Primary tauopathies are a group of neurodegenerative diseases in which tau is believed to be the major contributing factor of the neurodegenerative process. In primary tauopathies, there is a ...disassociation between tau (a microtubule-associated protein) and microtubules as a result of tau hyperphosphorylation. This disassociation between tau and microtubules results in tau fibrillization and inclusion formation as well as in microtubule dysfunction. There are different clinical syndromes associated with different primary tauopathies, and some clinical syndromes can be associated with multiple primary tauopathies. Hence, although some clinical syndromes are highly specific and almost diagnostic of a primary tauopathy, many are not, making it difficult to diagnose a primary tauopathy. Recently, radioligands that bind to tau and can be combined with positron emission tomography to detect fibrillary tau antemortem have been developed, although preliminary data suggest that these ligands may not be sensitive in detecting tau associated with many primary tauopathies. Another recent advancement in the field is evidence suggesting that tau may exhibit properties similar to those of prions, although infective transmission has not been shown. There have been a few clinical trials targeting tau and microtubule dysfunction, although none have had any disease-modifying effects. Understanding tau biology is critical to the development of pharmacological agents that could have disease-modifying effects on primary tauopathies.
In the past century, particularly the last decade, there has been enormous progress in our understanding of frontotemporal dementia, a non‐Alzheimer's type dementia. Large clinicopathological series ...have been published that have clearly demonstrated an overlap between the clinical syndromes subsumed under the term frontotemporal dementia and the progressive supranuclear palsy syndrome, corticobasal syndrome, and motor neuron disease. There have also been significant advancements in brain imaging, neuropathology, and molecular genetics that have led to different approaches to classification. Unfortunately, the field is complicated by a barrage of overlapping clinical syndromes and histopathological diagnoses that does not allow one to easily identify relations between individual clinical syndromic presentations and underlying neuropathology. This review deciphers this web of terminology and highlights consistent, and hence important, associations between individual clinical syndromes and neuropathology. These associations could ultimately allow the identification of appropriate patient phenotypes for future targeted treatments. Ann Neurol 2008;64:4–14
Rest in peace FTDP-17 Josephs, Keith A
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This scientific commentary refers to 'Retiring the term FTDP-17 as MAPT mutations are genetic forms of sporadic frontotemporal tauopathies' by Forrest et al. (doi:10.1093/brain/awx328).
Summary Background Three subtypes of Alzheimer's disease (AD) have been pathologically defined on the basis of the distribution of neurofibrillary tangles: typical AD, hippocampal-sparing AD, and ...limbic-predominant AD. Compared with typical AD, hippocampal-sparing AD has more neurofibrillary tangles in the cortex and fewer in the hippocampus, whereas the opposite pattern is seen in limbic-predominant AD. We aimed to determine whether MRI patterns of atrophy differ between these subtypes and whether structural neuroimaging could be a useful predictor of pathological subtype at autopsy. Methods We identified patients who had been followed up in the Mayo Clinic Alzheimer's Disease Research Center (Rochester, MN, USA) or in the Alzheimer's Disease Patient Registry (Rochester, MN, USA) between 1992 and 2005. To be eligible for inclusion, participants had to have had dementia, AD pathology at autopsy (Braak stage ≥IV and intermediate to high probability of AD), and an ante-mortem MRI. Cases were assigned to one of three pathological subtypes—hippocampal-sparing, limbic-predominant, and typical AD—on the basis of neurofibrillary tangle counts in hippocampus and cortex and ratio of hippocampal to cortical burden, without reference to neuronal loss. Voxel-based morphometry and atlas-based parcellation were used to compare patterns of grey matter loss between groups and with age-matched control individuals. Neuroimaging was obtained at the time of first presentation. To summarise pair-wise group differences, we report the area under the receiver operator characteristic curve (AUROC). Findings Of 177 eligible patients, 125 (71%) were classified as having typical AD, 33 (19%) as having limbic-predominant AD, and 19 (11%) as having hippocampal-sparing AD. Most patients with typical (98 78%) and limbic-predominant AD (31 94%) initially presented with an amnestic syndrome, but fewer patients with hippocampal-sparing AD (eight 42%) did. The most severe medial temporal atrophy was recorded in patients with limbic-predominant AD, followed by those with typical disease, and then those with hippocampal-sparing AD. Conversely, the most severe cortical atrophy was noted in patients with hippocampal-sparing AD, followed by those with typical disease, and then limbic-predominant AD. The ratio of hippocampal to cortical volumes allowed the best discrimination between subtypes (p<0·0001; three-way AUROC 0·52 95% CI 0·47–0·52; ratio of AUROC to chance classification 3·1 2·8–3·1). Patients with typical AD and non-amnesic initial presentation had a significantly higher ratio of hippocampal to cortical volumes (median 0·045 IQR 0·035–0·056) than did those with an amnesic presentation (0·041 0·031–0·057; p=0·001). Interpretation Patterns of atrophy on MRI differ across the pathological subtypes of AD. MRI regional volumetric analysis can reliably track the distribution of neurofibrillary tangle pathology and can predict pathological subtype of AD at autopsy. Funding US National Institutes of Health (National Institute on Aging).
