estrogen receptor modulators (SERMs) or GPER1 agonists that cross the blood-brain barrier to promote synaptic plasticity without peripheral oncogenic risks, combined with non-invasive brain stimulation (e.g., rTMS, tDCS) tuned to specific MoCA domain deficits.

Stratified Clinical Trials: Explicitly structuring neurorehabilitation clinical trials around sex as a biological variable (SABV), ensuring that therapeutic efficacy is independently evaluated across male and female sub-cohorts to optimize functional autonomy.

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Key Insights

Sex-Dimorphic Pathobiology: Post-stroke cognitive outcomes are driven by sex-specific cellular responses, including differential microglial inflammatory activation, mitochondrial vulnerability, and neurovascular unit integrity.

Domain-Specific Cognitive Fingerprints: MoCA domain index scores (visuospatial/executive, memory, language) expose distinct recovery trajectories between sexes, reflecting baseline structural lateralization and differential neuroendocrine receptor density (ERα, GPER1, AR).

Precision Neurorehabilitation Paradigms: Optimal post-stroke clinical recovery requires integrating sex-and-gender-based analysis (SGBA) into treatment plans, pairing tailored cognitive protocols with targeted neuroprotective interventions.

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References

1. Rajah, M. N., et al. (2021). *Biological sex differences in cerebrovascular risk factors, neuroinflammation, and post-stroke cognitive impairment.* Frontiers in Neuroendocrinology, 62, 100918. https://doi.org/10.1016/j.yfrne.2021.100918
2. Li, F., et al. (2023). *Sex-specific mechanisms of neurodegeneration and neuroprotection in ischemic stroke: Focus on estrogen and microglial phenotypes.* Progress in Neurobiology, 220, 102380. https://doi.org/10.1016/j.pneurobio.2022.102380
3. Paciaroni, M., & Caso, V. (2022). *Sex differences in stroke outcome and response to rehabilitation therapies: A clinical perspective.* Stroke, 53(5), 1512–1522. https://doi.org/10.1161/STROKEAHA.121.036890