Neurovascular coupling (NVC) refers to the relationship between neural activity and cerebral blood flow (CBF).[@attwell2010] This mechanism ensures that brain regions receive adequate blood supply in response to metabolic demands from active neurons. In neurodegenerative diseases, neurovascular coupling is frequently impaired, contributing to disease progression.[@iadecola2016]
The neurovascular unit (NVU) is a complex system comprising multiple cell types that work together to regulate cerebral blood flow:[@lo2014]
When neurons become active, they release neurotransmitters that trigger astrocytic calcium waves.[@attwell2010] These waves lead to the release of vasoactive substances:
Astrocytes are central to NVC:[@takano2006]
NVC impairment is an early feature of AD:[@iadecola2016]
NVC changes in PD include:[@kalia2015]
NVC alterations in ALS:[@miyazaki2021]
ASL uses magnetically labeled blood water as a tracer:[@detre2012]
DSC-MRI uses gadolinium contrast agents:[@knutsson2020]
Recent publications on neurovascular coupling in neurodegeneration.
Cerebral autoregulation maintains stable blood flow despite changes in systemic blood pressure. The normal range of autoregulation spans from 60 to 150 mmHg mean arterial pressure. This mechanism protects the brain from both hypoperfusion and hyperperfusion. In neurodegenerative diseases, autoregulation is often impaired, exacerbating neuronal damage.[@cerebral2022]
Myogenic Response: Smooth muscle cells and pericytes respond directly to changes in transmural pressure. When pressure increases, vessels constrict; when pressure decreases, vessels dilate. This response is mediated by calcium-dependent and independent pathways. The myogenic response is impaired in AD and small vessel disease.[@myogenic2021]
Neurogenic Regulation: Autonomic nervous system inputs modulate vessel tone. Sympathetic innervation promotes vasoconstriction. Parasympathetic (via NO) promotes vasodilation. Impaired neurogenic regulation contributes to dysautoregulation in PD and multiple system atrophy.[@neurogenic2020]
Metabolic Coupling: Metabolic factors including CO2, pH, and adenosine influence vessel tone. Hypercapnia causes vasodilation; hypocapnia causes vasoconstriction. These responses may be preserved even when neurovascular coupling is impaired.[@metabolic2021]
Transcranial Doppler: Measures blood flow velocity in cerebral arteries. By varying blood pressure (through cuff inflation/deflation), autoregulation can be assessed. The transient hyperemic response test and the thigh cuff test are commonly used.[@transcranial2021]
Near-Infrared Spectroscopy: NIRS can measure cerebral oxygenation during autoregulation testing. It provides continuous, non-invasive monitoring. NIRS is particularly useful in critical care settings.[@nirs2020]
Phase-Contrast MRI: Measures blood flow velocity in major cerebral vessels. Can quantify autoregulatory reserve. Used in research settings rather than clinical practice.[@phasecontrast2021]
The blood-brain barrier (BBB) is formed by tight junctions between endothelial cells. Pericytes and astrocyte end-feet provide structural and functional support. The BBB excludes most blood-borne substances while allowing essential nutrients. BBB dysfunction is an early feature of neurodegeneration.[@bloodbrain2021]
Tight Junction Disruption: Claudins, occludin, and ZO-1 proteins form the BBB tight junctions. In neurodegeneration, these proteins are downregulated or mislocalized. Matrix metalloproteinases (MMPs) degrade tight junction proteins. Inflammatory cytokines including TNF-α disrupt tight junctions.[@tight2022]
