MRI Scans and Genetic Testing

Confirming a diagnosis of ALSP requires interpreting high-tech brain imaging alongside precise genetic testing. While clinical symptoms—like changes in mood or movement—provide the first clues, they are not enough for a definitive diagnosis because they overlap with so many other conditions ^[1].

Today, the “gold standard” for diagnosis is the identification of a pathogenic (disease-causing) variant in the CSF1R gene, interpreted in the appropriate clinical context ^[2].

The MRI “Pattern”: Mapping the Damage

An MRI (Magnetic Resonance Imaging) is often the first tool doctors use to look for ALSP. However, because ALSP is rare, general radiologists may sometimes miss the subtle signs that distinguish it from Multiple Sclerosis or other dementias ^[3].

When reviewing an MRI, specialists look for a specific “pattern” of white matter damage that supports the diagnosis, though these features vary with disease stage and are not mandatory:

• Frontoparietal Predominance: The damage (seen as bright white spots on certain MRI views) is usually concentrated in the frontal and parietal lobes of the brain ^[4]. It is often asymmetric, meaning one side of the brain may look more affected than the other ^[5].
• Corpus Callosum Thinning: The corpus callosum is the bridge of nerve fibers that connects the left and right sides of the brain. In ALSP, this bridge often becomes visibly thin or involved ^[4][6].
• Diffusion-Restricted “Dots”: Using a specific MRI setting called DWI (Diffusion-Weighted Imaging), doctors may see small, persistent spots that look like tiny bright dots ^[4]. While this can represent acute stroke damage in other diseases, in ALSP these spots can persist for a long time and are a very strong clue ^[7].
• U-Fiber Sparing: ALSP typically affects the deeper white matter while leaving the “U-fibers” (the fibers just beneath the brain’s outer crust) untouched early on, though this can change as the disease progresses ^[8].

The “Stepping-Stone” Clue

In addition to an MRI, a CT scan can be incredibly helpful but is not automatically required. CT scans are better at seeing calcium than MRIs. In many ALSP patients, the scan will show small, “stepping-stone” calcifications (calcium deposits) deep in the white matter ^[9][10]. Finding these can help confirm the diagnosis when other tests are unclear, but their absence does not exclude ALSP.

Genetic Testing: The Definitive Answer

While the MRI shows the “where,” genetic testing shows the “why.” A definitive diagnosis of ALSP is made when a patient has a known disease-causing pathogenic variant in the CSF1R gene ^[2].

• Comprehensive Sequencing: It is important that the test looks at all “coding exons” (the parts of the gene that provide instructions) of the CSF1R gene. Some older or limited tests only looked at one specific part (the tyrosine kinase domain), but we now know pathogenic variants can occur in other areas of the gene as well ^[2].
• ACMG Classification: Not every genetic change is harmful. Geneticists use standards from the American College of Medical Genetics (ACMG) to classify a change as pathogenic (definitely causes disease), likely pathogenic, or a variant of uncertain significance (VUS) ^[6][11]. A VUS must not be used for predictive testing or to make a definitive diagnosis.

What if the CSF1R test is negative?

If a patient has all the symptoms and MRI findings of ALSP but the standard CSF1R test is negative, the search isn’t over. Doctors should consider expert review of the assay for deletions/duplications or mosaicism. There are also “mimics” that can look almost identical on a scan.

The most common mimic is AARS2-related leukoencephalopathy, which is typically biallelic (recessive) ^[8]. This condition often appears at a younger age and, in some women, is frequently associated with primary ovarian failure (early menopause), though it affects men as well ^[8][12]. If CSF1R is negative, doctors should order a broad adult-onset leukodystrophy panel or whole-exome/genome sequencing to look for the AARS2 gene along with other rare genetic markers ^[6][12].

Diagnostic Checklist for Discussions

When speaking with your neurologist, you can ask if they have checked for these specific findings in the reports:

• [ ] MRI: Frontal/parietal white matter lesions? ^[4]
• [ ] MRI: Thinning of the corpus callosum? ^[6]
• [ ] MRI: Persistent “dots” on the DWI (diffusion) sequence? ^[4]
• [ ] CT Scan: Are there “stepping-stone” calcifications? ^[9]
• [ ] Genetics: Was the whole CSF1R gene sequenced, and is the variant pathogenic? ^[2]
• [ ] Mimics: If CSF1R is negative, have we tested for AARS2 or performed expanded panels? ^[8]