July 2026 Research Update

Across this month’s papers, the clearest pattern was that no single test is being positioned as a stand-alone early diagnosis for progressive supranuclear palsy (PSP). Instead, researchers are building a toolkit: brain imaging measures that quantify specific brain region changes, plus structured movement, thinking/behavior, and blood-based markers that may help distinguish PSP from Parkinson's disease and other similar conditions. [1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13]

Several imaging studies reported that measuring patterns across brain regions may separate PSP from Parkinson's disease better than looking at one raw value alone. An automated MRI volume index derived from standard 3D T1 MRI separated PSP from Parkinson's disease and from multiple system atrophy groups with area-under-the-curve values around 0.87 to 0.95, performing similarly to a commonly used manual MRI index. [1]

Other MRI work focused on different tissue properties. A study using an MRI method sensitive to iron-related signals in the substantia nigra reported that a susceptibility-to-volume ratio, especially when paired with pons measurements, helped distinguish PSP from multiple system atrophy with an area-under-the-curve of 0.88, and it also reported results in an external validation group. [3]

Diffusion MRI, which measures microstructure rather than volume, showed that PSP-Richardson syndrome had the strongest differences in the midbrain and nearby pathways, and some diffusion metrics were more closely linked to clinical severity than others. The same study also noted that certain ways of correcting the data reduced how different the groups looked, suggesting results can depend on the analysis approach. [4]

Dopamine transporter brain scans were also studied for how well they separate conditions that can overlap clinically. One study found a putamen-predominant pattern in PSP, while behavioral-variant frontotemporal dementia with parkinsonism showed a caudate-predominant pattern, and a caudate-to-posterior-putamen ratio helped discriminate groups and was replicated in an independent cohort. [11]

A larger study of a related dopamine transporter SPECT scan used semi-quantitative ratios and machine learning to separate Parkinson's disease from atypical parkinsonian syndromes (including PSP), with some ratios reaching area-under-the-curve values up to 0.95. The model’s overall accuracy was 64%, which highlights that even with good specificity, there can still be misclassification when many diagnoses are considered at once. [2]

Not all potential "classic" clinical signals behaved as expected when measured precisely. Using high-speed eye tracking, researchers found PSP did not show selective impairment only in vertical eye movements; instead, both vertical and horizontal quick eye movements were slowed and disrupted, pointing to broader eye-movement system dysfunction rather than a strictly vertical-only problem. [5]

Structured thinking and behavior tests also showed group differences that could support earlier recognition of PSP in clinic settings. In a Malaysian cohort, a brief cognitive and neuropsychiatric scale separated PSP from Parkinson's disease groups, and the pattern differed by condition (for example, greater disinhibition in PSP compared with Parkinson's disease with dementia). [6]

In people whose main problem was primary progressive aphasia (a language-led condition), detailed language profiling matched to autopsy-confirmed disease causes showed that PSP-related cases had the lowest fluency compared with other tau-related diseases, while corticobasal degeneration showed more severe grammar and verb inflection problems. This suggests that careful language analysis may sometimes hint at the underlying brain disease, but the study also noted small subgroup sizes for some pathologies. [14]

Multiple blood-based approaches were explored, but most are still early-stage. One small study reported that a standard red blood cell measure (RDW-CV) was higher in PSP-Richardson syndrome than in Parkinson's disease, PSP-parkinsonism, or controls, while other red blood cell measures did not differ. [8]

Another exploratory blood study looked at circular RNA markers in immune cells and reported panels that separated PSP from controls (area under the curve 0.88) and PSP from Parkinson's disease (area under the curve 0.78) using internal validation, with calls for external confirmation given the small PSP sample and cross-sectional design. [7]

A different plasma protein panel study assessed which markers could be reliably measured and how they compared to existing assays, but most of its strong diagnostic performance was reported for Alzheimer's disease rather than PSP specifically. It did, however, show that some proteins tracked with overall disease stage across neurodegenerative conditions, which may be useful background as blood tests are refined. [9]

Researchers also tested whether simple, scalable motor measures could reflect PSP severity. A smartphone-based finger tapping test correlated with a mechanical tapping device and related to PSP motor severity scores in-clinic, but the authors emphasized the need to test it over time and in remote, unsupervised settings. [10]

One metabolomics study compared laboratory workflows for measuring many small molecules in blood and found that a phospholipid-removal method improved data quality. It also reported that Parkinson's disease and PSP-parkinsonism showed the clearest separation in these exploratory data, but the work requires targeted follow-up because the study did not have the highest-confidence chemical identifications. [12]

