dementia

see also:

• neurology
• Mental state - delirium vs dementia vs psychosis
• cognition
• Behavioural and Psychological Symptoms of Dementia (BPSD)

• dementia is a serious loss of cognitive ability in a previously unimpaired person, beyond what might be expected from normal aging.
• affected areas of cognition may be memory, attention, language, and problem solving.

• various types of brain injury, occurring as a single event resulting in long term cognitive deficit:
  • trauma
  • hypoxic events (eg. near drowning)
  • stroke (CVA)
  • prolonged seizures
  • acute hydrocephalus
  • meningitis
  • encephalitis
• substance abuse which may result in long term fixed cognitive deficits despite cessation of substance abuse:
  • alcoholic dementia
  • Wernicke's encephalopathy
  • Korsakoff's psychosis
  • other recreational substance abuse

• Alzheimer's disease (AD)
  • usually slow progression but may have a rapid progressive onset
  • most often, it is diagnosed in people over 65 years of age, although the less-prevalent early-onset Alzheimer's can occur much earlier.
    • people with Down's syndrome are at higher risk of developing early onset AD and often have amyloid plaques by age 40
  • predicted to affect 1 in 85 people globally by 2050
  • homozygous for APOE4 variant gene is a high risk and increases risk of earlier onset
    • present in 2-3% of European population and in 15% of those with AD
    • by age 65yrs, 95% will have abnormal levels of CSF beta amyloid and 75% will have positive brain scans for amyloid ¹⁾
  • in those who lack the apolipoprotein ε4 (APOE-ε4) allele:
    • long term (12-24 months) use of non-Aβ42-lowering NSAIDs appears to lower risk of all cause dementia as well as lowering AD risk with HR of 0.74 ²⁾
  • trials will commence in 2019 for an Ultrasound Rx which appears to clear amyloid build up and delay dementia ³⁾
  • early symptoms include:
    • inability in recalling recently observed events
    • subtle problems with the executive functions of attentiveness, planning, flexibility, and abstract thinking, or impairments in semantic memory (memory of meanings, and concept relationships)
    • apathy
    • the mean life expectancy following diagnosis is ~7 years with < 3% of individuals living more than 14 years after diagnosis
    • in 1991, the amyloid hypothesis postulated that amyloid beta (Aβ) deposits are the fundamental cause of the disease.Support for this postulate comes from the location of the gene for the amyloid beta precursor protein (APP) on chromosome 21, together with the fact that people with trisomy 21 (Down Syndrome) who have an extra gene copy almost universally exhibit AD by 40 years of age. Also APOE4, the major genetic risk factor for AD, leads to excess amyloid buildup in the brain before AD symptoms arise. Thus, Aβ deposition precedes clinical AD.
    • in 2009, this theory was updated, suggesting that a close relative of the beta-amyloid protein, and not necessarily the beta-amyloid itself, may be a major culprit in the disease. The theory holds that an amyloid-related mechanism that prunes neuronal connections in the brain in the fast-growth phase of early life may be triggered by aging-related processes in later life to cause the neuronal withering of Alzheimer's disease. N-APP, a fragment of APP from the peptide's N-terminus, is adjacent to beta-amyloid and is cleaved from APP by one of the same enzymes. N-APP triggers the self-destruct pathway by binding to a neuronal receptor called death receptor 6 (DR6, also known as TNFRSF21)
    • it now appears that tau modifies itself in a futile attempt with p-38 gamma protein to combat beta amyloid and ends up forming fibrous knots that prevent nutrients getting to neurons. Tau propagation is related to a cellular process called the UFMylation cascade ⁴⁾
• Lewy Body dementia (LBD)
  • a type of dementia closely allied to both Alzheimers and Parkinson's Diseases. It is characterized anatomically by the presence of Lewy bodies, clumps of alpha-synuclein and ubiquitin protein in neurons
  • often has a rapid or acute onset, with especially rapid decline in the first few months.
  • fluctuating cognition with great variations in attention and alertness from day to day and hour to hour
  • recurrent visual hallucinations in 75% pts
  • motor features of Parkinson's
  • often have frequent falls &/or postural hypotension/syncope
  • rapid eye movement sleep behavior disorder
  • one of the most clinically critical and distinctive features is hypersensitivity to neuroleptic and antiemetic medications that affect dopaminergic and cholinergic systems as they may become catatonic, lose cognitive function and/or develop life-threatening muscle rigidity (neuroleptic malignant syndrome (NMS))
• vascular or multi-infarct dementia
  • often small infarcts go unrecognised at the time of infarctions
  • may be due to antiphospholipid syndrome, CADASIL, MELAS, homocystinuria, moyamoya and Binswanger's disease
• frontotemporal lobar degeneration (FTLD)
  • the 2nd most common cause of dementia in those under 65yrs age, and the 4th most common cause in those over 65 yrs of age (when vascular and Lewy Body dementia become more common)
  • ~40% are genetic, and most have tau or ubiquitin inclusions on histology
  • 3 clinical subtypes:
    • behavioural-variant frontotemporal dementia
      • apathy or disinhibition
      • complex planning problems
      • frontal reflexes such as palmomental reflex sign
    • semantic dementia
      • fluent aphasia, anomia, impaired comprehension of word meaning, and visual associative agnosia (inability to match semantically-related pictures or objects)
      • presumably the type affecting actor Bruce Willis
    • progressive nonfluent aphasia
      • progressive difficulties with speech production - hesitant, effortful speech, return of childhood stutter
• repetitive brain trauma
  • eg. boxers (dementia pugilistica)
• Parkinson's disease with dementia
  • dementia onset is more than 1 year after the onset of Parkinson's (if dementia begins within 12 months of onset of Parkinson's then it is most likely to be Lewy Body Dementia)
• normal pressure hydrocephalus
  • wide based gait
• syphilis
• HIV / AIDS
• Lyme disease
• vitamin deficiency - eg. B12, folate or niacin
• adolescent behaviours such as alcohol or drug use
  • adolescent alcohol intoxication gives ~5x risk of young onset dementia (YOD) in men (median age onset 54yrs), this increases to 20x risk if combined with 2 other risk factors such as depression, antipsychotic use, substance abuse, FH father with dementia, stroke, high systolic BP, or being in lower 1/3rd percentiles for cognition or height. These 9 factors accounted for 68% of all cases of young onset dementia in the 0.5 million men followed up, 1 in 1000 of whom developed YOD. ⁵⁾