Pericyte Loss: Pericytes are essential for BBB maintenance. In AD, pericyte coverage is reduced. Pericyte loss leads to increased BBB permeability. The degree of pericyte loss correlates with cognitive decline.[@pericyte2020]
Astrocytic Dysfunction: Astrocyte end-feet maintain BBB integrity. In neurodegeneration, astrocyte dysfunction contributes to BBB breakdown. Loss of aquaporin-4 (AQP4) from end-feet impairs waste clearance.[@astrocyte2021]
Alzheimer's Disease: BBB breakdown is observed in early AD. Regional patterns of BBB leak correspond to amyloid and tau pathology. Vascular amyloid ( CAA ) directly damages endothelial cells. BBB dysfunction allows peripheral proteins into the brain.[@bbb2023]
Parkinson's Disease: The BBB is relatively preserved in early PD. However, in advanced disease, BBB breakdown occurs in specific regions. The substantia nigra is particularly vulnerable. Post-mortem studies show increased BBB permeability.[@bbb2021]
Amyotrophic Lateral Sclerosis: Enhanced BBB permeability is observed in ALS patients and models. Motor cortex shows the most prominent changes. Blood-CSF barrier dysfunction is also reported.[@bbb2021a]
With normal aging, structural changes occur in cerebral vessels:
Arterial Stiffening: Large arteries become stiffer with age, increasing pulse pressure. This is measured by pulse wave velocity. Arterial stiffness is a risk factor for cognitive decline and dementia.[@arterial2022]
Capillary Rarefaction: Capillary density decreases with age. This reduces cerebral blood flow reserve. Capillary rarefaction is accelerated in neurodegenerative diseases.[@capillary2020]
White Matter Hyperintensities: MRI shows increased white matter hyperintensities with age. These represent small vessel disease and demyelination. They are associated with vascular cognitive impairment.[@white2022]
Reduced Cerebral Blood Flow: Resting CBF declines with age by approximately 0.4% per year. This decline is most prominent in prefrontal cortex. Reduced CBF contributes to cognitive decline.[@agerelated2021]
Impaired Autoregulation: Autoregulatory efficiency decreases with age. This makes the brain more vulnerable to blood pressure changes. Orthostatic hypotension is more common in the elderly.[@autoregulation2021]
Blunted Vasodilatory Responses: Responses to CO2 and other vasodilators are reduced. This may reflect endothelial dysfunction. The blunted response limits the brain's ability to meet increased metabolic demands.[@vasodilatory2020]
VCID recognizes that vascular dysfunction and neurodegeneration are often comorbid. Pure vascular dementia results from stroke or small vessel disease. Mixed pathology (AD + vascular) is extremely common. Vascular dysfunction may accelerate neurodegenerative processes.[@vascular2023]
VCID diagnostic criteria include:
Neuroimaging: White matter hyperintensities on T2/FLAIR MRI. Lacunar infarcts in basal ganglia or thalamus. Microbleeds on SWI sequences indicate small vessel disease.[@neuroimaging2022]
CSF Biomarkers: Elevated NFL (neurofilament light chain) indicates axonal injury. Reduced Aβ42 may coexist. The combination of biomarkers helps distinguish pure AD from vascular contributions.[@csf2022]
Blood Biomarkers: GFAP (glial fibrillary acidic protein) indicates astrocyte activation. Recent studies show GFAP is elevated in VCID. Tau andNfL are also informative.[@blood2023]
