Contributor: Daniella Ladowski, M.Sc., University of Western Ontario (Doctoral Candidate)
Amyotrophic Lateral Sclerosis (ALS), also referred to as motor neuron disease, is a progressive disease affecting both upper and lower motor neurons. According to the El Escorial criteria  and its revisions [2-5], diagnosis is largely based on clinical and electrophysiological evidence of motor neuron dysfunction to the exclusion of other motor disorders. However, ALS may be conceptualized as a collection of disorders with numerous phenotypic variants, each with its own implications for prognosis and treatment [6-7]. One such variant is ALS with comorbid frontotemporal dementia (FTD).
One third to one half of individuals with ALS exhibit cognitive impairment in at least one domain, and approximately 15% meet criteria for FTD [8-9]. It is unlikely that ALS with FTD represents a discrete diagnostic category; rather, cognitive and behavioural symptoms that are characteristic of FTD appear to fall on a continuum in ALS . Among individuals with ALS, common cognitive symptoms include executive dysfunction (e.g., impaired verbal fluency, complex attention, cognitive flexibility) and to a lesser degree, language and memory impairment [10-12]. Behavioural abnormalities may also be prominent, including apathy, irritability, disinhibition, and impaired social cognition [12-14]. Based on the observation that individuals without dementia may exhibit clinically meaningful cognitive and behavioural changes, Strong and colleagues  proposed a classification system for frontotemporal syndromes in ALS, which characterizes syndromes that meet criteria for a dementia diagnosis [ALS-FTD and ALS-comorbid dementia (non-FTD)] as well as those that do not meet full criteria but represent significant impairments (ALS-behavioural impairment and ALS-cognitive impairment).
In addition to cognitive and behavioural symptomatology, ALS and FTD share common neuropathological features. In neuroimaging studies, cognitively-impaired individuals with ALS exhibit patterns of atrophy and hypometabolism/hypoperfusion in frontotemporal regions that are comparable to those observed in FTD [13,16-18]. Even in the absence of overt dementia, large-scale abnormalities in cortical thickness and functional connectivity have been detected in ALS [19-20]. In terms of pathogenesis, some genetic mutations and other biomarkers have been implicated in both ALS and FTD . For example, in 2006, Neumann and colleagues  discovered that TAR DNA-binding protein 43 (TDP-43) was the major disease protein in both ALS and FTD. In 2011, mutations of the C9ORF72 gene were shown to explain familial cases of co-occurring ALS and FTD linked to chromosome 9 [22-23]. These and other discoveries are further evidence of the disease continuum that accounts for ALS and FTD concordance.
Detection of cognitive impairment in individuals with ALS is essential for treatment planning. Individuals with ALS-FTD demonstrate lower rates of compliance with nutritional and respiratory interventions compared to individuals with ALS alone . Since these interventions are administered in advanced stages of the disease to prolong survival, noncompliance likely contributes to the shorter survival times observed among individuals with ALS-FTD compared to ALS alone [24-25]. Among individuals without FTD, executive impairment may also predict shorter survival in ALS, whereas more subtle or non-executive impairments are not thought to affect survival [25-26]. Greater cognitive impairment in ALS has also been linked to increased caregiver burden . Finally, capacity in healthcare decision-making is an important consideration in ALS, especially as it relates to end-of-life decisions. Given that cognitive symptoms often precede motor symptoms in ALS-FTD , it may be prudent to establish advance directives at the earliest signs of cognitive decline before decision-making becomes affected and speech/motor disturbances hinder communication. In light of these challenges, early neuropsychological assessment should be undertaken in order to best prepare patients, caregivers, and clinicians for the road ahead.
Beeldman, E., Raaphorst, J., Klein Twennaar, M., Govaarts, R., Pijnenburg, Y. A. L., de Haan, R. J., … Schmand, B. A. (2018). The cognitive profile of behavioural variant FTD and its similarities with ALS: A systematic review and meta-analysis. Journal of Neurology, Neurosurgery & Psychiatry. Advance online publication. http://doi.org/10.1136/jnnp-2017-317459
Abstract: Approximately 30% of patients with amyotrophic lateral sclerosis (ALS) have cognitive impairment and 8%–14% fulfil the criteria for behavioural variant frontotemporal dementia (bv-FTD). The cognitive profiles of ALS and bv-FTD have been reported to be comparable, but this has never been systematically investigated. We aimed to determine the cognitive profile of bv-FTD and examine its similarities with that of ALS, to provide evidence for the existence of a cognitive disease continuum encompassing bv-FTD and ALS. We therefore systematically reviewed neuropsychological studies on bv-FTD patients and healthy volunteers. Neuropsychological tests were divided in 10 cognitive domains and effect sizes were calculated for all domains and compared with the cognitive profile of ALS by means of a visual comparison and a Pearson’s r correlation coefficient. We included 120 studies, totalling 2425 bv-FTD patients and 2798 healthy controls. All cognitive domains showed substantial effect sizes, indicating cognitive impairment in bv-FTD patients compared to healthy controls. The cognitive domains with the largest effect sizes were social cognition, verbal memory and fluency (1.77–1.53). The cognitive profiles of bv-FTD and ALS (10 cognitive domains, 1287 patients) showed similarities on visual comparison and a moderate correlation 0.58 (p=0.13). When social cognition, verbal memory, fluency, executive functions, language and visuoperception were considered, i.e. the cognitive profile of ALS, Pearson’s r was 0.73 (p=0.09), which raised to 0.92 (p=0.03), when language was excluded in this systematic analysis of patients with a non-language subtype of FTD. The cognitive profile of bv-FTD consists of deficits in social cognition, verbal memory, fluency and executive functions and shows similarities with the cognitive profile of ALS. These findings support a cognitive continuum encompassing ALS and bv-FTD.
(Lecture) Pathology and current molecular classification of ALS/FTD
Presenter: Dr. Tibor Hortobagyi, Department of Neuropathology, University of Debrecen, Hungary
Dr. Hortobagyi provides a summary of neuropathological findings in ALS from the first candidate disease proteins and genetic mutations to the current state of knowledge, noting common biomarkers of ALS and FTD. This video begins with a general discussion of the importance of neuropathological investigation for the classification of neurodegenerative disorders.
(Seminar) Caregiver education program for ALS-FTD
Presenter: Dr. Susan Walsh, ALS Association of Greater Philadelphia, USA
This is the first part of a three-part educational seminar for caregivers of individuals with ALS and FTD. In this segment, Dr. Walsh provides background information on ALS and FTD. The second and third segments (also available on Youtube) describe practical strategies with respect to behaviour management and problem solving.
(Handout) ALS & Cognitive Changes
Publisher: ALS Society of Canada
This handout provides basic information on cognitive and behavioural changes in ALS. In the past, individuals with ALS and their caregivers have reported feeling under-informed about cognitive changes , so a handout such as this one can be helpful in starting important conversations about what to expect.
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Contributor: Yosefa Allegra Ehrlich, M.Phil., Ph.D. Candidate in Clinical Psychology, Queens College, City University of New York (CUNY)
The use of biomarkers in diagnosing Alzheimer’s disease (AD) in vivo is gaining popularity. Biomarkers refer to measureable characteristics that indicate the presence of biologic and/or pathologic processes (1). This shift is based on an expanding body of research indicating that in vivo methods validly estimate post-mortem AD pathologic changes that characterize the disease (2–5). The goals of incorporating biomarkers into the diagnosis include: clarifying the multifaceted etiology/pathophysiology (5), standardizing research terms (4,6), identifying individuals in preclinical phases (6,7), improving diagnostic accuracy (8), and developing more precise interventions (9).
Over the past decade, the National Institute on Aging and Alzheimer’s Association (NIAA-AA) and the International Working Group (IWG) have continually proposed new criteria for the diagnosis of AD. There are points of overlap as well as divergence between their suggested frameworks. In a position paper still under review (5), the NIAA-AA propose a definition of AD based on evidence of three biological markers of pathologic processes: (a) b-amyloid plaques, (b) phosphorylated tau (P-tau), (c) markers of neuronal injury (e.g., elevated CSF total tau (T-tau)) and cerebral hypometabolism and atrophy (10). Presence of b-amyloid deposition alone (with normal tau and no neurodegeneration) is considered Alzheimer’s pathologic change. A diagnosis of AD indicates evidence of both b-amyloid and P-tau. Neuronal injury is understood to emerge as a consequence of b-amyloid and tau and is not specific to AD pathology (11); accordingly, those markers are conceptualized to emerge in the later stages of the disease continuum and are not essential for a diagnosis. Importantly, these diagnostic states exist independently of clinical symptoms. The authors recognize that cognitive impairment generally corresponds with increased presence of biomarkers and suggest that clinical changes should be measured along six stages of increasing impairment with the first stage beginning with positive evidence of biomarkers. This framework reflects an effort to disentangle the presence of AD neuropathology (disease process) from the clinical syndrome (signs/symptoms).
