Why Therapeutic Trials Fail in Primary Tauopathies

Olfati, Nahid; Ghodsi, Hamidreza; Bayram, Ece; Litvan, Irene

doi:10.1002/mds.29322

Cited by 2 publications

(2 citation statements)

References 45 publications

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“…In many tauopathies considered secondary tauopathies, TAU is the most important co-pathology and may be critical to the developing neurodegeneration, e.g. for AD [ 111 ], which makes a clear distinction in some cases disputable. The genetic factors leading to TAU pathology as well as the pathomechanistic connections between the primary pathology and TAU in secondary tauopathies are often not fully understood.…”

Section: Secondary Tauopathiesmentioning

confidence: 99%

Genetic forms of tauopathies: inherited causes and implications of Alzheimer’s disease-like TAU pathology in primary and secondary tauopathies

Langerscheidt,

Wied,

Al Kabbani

et al. 2024

J Neurol

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Tauopathies are a heterogeneous group of neurologic diseases characterized by pathological axodendritic distribution, ectopic expression, and/or phosphorylation and aggregation of the microtubule-associated protein TAU, encoded by the gene MAPT. Neuronal dysfunction, dementia, and neurodegeneration are common features of these often detrimental diseases. A neurodegenerative disease is considered a primary tauopathy when MAPT mutations/haplotypes are its primary cause and/or TAU is the main pathological feature. In case TAU pathology is observed but superimposed by another pathological hallmark, the condition is classified as a secondary tauopathy. In some tauopathies (e.g. MAPT-associated frontotemporal dementia (FTD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and Alzheimer's disease (AD)) TAU is recognized as a significant pathogenic driver of the disease. In many secondary tauopathies, including Parkinson's disease (PD) and Huntington's disease (HD), TAU is suggested to contribute to the development of dementia, but in others (e.g. Niemann-Pick disease (NPC)) TAU may only be a bystander. The genetic and pathological mechanisms underlying TAU pathology are often not fully understood. In this review, the genetic predispositions and variants associated with both primary and secondary tauopathies are examined in detail, assessing evidence for the role of TAU in these conditions. We highlight less common genetic forms of tauopathies to increase awareness for these disorders and the involvement of TAU in their pathology. This approach not only contributes to a deeper understanding of these conditions but may also lay the groundwork for potential TAU-based therapeutic interventions for various tauopathies.

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Section: Secondary Tauopathiesmentioning

confidence: 99%

Genetic forms of tauopathies: inherited causes and implications of Alzheimer’s disease-like TAU pathology in primary and secondary tauopathies

Langerscheidt,

Wied,

Al Kabbani

et al. 2024

J Neurol

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“…Early diagnosis is important for clinical care, ensuring individuals can access vital support and benefits, plan for the future, and avoid incorrect diagnosis, inappropriate treatment, and miscommunication of prognosis. It is also a key consideration for advancing the translation of future therapeutic approaches into successful disease‐modifying agents 1 ; enabling individuals with PSP/CBS to be identified early in their disease course while they still meet eligibility criteria, such as independent ambulation, for disease‐modifying clinical trials and before the development of severe neurodegeneration decreases any potential benefit from disease‐modifying agents. Although diagnostic and exclusionary biomarkers may eventually facilitate the diagnostic process, they can only be used once an individual has sought healthcare input and is at least suspected to have a relevant clinical syndrome or specific diagnosis.…”

Section: Introductionmentioning

confidence: 99%

Total Patient Delay: A Comparison of Patient and Clinician/Health System Delays in the Diagnosis of Progressive Supranuclear Palsy and Corticobasal Syndrome

Swallow,

Murchie,

Counsell

2024

Movement Disord Clin Pract

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BackgroundEarly diagnosis in progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS) is important for clinical care and key to developing successful disease‐modifying agents. The patient‐dependent phases of decision‐making made before contact with a healthcare professional have been inadequately studied.ObjectivesTo evaluate the patient‐dependent phases of decision‐making from symptom onset, comparing this to clinician and/or health system delays within the overall diagnostic pathway.MethodsUsing the Anderson General Model of Total Patient Delay and a mixed‐methods approach in participants with PSP/CBS and their caregivers recruited to the Scottish PSP and CBS cohort, we quantified and evaluated the determinants of “appraisal”, “illness,” and “behavioral” delay, comparing this to the clinician and/or health system delays (“treatment” delay) within the overall time from symptom onset to diagnosis.ResultsThe time from index symptom onset to diagnosis was 3.26 (interquartile range [IQR] = 2.42, 4.75) years in PSP and 2.58 (IQR = 1.69, 4.08) years in CBS. Patient appraisal delay was 24 (IQR = 6, 60) weeks in PSP and 8 (IQR = 5, 24) weeks in CBS, illness delay 0 (IQR = −14, 0) weeks in PSP and 0 (IQR = −4, 0) weeks in CBS, with little perceived behavioral delay. Determinants of delay included the non‐specificity of symptoms, normalization of symptoms within the context of age or normal physiological variability, and the extent of insight into new somatic symptoms.ConclusionsAlthough patient appraisal delay contributes to overall diagnostic delay in PSP/CBS, the greater proportion of overall diagnostic delay arises after contact with a healthcare professional (treatment delay).

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Why Therapeutic Trials Fail in Primary Tauopathies

Cited by 2 publications

References 45 publications

Genetic forms of tauopathies: inherited causes and implications of Alzheimer’s disease-like TAU pathology in primary and secondary tauopathies

Genetic forms of tauopathies: inherited causes and implications of Alzheimer’s disease-like TAU pathology in primary and secondary tauopathies

Total Patient Delay: A Comparison of Patient and Clinician/Health System Delays in the Diagnosis of Progressive Supranuclear Palsy and Corticobasal Syndrome

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