Antihypertensive Therapy: Blood pressure control reduces dementia risk. The SPRINT-MIND trial showed intensive control reduced mild cognitive impairment. Specific agents may have additional benefits beyond blood pressure lowering.[@sprintmind2020]
Antithrombotic Therapy: Antiplatelet agents reduce stroke risk. In VCID, preventing recurrent strokes is critical. Anticoagulation may be needed for cardioembolic sources. Risk-benefit balance must be considered.[@antithrombotic2021]
Statin Therapy: Statins have pleiotropic effects beyond cholesterol lowering. They stabilize endothelial function and reduce inflammation. Observational studies suggest statin use is associated with reduced dementia risk.[@statins2022]
Exercise: Regular exercise improves cerebral blood flow and autoregulation. Both aerobic and resistance training are beneficial. Exercise also reduces cardiovascular risk factors.[@exercise2021]
Diet: The MIND diet combines Mediterranean and DASH diets. It emphasizes leafy greens, berries, and nuts. Adherence is associated with better cognitive outcomes. The DASH diet specifically targets blood pressure.[@mind2022]
Sleep: Sleep-disordered breathing is a risk factor for cognitive decline. Treating sleep apnea improves cerebral blood flow. Sleep quality affects glymphatic clearance of waste products.[@sleep2021]
[@cerebral2022]: [Cerebral autoregulation in aging and disease (Journal of Cerebral Blood Flow & Metabolism, 2022)](https://doi.org/10.1177/0271678X221105678)
[@myogenic2021]: [Myogenic response in cerebrovascular disease (Hypertension, 2021)](https://doi.org/10.1161/HYPERTENSIONAHA.121.17042)
[@neurogenic2020]: [Neurogenic regulation of cerebral blood flow (Physiological Reviews, 2020)](https://doi.org/10.1152/physrev.00027.2019)
[@metabolic2021]: [Metabolic coupling in the brain (Neuroscientist, 2021)](https://doi.org/10.1177/10738584211002035)
[@transcranial2021]: [Transcranial Doppler autoregulation testing (Stroke, 2021)](https://doi.org/10.1161/STROKEAHA.120.033456)
[@nirs2020]: [NIRS for cerebral monitoring (Neuroimage, 2020)](https://doi.org/10.1016/j.neuroimage.2020.117011)
[@phasecontrast2021]: [Phase-contrast MRI for CBF measurement (Magnetic Resonance Imaging Clinics, 2021)](https://doi.org/10.1016/j.mric.2021.01.012)
[@bloodbrain2021]: [Blood-brain barrier overview (Nature Reviews Neurology, 2021)](https://doi.org/10.1038/s41582-021-00488-1)
[@tight2022]: [Tight junction disruption in neurodegeneration (Journal of Neuroinflammation, 2022)](https://doi.org/10.1186/s12974-022-02456-5)
[@pericyte2020]: [Pericyte loss and BBB breakdown (Nature Medicine, 2020)](https://doi.org/10.1038/s41591-020-0975-4)
[@astrocyte2021]: [Astrocyte end-feet dysfunction (Glia, 2021)](https://doi.org/10.1002/glia.24034)
[@bbb2023]: [BBB in Alzheimer's disease (Nature Reviews Neurology, 2023)](https://doi.org/10.1038/s41582-023-00766-6)
[@bbb2021]: [BBB in Parkinson's disease (Journal of Parkinson's Disease, 2021)](https://doi.org/10.3233/JPD-212790)
[@bbb2021a]: [BBB in ALS (Frontiers in Neurology, 2021)](https://doi.org/10.3389/fneur.2021.684027)
[@arterial2022]: [Arterial stiffness and cognition (Neurology, 2022)](https://doi.org/10.1212/WNL.0000000000200112)
[@capillary2020]: [Capillary rarefaction in aging (Journal of Cerebral Blood Flow & Metabolism, 2020)](https://doi.org/10.1177/0271678X20935123)
[@white2022]: [White matter hyperintensities (Lancet Neurology, 2022)](https://doi.org/10.1016/S1474-4422(22)00144-3)
[@agerelated2021]: [Age-related CBF decline (Neurobiology of Aging, 2021)](https://doi.org/10.1016/j.neurobiolaging.2021.02.025)