The IWG-2 criteria for AD (9,3,2,12,13) also require in vivo evidence of pathology ((a)decreased CSF b-amyloid and increased CSF P- and T-tau, (b) increased amyloid PET, (c) AD autosomal mutation) for an AD diagnosis. Similar to the NIA-AA, the IWG-2 agrees that biomarkers can be detectable in pre-clinical (asymptomatic) states and calls for a continuum-based understanding of disease course. However, the groups’ definitions diverge regarding clinical phenotypic expression. The IWG-2 criteria call for evidence of cognitive disturbance, primarily episodic memory impairment, in issuing a diagnosis. In the preclinical stage, patients with MCI and positive biomarkers receive a diagnosis of MCI due to AD or, interchangeably, prodromal AD (3,12,13). A diagnosis of typical AD is only distinguished by the degree of cognitive impairment (2). By including the cognitive criterion in the diagnosis, the authors are conceptualizing AD as both biological and syndromic (clinico-pathological).
While the definition of an AD diagnosis remains unresolved, the utility and validity of biomarkers measured via imaging and CSF markers have been well demonstrated (14). Fibrillary b-amyloid deposition associated with AD can be validly and reliably measured in vivo via increased amyloid PET binding and low CSF Ab42 (15). Pathologic tau deposition in AD can be assessed through newly developed PET ligands that show elevated cortical tau binding as well as elevated P-tau CSF markers (15,16). Neuronal injury is measured via cortical atrophy (on MRI) and/or hypometabolism (on FDG PET) generally in medial temporal, medial parietal, and lateral temporal-parietal cortices (17).
Limitations of incorporating biomarkers in AD diagnoses apply in both research and clinical settings. Despite increased validity, none of the in vivo biomarker tools are as sensitive as histology (18). The lack of consensus among researchers on diagnostic criteria limits standardization and generalizability of findings. There are also no clear numeric cut-offs by which to categorize biomarker levels; while some have proposed continuous measurements (5), this complicates researchstandardization as well as clinical translation. The primary clinical concern surrounds poor specificity and sensitivity of biomarkers to clinical symptoms associated with AD (19). Between 30 to 40% of individuals with no cognitive impairment (asymptomatic) show biological abnormalities in vivo and on autopsy (20,21), while 10 to 30% of individuals with clinical signs of AD-related dementia have clean autopsies (22). This has led to the proposal of including additional factors (e.g., vascular) as biomarkers (23) to increase prognostic reliability. Further clinical challenges include prohibitive costs, limited accessibility, inconsistent regulatory approval, and uncertain insurance reimbursement (12). Finally, as in many areas of research, more population-based studies are needed to validate the utility of biomarkers in diverse ethnic groups (24).
Highlighted Abstract: Fluid and imaging biomarkers for Alzheimer's disease: Where we stand and where to head to.
There is increasing evidence that a number of potentially informative biomarkers for Alzheimer disease (AD) can improve the accuracy of diagnosing this form of dementia, especially when used as a panel of diagnostic assays and interpreted in the context of neuroimaging and clinical data. Moreover, by combining the power of CSF biomarkers with neuroimaging techniques to visualize Aβ deposits (or neurodegenerative lesions), it might be possible to better identify individuals at greatest risk for developing MCI and converting to AD. The objective of this article was to review recent progress in selected imaging and chemical biomarkers for prediction, early diagnosis and progression of AD. We present our view point of a scenario that places CSF and imaging markers on the verge of general utility based on accuracy levels that already match (or even surpass) current clinical precision.
Henriques, A. D., Benedet, A. L., Camargos, E. F., Rosa-Neto, P., & Nóbrega, O. T. (2018). Fluid and imaging biomarkers for Alzheimer’s disease: Where we stand and where to head to. Experimental Gerontology, (January), 1–9. http://doi.org/10.1016/j.exger.2018.01.002
Other Media and Resources:
Webinar- Hear Clifford Jack, MD present his conceptualization of biomarker stages
Webinar- Learn about the development and uses of the AlzBiomarker database
Webinar- Biomarkers, cognition, and cognitive reserve in AD
Bondi, M.W., Edmonds, E.C., Salmon, D.P., 2017. Alzheimer’s Disease: Past, Present, and Future. J. Int. Neuropsychol. Soc. 23, 818–831.
Frisoni, G. B., Boccardi, M., Barkhof, F., Blennow, K., Cappa, S., Chiotis, K., … Winblad, B. (n.d.). A Strategic Research Agenda to the Biomarker-Based Diagnosis of Prodromal Alzheimer’s Disease, 1–39. http://discovery.ucl.ac.uk/1567593/1/Frisoni_Strategic_roadmap_early_diagnosis.pdf
Frisoni, G. B., Boccardi, M., Barkhof, F., Blennow, K., Cappa, S., Chiotis, K., … Winblad, B. (2017). Strategic roadmap for an early diagnosis of Alzheimer’s disease based on biomarkers. The Lancet Neurology, 16(8), 661–676. http://doi.org/10.1016/S1474-4422(17)30159-X
Jack, C. R. J., Bennet, D. A., Blennow, K., Carrillo, M. C., Dunn, B., Elliot, C., … Sperling, R. (n.d.). NIA-AA Research Framework: Towards a Biological Definition of Alzheimer’s Disease. https://alz.org/aaic/_downloads/draft-nia-aa-7-18-17.pdf
Vanderschaeghe, G., Dierickx, K., Vandenberghe, R., 2018. Review of the Ethical Issues of a Biomarker-Based Diagnoses in the Early Stage of Alzheimer’s Disease. J. Bioeth. Inq. 1–12.
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Contributor: Briana Brukilacchio, M.Ed., The University of Texas at Austin, PhD Program in School Psychology
An estimated 15% of all patients with focal epilepsy syndromes do not experience substantial relief when treated with anticonvulsant medications alone . For these patients with intractable epilepsy, surgical intervention is often indicated . In order to maximize postoperative benefits and minimize the risk of associated impairments, such patients undergo presurgical epilepsy evaluations prior to treatment . Evaluations are conducted by a multidisciplinary team and typically include reports of clinical semiology (signs and symptoms of the seizure activity), structural and functional neuroimaging, electroencephalography (EEG) video telemetry, and neuropsychological testing. Primary goals of the presurgical evaluation are to map the epileptogenic area (a conceptual area of the cortex, believed to be indispensable in the generation of seizure activity; [1, 4]) and eloquent cortex (critical language, sensorimotor, and memory areas which are avoided as much as possible during surgery) to guide surgical procedures and predict postsurgical functioning. With regard to language, the primary objective is to identify the dominant hemisphere involved in language functions (i.e. language laterality ), although noninvasive imaging modalities have made it possible to map discrete language functions with improved spatial and temporal detail.
The intracarotid amobarbital procedure (Wada test; ) remains the current gold-standard in a clinical evaluation of language laterality. However, the procedure can include medical complications in up to 3% of cases and provides relatively crude hemispheric data . Limitations of the Wada test have led to developments in non-invasive neuroimaging modalities [8, 9], primarily functional Magnetic Resonance Imaging (fMRI) and magnetoencephalography (MEG). fMRI measures blood oxygenation levels as a proxy for brain activity in response to cognitive tasks. An alternative method known as resting state fMRI, tracks blood oxygenation levels in the absence of an explicit task as a proxy for large-scale brain activity . Alternatively, MEG measures electromagnetic fluctuations outside the skull as a proxy for brain activity and this method has higher spatial and temporal sensitivity compared to fMRI. The most common MEG analysis used in language laterality is dipole fitting, which fits single or multiple dipoles within the brain and indicates their corresponding strength and orientation . An advanced method of signal processing and source localization in MEG, called beamforming, has recently allowed for meaningful data to be extracted from patients with metal implants (e.g. shunts, braces, and vagus nerve stimulators) which normally cause artifacts that render neuroimaging data uninterpretable .
