Summary C9orf72 hexanucleotide repeat expansions are the most common cause of familial frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) worldwide. The clinical presentation is ...often indistinguishable from classic FTD or ALS, although neuropsychiatric symptoms are more prevalent and, for ALS, behavioural and cognitive symptoms occur more frequently. Pathogenic repeat length is in the hundreds or thousands, but the minimum length that increases risk of disease, and how or whether the repeat size affects phenotype, are unclear. Like in many patients with FTD and ALS, neuronal inclusions that contain TARDBP are seen, but are not universal, and the characteristic pathological finding is of dipeptide repeat (DPR) proteins, formed by unconventional repeat-associated non-ATG translation. Possible mechanisms of neurodegeneration include loss of C9orf72 protein and function, RNA toxicity, and toxicity from the DPR proteins, but which of these is the major pathogenic mechanism is not yet certain.
Hearing and dementia: from ears to brain Johnson, Jeremy C S; Marshall, Charles R; Weil, Rimona S ...
Brain (London, England : 1878),
03/2021, Letnik:
144, Številka:
2
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The association between hearing impairment and dementia has emerged as a major public health challenge, with significant opportunities for earlier diagnosis, treatment and prevention. However, the ...nature of this association has not been defined. We hear with our brains, particularly within the complex soundscapes of everyday life: neurodegenerative pathologies target the auditory brain, and are therefore predicted to damage hearing function early and profoundly. Here we present evidence for this proposition, based on structural and functional features of auditory brain organization that confer vulnerability to neurodegeneration, the extensive, reciprocal interplay between 'peripheral' and 'central' hearing dysfunction, and recently characterized auditory signatures of canonical neurodegenerative dementias (Alzheimer's disease, Lewy body disease and frontotemporal dementia). Moving beyond any simple dichotomy of ear and brain, we argue for a reappraisal of the role of auditory cognitive dysfunction and the critical coupling of brain to peripheral organs of hearing in the dementias. We call for a clinical assessment of real-world hearing in these diseases that moves beyond pure tone perception to the development of novel auditory 'cognitive stress tests' and proximity markers for the early diagnosis of dementia and management strategies that harness retained auditory plasticity.
To investigate serum neurofilament light chain (NfL) concentrations in frontotemporal dementia (FTD) and to see whether they are associated with the severity of disease.
Serum samples were collected ...from 74 participants (34 with behavioral variant FTD bvFTD, 3 with FTD and motor neuron disease and 37 with primary progressive aphasia PPA) and 28 healthy controls. Twenty-four of the FTD participants carried a pathogenic mutation in C9orf72 (9), microtubule-associated protein tau (MAPT; 11), or progranulin (GRN; 4). Serum NfL concentrations were determined with the NF-Light kit transferred onto the single-molecule array platform and compared between FTD and healthy controls and between the FTD clinical and genetic subtypes. We also assessed the relationship between NfL concentrations and measures of cognition and brain volume.
Serum NfL concentrations were higher in patients with FTD overall (mean 77.9 pg/mL SD 51.3 pg/mL) than controls (19.6 pg/mL SD 8.2 pg/mL; p < 0.001). Concentrations were also significantly higher in bvFTD (57.8 pg/mL SD 33.1 pg/mL) and both the semantic and nonfluent variants of PPA (95.9 and 82.5 pg/mL SD 33.0 and 33.8 pg/mL, respectively) compared with controls and in semantic variant PPA compared with logopenic variant PPA. Concentrations were significantly higher than controls in both the C9orf72 and MAPT subgroups (79.2 and 40.5 pg/mL SD 48.2 and 20.9 pg/mL, respectively) with a trend to a higher level in the GRN subgroup (138.5 pg/mL SD 103.3 pg/mL). However, there was variability within all groups. Serum concentrations correlated particularly with frontal lobe atrophy rate (r = 0.53, p = 0.003).
Increased serum NfL concentrations are seen in FTD but show wide variability within each clinical and genetic group. Higher concentrations may reflect the intensity of the disease in FTD and are associated with more rapid atrophy of the frontal lobes.
In this issue of Neuron, Raj et al. (2012) and Zhou et al. (2012) use graph theory to suggest that neurodegenerative diseases spread diffusively via intrinsic brain networks. These studies provide a ...powerful model for understanding and predicting disease-specific profiles of neurodegeneration.
Variant syndromes of Alzheimer disease (AD), led by deficits that extend beyond memory dysfunction, are of considerable clinical and neurobiological importance. Such syndromes present major ...challenges for both diagnosis and monitoring of disease, and serve to illustrate the apparent paradox of a clinically diverse group of disorders underpinned by a common histopathological substrate. This Review focuses on the most common variant AD phenotypes: posterior cortical atrophy, logopenic variant primary progressive aphasia and frontal variant AD. The neuroanatomical, molecular and pathological correlates of these phenotypes are highlighted, and the heterogeneous clinical presentations of the syndromes are discussed in the context of the emerging network paradigm of neurodegenerative disease. We argue that these apparently diverse clinical phenotypes reflect the differential involvement of a common core temporoparietofrontal network that is vulnerable to AD. According to this interpretation, the network signatures corresponding to AD variant syndromes are produced by genetic and other modulating factors that have yet to be fully characterized. The clinical and neurobiological implications of this network paradigm in the quest for disease-modifying treatments are also explored.