Finally, a single-patient imaging case report illustrated how MRI signs linked to midbrain shrinkage (often described with nickname signs) can support diagnosing a cerebellar form of PSP in the right clinical context. Because it describes one person, it mainly serves as an example rather than proof of how well these signs work in the broader PSP population. [13]

For patients and caregivers, this set of studies mainly indicates how diagnosis may become more evidence-based over time: by combining measurable patterns from brain scans with structured tests of movement, eye movements, and thinking/behavior, plus blood markers still under study. Right now, many of the newer blood and digital tools are best viewed as background research because several were exploratory, cross-sectional, or need external validation, while some imaging approaches showed moderate accuracy in larger samples but are not perfect at separating all similar conditions.

Across these studies, outcome prediction in progressive supranuclear palsy (PSP) was explored using three different kinds of biomarkers: spinal fluid proteins related to Alzheimer changes, blood immune cell patterns, and brain imaging patterns of tau build-up and brain shrinkage. Overall, the results suggest that some measurable biological signals can help explain why PSP progresses faster in some people than others, but the strength of evidence and readiness for routine use varies by test. Imaging-based staging appeared to track day-to-day clinical progression more closely than a tau scan stage, while spinal fluid Alzheimer-type markers were linked to shorter survival in a subgroup. [15] [16] [17]

In a cohort of 85 newly diagnosed PSP patients, a subgroup had a spinal fluid pattern that looked like Alzheimer disease biology, and this subgroup had shorter survival than PSP patients without that pattern. The ratio between two spinal fluid proteins (p-tau divided by A beta 42) stood out as the strongest independent predictor of mortality in that study, even though this Alzheimer-type signature was not tied to a particular PSP clinical subtype or baseline severity. [15]

In 150 PSP patients who had brain magnetic resonance imaging (MRI) and a tau positron emission tomography (PET) scan, researchers found two broad patterns of disease spread: one starting mainly in deeper brain regions and another with earlier outer brain (cortical) involvement. The tau PET staging tended to change earlier than MRI staging, but MRI-based stages matched clinical progression more closely over time, suggesting MRI changes may be more reflective of how symptoms evolve. [16]

In a mixed group of neurodegenerative conditions that included 58 people with PSP, certain blood T-cell patterns were linked to prognosis across diseases, including a component marked by higher naive CD4 T cells and lower Th1 effector-memory cells that predicted mortality. However, the study also found that established blood markers of brain injury and Alzheimer-type change (not the T-cell profiles) gave better accuracy for distinguishing diagnoses, and the immune findings were described as exploratory and in need of replication. [17]

For patients and caregivers, this month’s research supports the idea that PSP can follow different biological paths, and that measurable markers from spinal fluid, blood, or brain scans may help estimate pace of progression in research settings. Right now, the spinal fluid Alzheimer-type signal and the blood immune-cell patterns mainly add background about why outcomes differ, because these results come from observational cohorts and need confirmation across more centers and over longer follow-up. MRI-based staging and subtype patterns may be more directly connected to symptom change over time, but they still represent research tools rather than definitive predictors for an individual person.

Across this treatment analysis in progressive supranuclear palsy (PSP), results suggested that response to a drug may differ between women and men, and that biological markers in spinal fluid may not link to daily functioning in the same way for both sexes. The evidence here comes from a sex-stratified, longitudinal analysis and points to mixed effects overall but more consistent improvement signals in women. [18]

When researchers accounted for time, sex, and treatment together, they found a statistically significant treatment effect favoring women on the FDA-recommended PSPRS-10 scale over 52 weeks. Women also showed improvements on several cognition test areas (including overall score and language-related measures), while the same pattern was not reported for men in this summary. [18]

Links between a spinal fluid tau ratio (p-tau to total tau) and functional outcomes moved in opposite directions by sex, suggesting the same biomarker could mean different things in women versus men. The study also noted that activities of daily living measures appeared particularly important for predicting women-specific final functioning scores. [18]

For patients and caregivers, this study mainly adds context about why a treatment might appear to help some people more than others, and why research studies may need to report results separately for women and men. It does not show that davunetide is broadly effective for everyone with PSP, but it suggests that sex could influence both symptom changes (thinking and movement) and how spinal fluid tau markers relate to day-to-day abilities. What remains uncertain is whether these differences would repeat in new, prospectively designed trials and how they should be used in future treatment development.