Noninvasive imaging tools are used with a wide variety of language tasks and analytic methods, therefore they have contributed substantially to language mapping in presurgical epilepsy cases. Laterality indices can be quantified and classified by adjusting a multitude of parameters including p-values at a voxel level, threshold levels, baseline and active windows, etc. . Language laterality has been assessed across numerous tasks, including a variety of verbal fluency tasks (e.g. phonemic fluency, verb generation), passive speech listening, text reading, phonemic judgment, semantic decision, sentence comprehension, and naming . Although the strength and pattern of lateralization varies across tasks and is thought to represent true variability in language networks, laterality indices are strongest in verbal fluency tasks . For instance, verb generation and phonemic fluency tasks produce strong laterality indices in frontal regions [13, 14, 15], and semantic fluency tasks produce strong laterality indices in temporoparietal regions .
There are numerous challenges and potential gains associated with the implementation of fMRI, MEG, and other noninvasive imaging modalities in presurgical evaluations. Challenges primarily include the lack of normative data against which patients can be compared (especially in pediatrics ) and insufficient guidelines to direct task selection, analysis, and interpretation [3, 5]. For these reasons, the Wada test remains the current gold-standard in clinical practice, although many epilepsy centers have integrated fMRI and MEG into presurgical evaluations to further validate or expand upon neuropsychological findings .
A particularly promising application for noninvasive imaging is the development of passive language tasks. Noncompliant and pediatric patients experience difficulty with standard task demands, such as verbal fluency paradigms. However, passive tasks (e.g. listening to a story) require minimal attentional and linguistic demands, therefore they may yield valid laterality indices in patients who otherwise would be considered untestable due to clinical complications or developmental limitations .
Title: Language lateralization of a bilingual person with epilepsy using a combination of
fMRI and neuropsychological assessment findings
Citation: O’Grady, C., Omisade, A., & Sadler, R. M. (2016). Language lateralization of a bilingual person with epilepsy using a combination of fMRI and neuropsychological assessment findings. Neurocase, 22(5), 436-442.
Abstract: This report describes the findings of language functional magnetic resonance imaging (fMRI) in a left-handed Urdu and English speaker with right hemisphere-originating epilepsy and unclear language dominance. fMRI is a reliable method for determining hemispheric language dominance in presurgical planning. However, the effects of bilingualism on language activation depend on many factors including age of acquisition and proficiency in the tested language, and morphological properties of the language itself. This case demonstrates that completing fMRI in both spoken languages and interpreting the results within the context of a neuropsychological assessment are essential in arriving at accurate conclusions about language distribution in bilingual patients.
1. Engel, J. (1993). Update on surgical treatment of the epilepsies Summary of The Second International Palm Desert Conference on the Surgical Treatment of the Epilepsies (1992). Neurology, 43(8), 1612-1612.
2. Rosenow, F., & Lüders, H. (2001). Presurgical evaluation of epilepsy. Brain, 124(9), 1683-1700.
3. Bradshaw, A. R., Bishop, D. V., & Woodhead, Z. V. (2017). Methodological considerations in assessment of language lateralisation with fMRI: a systematic review. PeerJ, 5, e3557.
4. Jehi, L. (2018). The Epileptogenic Zone: Concept and Definition. Epilepsy Currents, 18(1), 12-16.
5. Bradshaw, A. R., Thompson, P. A., Wilson, A. C., Bishop, D. V., & Woodhead, Z. V. (2017). Measuring language lateralisation with different language tasks: a systematic review. PeerJ, 5, e3929.
6. Wada, J., & Rasmussen, T. (1960). Intracarotid injection of sodium amytal for the lateralization of cerebral speech dominance: experimental and clinical observations. Journal of Neurosurgery, 17(2), 266-282.
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8. Gaillard, W. D. (2000). Structural and functional imaging in children with partial epilepsy. Mental retardation and developmental disabilities research reviews, 6(3), 220-226.
9. Verrotti, A., Pizzella, V., Trotta, D., Madonna, L., Chiarelli, F., & Romani, G. L. (2003). Magnetoencephalography in pediatric neurology and in epileptic syndromes. Pediatric neurology, 28(4), 253-261.
10. Thomason, M. E., Dennis, E. L., Joshi, A. A., Joshi, S. H., Dinov, I. D., Chang, C., ... & Glover, G. H. (2011). Resting-state fMRI can reliably map neural networks in children. Neuroimage, 55(1), 165-175.
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12. Stapleton-Kotloski, J. R., Kotloski, R. J., Boggs, J. A., Popli, G., O’Donovan, C. A., Couture, D. E., ... & Godwin, D. W. (2014). Localization of interictal epileptiform activity using magnetoencephalography with synthetic aperture magnetometry in patients with a vagus nerve stimulator. Frontiers in neurology, 5, 244.
13. Kleinhans, N. M., Müller, R. A., Cohen, D. N., & Courchesne, E. (2008). Atypical functional lateralization of language in autism spectrum disorders. Brain research, 1221, 115-125.
14. Ruff, I. M., Brennan, N. P., Peck, K. K., Hou, B. L., Tabar, V., Brennan, C. W., & Holodny, A. I. (2008). Assessment of the language laterality index in patients with brain tumor using functional MR imaging: effects of thresholding, task selection, and prior surgery. American journal of neuroradiology, 29(3), 528-535.
15. Sanjuán, A., Bustamante, J. C., Forn, C., Ventura-Campos, N., Barrós-Loscertales, A., Martínez, J. C., ... & Ávila, C. (2010). Comparison of two fMRI tasks for the evaluation of the expressive language function. Neuroradiology, 52(5), 407-415.
16. Jensen-Kondering, U. R., Ghobadi, Z., Wolff, S., Jansen, O., & Ulmer, S. (2012). Acoustically presented semantic decision-making tasks provide a robust depiction of the temporo-parietal speech areas. Journal of Clinical Neuroscience,19(3), 428-433.
17. Collinge, S., Prendergast, G., Mayers, S. T., Marshall, D., Siddell, P., Neilly, E., ... & Zaman, A. (2017). Pre-surgical mapping of eloquent cortex for paediatric epilepsy surgery candidates: Evidence from a review of advanced functional neuroimaging. Seizure-European Journal of Epilepsy, 52, 136-146.
18. Arya, R., Wilson, J. A., Fujiwara, H., Vannest, J., Byars, A. W., Rozhkov, L., ... & Horn, P. S. (2018). Electrocorticographic high‐gamma modulation with passive listening paradigm for pediatric extraoperative language mapping. Epilepsia, 59(4), 792-801.
Bradshaw, A. R., Thompson, P. A., Wilson, A. C., Bishop, D. V., & Woodhead, Z. V. (2017). Measuring language lateralisation with different language tasks: a systematic review. PeerJ, 5, e3929.
Collinge, S., Prendergast, G., Mayers, S. T., Marshall, D., Siddell, P., Neilly, E., ... & Zaman, A. (2017). Pre-surgical mapping of eloquent cortex for paediatric epilepsy surgery candidates: Evidence from a review of advanced functional neuroimaging. Seizure-European Journal of Epilepsy, 52, 136-146.
Arya, R., Wilson, J. A., Fujiwara, H., Vannest, J., Byars, A. W., Rozhkov, L., ... & Horn, P. S. (2018). Electrocorticographic high‐gamma modulation with passive listening paradigm for pediatric extraoperative language mapping. Epilepsia, 59(4), 792-801.
Additional Media and Resources
Guide to MEG by the Martinos Center at Massachusetts General Hospital: http://www.nmr.mgh.harvard.edu/meg/pdfs/talks/Cleve_Cohen_WithNotes2g.pdf
MATLAB Tutorial on Beamforming for MEG: http://www.fieldtriptoolbox.org/tutorial/natmeg/beamforming
Video of Wada Test by the Cleveland Clinic: https://youtu.be/N5_nX_LZ834
Video Description of the Epilepsy Presurgical Evaluation from the Epilepsy Foundation of America: https://youtu.be/UilImOfg7DM
Guidelines for using fMRI for presurgical evaluation of epilepsy: https://www.neurologyadvisor.com/epilepsy/epilepsy-surgery-evaluation-with-functional-mri-guidelines/article/632221/
Contributor: Thomas R. Valentine, M.A., PhD Candidate in Clinical Psychology, The Ohio State University
Anticholinergic medications are a diverse class of drugs that block the binding of the neurotransmitter acetylcholine to receptors in the central and peripheral nervous system . These agents treat a variety of physical and mental health conditions, including seasonal allergies, gastrointestinal distress, overactive bladder, insomnia, anxiety, and depression. Anticholinergic medications are thus widely used, with prevalence rates amongst older adults ranging from 14-50% . These medications can, however, produce significant adverse effects, including decrements in cognitive functioning, especially when multiple anticholinergics are taken concurrently .
