Limbic Predominant Age Related TDP 43 Encephalopathy

3 Interesting Facts of Limbic Predominant Age Related TDP 43 Encephalopathy

  1. Limbic predominant age-related TDP-43 encephalopathy (LATE) is a form of TDP-43 (TDP-43 or transactive response DNA binding protein 43 kDa) proteinopathy that causes progressive memory loss in older adults in a manner similar to Alzheimer disease (AD).
  2. •TDP-43 intraneuronal cytoplasmic inclusions in the medial temporal lobe are the main pathologic marker and can occur with or without coexisting hippocampal sclerosis (HS). It is often comorbid with other neurodegenerative diseases such as AD.
  3. •LATE typically manifests as an amnestic dementia because of the medial temporal location of the TDP-43 aggregates, and thus in vivo patients are often diagnosed with AD. It is typically a disease of the very old. The clinical picture is also influenced by co-occurring pathology.

Synonyms

  • •LATE encompasses several previously used designations related to TDP-43 proteinopathy that can be associated with cognitive impairment, including hippocampal sclerosis, hippocampal sclerosis of aging, hippocampal sclerosis dementia, cerebral age-related TDP-43 with sclerosis, and TDP-43 pathologies in the elderly
  • •Limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC)

Incidence of Limbic Predominant Age Related TDP 43 Encephalopathy

  • LATE-NC is present in >20% (up to 50%) of individuals past 80 yr.

Prevalence

Rates of TDP-43 proteinopathy increase at more advanced ages, whereas incidents of severe AD cases become less common as individuals attain such advanced age. TDP-43 pathology in patients with AD is mostly seen in the oldest-old and those with more severe clinical phenotype; between 20% and 50% of AD cases, and 75% of severe cases, exhibit pathophysiologic TDP-43.

Predominant Age

  • Advanced age (>80 yr)

Risk Factors

  • Advanced age

Genetics

  • Five alleles have been associated with LATE: GRN, TMEM106B, TARDBP, valosin-containing protein (VCP), and C9ORF72.

Symptoms & Clinical Presentation of Limbic Predominant Age Related TDP 43 Encephalopathy

  • •LATE is associated with progressive memory deficits, in particular episodic memory deficits, but progresses to other cognitive domains as the disease progresses.
  • •Preliminary evidence suggests that individuals with relatively “pure” LATE (lacking severe comorbid pathologies) decline more gradually compared to those with “pure” AD. Those with comorbid LATE and AD decline faster and have more severe cognitive impairment than those with either LATE or AD alone.
  • •The concurrent presence of TDP-43 pathology and hippocampal sclerosis is associated with deficits in episodic and semantic memory. However, the occurrence of TDP-43 pathology alone is linked only to poorer episodic memory.
  • •Pathology is most frequently evident in the medial temporal lobe, correlating with a loss of episodic memory. Other studies have identified TDP-43 deposition in the ventral striatum and basal forebrain, linked to poorer performance on memory, language, and executive tests.
  • •Individuals with perivascular TDP-43 pathology also frequently exhibit cardiovascular symptoms such as hypertension and cerebral microinfarcts.
  • •Individuals with pathologic changes in TDP-43 are more likely to show indifference, loss of compassion, stereotyped behavior, and action disorder.

What causes Limbic Predominant Age Related TDP 43 Encephalopathy?

  • •LATE is caused by TDP-43 proteinopathy. In the pathogenesis of LATE, the normal TDP-43 protein loses its immunoreactivity and begins to accumulate in the nuclei, cytoplasm, and cell processes (neurites) of neurons, oligodendrocytes, and astrocytes.
  • •As LATE progresses, brain atrophy due to TDP-43 deposition occurs in three stages: Amygdala (stage 1); hippocampus (stage 2); and middle frontal gyrus (MFG) (stage 3).
  • •In certain cases, TDP-43 aggregation and associated pathology may be a secondary consequence of some upstream neurodegenerative, developmental, or stress-induced influence.

How is Limbic Predominant Age Related TDP 43 Encephalopathy diagnosed?

  • •As with most other proteinopathies, LATE can only be formally diagnosed on autopsy.
  • •Symptoms that suggest LATE versus other forms of dementia:
    • 1.There are no diagnostic tools for the definitive antemortem detection of LATE.
    • 2.On autopsy, the distinguishing factor of LATE is TDP-43 pathology in medial temporal lobe structures with or without hippocampal sclerosis. The anatomic distribution of TDP-43 proteinopathy is stage 1 in the amygdala only, stage 2 in both amygdala and hippocampus, and stage 3 in amygdala, hippocampus, and middle frontal gyrus.

Differential Diagnosis

  • •AD
  • •Vascular dementia
  • •Argyrophilic grain disease
  • •Frontotemporal lobar degeneration associated with TDP-43 inclusions

Workup

  • Neuropsychologic tests similar to those used to diagnose AD can be used, such as the Mini-Mental State Examination (MMSE). However, there are currently no neuropsychologic tests or neuropsychiatric, motor, or autonomic signs that distinguish LATE from other degenerative disorders.

Laboratory Tests

  • There are currently no known biomarkers specific to LATE.

Imaging Studies

  • MRI may show hippocampal atrophy, especially in LATE with hippocampal sclerosis. Amyloid and tau PET will be negative in pure LATE but may not be in comorbid LATE and AD. There is no TDP-43 fluid marker or PET ligand, but research is ongoing.

Referral

  • Neurologist with expertise in dementia

What is the Prognosis?

Pure LATE has a slower rate of progression than AD. Mixed LATE and AD cases have more rapid progression than AD alone.

  • •Stage 1
    • 1.Average age at death: 89.9
    • 2.% Normal clinical diagnosis: 33.5
    • 3.% MCI (mild cognitive impairment) or dementia: 66.5
    • 4.% with comorbid hippocampal sclerosis (HS) pathology: 3.5
  • •Stage 2
    • 1.Average age at death: 91.8
    • 2.% Normal clinical diagnosis: 18.9
    • 3.% MCI or dementia: 81.1
    • 4.% with comorbid HS pathology: 13.6
  • •Stage 3
    • 1.Average age at death: 91.9
    • 2.% Normal clinical diagnosis: 7.6
    • 3.% MCI or dementia: 92.4
    • 4.% with comorbid HS pathology: 42.9

How is this prevented?

  • Undetermined; possibly similar to AD
  • Suggested Readings
  • Huang W., et al.: TDP-43: from Alzheimer’s disease to limbic-predominant age-related TDP-43 encephalopathy. Front Mol Neurosci 2020; 13 (26): https://www.ncbi.nlm.nih.gov/pubmed/32180703.
  • Nelson P.T., et al.: Limbic-predominant age-related TDP-43 encephalopathy (late): consensus working group report. Brain 2019; 142 (6): pp. 1503-1527. https://www.ncbi.nlm.nih.gov/pubmed/31039256.
  • Zhang L., et al.: TDP-43 and limbic-predominant age-related TDP-43 encephalopathy. Front Aging Neurosci 2019; 11: pp. 376.
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