Neurodegenerative disease: MRI biomarkers - a precision medicine tool in neurology?

Two new studies highlight the potential of neuroimaging to aid the differential diagnosis of neurodegenerative disease, for both clinical practice and emerging trials. Although this approach holds great promise, meaningful implementation of neuroimaging as part of a tailored precision medicine strategy may require additional imaging and non-imaging biomarkers.

Independent prescribing by hospital pharmacists: Patterns and practices in a Canadian province.

Purpose: Results of a survey to determine the frequency of prescribing by Canadian hospital pharmacists with independent prescribing authority are reported.

Methods: A Web-based questionnaire was used to collect data on the prescribing activities of a designated group of hospital-affiliated pharmacists in the province of Alberta who had been granted "additional prescribing authorization" (APA) through a peer-review process and were providing clinical pharmacy services in inpatient and/or outpatient settings at the time of the survey (January-March 2014). Descriptive statistics and logistic regression analysis were used to determine the median weekly frequency of prescribing, factors associated with increased use of APA, and perceived prescribing barriers and enablers.

Apathy in Frontotemporal Degeneration: Neuroanatomical Evidence of Impaired Goal-directed Behavior.

Background: Apathy, the major manifestation of impaired goal-directed behavior (GDB), is the most common neuropsychiatric syndrome associated with behavioral variant frontotemporal degeneration (bvFTD). The behavioral and biological mechanisms of apathy, however, are not well understood. We hypothesized that GDB has multiple components-including at least initiation, planning and motivation-and that GDB is supported by a network of multiple frontal brain regions.

Circulating concentrations of glucagon-like peptide 1, glucose-dependent insulinotropic peptide, peptide YY, and insulin in client-owned lean, overweight, and diabetic cats.

Our objectives were to measure plasma concentrations of glucagon-like peptide 1 (GLP-1), glucose-dependent insulinotropic peptide (GIP), and peptide YY (PYY) in client-owned newly diagnosed diabetic cats and nondiabetic lean or overweight cats and to determine whether circulating concentrations of these hormones differed between study groups and if they increased postprandially as seen in other species. A total of 31 cats were recruited and placed into 1 of 3 study groups: lean (body condition score 4-5 on a scale of 1-9; n = 10), overweight (body condition score 6-8; n = 11), or diabetic (n = 10). Diabetics were newly diagnosed and had not had prior insulin therapy.

Deep clinical and neuropathological phenotyping of Pick disease.

Objective: To characterize sequential patterns of regional neuropathology and clinical symptoms in a well-characterized cohort of 21 patients with autopsy-confirmed Pick disease.

Methods: Detailed neuropathological examination using 70μm and traditional 6μm sections was performed using thioflavin-S staining and immunohistochemistry for phosphorylated tau, 3R and 4R tau isoforms, ubiquitin, and C-terminally truncated tau. Patterns of regional tau deposition were correlated with clinical data.

Processing ambiguity in a linguistic context: decision-making difficulties in non-aphasic patients with behavioral variant frontotemporal degeneration.

Some extent of ambiguity is ubiquitous in everyday conversations. For example, words have multiple meaning and very common pronouns, like "he" and "she" (anaphoric pronouns), have little meaning on their own and refer to a noun that has been previously introduced in the discourse. Ambiguity triggers a decision process that is not a subroutine of language processing but rather a more general domain resource.

Semi-Automated Digital Image Analysis of Pick's Disease and TDP-43 Proteinopathy.

Digital image analysis of histology sections provides reliable, high-throughput methods for neuropathological studies but data is scant in frontotemporal lobar degeneration (FTLD), which has an added challenge of study due to morphologically diverse pathologies. Here, we describe a novel method of semi-automated digital image analysis in FTLD subtypes including: Pick's disease (PiD, n=11) with tau-positive intracellular inclusions and neuropil threads, and TDP-43 pathology type C (FTLD-TDPC, n=10), defined by TDP-43-positive aggregates predominantly in large dystrophic neurites. To do this, we examined three FTLD-associated cortical regions: mid-frontal gyrus (MFG), superior temporal gyrus (STG) and anterior cingulate gyrus (ACG) by immunohistochemistry.