The adverse effects on cognitive functioning of taking multiple anticholinergic medications—termed “anticholinergic cognitive burden”—are well-documented. A review of studies from 1966 to 2008 examining anticholinergic cognitive burden in older adults demonstrated that in 25 of 27 studies, there was a significant association between anticholinergics and delirium, cognitive impairment, or dementia . Associations have been found between anticholinergic medication use and decrements in a variety of cognitive domains, including complex attention, verbal and visual memory, verbal fluency, executive functioning, and processing speed [5-11]. Longitudinal investigations suggest a relationship between anticholinergic use and declines in cognition over time . Recent studies of individuals with specific physical and mental health conditions, such as Parkinson’s disease, multiple sclerosis, and schizophrenia, have likewise demonstrated a significant relationship between anticholinergic medications and adverse effects on cognitive performance [9, 12-13].
Several tools have been developed to assist researchers and clinicians in assessing anticholinergic cognitive burden in research participants and patients. The Anticholinergic Cognitive Burden (ACB) scale , developed by the Aging Brain Program of the Indiana University Center for Aging Research, is the most frequently validated expert-based anticholinergic rating scale . The ACB scale provides a scoring key in which medications with possible anticholinergic effects (e.g., bupropion, metoprolol) are assigned a value of 1 and “definite” anticholinergics (e.g., paroxetine, diphenhydramine) are assigned values of 2 or 3 . Values are summed to represent total anticholinergic cognitive burden. Studies utilizing the ACB scale in older adults have demonstrated that the number of definite anticholinergics taken is associated with risk for developing cognitive impairment over a six-year period . Each one-point increase in the ACB total score has been found to be associated with a decline in MMSE score of .33 points over two years and a 26% increase in risk of death .
As evidence supporting the adverse effects of anticholinergic medications on cognitive functioning has accumulated, professional healthcare organizations have issued clinical practice guidelines regarding prescription of these drugs. The American Geriatrics Society’s Beers Criteria include a list of medications with strong anticholinergic properties that are deemed “to be avoided in older adults” . These include a variety of antihistamines, antidepressants, antimuscarinics, antiparkinson agents, antipsychotics, antispasmodics, and skeletal muscle relaxants. The American Urogynecologic Society provides guidelines for the treatment of women with overactive bladder, stating that providers considering pharmacotherapy with anticholinergic medications should “counsel patients about the associated risks, prescribe the lowest effective dose, and consider alternative therapies in patients at increased risk” .
The possible implications for public health of increased attention to anticholinergic effects on cognition are considerable. Anticholinergic cognitive burden represents a potentially modifiable risk factor for cognitive decline. Indeed, discontinued use of anticholinergic medications is associated with cognitive risk reduction . Refinement of anticholinergic rating scales and wider adoption of evidence-based clinical practice guidelines may lead to better-informed medical decision-making and ultimately improve quality of life for those with physical and mental health conditions.
Highlighted Abstract: Anticholinergic drugs and functional, cognitive impairment and behavioral disturbances in patients from a memory clinic with subjective cognitive decline or neurocognitive disorders.
Background: Drugs with anticholinergic properties may be associated with various adverse clinical effects. The relationship between the anticholinergic (AC) burden and functional, global cognitive performance and behavior disturbances was assessed among elderly patients. Methods: A cross-sectional study was conducted between January 2012 and June 2014 in a memory clinic among outpatients living at home and with subjective cognitive decline (SCD) or neurocognitive disorders (NCD). The AC burden was measured using the Anticholinergic Drug Scale (ADS), the Anticholinergic Risk Scale (ARS), the Anticholinergic Cognitive Burden (ACB), Chew’s score, Han’s score, and the number of drugs with AC activity. Functional, cognitive performance and behavior disturbances were assessed using the Instrumental Activities of Daily Living (IADL) scale (IADL), the Mini Mental State Examination (MMSE), and the Neuropsychiatric Inventory (NPI). Results: Among 473 included patients, 46.3% were at major NCD. Patients took on average 5.3 ± 2.6 drugs. MMSE was lower when Han’s score (p = 0.04) and number of AC drugs were higher (p < 0.001). IADL was lower when AC burden was higher, whatever the AC measurement. NPI was higher when ACB, Han’s score, and number of AC drugs were higher. After adjustment, all AC scores remained associated with IADL, while Han’s score and number of drugs with AC remained associated with the MMSE. Conclusions: In patients with SCD or NCD, AC burden is associated with lower functional score, whereas the cross-sectional association between AC burden and cognitive performance or behavioral disturbance varies according to AC scores. Particular attention should be paid when prescribing drugs with AC properties, especially among patients with memory complaints.
Dauphinot, V., Mouchoux, C., Veillard, S., Delphin-Combe, F., & Krolak-Salmon, P. (2017). Anticholinergic drugs and functional, cognitive impairment and behavioral disturbances in patients from a memory clinic with subjective cognitive decline or neurocognitive disorders. Alzheimer’s Research & Therapy, 9. https://doi.org/10.1186/s13195-017-0284-4
Other Media and Resources
Conference Presentation – The British Association of Urological Surgeons – “The Anticholinergic Burden”
Website - American Geriatrics Society – “Beers Criteria Pocketcard”
Handout – Health in Aging Foundation – Patient Tip Sheet on “Medications Older Adults Should Avoid”
Handout – Health in Aging Foundation – Patient Tip Sheet on “Alternatives for Medications on the Beers Criteria”
American Geriatrics Society 2015 Beers Criteria Update Expert Panel. (2015). American Geriatrics Society 2015 updated Beers Criteria for potentially inappropriate medication use in older adults. Journal of the American Geriatrics Society, 63(11), 2227–2246. https://doi.org/10.1111/jgs.13702
Campbell, N., Boustani, M., Limbil, T., Ott, C., Fox, C., Maidment, I., … Gulati, R. (2009). The cognitive impact of anticholinergics: A clinical review. Clinical Interventions in Aging, 4, 225–233.
Gray, S. L., & Hanlon, J. T. (2016). Anticholinergic medication use and dementia: Latest evidence and clinical implications. Therapeutic Advances in Drug Safety, 7(5), 217–224.https://doi.org/10.1177/2042098616658399
Hanlon, J. T., Semla, T. P., & Schmader, K. E. (2015). Alternative medications for medications included in the Use of High-Risk Medications in the Elderly and Potentially Harmful Drug–Disease Interactions in the Elderly quality measures. Journal of the American Geriatrics Society, 63(12), e8–e18. https://doi.org/10.1111/jgs.13807
Naples, J. G., Marcum, Z. A., Perera, S., Gray, S. L., Newman, A. B., Simonsick, E. M., … Hanlon, J. T. (2015). Concordance among anticholinergic burden scales. Journal of the American Geriatrics Society, 63(10), 2120–2124. https://doi.org/10.1111/jgs.13647
Salahudeen, M. S., Duffull, S. B., & Nishtala, P. S. (2015). Anticholinergic burden quantified by anticholinergic risk scales and adverse outcomes in older people: A systematic review. BMC Geriatrics, 15. https://doi.org/10.1186/s12877-015-0029-9
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2.Ness, J., Hoth, A., Barnett, M. J., Shorr, R. I., & Kaboli, P. J. (2006). Anticholinergic medications in community-dwelling older veterans: Prevalence of anticholinergic symptoms, symptom burden, and adverse drug events. The American Journal of Geriatric Pharmacotherapy, 4(1), 42–51. https://doi.org/10.1016/j.amjopharm.2006.03.008
3.Boustani, M., Campbell, N., Munger, S., Maidment, I., & Fox, C. (2008). Impact of anticholinergics on the aging brain: A review and practical application. Aging Health, 4, 311–320. https://doi.org/10.2217/1745509X.4.3.311
4.Campbell, N., Boustani, M., Ott, C., Fox, C., Maidment, I., Schubert, C. C., … Gulati, R. (2009). The cognitive impact of anticholinergics: A clinical review. Clinical Interventions in Aging, 4, 225–233.
