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IntroductionIdentifying clinical measures that track disease in the earliest stages of frontotemporal lobar degeneration (FTLD) is important for clinical trials. Familial FTLD provides a unique paradigm to study early FTLD. Executive dysfunction is a clinically relevant hallmark of FTLD and may be a marker of disease progression.MethodsNinety-three mutation carriers with no symptoms or minimal/questionable symptoms (MAPT, n = 31; GRN, n = 28; C9orf72, n = 34; Clinical Dementia Rating scale plus NACC FTLD Module < 1) and 78 noncarriers enrolled through Advancing Research and Treatment in Frontotemporal Lobar Degeneration/Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects studies completed the Executive Abilities: Measures and Instruments for Neurobehavioral Evaluation and Research (NIH-EXAMINER) and the UDS neuropsychological battery. Linear mixed-effects models were used to identify group differences in cognition at baseline and longitudinally. We examined associations between cognition, clinical functioning, and magnetic resonance imaging volumes.ResultsNIH-EXAMINER scores detected baseline and differences in slopes between carriers and noncarriers, even in carriers with a baseline Clinical Dementia Rating scale plus NACC FTLD Module = 0. NIH-EXAMINER declines were associated with worsening clinical symptoms and brain volume loss.DiscussionThe NIH-EXAMINER is sensitive to cognitive changes in presymptomatic familial FTLD and is a promising surrogate endpoint.

Primary progressive aphasia (PPA) is associated with progressive loss of language functions in the context of irreversible neurodegeneration, for which there is no cure. Speech-language therapy can help preserve language abilities, and most promisingly, interventions like transcranial direct current stimulation (tDCS) have been shown to augment the effectiveness of therapy. However, the underlying mechanism for this enhancement is unknown. We evaluated the behavioural and physiological (using resting-state magnetoencephalography [rsMEG]) effects of contemporary naming treatment provided with tDCS in a patient with an advanced case of nonfluent variant PPA (P01; 67 year old male). P01 was mute but had preserved written abilities, which we aimed to enhance with written naming therapy and excitatory or anodal-tDCS. We hypothesized greater improvement in written performance, particularly immediate gains, maintenance, and generalization, after anodal- than sham-tDCS. Additionally, reductions in oscillatory abnormal activity, as indicated by rsMEG, were expected after repeated sessions of anodal-tDCS with the naming treatment. A written picture naming therapy was paired with five sessions of anodal and five sessions of sham high-definition tDCS over two weeks. Anatomical and neurophysiological abnormalities were mapped with structural-MRI and rsMEG, respectively. TDCS was targeted towards an anatomically intact left supramarginal gyrus. The therapy-induced changes in written performance were evaluated on both trained and untrained pictures using Levenshtein Distances (LD). The neurophysiological changes were evaluated by comparing spectral relative power estimates in frequency bands ranging from delta to low-gamma (1–50 Hz), before and after therapy. All evaluations were completed immediately after therapy with sham- and anodal-tDCS, and at a 3-month follow-up. Compared to sham-tDCS, anodal-tDCS augmented the immediate therapy-induced gains on trained items, as indicated by reductions in LD scores, reflecting improvement in written performance, particularly for more difficult target words. Neural activity at the stimulation spot and in surrounding and remote regions exhibited reduced oscillatory slowing, both immediately after one session (short-term) and after completion of five sessions (long-term) of anodal-tDCS compared to sham-tDCS. This is manifested as decreased theta (1–4 Hz) and increased beta and low-gamma (15–50 Hz) power. No additional gains with anodal-tDCS were found on untrained items (generalization) or at 3-month follow-up (maintenance). Our findings suggest that five sessions of anodal-tDCS can improve written performance by partially reversing abnormal neural activity and thus boosting the functional capacity of the structurally intact cortex. Longer duration of treatment may be needed for additional gains in maintenance and generalization with anodal-tDCS. [ABSTRACT FROM AUTHOR]

Dementias with predominant language involvement, called primary progressive aphasias provide us with unique insight into systematic breakdown of language in neurodegenerative diseases and the structures and networks involved. Clinical and neuroimaging models quite distinct from those seen in stroke aphasias have evolved. In this short overview, we will discuss the cognitive processes involved in expressive and receptive verbal communication and how these processes are affected in the different variants of primary progressive aphasia producing distinctive clinical patterns. We will also discuss the brain's language network and how different components of the network break down in each of the primary progressive aphasia variants.

