What causes neurological problems or dementia?

Causes of Neurological Problems and Dementia

Neurological problems and dementia are caused by multiple distinct pathologies that damage brain tissue and disrupt neural function, with Alzheimer's disease and cerebrovascular disease being the most common underlying causes.

Primary Causes of Dementia

Alzheimer's Disease

• Characterized by the accumulation of two key pathological proteins 1:
  • Amyloid-beta (Aβ) plaques
  • Hyperphosphorylated tau (forming neurofibrillary tangles)
• Biomarkers include 1:
  • Core 1: Aβ (detected via PET, CSF, plasma) and hyperphosphorylated tau
  • Core 2: AD tau proteinopathy (specific tau species, tau PET)
• Presents with 1:
  • Insidious onset over months to years
  • Progressive worsening of cognition
  • Typically amnestic presentation (memory impairment)
  • Can also present with language deficits, visuospatial problems, or executive dysfunction

Cerebrovascular Disease

• Second most common cause (15-20% of dementia cases) 1
• Pathophysiology involves 1:
  • Neuronal damage from ischemia
  • Infarcts (large and small)
  • Hemorrhage
  • White matter disease
• Four clinical patterns 1:
  • Subcortical ischemic vascular dementia
  • Post-stroke dementia
  • Multi-infarct dementia
  • Mixed dementia (vascular + other pathology)
• Risk factors include hypertension, dyslipidemia, diabetes, smoking, and atrial fibrillation 1

Lewy Body Disorders

• Includes Parkinson's disease dementia and dementia with Lewy bodies 1
• Characterized by alpha-synuclein protein deposits in neurons
• Makes up approximately 8% of dementia cases 1
• Features include 1:
  • Parkinsonism
  • Visual hallucinations
  • Fluctuating cognition
  • REM sleep behavior disorder

Frontotemporal Dementia

• Characterized by atrophy in frontal and temporal lobes
• Presents with 1:
  • Behavioral changes
  • Language impairment
  • Executive dysfunction
  • Often earlier onset than Alzheimer's disease

Other Important Causes

Potentially Reversible Causes

• Though rare (less than 1.5% of cases are fully reversible), important to identify 1:
  • Vitamin B12 deficiency
  • Hypothyroidism
  • Normal pressure hydrocephalus
  • Medication side effects
  • Chronic infections
  • Brain tumors

Mixed Pathologies

• Most dementia cases (especially in older adults) involve multiple pathologies 1, 2
• Mixed Alzheimer's and vascular pathology is extremely common
• The probability of mixed disease increases with age 1

Risk Factors

Non-modifiable Risk Factors

• Age (strongest risk factor) 1
• Genetic factors 1:
  • Family history of Alzheimer's disease
  • Apolipoprotein ε4 genotype
  • Specific gene mutations (amyloid precursor protein, presenilin 1, presenilin 2)
  • Down syndrome

Modifiable Risk Factors

• Vascular risk factors 1, 3:
  • Hypertension (contributes to 54.8% of stroke DALYs)
  • Unhealthy diet (contributes to 30.0% of stroke DALYs)
  • Smoking (contributes to 15.1% of dementia DALYs)
  • Obesity (contributes to 12.5% of dementia DALYs)
• Lifestyle factors 1:
  • Low educational level
  • Head trauma
  • Physical inactivity
  • Social isolation

Pathophysiological Mechanisms

Neurodegeneration

• Progressive loss of neurons and synapses
• Disruption of neural networks
• Accumulation of abnormal proteins (amyloid, tau, alpha-synuclein)
• Neuroinflammation

Vascular Mechanisms

• Large vessel disease (atherosclerosis leading to strokes)
• Small vessel disease (arteriolosclerosis leading to lacunar infarcts)
• Cerebral amyloid angiopathy
• Microhemorrhages and microinfarcts
• Blood-brain barrier dysfunction 4

Clinical Implications

Diagnosis

• Requires comprehensive assessment including 1:
  • History of cognitive decline
  • Objective cognitive testing
  • Functional assessment
  • Neuroimaging
  • Biomarker testing when appropriate

Treatment Approaches

• Management of vascular risk factors 5
• Symptomatic treatments:
  • Cholinesterase inhibitors (e.g., rivastigmine) for Alzheimer's and Parkinson's disease dementia 6
  • Memantine for moderate to severe Alzheimer's disease
  • Management of behavioral symptoms 4
• Non-pharmacological approaches 2:
  • Cognitive engagement
  • Physical exercise
  • Social interaction

Prevention

• Aggressive management of vascular risk factors 3, 5
• Lifestyle modifications:
  • Physical activity
  • Cognitive stimulation
  • Mediterranean diet
  • Smoking cessation

Important Caveats

• Dementia is a syndrome, not a single disease 7
• Multiple pathologies often coexist, especially in older adults 1, 2
• The clinical presentation may not clearly indicate the underlying pathology
• Biomarker evidence can increase diagnostic certainty but is not always available or definitive 1
• Despite advances in understanding pathophysiology, disease-modifying treatments remain limited 7