5.Lechevallier-Michel, N., Molimard, M., Dartigues, J.-F., Fabrigoule, C., & Fourrier-Réglat, A. (2005). Drugs with anticholinergic properties and cognitive performance in the elderly: Results from the PAQUID Study. British Journal of Clinical Pharmacology, 59(2), 143–151. https://doi.org/10.1111/j.1365-2125.2004.02232.x
6.Minzenberg, M. J., Poole, J. H., Benton, C., & Vinogradov, S. (2004). Association of anticholinergic load with impairment of complex attention and memory in schizophrenia. The American Journal of Psychiatry, 161(1), 116–124. https://doi.org/10.1176/appi.ajp.161.1.116
7.Bottiggi, K. A., Salazar, J. C., Yu, L., Caban-Holt, A. M., Ryan, M., Mendiondo, M. S., & Schmitt, F. A. (2006). Long-term cognitive impact of anticholinergic medications in older adults. The American Journal of Geriatric Psychiatry: Official Journal of the American Association for Geriatric Psychiatry, 14(11), 980–984. https://doi.org/10.1097/01.JGP.0000224619.87681.71
8.Carrière, I., Fourrier-Reglat, A., Dartigues, J.-F., Rouaud, O., Pasquier, F., Ritchie, K., & Ancelin, M.-L. (2009). Drugs with anticholinergic properties, cognitive decline, and dementia in an elderly general population: The 3-city study. Archives of Internal Medicine, 169(14), 1317–1324. https://doi.org/10.1001/archinternmed.2009.229
9.Cruce, R., Vosoughi, R., & Freedman, M. S. (2012). Cognitive impact of anticholinergic medication in MS: Adding insult to injury? Multiple Sclerosis and Related Disorders, 1(4), 156–161. https://doi.org/10.1016/j.msard.2012.05.002
10.Hilmer, S. N., Mager, D. E., Simonsick, E. M., Cao, Y., Ling, S. M., Windham, B. G., … Abernethy, D. R. (2007). A drug burden index to define the functional burden of medications in older people. Archives of Internal Medicine, 167(8), 781–787. https://doi.org/10.1001/archinte.167.8.781
11.Block, C. K., Logue, E., Thaler, N. S., Scarisbrick, D. M., Mahoney, J. J., Scott, J., & Duff, K. (2015). The interaction between medical burden and anticholinergic cognitive burden on neuropsychological function in a geriatric primary care sample. Archives of Clinical Neuropsychology, 30(2), 105–113. https://doi.org/10.1093/arclin/acu073
12.Ehrt, U., Broich, K., Larsen, J. P., Ballard, C., & Aarsland, D. (2010). Use of drugs with anticholinergic effect and impact on cognition in Parkinson’s disease: A cohort study. Journal of Neurology, Neurosurgery, and Psychiatry, 81(2), 160–165. https://doi.org/10.1136/jnnp.2009.186239
13.Ogino, S., Miyamoto, S., Miyake, N., & Yamaguchi, N. (2014). Benefits and limits of anticholinergic use in schizophrenia: Focusing on its effect on cognitive function. Psychiatry and Clinical Neurosciences, 68(1), 37–49. https://doi.org/10.1111/pcn.12088
14.Salahudeen, M. S., Duffull, S. B., & Nishtala, P. S. (2015). Anticholinergic burden quantified by anticholinergic risk scales and adverse outcomes in older people: A systematic review. BMC Geriatrics, 15. https://doi.org/10.1186/s12877-015-0029-9
15.Campbell, N. L., Boustani, M. A., Lane, K. A., Gao, S., Hendrie, H., Khan, B. A., … Hall, K. (2010). Use of anticholinergics and the risk of cognitive impairment in an African American population. Neurology, 75(2), 152–159. https://doi.org/10.1212/WNL.0b013e3181e7f2ab
16.Fox, C., Richardson, K., Maidment, I. D., Savva, G. M., Matthews, F. E., Smithard, D., … Brayne, C. (2011). Anticholinergic medication use and cognitive impairment in the older population: The Medical Council Cognitive Function and Ageing Study. Journal of the American Geriatrics Society, 59(8), 1477–1483. https://doi.org/10.1111/j.1532-5415.2011.03491.x
17.American Geriatrics Society 2015 Beers Criteria Update Expert Panel. (2015). American Geriatrics Society 2015 updated Beers Criteria for potentially inappropriate medication use in older adults. Journal of the American Geriatrics Society, 63(11), 2227–2246. https://doi.org/10.1111/jgs.13702
18.American Urogynecologic Society Guidelines Committee. (2017). AUGS consensus statement: Association of anticholinergic medication use and cognition in women with overactive bladder. Female Pelvic Medicine & Reconstructive Surgery, 23(3), 177–178. https://doi.org/10.1097/SPV.0000000000000423
Contributor: Robmarie Lopez-Soto, M.S., PhD Candidate in Clinical Psychology, Ponce Health Sciences University
Bipolar Disorder (BD) is a neuropsychiatric illness that is the sixth leading cause of disability worldwide . BD is characterized by alternating manic and depressive mood episodes, with interspersed periods of euthymia that vary in length depending on biochemical, clinical and psychosocial factors implicated in age of illness onset, mood episode frequency and severity of clinical progression [2, 3]. Studies in which genetic susceptibility for BD is assessed report that the Brain Derived Neurotrophic Factor (BDNF) val66met polymorphism (val/met) is significantly involved in illness chronicity and neuroprogression, a more severe clinical course characterized by earlier age of illness onset (BD type I: ~11 yrs. earlier than those with val/val) frequent mood episodes (4 additional episodes per year), higher rate of medical comorbidities, neurocognitive impairment and functional decline [3-5]. In a biochemical sense, neuroprogression can be defined as the process through which the CNS reacts to repeated neurotoxic injury (i.e., inflammation and oxidative stress) . While BD clinical staging models   have been developed to assess neuroprogression and treatment outcomes, recent evidence-based efforts have been made to incorporate neuroinflammatory correlates as the high prevalence of medical comorbidity (i.e., cardiometabolic and endocrine disorders) suggests that shared mechanistic pathways mediated by inflammation may underlie BD neuroprogression.
In BD, mood episodes have been shown to correlate with elevated levels of pro-inflammatory cytokines IL-6, IL-10 and TNF-a – which have also been found abundantly in the orbitofrontal cortex in post-mortem studies of subjects with BD who completed suicide [8, 9]. In tandem with pro-inflammatory and oxidative stress upregulation, a significant decrease in anti-inflammatory cytokines and neurotrophins emerges during acute mood episodes and is related to the white matter hyperintensities that increase with number of manic episodes [3, 10]. Likewise, cardiometabolic and immunologic illnesses often emerge as a result of chronic pro-inflammatory upregulation, and are a marker of illness progression for BD .
BDNF is a protein essential for neuronal survival and synaptic functioning and has been shown to be significantly decreased during acute manic and depressive episodes, and chronically decreased during late stages [3, 8]. Similarly, BD carriers of the val/met polymorphism present significantly lower levels of serum BDNF compared to carriers of val/val variants, which translates to lower synaptic secretion and distribution of BDNF. Therefore, neuroanatomic correlates such as lower volumetric densities in the hippocampus [4, 11, 12], smaller bilateral anterior cingulate gyrus volumes , and reduced gray matter volume in the DLPFC , and larger ventricles  become pronounced in late stages of the illness. Congruently, subjects with BD tend to show pervasive impairments in verbal memory, selective attention and executive functioning , while impairments in verbal fluency are most often associated with depressive states, low serum BDNF levels and the val/met polymorphism [3, 13].
Some controversy remains in regard to neuroprogression, as emerging longitudinal studies  have found that some proposed correlates (i.e., neurocognitive impairment) remain stable regardless of mood episode frequency. Genetic endophenotypes (e.g., BDNF val/met polymorphism), medication type, and treatment adherence may partly modulate any fluctuations in neurocognitive functioning, as lithium is known to exert neuroprotective effects – primarily, by modulating BDNF regulation and anti-inflammatory cytokines [15, 16]. Similarly, residual symptoms tend to become unremitting during late stages of BD and may persistently burden baseline neurocognitive functioning . Because manifestations of BD are often complex and heterogeneous, future research efforts focused on the assessment of biochemical and neurocognitive correlates of neuroprogression may lead to further understanding the prognosis and treatment outcome for patients affected by this variant of BD.