Across two exploratory brain-scan studies, tau (a protein that builds up abnormally in PSP) did not look like a single uniform problem. Instead, results point to two related pathways: local tau in deep brain regions lining up with movement symptoms, and wider network effects lining up with cognitive symptoms. [19] [20]

In 37 people with PSP-Richardson's syndrome, tau deposits in deep brain areas were linked to a connected set of brain regions involved in action control and frontoparietal functions (often used for attention, planning, and flexible thinking). Motor symptoms tracked more with the amount of tau in the primary deep brain deposits, while cognitive test performance tracked more with how strongly those tau deposits connected to the broader tau-related network. [19]

In a separate study of 20 people with PSP who had evidence of reduced monoamine signaling on PET imaging, higher tau levels related to more disruption of monoamine function in the caudate and putamen (deep brain areas important for movement). This relationship was not seen in the substantia nigra in that analysis, showing that tau and monoamine changes may not match up the same way in every region. [20]

For patients and caregivers, this research mainly adds background on why PSP can cause different types of symptoms (movement, balance, eye movement changes, and also thinking or planning difficulties). These studies support the idea that cognitive symptoms may reflect how tau affects connected brain networks, not only where tau sits, while some motor symptoms may relate more directly to deep brain tau and monoamine disruption. It is still uncertain how well these scan patterns predict an individual person's day-to-day symptoms over time, because the studies were cross-sectional and relatively small. [19] [20]

Across multiple types of evidence (a large MRI meta-analysis, a large autopsy cohort, and several smaller postmortem tissue studies), PSP-related changes repeatedly involved deep brain regions such as the midbrain, thalamus, and caudate, plus linked cortical regions that help coordinate attention, body awareness, and emotion. Several papers also highlighted that PSP biology is not only about neurons: glial cells, immune-related microglia, and blood-vessel cells show measurable changes in brain tissue. [21] [22] [23] [24] [25]

A meta-analysis pooling MRI studies (333 PSP patients) found the most consistent gray matter loss in the bilateral thalamus and midbrain, plus the left anterior-dorsal insula and both caudate nuclei. Follow-up analyses suggested these areas fit within a connected salience-network-like system, and the spatial pattern of loss overlapped maps of dopaminergic, serotonergic, and especially cholinergic receptor distributions, pointing to vulnerability across multiple brain chemical systems. [21]

In a large autopsy dataset (297 people with PSP pathology), people classified as "incident" PSP (identified at autopsy but not previously known) were older and were often not clinically diagnosed with PSP, and they tended to have fewer classic PSP clinical features recorded. "Prevalent" PSP cases showed greater overall pathological tau burden, with more tau pathology in the frontal cortex and higher neurofibrillary tangle density in the putamen, while incident cases had relatively more tufted astrocytes in some regions. [22]

In a small postmortem study (4 PSP brains), the protein SRRM2 was markedly increased in midbrain neurons and commonly overlapped with a phosphorylated form of tau, while tufted astrocytes showed low SRRM2 but near-complete overlap where both signals were present. This points to cell-type-specific ways tau pathology may interact with other cellular proteins in PSP. [23]

Another postmortem mapping study measured CSF1R mRNA-positive microglia (an immune cell type in the brain) across six cortical regions and found only modest, region-specific increases in PSP, including in the angular gyrus. Exploratory analyses suggested regions with higher CSF1R-positive microglia could coincide with more preserved presynaptic markers, but this was an early-stage observation meant to inform how future CSF1R-targeted PET scans might be interpreted. [24]

A separate postmortem gene-expression study of brain blood-vessel cells compared Alzheimer's disease with primary tauopathies (including PSP) and found a heat-shock stress response across diseases, but more vascular remodeling in Alzheimer's disease than in the primary tauopathies. In PSP, this suggests vascular-related changes are present but may be less dominated by large remodeling changes than in Alzheimer's disease, based on the brain region studied. [25]

For patients, these studies help explain why PSP commonly affects balance, eye movements, speech, and thinking: the repeatedly implicated brain regions are involved in movement control and in selecting what to pay attention to and how to respond. The work also shows PSP is biologically complex, involving multiple brain chemical systems and several cell types (neurons, astrocytes, microglia, and blood-vessel cells), but much of this evidence comes from cross-sectional MRI pooling and postmortem tissue, so it cannot yet tell how fast changes happen or which changes matter most for a particular person. Overall, this is mainly background research that can guide future testing and imaging approaches rather than changing current care. [21] [22] [23] [24] [25]