How the brain learns how few are "many": An fMRI study of the flexibility of quantifier semantics.

Previous work has shown that the meaning of a quantifier such as "many" or "few" depends in part on quantity. However, the meaning of a quantifier may vary depending on the context, e.g.

Beyond words: Pragmatic inference in behavioral variant of frontotemporal degeneration.

When the message of a speaker goes beyond the literal or logical meaning of the sentences used, a pragmatic inference is required to understand the complete meaning of an utterance. Here we study one example of pragmatic inference, called scalar implicature. Such an inference is required when a weaker term "some" is used in a sentence like "Some of the students passed the exam" because the speaker presumably had a reason not to use a stronger term like "all".

Estimating frontal and parietal involvement in cognitive estimation: a study of focal neurodegenerative diseases.

We often estimate an unknown value based on available relevant information, a process known as cognitive estimation. In this study, we assess the cognitive and neuroanatomic basis for quantitative estimation by examining deficits in patients with focal neurodegenerative disease in frontal and parietal cortex. Executive function and number knowledge are key components in cognitive estimation.

Semi-automated quantification of C9orf72 expansion size reveals inverse correlation between hexanucleotide repeat number and disease duration in frontotemporal degeneration.

We investigated whether chromosome 9 open reading frame 72 hexanucleotide repeat expansion (C9orf72 expansion) size in peripheral DNA was associated with clinical differences in frontotemporal degeneration (FTD) and amyotrophic lateral sclerosis (ALS) linked to C9orf72 repeat expansion mutations. A novel quantification workflow was developed to measure C9orf72 expansion size by Southern blot densitometry in a cross-sectional cohort of C9orf72 expansion carriers with FTD (n = 39), ALS (n = 33), both (n = 35), or who are unaffected (n = 21). Multivariate linear regressions were performed to assess whether C9orf72 expansion size from peripheral DNA was associated with clinical phenotype, age of disease onset, disease duration and age at death.

If so many are "few," how few are "many"?

The scope of reference of a word's meaning can be highly variable. We present a novel paradigm to investigate the flexible interpretation of word meaning. We focus on quantifiers such as "many" or "few," a class of words that depends on number knowledge but can be interpreted in a flexible manner.

Occupational attainment influences survival in autopsy-confirmed frontotemporal degeneration.

Objective: To examine the influence of occupational attainment and education on survival in autopsy-confirmed cases of frontotemporal lobar degeneration (FTLD) and Alzheimer disease (AD).

Methods: We performed a retrospective chart review of 83 demographically matched, autopsy-confirmed FTLD (n = 34) and AD (n = 49) cases. Each patient's primary occupation was classified and ranked.

Impaired cognitive flexibility in amyotrophic lateral sclerosis.

Background And Objective: Up to half of patients with amyotrophic lateral sclerosis (ALS) may have cognitive difficulty, but most cognitive measures are confounded by a motor component. Studies relating impaired cognition in ALS to disease in gray matter and white matter are rare. Our objective was to assess executive function in patients with ALS using a simple, untimed measure with minimal motor demands, and to relate performance to structural disease.

Physician perspectives on care of individuals with severe mobility impairments in primary care in Southwestern Ontario, Canada.

Despite the high health risks associated with severe mobility impairments, individuals with physical disabilities are less likely to receive the same level of primary care as able-bodied persons. This study explores family physicians' perspectives on primary care for individuals with mobility impairments to identify and better understand the challenges that prevent equitable service delivery to this group of patients. Semi-structured interviews were conducted in the autumn of 2012 with a purposeful sample of 20 family physicians practising in Southwestern Ontario to gather their perspectives of the personal and professional barriers to healthcare delivery for individuals with mobility impairments, including perceptions of challenges, contributing reasons and possible improvements.