TDP-43 was first reported to be a key biological component of frontotemporal lobar degeneration and amyotrophic lateral sclerosis in 2006.1 Subsequently, findings suggested that TDP-43 immunoreactive ...lesions were also frequently present in the brains of patients with pathologically confirmed Alzheimer's disease.2 More recently, TDP-43 has been implicated in memory loss, hippocampal volume loss, and rate of hippocampal atrophy in people with Alzheimer's disease3,4 and in broader cohorts of community-based older adults.5 These findings have catapulted TDP-43 into the limelight. ...my colleagues and I have not found any effects of TDP-43 proteinopathy on clinical or neuroimaging outcomes in cognitively healthy people with primary age-related tauopathy.10 The findings by Yang and colleagues7 are also limited to the population from the Religious Orders Study and the Rush Memory and Aging Project, and might not necessarily generalise to other populations, particularly since 1010 (97%) self-reported their race to be white. ...although the Alzheimer's research establishment focuses predominantly on amyloid-β and paired helical filament tau, those who believe in the relevance of TDP-43 need to consider the next important steps.
Apraxia of speech (AOS) can be caused by neurodegenerative disease and sometimes is its presenting sign (i.e., primary progressive apraxia of speech, PPAOS). During the last several decades, our ...understanding of PPAOS has evolved from clinical recognition to a fuller understanding of its core and associated clinical features, its distinction from but relationship with primary progressive aphasia, its temporal course and eventual progression to include other neurological deficits, and its neuroimaging correlates and underlying pathology.
This paper provides a comprehensive summary of the literature that has built the current knowledge base about PPAOS and progressive AOS as it co-occurs with progressive aphasia. It reviews the history of its emergence as a recognized syndrome; its relationship with the agrammatic/nonfluent variant of primary progressive aphasia; its salient perceptual features and subtypes; the acoustic and structural/physiological imaging measures that index its presence, severity, and distinction from aphasia; and principles and available data regarding its management and care.
A broad summary of what is known about AOS as a manifestation of neurodegenerative disease.
Primary progressive apraxia of speech is a recognizable syndrome that can be distinguished from other neurodegenerative conditions that affect speech and language.
Abbreviations
AAC = augmentative and alternative communication; AES = Articulatory Error Score; ALS = amyotrophic lateral sclerosis; AOS = apraxia of speech; AOS+PAA = AOS plus the agrammatic/nonfluent variant of PPA; ASRS = Apraxia of Speech Rating Scale; CBD = corticobasal degeneration; CBS = corticobasal syndrome; DAOS = dominant AOS - aphasia present but AOS more severe; MSD = motor speech disorders; nfPPA = nonfluent variant of PPA, with or without AOS; NVOA = nonverbal oral apraxia; PAOS = progressive AOS, with or without aphasia; PAA = agrammatic variant of PPA, without AOS; PPA = primary progressive aphasia, with or without AOS; PPAOS = primary progressive AOS - no aphasia; PSP = progressive supranuclear palsy; SMA = supplementary motor area.
