What causes diffuse cerebral atrophy?

Causes of Diffuse Cerebral Atrophy

Diffuse cerebral atrophy is primarily caused by neurodegenerative diseases, particularly Alzheimer's disease, followed by vascular pathology, traumatic brain injury, and genetic disorders like CSF1R-related leukoencephalopathy. 1, 2

Neurodegenerative Causes

Alzheimer's Disease

• Most common cause of diffuse cerebral atrophy in older adults
• Characterized by:
  • Accumulation of amyloid-beta plaques and tau protein tangles
  • Progressive loss of neurons and synapses
  • Medial temporal atrophy affecting amygdala and hippocampus
  • Enlargement of temporal horn
  • Moderate cortical atrophy in multimodal association cortices and limbic structures
  • Enlarged sulcal spaces with atrophy of gyri in frontal and temporal cortices 1

Other Neurodegenerative Disorders

• Behavioral variant Frontotemporal Dementia (bvFTD)
  • Causes frontal and anterior temporal pole atrophy
  • Can be distinguished from psychiatric disorders by presence of atrophy on MRI 1
• Lewy Body Dementia (DLB)
  • Shows less hippocampal and medial temporal lobe atrophy than AD
  • Greater subcortical structure atrophy (thalamus, caudate, amygdala, ventral diencephalon, substantia nigra, midbrain) 1

Vascular Causes

Vascular Cognitive Impairment/Vascular Dementia

• Three main mechanisms:
  • Large vessel strokes (macroangiopathy, arteriosclerosis)
  • Small vessel disease (microangiopathy, arteriolosclerosis)
  • Microhemorrhages 1
• Hypertension is associated with incident lacunar infarcts but shows inconsistent association with progression of cerebral atrophy 3
• Cerebral Autosomal-Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL)
  • Hereditary small-artery vasculopathy
  • Characterized by migraine with aura, strokes, progressive subcortical dementia 1

Traumatic Brain Injury (TBI)

• Moderate-to-severe TBI can cause:
  • Brain tissue loss of approximately 5% per year
  • Both generalized atrophy (across entire brain) and focal atrophy
  • Common regions of focal atrophy:
    • Gray matter: thalamus, hippocampus, cerebellum
    • White matter: corpus callosum, corona radiata, brainstem
  • Characteristic features include widening of cortical sulci, enlargement of ventricles, and cortical thinning 2

Genetic/Hereditary Causes

CSF1R-related Leukoencephalopathy

• Associated with progressive white matter lesions and brain atrophy
• Diffuse brain atrophy, enlargement of lateral ventricles, or generalized infratentorial atrophy may be present
• Characterized by brain parenchymal calcifications (75% of cases) and white matter hypodensities 1

Other Genetic Causes

• Spinocerebellar ataxias
• Friedreich's ataxia
• Ataxia-telangiectasia 4

Rapidly Progressive Dementias

• Prion diseases (e.g., Creutzfeldt-Jakob disease) - 62% of rapidly progressive dementias
• Other causes include:
  • Other neurodegenerative diseases (15%)
  • Autoimmune conditions (8%)
  • Infectious diseases (4%)
  • Psychiatric disorders (2%)
  • Cancer (2%)
  • Toxic-metabolic conditions (2%)
  • Vascular disorders (2%)
  • Leukoencephalopathies (4%) 1

Diagnostic Approach

Neuroimaging

• Brain MRI with T1 and FLAIR sequences including coronal cuts is the preferred initial imaging modality
• CT with coronal views only if MRI not available or contraindicated
• FDG-PET in ambiguous diagnostic cases without clear CT/MRI fronto-temporal atrophy 1
• Volumetric analysis can reveal both gray and white matter atrophy patterns specific to different conditions 1

Additional Testing

• CSF analysis of amyloid-β42, tau, and p-tau to rule out Alzheimer's disease
• Consider serum or CSF neurofilament light chain (NfL) to differentiate bvFTD from psychiatric disorders 1

Key Points to Remember

• Cerebral atrophy is not a diagnosis but a finding that requires investigation for underlying etiology
• Pattern of atrophy (diffuse vs. focal, cortical vs. subcortical) can help narrow differential diagnosis
• Age-related atrophy occurs naturally but at a much slower rate than pathological atrophy
• Potentially reversible causes (autoimmune, infectious, psychiatric, cancer, toxic-metabolic) should be considered, especially in rapidly progressive cases 1
• No correlation has been found between the presence or severity of diffuse EEG abnormalities and the degree of cerebral atrophy 5