C9orf72 promoter hypermethylation is neuroprotective: Neuroimaging and neuropathologic evidence.

Objective: To use in vivo neuroimaging and postmortem neuropathologic analysis in C9orf72 repeat expansion patients to investigate the hypothesis that C9orf72 promoter hypermethylation is neuroprotective and regionally selective.

Methods: Twenty patients with a C9orf72 repeat expansion participating in a high-resolution MRI scan and a clinical examination and a subset of patients (n = 11) were followed longitudinally with these measures. Gray matter (GM) density was related to C9orf72 promoter hypermethylation using permutation-based testing.

Getting on the same page: the neural basis for social coordination deficits in behavioral variant frontotemporal degeneration.

For social interactions to be successful, individuals must establish shared mental representations that allow them to reach a common understanding and "get on the same page". We refer to this process as social coordination. While examples of social coordination are ubiquitous in daily life, relatively little is known about the neuroanatomic basis of this complex behavior.

Placental adaptations in growth restriction.

The placenta is the primary interface between the fetus and mother and plays an important role in maintaining fetal development and growth by facilitating the transfer of substrates and participating in modulating the maternal immune response to prevent immunological rejection of the conceptus. The major substrates required for fetal growth include oxygen, glucose, amino acids and fatty acids, and their transport processes depend on morphological characteristics of the placenta, such as placental size, morphology, blood flow and vascularity. Other factors including insulin-like growth factors, apoptosis, autophagy and glucocorticoid exposure also affect placental growth and substrate transport capacity.

Frontotemporal lobar degeneration: defining phenotypic diversity through personalized medicine.

Frontotemporal lobar degeneration (FTLD) comprises two main classes of neurodegenerative diseases characterized by neuronal/glial proteinaceous inclusions (i.e., proteinopathies) including tauopathies (i.

White matter disease contributes to apathy and disinhibition in behavioral variant frontotemporal dementia.

Objective: To relate changes in fractional anisotropy associated with behavioral variant frontotemporal dementia to measures of apathy and disinhibition.

Background: Apathy and disinhibition are the 2 most common behavioral features of behavioral variant frontotemporal dementia, and these symptoms are associated with accelerated patient decline and caregiver stress. However, little is known about how white matter disease contributes to these symptoms.

Deficits in sentence expression in amyotrophic lateral sclerosis.

Quantitative examinations of speech production in amyotrophic lateral sclerosis (ALS) are rare. To identify language features minimally confounded by a motor disorder, we investigated linguistic and motor sources of impaired sentence expression in ALS, and we related deficits to gray matter (GM) and white matter (WM) MRI abnormalities. We analyzed a semi-structured speech sample in 26 ALS patients and 19 healthy seniors for motor- and language-related deficits.

Hypermethylation of repeat expanded C9orf72 is a clinical and molecular disease modifier.

C9orf72 promoter hypermethylation inhibits the accumulation of pathologies which have been postulated to be neurotoxic. We tested here whether C9orf72 hypermethylation is associated with prolonged disease in C9orf72 mutation carriers. C9orf72 methylation was quantified from brain or blood using methylation-sensitive restriction enzyme digest-qPCR in a cross-sectional cohort of 118 C9orf72 repeat expansion carriers and 19 non-carrier family members.

Counting or chunking? Mathematical and heuristic abilities in patients with corticobasal syndrome and posterior cortical atrophy.

A growing amount of empirical data is showing that the ability to manipulate quantities in a precise and efficient fashion is rooted in cognitive mechanisms devoted to specific aspects of numbers processing. The analog number system (ANS) has a reasonable representation of quantities up to about 4, and represents larger quantities on the basis of a numerical ratio between quantities. In order to represent the precise cardinality of a number, the ANS may be supported by external algorithms such as language, leading to a "precise number system".