Across these papers, the picture is that progressive supranuclear palsy (PSP) may have a long phase before diagnosis when certain health problems and lifestyle patterns show up more often, but research is still working out which early features truly help separate PSP from other movement disorders. One study used existing health data to look backward from diagnosis, while the other describes a forward-looking study designed to collect early clinical and biological clues over several years. [26] [27]

In the UK Biobank analysis (240 PSP cases and 2400 matched controls), people later diagnosed with PSP had higher odds of having had depression, delirium, and functional gastrointestinal disorders before their PSP diagnosis. Depression and delirium were still linked to higher PSP risk even when the researchers looked 5 to 10 years before diagnosis, suggesting these issues can appear well before PSP is recognized. [26]

The same UK Biobank study reported that a history of cancer was less common in people who later developed PSP than in matched controls. It also found that body mass index (BMI) and alcohol intake did not show a simple straight-line pattern with risk; instead, risk varied in a nonlinear way across levels of BMI and alcohol use, including heavier alcohol consumption being linked to higher risk. [26]

A separate paper describes the ExPRESS study plan, which aims to enroll 500 people soon after a first specialist visit for new parkinsonism and follow them for 4 years to confirm diagnoses and identify early predictors of Parkinson-plus syndromes (including PSP) versus Parkinson's disease. In a subgroup, it will add blood and DNA testing, and in smaller subsets tests such as spinal fluid collection, skin biopsy, brain scans, cognitive testing, and digital measures, to see which combinations best predict later diagnosis. [27]

For patients and caregivers, these studies mainly provide background on why PSP can be hard to spot early and which types of earlier health issues researchers are investigating. The UK Biobank results suggest that mood symptoms, episodes of acute confusion, and functional gut problems may occur years before a PSP diagnosis in some people, but they do not prove these problems cause PSP or that they can identify PSP on their own. The ExPRESS study is aimed at improving early identification by tracking people forward in time with detailed clinical and biomarker data, but results are not yet available, so it remains uncertain which early predictors will be most reliable in real-world care. [26] [27]

Across this paper, the main message is that a condition caused by changes in the POLG gene can sometimes closely resemble progressive supranuclear palsy (PSP), including both symptoms and brain imaging patterns. This was shown in a single-person case report, so it cannot tell how often this happens, but it highlights why PSP-like symptoms can occasionally have another underlying cause. [28]

In one 70-year-old man, symptoms included a PSP/frontotemporal dementia-like pattern with rigid, slowed movement, vertical eye movement problems, and cognitive changes (including executive and word-finding difficulties). Brain imaging also appeared PSP-like, including a "hummingbird sign" on MRI and areas of reduced brain metabolism on a PET scan. [28]

Genetic testing found two POLG variants (one described as pathogenic and one as likely pathogenic), and the patient also had multisystem issues including abnormal blood counts and liver disease. The report also noted that levodopa led to partial symptom improvement, while spinal fluid markers for Alzheimer disease were normal and a prion test was negative. [28]

For patients and caregivers, this paper mainly serves as background context: a PSP-like diagnosis is usually based on a pattern of symptoms and tests, but rarely, another condition can look very similar. This report suggests that when PSP-like symptoms occur together with problems outside the brain (such as liver or blood abnormalities), clinicians may consider broader testing to look for other explanations; however, this was only one person, so it does not show how common this situation is or which groups are most affected. [28]

Across this month's research in this topic, the main pattern was that differences in body composition (especially in the legs) lined up with whether people had orthostatic hypotension, meaning a blood pressure drop when standing. The evidence is exploratory and cannot show cause and effect, but it suggests muscle and fluid distribution may help explain why some people have these symptoms and others do not. [29]

In a cross sectional study of 86 people seen in a parkinsonism multidisciplinary clinic, orthostatic hypotension was found in 45.3% overall, with a higher rate in multiple system atrophy and a lower rate in progressive supranuclear palsy. [29]

Measures based on bioelectrical impedance (a body composition test) suggested two leg related factors were most informative: appendicular skeletal muscle index (a measure that reflects limb muscle mass) and a lower limb extracellular water index (a measure related to fluid outside cells in the legs). Higher appendicular skeletal muscle index independently linked to a smaller drop in systolic blood pressure after standing for 3 minutes, meaning people with more limb muscle tended to have less of a blood pressure fall in this dataset. [29]

For people living with progressive supranuclear palsy and families, this study mainly provides background about why lightheadedness or dizziness on standing may differ across parkinsonism conditions and across individuals. It also suggests that simple body composition measures might someday help researchers understand or estimate risk of orthostatic hypotension, but this needs confirmation in larger studies and does not yet show that changing muscle or fluid measures would change symptoms. [29]