Abstract: Longitudinal relationship between clinical course and neurocognitive impairments in bipolar disorder (2017)
Background: The aim of this study was to estimate the relationship between clinical course and trajectory of neurocognitive functioning during a follow-up period in a sample of euthymic bipolar patients. Methods: Fifty-one patients with BD performed two-neurocognitive assessment separated by a period of at least 48 months. The clinical course during the follow-up period was documented by: three measures 1) number of affective episodes, 2) time spent ill, and 3) mood instability. Results: Patients were followed-up for a mean period of 73.21 months. Neurocognitive performance tended to be stable throughout the follow-up. Performance in verbal memory and executive functions at the end of study were related with the number of hypo/manic episodes and time spent with hypo/manic symptoms during the followup. None of the clinical measures considered were related to changes in neurocognitive performance over the follow-up period. Limitations: The relatively small sample size limits the value of subgroup analysis. The study design does not rule out some risk of selection bias. Conclusions: Although there may be a positive relationship between number of episodes and neurocognitive deficits in patients with bipolar disorder, successive episodes do not seem to modify the trajectory of neurocognitive functioning over time. Theoretical implications of these findings are discussed.
Martino, D., Igoa, A., Marengo, E., Scápola, M. and Strejilevich, S. (2018). Longitudinal relationship between clinical course and neurocognitive impairments in bipolar disorder. Journal of Affective Disorders, 225, pp.250-255.
Other Media and Resources
Website – International Society for Bipolar Disorders
Website – International Bipolar Foundation
Documentary - Ride the Tiger: A Guide Through the Bipolar Brain (PBS)
Description (from PBS)
A one-hour documentary that tells the stories of individuals with bipolar disorder. Nearly 6 million Americans have been diagnosed with bipolar disorder and yet little is known about how the illness manifests itself in our brains. Ride the Tiger tells the stories of accomplished individuals who have been diagnosed with bipolar, and explores treatment options.
Webinar - Flavio Kapczinski on "Neuroprogression and immune activation in bipolar disorder" at the World Congress of Psychiatry 2017, Berlin.
Webinar - Aging Too Soon? Premature Brain and Biological Aging In Bipolar Disorder
With Dr. Lisa Eyler
Description (directly from IBPF)
People with bipolar disorder suffer from more age-related physical illnesses and live shorter lives than those without the disorder, leading to the idea that bipolar disorder is a condition that affects the whole body and involves an acceleration of the normal aging process. Immune and inflammatory pathways may be involved in the altered course of aging in bipolar disorder. In this talk, Dr. Eyler will review evidence for altered brain aging in BD and for changes in aging-related inflammatory pathways. She will present data from her own magnetic resonance imaging study of brain aging which used multiple measures of brain structural and functional integrity to create a “brain age” prediction for each participant. She will also present initial results from her ongoing longitudinal study of inflammation, mood, and cognition in BD. The implication of these findings for treatment and prognosis will be discussed.
Elshahawi, H. H., Essawi, H., Rabie, M. A., Mansour, M., Beshry, Z. A., & Mansour, A. N. (2011). Cognitive functions among euthymic bipolar I patients after a single manic episode versus recurrent episodes. Journal of Affective Disorders, 130(1-2), 180-191. doi:10.1016/j.jad.2010.10.027
Maletic, V., & Raison, C. (2014). Integrated Neurobiology of Bipolar Disorder. Frontiers in Psychiatry, 5. doi:10.3389/fpsyt.2014.00098
Muneer, A. (2016). Staging Models in Bipolar Disorder: A Systematic Review of the Literature. Clinical Psychopharmacology and Neuroscience, 14(2), 117-130. doi:10.9758/cpn.2016.14.2.117
Rheenen, T. E., Meyer, D., & Rossell, S. L. (2014). Pathways between neurocognition, social cognition and emotion regulation in bipolar disorder. Acta Psychiatrica Scandinavica, 130(5), 397-405. doi:10.1111/acps.12295
Solé, B., Jiménez, E., Torrent, C., Reinares, M., Bonnin, C. D., Torres, I., . . . Vieta, E. (2017). Cognitive Impairment in Bipolar Disorder: Treatment and Prevention Strategies. International Journal of Neuropsychopharmacology, 20(8), 670-680. doi:10.1093/ijnp/pyx032
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4. Maletic, V. and C. Raison, Integrated neurobiology of bipolar disorder. Front Psychiatry, 2014. 5: p. 98.
5. Correll, C.U., et al., Cardiometabolic comorbidities, readmission, and costs in schizophrenia and bipolar disorder: a real-world analysis. Ann Gen Psychiatry, 2017. 16: p. 9.
6. Berk, M., et al., From neuroprogression to neuroprotection: implications for clinical care. Med J Aust, 2010. 193(4 Suppl): p. S36-40.
7. Kapczinski, F., et al., Clinical implications of a staging model for bipolar disorders. Expert Rev Neurother, 2009. 9(7): p. 957-66.
8. Bauer, I.E., et al., Inflammatory mediators of cognitive impairment in bipolar disorder. J Psychiatr Res, 2014. 56: p. 18-27.
9. Courtet, P., et al., Neuroinflammation in suicide: Toward a comprehensive model. World J Biol Psychiatry, 2016. 17(8): p. 564-586.
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Contributor: Amelia Howard, M.S.- Azusa Pacific University, Department of Clinical Psychology, Psy.D. Program (Doctoral Student)
Cannabinoids or delta-9-tetrahydrocannabinol (Δ9-THC) is commonly referred to as Marijuana . There are over 180 million users worldwide and 22.2 million users in the US [1-2]. A comprehensive review of published studies, case series, and case reports revealed that 3,582 children, age 12 years or less, unintentionally ingested cannabis . Ingestion may occur through prenatal exposure, childhood exposures (i.e., passive smoke, edible products, or unsecured joints), and adolescent use [2-3]. Whether through direct or indirect ingestion, marijuana affects seemingly all facets of childhood neurodevelopment .
As of November 2016, 28 states and the District of Columbia have approved legislation legalizing medical marijuana [4-5]. Among these states, nine allow marijuana use for recreational purposes [2, 5]. The legalization of cannabinoid use varies from state to state. For example, in California, cannabis legislation (Proposition 63) has recognized the potency and availability of products; which asserts authority to impose limits on potency levels . New York and Minnesota allow cannabis use with restrictions on smoking Δ9-THC .Colorado generated $2.39 billion in 2015 from legal cannabis sales. Not to mention in 2002 and 2014, the pervasiveness of cannabinoid use with no risk increased from 5.6% to 15.1% while the perceived concerns of cannabis use decreased from 50.4% to 33.3% . However, marijuana is illegal under federal law and remains classified as a Schedule I drug because of its potential for adverse repercussions such as the high potential for abuse, severe psychological and physical dependence [4-6]. In like manner, synthetic cannabinoids have been available since the early 2000s but were made illegal in 2012 under the Synthetic Drug Abuse Act .
Despite the popularity of cannabis and approved state legalization-marijuana has been linked to several short and long-term consequences among the pediatric population . For instance, risk factors include impaired working and episodic memory, decreased motor coordination, diminished executive functioning, difficulty with abstract reasoning, as well as acute paranoia or psychosis, risk of chronic psychotic disorders, altered brain development, poor educational and vocational outcomes, psychomotor impairments, and the development of cannabis addiction [6,8-9]. Children may exhibit chest pain, palpitations, and electrocardiographic changes consistent with myocardial ischemia after exposure to Δ9-THC or smoking K2 (one of the most widely used synthetic cannabinoids) . Moreover, in a documented case, an adolescent user was directly linked to an altered mental state parallel to a psychotic episode . In another example, an infant (indirect exposure) was found to be somnolent, agitated, with an altered mental state, tachypnea (62 breaths/min), and tachycardia (187 beats/min) . Hence, it is essential to understand the impact on this population given their neurobiological and psychosocial vulnerabilities [4, 10].
The primary psychoactive component of cannabis are mediated by the cannabinoid type 1 receptor (CB1) via activation of the mesolimbic dopamine system (i.e., the brain’s reward system) . CB1 receptors are widely distributed in fetal and neonatal brains [1, 11]. A disruption in CB1 receptor signaling can lead to the onset of cognitive deficits and anatomical abnormalities found in the prefrontal cortex (PFC) and hippocampus regions . Long-term use is correlated with a dose-dependent decrease in dopamine synthesis capacity in the striatum and modulation of genes connected with schizophrenia [8-9]. Animal model studies have proved that exposure to Δ9-THS in neonatal rats induces cell death in the cerebral cortex and leads to dysregulation of emotional processes, a decrease in social behavior, and reduced coping strategies . What's more, clinical trials and literature substantiate the claim that cannabinoids may lead to impaired brain maturation . Brain maturation may alter phenotypes later in life producing similar traits to psychotic or depressive-like behaviors .Thus, marijuana use increases the risk of cognitive deficits, structural alterations, and psychosis among individuals exposed in their formative years [3, 8, 10].