Abstract Primary progressive aphasia (PPA) is a neurodegenerative disorder with language impairment as the primary feature. Different subtypes have been described and the 3 best characterized are ...progressive nonfluent aphasia (PNFA), semantic dementia (SD) and logopenic/phonological aphasia (LPA). Of these subtypes, LPA is most commonly associated with Alzheimer's disease (AD) pathology. However, the features of PPA associated with AD have not been fully defined. Here we retrospectively identified 14 patients with PPA and either pathologically confirmed AD or cerebrospinal fluid (CSF) biomarkers consistent with AD. Analysis of neurological and neuropsychological features revealed that all patients had a syndrome of LPA with relatively nonfluent spontaneous speech, phonemic errors, and reduced digit span; most patients also had impaired verbal episodic memory. Analysis of the pattern of cortical thinning in these patients revealed left posterior superior temporal, inferior parietal, medial temporal, and posterior cingulate involvement and in patients with more severe disease, increasing involvement of left anterior temporal and frontal cortices and right hemisphere areas in the temporo-parietal junction, posterior cingulate, and medial temporal lobe. We propose that LPA may be a “unihemispheric” presentation of AD, and discuss this concept in relation to accumulating evidence concerning language dysfunction in AD.
Visual dysfunction in Parkinson's disease Weil, Rimona S; Schrag, Anette E; Warren, Jason D ...
Brain (London, England : 1878),
11/2016, Letnik:
139, Številka:
11
Journal Article
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Patients with Parkinson's disease have a number of specific visual disturbances. These include changes in colour vision and contrast sensitivity and difficulties with complex visual tasks such as ...mental rotation and emotion recognition. We review changes in visual function at each stage of visual processing from retinal deficits, including contrast sensitivity and colour vision deficits to higher cortical processing impairments such as object and motion processing and neglect. We consider changes in visual function in patients with common Parkinson's disease-associated genetic mutations including GBA and LRRK2 . We discuss the association between visual deficits and clinical features of Parkinson's disease such as rapid eye movement sleep behavioural disorder and the postural instability and gait disorder phenotype. We review the link between abnormal visual function and visual hallucinations, considering current models for mechanisms of visual hallucinations. Finally, we discuss the role of visuo-perceptual testing as a biomarker of disease and predictor of dementia in Parkinson's disease.
The diagnosis of young-onset dementia Rossor, Martin N, Prof; Fox, Nick C, Prof; Mummery, Catherine J, FRCP ...
Lancet neurology,
08/2010, Letnik:
9, Številka:
8
Journal Article
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Summary A diagnosis of dementia is devastating at any age but diagnosis in younger patients presents a particular challenge. The differential diagnosis is broad as late presentation of metabolic ...disease is common and the burden of inherited dementia is higher in these patients than in patients with late-onset dementia. The presentation of the common degenerative diseases of late life, such as Alzheimer's disease, can be different when presenting in the fifth or sixth decade. Moreover, many of the young-onset dementias are treatable. The identification of causative genes for many of the inherited degenerative dementias has led to an understanding of the molecular pathology, which is also applicable to later-onset sporadic disease. This understanding offers the potential for future treatments to be tailored to a specific diagnosis of both young-onset and late-onset dementia.
Frontotemporal dementia (FTD) is a clinically, pathologically and genetically heterogeneous disorder. Mutations in a number of genes are associated with FTD, although until recently only two ...progranulin (GRN) and microtubule-associated protein tau (MAPT) were known to be major causes of the disease. This review describes recent progress in identifying clinical and neuroanatomical phenotypes associated with autosomal-dominant FTD.
Around a third to a half of FTD patients have an autosomal dominant pattern of inheritance. Up to 10% of patients have a mutation in GRN and a similar proportion have a mutation in MAPT. Recently a group of patients have been shown to have a hexanucleotide repeat expansion in the noncoding region of chromosome 9 open reading frame 72 (C9ORF72). A further group of patients have an autosomal dominant family history but no mutations in any of the known genes including a group of patients who have the same pathology as GRN mutations (type A TDP-43 pathology) but are negative for GRN mutations. Clinical phenotypes vary across the different mutations. Neuroimaging studies show that GRN and MAPT mutations have distinct patterns of atrophy--asymmetric fronto-temporo-parietal atrophy with GRN versus relatively symmetric medial temporal and orbitofrontal lobe atrophy with MAPT mutations. Neuroimaging of patients with an expansion in C9ORF72 has yet to be studied in detail.
Genetic FTD is heterogeneous but certain phenotypic signatures of the major causative genes can be identified.
Objectives: Primary progressive aphasia (PPA) is a language led dementia characterised by progressive speech and language difficulties. Impairment focused PPA interventions that seek to remediate, ...alleviate or improve symptoms, dominate the research literature. Yet speech and language therapists (SLTs) report prioritising functional communication interventions (FCIs), which target engagement in an activity and participation in life situations. This systematic review investigates the research literature on FCIs for PPA to identify the key components of these interventions and their effectiveness.
Method: A systematic search of databases identified 19 studies published between 1998 and 2018. Data were extracted from the articles using the Intervention Taxonomy adaptation (ITAX).
Results: Results show that the two most common components of FCIs are to build on communication strategies people currently use, and to practise these strategies with a communication partner. There are variations in the interventions, such as location and dosage. All 19 studies report improvements, of which eight report statistically significant results. Forty-two different measures are used across the 19 studies.
Conclusion: This study highlights that building on existing strategies and practising these with a CP, are key components of FCIs for people with PPA, yet there remains a lack of clarity around optimal dosage. Further rigorous research using a core set of outcome measures is a priority in this area.
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