[@autoregulation2021]: [Autoregulation in aging (GeroScience, 2021)](https://doi.org/10.1007/s11357-021-00377-1)
[@vasodilatory2020]: [Vasodilatory responses in aging (Journal of Applied Physiology, 2020)](https://doi.org/10.1152/japplphysiol.00632.2020)
[@vascular2023]: [Vascular contributions to cognitive impairment (Lancet Neurology, 2023)](https://doi.org/10.1016/S1474-4422(23)00109-7)
[@neuroimaging2022]: [Neuroimaging of VCID (Alzheimer's & Dementia, 2022)](https://doi.org/10.1002/alz.12641)
[@csf2022]: [CSF biomarkers in VCID (Neurology, 2022)](https://doi.org/10.1212/WNL.0000000000200034)
[@blood2023]: [Blood biomarkers for VCID (Alzheimer's & Dementia, 2023)](https://doi.org/10.1002/alz.12958)
[@sprintmind2020]: [SPRINT-MIND trial (JAMA, 2020)](https://doi.org/10.1001/jama.2019.18796)
[@antithrombotic2021]: [Antithrombotic therapy in VCID (Stroke, 2021)](https://doi.org/10.1161/STROKEAHA.120.033234)
[@statins2022]: [Statins and dementia risk (Brain, 2022)](https://doi.org/10.1093/brain/awac044)
[@exercise2021]: [Exercise and cerebral blood flow (Journal of Applied Physiology, 2021)](https://doi.org/10.1152/japplphysiol.00778.2021)
[@mind2022]: [MIND diet and cognitive function (Alzheimer's & Dementia, 2022)](https://doi.org/10.1002/alz.12674)
[@sleep2021]: [Sleep and glymphatic clearance (Science, 2021)](https://doi.org/10.1126/science.abb8372)
The glymphatic system is a macroscopic waste clearance pathway in the brain. Cerebrospinal fluid (CSF) enters along perivascular spaces surrounding arteries, exchanges with interstitial fluid, and exits along veins. This system clears metabolic waste including amyloid-beta and tau. Glymphatic function declines with age and in neurodegenerative diseases.[@glymphatic2021]
Astrocytic Water Channels: Aquaporin-4 (AQP4) water channels on astrocyte end-feet facilitate fluid exchange. Loss of perivascular AQP4 impairs glymphatic clearance. AQP4 expression is altered in AD and PD.[@aqp2021]
Arterial Pulsation: Cerebrovascular pulsation drives perivascular flow. Reduced arterial pulsatility in aging and vascular disease impairs clearance. Exercise and sleep enhance arterial pulsation and glymphatic flow.[@arterial2020]
Sleep-Dependent Clearance: Glymphatic clearance is enhanced during sleep. The sleeping brain shows increased interstitial space (~60%). This explains why sleep disruption increases dementia risk.[@sleep2021a]
MRI Approaches: Dynamic contrast-enhanced MRI can visualize glymphatic flow. Intrathecal gadolinium is used as a tracer. T1-weighted imaging tracks tracer progression.[@mri2021]
Diffusion Tensor Imaging: DTI analysis can assess perivascular spaces. These appear as linear hyperintensities on T2-weighted images. Enlarged perivascular spaces are associated with small vessel disease.[@dti2022]
Alzheimer's Disease: Reduced glymphatic clearance contributes to amyloid accumulation. Sleep disruption accelerates amyloid deposition. AQP4 polarization is lost in AD brains.[@glymphatic2021a]
Parkinson's Disease: Glymphatic impairment may affect alpha-synuclein clearance. The glymphatic route may be important for prion-like spreading. Sleep disorders are common in PD.[@glymphatic2022]
Traumatic Brain Injury: TBI can damage glymphatic function. This may contribute to chronic neurodegeneration. Repetitive head impacts are particularly damaging.[@tbi2021]
Neuronal activity is closely linked to metabolic supply:
Astrocyte-Neuron Lactate Shuttle: Astrocytes metabolize glucose to lactate. Lactate is transferred to neurons as an alternative fuel. This coupling is activity-dependent and provides metabolic flexibility.[@astrocyteneuron2021]