Dementias with predominant language involvement, called primary progressive aphasias provide us with unique insight into systematic breakdown of language in neurodegenerative diseases and the structures and networks involved. Clinical and neuroimaging models quite distinct from those seen in stroke aphasias have evolved. In this short overview, we will discuss the cognitive processes involved in expressive and receptive verbal communication and how these processes are affected in the different variants of primary progressive aphasia producing distinctive clinical patterns. We will also discuss the brain's language network and how different components of the network break down in each of the primary progressive aphasia variants. [ABSTRACT FROM AUTHOR]

Introduction: Identifying clinical measures that track disease in the earliest stages of frontotemporal lobar degeneration (FTLD) is important for clinical trials. Familial FTLD provides a unique paradigm to study early FTLD. Executive dysfunction is a clinically relevant hallmark of FTLD and may be a marker of disease progression. Methods: Ninety‐three mutation carriers with no symptoms or minimal/questionable symptoms (MAPT, n = 31; GRN, n = 28; C9orf72, n = 34; Clinical Dementia Rating scale plus NACC FTLD Module < 1) and 78 noncarriers enrolled through Advancing Research and Treatment in Frontotemporal Lobar Degeneration/Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects studies completed the Executive Abilities: Measures and Instruments for Neurobehavioral Evaluation and Research (NIH‐EXAMINER) and the UDS neuropsychological battery. Linear mixed‐effects models were used to identify group differences in cognition at baseline and longitudinally. We examined associations between cognition, clinical functioning, and magnetic resonance imaging volumes. Results: NIH‐EXAMINER scores detected baseline and differences in slopes between carriers and noncarriers, even in carriers with a baseline Clinical Dementia Rating scale plus NACC FTLD Module = 0. NIH‐EXAMINER declines were associated with worsening clinical symptoms and brain volume loss. Discussion: The NIH‐EXAMINER is sensitive to cognitive changes in presymptomatic familial FTLD and is a promising surrogate endpoint. [ABSTRACT FROM AUTHOR]

Purpose: To assess the binding of the PET tracer [18F]THK5351 in patients with different primary progressive aphasia (PPA) variants and its correlation with clinical deficits. The majority of patients with nonfluent variant (NFV) and logopenic variant (LV) PPA have underlying tauopathy of the frontotemporal lobar or Alzheimer disease type, respectively, while patients with the semantic variant (SV) have predominantly transactive response DNA binding protein 43-kDa pathology.Methods: The study included 20 PPA patients consecutively recruited through a memory clinic (12 NFV, 5 SV, 3 LV), and 20 healthy controls. All participants received an extensive neurolinguistic assessment, magnetic resonance imaging and amyloid biomarker tests. [18F]THK5351 binding patterns were assessed on standardized uptake value ratio (SUVR) images with the cerebellar grey matter as the reference using statistical parametric mapping. Whole-brain voxel-wise regression analysis was performed to evaluate the association between [18F]THK5351 SUVR images and neurolinguistic scores. Analyses were performed with and without partial volume correction.Results: Patients with NFV showed increased binding in the supplementary motor area, left premotor cortex, thalamus, basal ganglia and midbrain compared with controls and patients with SV. Patients with SV had increased binding in the temporal lobes bilaterally and in the right ventromedial frontal cortex compared with controls and patients with NFV. The whole-brain voxel-wise regression analysis revealed a correlation between agrammatism and motor speech impairment, and [18F]THK5351 binding in the left supplementary motor area and left postcentral gyrus. Analysis of [18F]THK5351 scans without partial volume correction revealed similar results.Conclusion: [18F]THK5351 imaging shows a topography closely matching the anatomical distribution of predicted underlying pathology characteristic of NFV and SV PPA. [18F]THK5351 binding correlates with the severity of clinical impairment. [ABSTRACT FROM AUTHOR]

Artistic ability and creativity are defining characteristics of human behavior. Behavioral neurology, as a specialty, believes that even the most complex behaviors can be modeled and understood as the summation of smaller cognitive functions. Literature from individuals with specific brain lesions has helped to map out these smaller regions of cognitive abilities. More recently, models based on neurodegenerative conditions, especially from the frontotemporal dementias, have allowed for greater nuanced investigations into the various functional anatomies necessary for artistic behavior and possibly the underlying networks that promote creativity., (© 2013 Elsevier B.V. All rights reserved.)