• Huntington's disease
• fragile X carriers
  • Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late onset neurodegenerative disorder associated with problems with movement (intentional tremor, Parkinsonism), memory, dysautonomia and peripheral neuropathy. This is clinically different to Fragile X syndrome.
• familial Alzheimer's disease
• other Alzheimer's disease
  • 80% heritability
  • two new genetic variants and 95 new gene interactions (epistasis) that may modulate the effects of variants in Alzheimer’s discovered by CSIRO in 2023
  • H63D variant of HFE gene which is linked to haemochromatosis, doubles risk of dementia in men ⁶⁾
• SCA17 (dominant inheritance)
• adrenoleukodystrophy (X-linked)
• Gaucher's disease type 3
• metachromatic leukodystrophy
• Niemann-Pick disease type C
• pantothenate kinase-associated neurodegeneration
• Tay-Sachs disease
• Wilson's disease

• BMAA toxin from blue green algae
  • high levels of the BMAA toxin produced by blue green algae has been shown to produce brain tangles and amyloid deposits in vervets and this was partly reduced by supplementing their diet with L-serine ⁷⁾
    • Chammoro villagers from the Pacific island of Guam developed a dementia syndrome from eating flour made from the seeds of cycads, the roots of which were exposed to blue green algae and the BMAA toxin
    • might be wise to avoid exposure to BMAA and avoid swimming or drinking water from rivers and lakes with this, and perhaps reduce consumption of seafoods which are exposed to it such as mussels, prawns and crabs which feed on the algae, but don't take L-serine supplements until they are proven safe
• aberrant S-nitrosylation reactions (due to PM2.5, nitrates, etc) contribute to some forms of cancer, autism, Alzheimer's disease, Parkinson's disease and other conditions
  • S-nitrosylation of protein CRTC1, impairs its ability to regulate genes that are critical for forming and maintaining connections between brain cells, an essential process for learning and long-term memory⁸⁾
• chronic gingivitis appears to have a role
• low dietary magnesium intake
  • there appears to be a protective effect of higher dietary magnesium (550mg/day compared to “normal” intake of 300mg/d) on reducing brain aging, reduction in brain size and dementia ⁹⁾
• loneliness under age 80yrs appears to increase risk of dementia 3-fold according to a 2022 study of 2,300 participants in the population-based Framingham Study, and lonely participants without dementia had signs of cognitive problems, including poorer executive function, lower total cerebral volume and greater brain white-matter injury.

• Behçet's disease
• multiple sclerosis
• sarcoidosis
• Sjögren's syndrome
• systemic lupus erythematosus

• Alzheimer's disease
• dementia with Lewy bodies
• frontotemporal lobar degeneration
• Creutzfeldt-Jakob disease typically causes a dementia which worsens over weeks to months
• progressive multifocal leukoencephalopathy (PML)
• NB. encephalopathy or delirium may develop relatively slowly and resemble dementia