Within the pediatric population, the exposure of Δ9-THC may also restrict neurodevelopment. Prenatal cannabis use is linked to aberrant behaviors in newborns, impaired inhibitory control, delinquency, and increased risk of drug abuse later in life [4, 12-13]. Fetal exposure increases the level of the maternal cytokine (IL-8) that is related to significant decreases in left entorhinal cortex volumes (similar to individuals with schizophrenia) . Additionally, cannabis-exposed children are found to have thicker frontal cortices, a thicker superior frontal area of the left hemisphere, and a wider frontal lobe in the right hemisphere . A possible interpretation for the thicker prefrontal cortex is altered neurodevelopmental maturation . The emotional immaturity and underdeveloped cortices of adolescent make them particularly susceptible to deceptive marketing targets (i.e., marijuana posing little risk) [4, 6]. Conversely, in a cross-sectional study, few providers considered themselves entirely knowledgeable about the health risks associated with marijuana . Epidemiological studies provide substantial evidence to warrant a public health message that the unintentional exposure of cannabis among the pediatric population increases the risk of psychotic disorders and neurodevelopmental deficits [3, 8]. In conclusion, the inconsistencies between public perceptions, legislation, and the knowledge (or lack thereof) of medical professionals compared to the substantiated risks are alarming. Accordingly, more research and training is needed to provide clarity of the cannabinoid effects on children’s cognitive and neurodevelopment.
Chronic Cannabinoid Exposure During Adolescence Leads to Long-Term Structural and Functional Changes in the Prefrontal Cortex
Abstract (taken directly from ncbi.nlm.nih.gov)
In many species, adolescence is a critical phase in which the endocannabinoid system can regulate the maturation of important neuronal networks that underlie cognitive function. Therefore, adolescents may be more susceptible to the neural consequences of chronic cannabis abuse. We reported previously that chronically exposing adolescent rats to the synthetic cannabinoid agonist CP55,940 leads to impaired performances in adulthood i.e. long-lasting deficits in both visual and spatial short-term working memories. Here, we examined the synaptic structure and function in the prefrontal cortex (PFC) of adult rats that were chronically treated with CP55,940 during adolescence. We found that chronic cannabinoid exposure during adolescence induces long-lasting changes, including (1) significantly altered dendritic arborization of pyramidal neurons in layer II/III in the medial PFC (2) impaired hippocampal input-induced synaptic plasticity in the PFC and (3) significant changes in the expression of PSD95 (but not synaptophysin or VGLUT3) in the medial PFC. These changes in synaptic structure and function in the PFC provide key insight into the structural, functional and molecular underpinnings of long-term cognitive deficits induced by adolescent cannabinoid exposure. They suggest that cannabinoids may impede the structural maturation of neuronal circuits in the PFC, thus leading to impaired cognitive function in adulthood.
Journal of European Neuropsychopharmacology Article Site Link with PDF Download:
Chronic cannabinoid exposure during adolescence leads to long-term structural and functional changes in the prefrontal cortex
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Chronic cannabinoid exposure during adolescence leads to long-term structural and functional changes in the prefrontal cortex
Eur Neuropsychopharmacol. 2016 Jan;26(1):55-64. doi: 10.1016/j.euroneuro.2015.11.005. Epub 2015 Dec 3.
Other Media and Resources
Website: National Institute of Drug Abuse-Medical Marijuana
Website: National Conference of State Legislatures (NCSL) -Marijuana Laws
Documentary: How the Brain Works and Responds to Marijuana (THC).
How the Brain Works and Responds to THC
Lecture Abstract (Taken directly from NIDA):
Cannabis contains at least 60 types of cannabinoids, chemical compounds that act on receptors throughout our brain. THC, or Tetrahydrocannabinol, is the chemical responsible for most of marijuana’s effects, including the euphoric high. THC resembles another cannabinoid naturally produced in our brains, anandamide, which regulates our mood, sleep, memory, and appetite.
Podcast: Marijuana's Health Effects-Top Scientists Weigh In
Marijuana's Health Effects: Top Scientists Weigh In
Speakers (Titles taken directly from npr.org):
So far, more than half of all U.S. states have legalized marijuana for medical use, and eight (plus the District of Columbia) have legalized the drug for recreational use. Varieties of cannabis available today are more potent than ever and come in many forms, including oils and leaves that can be vaped, and lots of edibles, from brownies and cookies to candies — even cannabis gummy bears.
A report published Thursday by the National Academies of Sciences, Engineering and Medicine analyzed more than 10,000 studies to see what could conclusively be said about the health effects of all this marijuana. And despite the drug's increasing popularity — a recent survey suggests about 22 million American adults have used the drug in the last month — conclusive evidence about its positive and negative medical effects is hard to come by, the researchers say.
"The adolescent brain is very sensitive to these kinds of substances," McCormick says. "So they continue to use it — and may use it in increasing amounts — and are at risk for developing problematic cannabis use."
Newspaper: Pregnant Women Turn to Marijuana-Possibly Harming Infants
NYT: Pregnant Women Turn to Marijuana- Possibly Harming Infants
Speakers (Titles taken directly from nytimes.com):
Often pregnant women presume that cannabis has no consequences for developing infants. But preliminary research suggests otherwise: Marijuana’s main psychoactive ingredient — tetrahydrocannabinol, or THC — can cross the placenta to reach the fetus, experts say, potentially harming brain development, cognition and birth weight. THC can also be present in breast milk.
In the federal survey, published online in December, almost 4 percent of mothers-to-be said they had used marijuana in the past month in 2014, compared with 2.4 percent in 2002. (By comparison, roughly 9 percent of pregnant women ages 18 to 44acknowledge using alcohol in the previous month.)
Several studies have found changes in the brains of fetuses, 18 to 22 weeks old, linked to maternal marijuana use. In male fetuses who were exposed, for instance, researchers have noted abnormal function of the amygdala, the part of the brain that regulates emotion.
In a statement, C.D.C. officials expressed concern about memory and attention problems among children exposed to THC in utero.
Abnormal White Matter Integrity in Synthetic Cannabinoid Users [Abnormal white matter integrity in synthetic cannabinoid users. European Neuropsychopharmacology, 261818-1825. doi:10.1016/j.euroneuro.2016.08.015].
An Introduction to the Endogenous Cannabinoid System [Lu, H., & Mackie, K. (2016). An introduction to the endogenous cannabinoid system. Biological Psychiatry, 79(7), 516-525. doi:10.1016/j.biopsych.2015.07.028]
Increasing Legalization [Thomas, A. A., Moser, E., Dickerson-Young, T., & Mazor, S. (2017). A review of pediatric marijuana exposure in the setting of increasing legalization. Clinical Pediatric Emergency Medicine, 18(Toxicology), 159-162. doi:10.1016/j.cpem.2017.07.003]
Marijuana and Madness: Associations Between Cannabinoids and Psychosis [Ranganathan, M., Skosnik, P. D., & D’Souza, D. C. (2016). Marijuana and madness: Associations between cannabinoids and psychosis. Biological Psychiatry, 79(7), 511-513. doi:10.1016/j.biopsych.2016.02.007.]
Neurotoxicology of cannabis and THC: A review of chronic exposure studies in animals [Scallet, A. C. (1991). Neurotoxicology of cannabis and THC: A review of chronic exposure studies in animals. Pharmacology, Biochemistry, And Behavior, 40(3), 671-676. ]
A Review of Pediatric Marijuana Exposure in the Setting of The Role of Cannabinoids in Neuroanatomic Alterations in Cannabis Users [Lorenzetti, V., Solowij, N., & Yücel, M. (2016). Review: The role of cannabinoids in neuroanatomic alterations in cannabis users. Biological Psychiatry, 79(Cannabinoids and Psychotic Disorders), e17-e31. doi:10.1016/j.biopsych.2015.11.013]
Contributor: Zach Greth, BS –University of North Carolina at Charlotte
Concerns over malingering and invalid symptom reporting continue to escalate within clinical and forensic settings. Recent rates suggest some 19-68% of U.S. Social Security Administration (SSA) disability claims have been reported to include elements of compromised effort and feigning during clinical evaluation . This can be problematic if claimants are erroneously compensated for cognitive dysfunction that is not valid. Total losses due to malingered neurocognitive disorder are elusive because the SSA’s fraudulent disability classification is broad. Some reports revealed nearly $2-5 billion in “improper payments” in 2015 alone . A calculated, multifactorial approach to assessment is therefore necessary to help characterize the nature and severity of sequelae, if any, following neurological insult. The American Academy of Clinical Neuropsychology (AACN) provided some of the following recommendations for proper evaluation in such cases:
Clinical cases that include litigation for protracted recovery of concussion are especially relevant [1,4,6,8,9]. Robust literature highlights infrequent performance patterns for some individuals with post-concussive complaints that are not congruent with the extent of injury, or duration of continued symptom presentation [1,4,6,8,9]. Performance validity testing (PVT) and symptom validity testing (SVT) can help determine the nature of these neurocognitive inconsistencies (i.e., malingering, variable motivation). Results on both are compared to base rates in several other clinical populations. For example, several PVTs (e.g., Test of Memory Malingering, Medical Symptom Validity Test) are generally insensitive to cognitive impairment, meaning those with genuine, neurocognitive dysfunction can still perform above established cutoffs [2,8]. Research has shown that post-concussive patients have higher failure rates than genuinely impaired patients on PVTs [1,3,4,6,8,9]. Similarly, they may over-report the severity of their symptoms at a rate unusual even for patients with severe psychopathology [3,9]. The use of PVT’s and SVT’s is thereby incumbent to the neuropsychological assessment [2,3,9].