The gold standard for a definitive diagnosis of Parkinson disease (PD) is the pathologic finding of aggregated α-synuclein into Lewy bodies and for Alzheimer disease (AD) aggregated amyloid into ...plaques and hyperphosphorylated tau into tangles. Implicit in this clinicopathologic-based nosology is the assumption that pathologic protein aggregation at autopsy reflects pathogenesis at disease onset. While these aggregates may in exceptional cases be on a causal pathway in humans (e.g., aggregated α-synuclein in SNCA gene multiplication or aggregated β-amyloid in APP mutations), their near universality at postmortem in sporadic PD and AD suggests they may alternatively represent common outcomes from upstream mechanisms or compensatory responses to cellular stress in order to delay cell death. These 3 conceptual frameworks of protein aggregation (pathogenic, epiphenomenon, protective) are difficult to resolve because of the inability to probe brain tissue in real time. Whereas animal models, in which neither PD nor AD occur in natural states, consistently support a pathogenic role of protein aggregation, indirect evidence from human studies does not. We hypothesize that (1) current biomarkers of protein aggregates may be relevant to common pathology but not to subgroup pathogenesis and (2) disease-modifying treatments targeting oligomers or fibrils might be futile or deleterious because these proteins are epiphenomena or protective in the human brain under molecular stress. Future precision medicine efforts for molecular targeting of neurodegenerative diseases may require analyses not anchored on current clinicopathologic criteria but instead on biological signals generated from large deeply phenotyped aging populations or from smaller but well-defined genetic–molecular cohorts.
Flortaucipir (FTP) PET is a key imaging technique to evaluate tau burden indirectly. However, it appears to have greater utility for 3R+4R tau found in Alzheimer's disease (AD), compared to other ...non-AD tauopathies. The purpose of this study is to determine how flortaucipir uptake links to neuropathologically determined tau burden in AD and non-AD tauopathies. We identified nine individuals who had undergone antemortem tau-PET and postmortem neuropathological analyses. The cohort included three patients with low, moderate, and high AD neuropathologic changes (ADNC), five patients with a non-AD tauopathy (one Pick's disease, three progressive supranuclear palsies, and one globular glial tauopathy), and one control without ADNC. We compared regional flortaucipir PET uptake with tau burden using an anti-AT8 antibody. There was a very good correlation between flortaucipir uptake and tau burden in those with ADNC although, in one ADNC patient, flortaucipir uptake and tau burden did not match due to the presence of argyrophilic grains disease. Non-AD patients showed lower flortaucipir uptake globally compared to ADNC patients. In the non-AD patients, some regional associations between flortaucipir uptake and histopathological tau burden were observed. Flortaucipir uptake is strongly linked to underlying tau burden in patients with ADNC but there are instances where they do not match. On-the-other hand, flortaucipir has a limited capacity to represent histopathological tau burden in non-AD patients although there are instances where regional uptake correlates with regional tau burden. There is a definite need for the development of future generations of tau-PET ligands that can detect non-AD tau.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Current criteria for the clinical diagnosis of pathologically confirmed corticobasal degeneration (CBD) no longer reflect the expanding understanding of this disease and its clinicopathologic ...correlations. An international consortium of behavioral neurology, neuropsychology, and movement disorders specialists developed new criteria based on consensus and a systematic literature review. Clinical diagnoses (early or late) were identified for 267 nonoverlapping pathologically confirmed CBD cases from published reports and brain banks. Combined with consensus, 4 CBD phenotypes emerged: corticobasal syndrome (CBS), frontal behavioral-spatial syndrome (FBS), nonfluent/agrammatic variant of primary progressive aphasia (naPPA), and progressive supranuclear palsy syndrome (PSPS). Clinical features of CBD cases were extracted from descriptions of 209 brain bank and published patients, providing a comprehensive description of CBD and correcting common misconceptions. Clinical CBD phenotypes and features were combined to create 2 sets of criteria: more specific clinical research criteria for probable CBD and broader criteria for possible CBD that are more inclusive but have a higher chance to detect other tau-based pathologies. Probable CBD criteria require insidious onset and gradual progression for at least 1 year, age at onset ≥ 50 years, no similar family history or known tau mutations, and a clinical phenotype of probable CBS or either FBS or naPPA with at least 1 CBS feature. The possible CBD category uses similar criteria but has no restrictions on age or family history, allows tau mutations, permits less rigorous phenotype fulfillment, and includes a PSPS phenotype. Future validation and refinement of the proposed criteria are needed.
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