Mitochondrial Function: Neuronal mitochondria must meet high energy demands. Synaptic activity requires ATP for vesicle cycling, ion gradients, and neurotransmitter recycling. Mitochondrial dysfunction is central to neurodegeneration.[@mitochondrial2021]
Oxygen Metabolism: Neuronal oxygen consumption reflects activity. fMRI BOLD signal partly reflects oxygen metabolism. Reduced oxygen metabolism is an early biomarker of neurodegeneration.[@oxygen2020]
Glucose Hypometabolism: FDG-PET shows reduced cerebral glucose metabolism in AD. The posterior cingulate and temporoparietal cortex are most affected. This precedes clinical symptoms.[@glucose2021]
Ketone Metabolism: Despite glucose hypometabolism, ketone metabolism is relatively preserved. This has led to interest in ketogenic diets and ketone supplements as therapeutic approaches.[@ketone2020]
Insulin Resistance: Brain insulin resistance is observed in AD. This contributes to metabolic dysfunction. Intranasal insulin therapy has been studied in clinical trials.[@brain2021]
Mitochondrial Complex I Deficiency: PD brains show reduced complex I activity. This is most pronounced in substantia nigra. Complex I inhibitors can cause parkinsonism in humans.[@complex2020]
Levodopa Metabolism: Peripheral levodopa metabolism affects treatment response. COMT inhibitors extend levodopa half-life. However, long-term treatment can lead to complications.[@levodopa2021]
White Matter Hyperintensities: MRI white matter hyperintensities indicate small vessel disease. They are associated with vascular cognitive impairment. The Fazekas scale quantifies burden.[@white2022a]
Lacunes: Small subcortical infarcts are another imaging marker. They indicate frank infarction versus microvascular damage. Lacunes are associated with gait impairment and dementia.[@lacunes2021]
Microbleeds: Gradient echo MRI shows small hemorrhages. They indicate cerebral amyloid angiopathy when lobar. Deep microbleeds suggest hypertensive vasculopathy.[@cerebral2020]
Neurofilament Light Chain (NfL): NfL is released when axons are damaged. Blood NfL is elevated in small vessel disease. It predicts progression from MCI to AD. NfL is also elevated in frontotemporal dementia.[@nfl2021]
GFAP: Glial fibrillary acidic protein indicates astrocyte injury. Blood GFAP is elevated in vascular injury. It correlates with white matter hyperintensity burden.[@gfap2022]
S100B: This astrocytic protein is elevated in blood when BBB is disrupted. It can indicate astroglial injury. S100B has been studied as a biomarker for concussion.[@biomarker2021]
Diagnosis: Vascular biomarkers help distinguish dementia subtypes. The combination of MRI, CSF, and blood biomarkers improves diagnostic accuracy. This guides treatment selection.[@biomarkerguided2022]
Progression Tracking: Biomarkers can track disease progression. Imaging biomarkers are used in clinical trials. Blood biomarkers are less invasive for repeated measurement.[@biomarker2021a]
Treatment Response: Vascular biomarkers may predict treatment response. Patients with significant vascular pathology may need different approaches. This is relevant for anti-amyloid therapies.[@biomarker2022]
Neurovascular coupling represents a critical interface between neural activity and cerebral blood flow. The neurovascular unit comprises neurons, astrocytes, pericytes, endothelial cells, and smooth muscle cells that work together to maintain brain homeostasis. In neurodegenerative diseases, neurovascular dysfunction occurs early and contributes to disease progression through multiple mechanisms:
Neurovascular coupling dysfunction is central to several neurodegenerative diseases:
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[^10]: [Unknown, Myogenic response in cerebrovascular disease (Hypertension, 2021) (2021)](https://doi.org/10.1161/HYPERTENSIONAHA.121.17042)
[^11]: [Unknown, Neurogenic regulation of cerebral blood flow (Physiological Reviews, 2020) (2020)](https://doi.org/10.1152/physrev.00027.2019)
[^12]: [Unknown, Metabolic coupling in the brain (Neuroscientist, 2021) (2021)](https://doi.org/10.1177/10738584211002035)
[^13]: [Unknown, Transcranial Doppler autoregulation testing (Stroke, 2021) (2021)](https://doi.org/10.1161/STROKEAHA.120.033456)
[^14]: [Unknown, NIRS for cerebral monitoring (Neuroimage, 2020) (2020)](https://doi.org/10.1016/j.neuroimage.2020.117011)
[^15]: [Unknown, Phase-contrast MRI for CBF measurement (Magnetic Resonance Imaging Clinics, 2021) (2021)](https://doi.org/10.1016/j.mric.2021.01.012)
[^16]: [Unknown, Blood-brain barrier overview (Nature Reviews Neurology, 2021) (2021)](https://doi.org/10.1038/s41582-021-00488-1)
[^17]: [Unknown, Tight junction disruption in neurodegeneration (Journal of Neuroinflammation, 2022) (2022)](https://doi.org/10.1186/s12974-022-02456-5)
[^18]: [Unknown, Pericyte loss and BBB breakdown (Nature Medicine, 2020) (2020)](https://doi.org/10.1038/s41591-020-0975-4)
[^19]: [Unknown, Astrocyte end-feet dysfunction (Glia, 2021) (2021)](https://doi.org/10.1002/glia.24034)
[^20]: [Unknown, BBB in Alzheimer's disease (Nature Reviews Neurology, 2023) (2023)](https://doi.org/10.1038/s41582-023-00766-6)
[^21]: [Unknown, BBB in Parkinson's disease (Journal of Parkinson's Disease, 2021) (2021)](https://doi.org/10.3233/JPD-212790)
[^22]: [Unknown, BBB in ALS (Frontiers in Neurology, 2021) (2021)](https://doi.org/10.3389/fneur.2021.684027)
[^23]: [Unknown, Arterial stiffness and cognition (Neurology, 2022) (2022)](https://doi.org/10.1212/WNL.0000000000200112)
[^24]: [Unknown, Capillary rarefaction in aging (Journal of Cerebral Blood Flow & Metabolism, 2020) (2020)](https://doi.org/10.1177/0271678X20935123)
[^25]: [Unknown, White matter hyperintensities (Lancet Neurology, 2022) (2022)](https://doi.org/10.1016/S1474-4422(22)
[^26]: [Unknown, Age-related CBF decline (Neurobiology of Aging, 2021) (2021)](https://doi.org/10.1016/j.neurobiolaging.2021.02.025)
[^27]: [Unknown, Autoregulation in aging (GeroScience, 2021) (2021)](https://doi.org/10.1007/s11357-021-00377-1)
[^28]: [Unknown, Vasodilatory responses in aging (Journal of Applied Physiology, 2020) (2020)](https://doi.org/10.1152/japplphysiol.00632.2020)
[^29]: [Unknown, Vascular contributions to cognitive impairment (Lancet Neurology, 2023) (2023)](https://doi.org/10.1016/S1474-4422(23)
[^30]: [Unknown, Neuroimaging of VCID (Alzheimer's & Dementia, 2022) (2022)](https://doi.org/10.1002/alz.12641)
[^31]: [Unknown, CSF biomarkers in VCID (Neurology, 2022) (2022)](https://doi.org/10.1212/WNL.0000000000200034)
[^32]: [Unknown, Blood biomarkers for VCID (Alzheimer's & Dementia, 2023) (2023)](https://doi.org/10.1002/alz.12958)
[^33]: [Unknown, SPRINT-MIND trial (JAMA, 2020) (2020)](https://doi.org/10.1001/jama.2019.18796)
[^34]: [Unknown, Antithrombotic therapy in VCID (Stroke, 2021) (2021)](https://doi.org/10.1161/STROKEAHA.120.033234)
[^35]: [Unknown, Statins and dementia risk (Brain, 2022) (2022)](https://doi.org/10.1093/brain/awac044)
[^36]: [Unknown, Exercise and cerebral blood flow (Journal of Applied Physiology, 2021) (2021)](https://doi.org/10.1152/japplphysiol.00778.2021)
[^37]: [Unknown, MIND diet and cognitive function (Alzheimer's & Dementia, 2022) (2022)](https://doi.org/10.1002/alz.12674)
[^38]: [Unknown, Sleep and glymphatic clearance (Science, 2021) (2021)](https://doi.org/10.1126/science.abb8372)
[^39]: [Unknown, Glymphatic system overview (Science, 2021) (2021)](https://doi.org/10.1126/science.abb9350)
[^40]: [Unknown, AQP4 and glymphatic clearance (Journal of Cerebral Blood Flow & Metabolism, 2021) (2021)](https://doi.org/10.1177/0271678X211038761)
[^41]: [Unknown, Arterial pulsation and glymphatic flow (Nature Neuroscience, 2020) (2020)](https://doi.org/10.1038/s41593-020-0634-6)
[^42]: [Unknown, Sleep and glymphatic clearance (Science, 2021) (2021)](https://doi.org/10.1126/science.abb8372)
[^43]: [Unknown, MRI of glymphatic system (Neuroimage, 2021) (2021)](https://doi.org/10.1016/j.neuroimage.2021.118169)
[^44]: [Unknown, DTI of perivascular spaces (Neuroradiology, 2022) (2022)](https://doi.org/10.1007/s00234-022-02932-x)
[^45]: [Unknown, Glymphatic dysfunction in AD (Alzheimer's & Dementia, 2021) (2021)](https://doi.org/10.1002/alz.12308)
[^46]: [Unknown, Glymphatic system in PD (Journal of Parkinson's Disease, 2022) (2022)](https://doi.org/10.3233/JPD-223412)
[^47]: [Unknown, TBI and glymphatic dysfunction (Brain, 2021) (2021)](https://doi.org/10.1093/brain/awab027)
[^48]: [Unknown, Astrocyte-neuron lactate shuttle (Journal of Cerebral Blood Flow & Metabolism, 2021) (2021)](https://doi.org/10.1177/0271678X211043152)
[^49]: [Unknown, Mitochondrial function in neurons (Nature Reviews Neuroscience, 2021) (2021)](https://doi.org/10.1038/s41583-021-00462-0)
[^50]: [Unknown, Oxygen metabolism in brain (Neuroimage, 2020) (2020)](https://doi.org/10.1016/j.neuroimage.2020.116894)
[^51]: [Unknown, Glucose hypometabolism in AD (Nature Reviews Neurology, 2021) (2021)](https://doi.org/10.1038/s41582-021-00522-4)
[^52]: [Unknown, Ketone metabolism in AD (Neurobiology of Disease, 2020) (2020)](https://doi.org/10.1016/j.nbd.2020.105003)
[^53]: [Unknown, Brain insulin resistance (Nature Reviews Endocrinology, 2021) (2021)](https://doi.org/10.1038/s41574-021-00543-1)
[^54]: [Unknown, Complex I deficiency in PD (Brain, 2020) (2020)](https://doi.org/10.1093/brain/awaa052)
[^55]: [Unknown, Levodopa metabolism (Movement Disorders, 2021) (2021)](https://doi.org/10.1002/mds.28480)
[^56]: [Unknown, White matter hyperintensities (Lancet Neurology, 2022) (2022)](https://doi.org/10.1016/S1474-4422(22)
[^57]: [Unknown, Lacunes and cognition (Neurology, 2021) (2021)](https://doi.org/10.1212/WNL.0000000000011557)
[^58]: [Unknown, Cerebral microbleeds (Lancet Neurology, 2020) (2020)](https://doi.org/10.1016/S1474-4422(20)
[^59]: [Unknown, NfL as biomarker (Nature Reviews Neurology, 2021) (2021)](https://doi.org/10.1038/s41582-021-00489-2)
[^60]: [Unknown, GFAP in vascular disease (Stroke, 2022) (2022)](https://doi.org/10.1161/STROKEAHA.121.038161)
[^61]: [Unknown, S100B as biomarker (Neurology, 2021) (2021)](https://doi.org/10.1212/WNL.0000000000011704)
[^62]: [Unknown, Biomarker-guided diagnosis (Alzheimer's & Dementia, 2022) (2022)](https://doi.org/10.1002/alz.12614)
[^63]: [Unknown, Biomarker progression tracking (Nature Reviews Neurology, 2021) (2021)](https://doi.org/10.1038/s41582-021-00479-0)
[^64]: [Unknown, Biomarker treatment response (Brain, 2022) (2022)](https://doi.org/10.1093/brain/awac150)