PVT’s and SVT’s are often used interchangeably in the literature. However, recent research suggests that PVT’s and SVT’s are mutually exclusive, and should be examined independently of each other . Feigned cognitive impairment is not synonymous with symptom exaggeration. Examinees may “pass” several standalone and embedded PVTs, but endorse several symptomatic complaints that are vague, infrequent, or inconsistent [3, 9]. This can have major implications on the entire evaluation, including the clinician’s interpretation, treatment planning, and patient recovery. The clinician may need to further evaluate the individual’s psychological overlay, and increase communication with other treating clinicians. Van Dyke, Millis, Axelrod, and Hanks highlighted these differences, and encourage providers use a multifaceted approach to their work .
The current study aimed to clarify the relationship among the constructs involved in neuropsychological assessment, including cognitive performance, symptom self-report, performance validity, and symptom validity. Participants consisted of 120 consecutively evaluated individuals from a veteran's hospital with mixed referral sources. Measures included the Wechsler Adult Intelligence Scale-Fourth Edition Full Scale IQ (WAIS-IV FSIQ), California Verbal Learning Test-Second Edition (CVLT-II), Trail Making Test Part B (TMT-B), Test of Memory Malingering (TOMM), Medical Symptom Validity Test (MSVT), WAIS-IV Reliable Digit Span (RDS), Post-traumatic Check List-Military Version (PCL-M), MMPI-2 F scale, MMPI-2 Symptom Validity Scale (FBS), MMPI-2 Response Bias Scale (RBS), and the Postconcussive Symptom Questionnaire (PCSQ). Six different models were tested using confirmatory factor analysis (CFA) to determine the factor model describing the relationships between cognitive performance, symptom self-report, performance validity, and symptom validity. The strongest and most parsimonious model was a three-factor model in which cognitive performance, performance validity, and self-reported symptoms (including both standard and symptom validity measures) were separate factors. The findings suggest failure in one validity domain does not necessarily invalidate the other domain. Thus, performance validity and symptom validity should be evaluated separately.
Van Dyke, S., Millis, S., Axelrod, B., & Hanks, R. (2013). Assessing effort: Differentiating performance and symptom validity. The Clinical Neuropsychologist, 27(8), 1234-1246.
Multimedia Sources on Performance and Symptom Validity Testing:
Symptom Validity Testing (SVT)
The speakerin this video provides a brief overview of SVTin the context of neuropsychological assessment, as well as examples of common validity measures used. See related videos on side panel for additional information.
Dr. Rick Frederick on Multiple Measures of Malingering
Dr. Frederick, a forensic psychologist, presents a lecture about the nature and assessment of malingering during evalutation. He explains how administering too many PVTs can become problematic.
 Denning, J. (2012). The efficiency and accuracy of the Test of Memory Malingering trial 1, errors on the first 10 items of the test of memory malingering, and five embedded measures in predicting invalid test performance. Archives of Clinical Neuropsychology: The Official Journal of the National Academy of Neuropsychologists, 27(4), 417-432.
 Heilbronner, R., Sweet, J., Morgan, J., Larrabee, G., & Millis, S. (2010). American Academy of Clinical Neuropsychology consensus conference statement on the neuropsychological assessment of effort, response bias, and malingering. The Clinical Neuropsychologist, 23(7), 1093-1129.
 Holdnack, J., Millis, S., Larrabee, G., & Iverson, G. (2013). Assessing performance validity with the ACS.WAIS-IV, WMS-IV, and ACS: Advanced Clinical Interpretation. 331-365. 10.1016/B978-0-12-386934-0.00007-9.
 O'Bryant, S., Engel, L., Kleiner, J., Vasterling, J., & Black, F. (2007). Test of Memory Malingering (TOMM) trial 1 as a screening measure for insufficient effort. The Clinical Neuropsychologist, 21(3), 511-521.
 Probasco, J. (2015). Social Security fraud: What is it costing taxpayers? Investopedia, LLC.
 Psychological Testing in the Service of Disability Determination (1st ed.). (2015). Washington, DC: National Academies Press.
 Schoenberg, M., & Scott, J. (2011). The little black book of neuropsychology: A syndrome-based approach. New York, NY: Springer Science+Business Media.
 Tombaugh, T. (1996). Test of Memory Malingering. Toronto, Canada: MultiHealth Systems.
 Van Dyke, S., Millis, S., Axelrod, B., & Hanks, R. (2013). Assessing effort: Differentiating performance and symptom validity. The Clinical Neuropsychologist, 27(8), 1234-1246.
Contributor: Erin Kaseda, Brigham Young University, Neuroscience undergraduate & ANST Member
Overview: It is estimated that between 5-10% of children and adolescents in the United States have been diagnosed with attention-deficit/hyperactivity disorder (ADHD) . Developmentally appropriate self-regulation allows for social flexibility and goal-oriented motivation; traits often diminished in children with ADHD . Pediatric ADHD populations typically experience attention and academic problems and diminished peer and family relationships. Parent-child relationships experience increased conflict and poorer parenting practices . Interpersonal difficulties among both peers and family members and academic stress put children with ADHD at risk for comorbid disorders, including depression, anxiety, and oppositional defiant disorder (ODD), and may lead to an increased risk for suicide, the third leading cause of death among adolescents in the United States.
A wide number of deficits typically associated with ADHD may be a result of poor inhibitory control . Understanding the correlates of inhibitory control in adolescents with ADHD is significant for research and clinical practice on quality of life and improved social and behavioral outcomes. Go/No-go tasks are valuable in assessing inhibitory control. In this paradigm, participants are instructed to perform the same motor response for the majority of the task cues, and suppress the go-response to a restricted number of deviant trials (i.e., no-go trials) . These tasks are widely used to study inhibitory control in various populations and can be used in conjunction with physiological data collection, such as during a functional MRI scan, or can be used alone, offering insight based on response speed and accuracy.
One study examined the default mode network (DMN), comprised of the medial prefrontal cortex and medial and lateral parietal legions, which has been shown to be associated with goal-directed behavior ). In typically developing children, the DMN was significantly deactivated during inhibitory control Go/No-go tasks, regardless of the motivational incentive to perform well at the task. In subjects with ADHD, DMN activation was high during low-incentive inhibitory control tasks. However, when those subjects were given a high incentive to perform well at the Go/No-go task, their DMN activation was normalized to the same level as their typically-developing peers. A similar study showed that in a stop signal task, a variation of the go/no-go task, task performance itself was significantly improved in children with ADHD when given a high incentive to perform well, raising their performance level to that of typically developing children . These conclusions offer a potential direction for parents and educators in techniques in improving inhibitory control in adolescents with ADHD.
Interventions that target strengthening inhibitory control during adolescence may decrease the severity of negative behaviors related to inattention and impulsivity. Incentive-based interventions are beginning to gain attention in public health and education settings. One study found that monetary incentives resulted in complete abstinence from smoking in 64% of adult smokers with ADHD, a group that smokes at a rate significantly higher than the general population . Another study examined self-imposed incentives on therapeutic assignment completion in college students with ADHD . Further investigation is needed to offer rigorous support for pediatric interventions specifically designed to improve inhibitory control among individuals with ADHD.
Highlighted Abstract: The problems children with attention-deficit/hyperactivity disorder (ADHD) encounter in tasks measuring inhibitory control are often theoretically related to deficits in cognitive processes. This study investigated the effects of different motivational incentives on the ability of children to inhibit intended or ongoing actions. In a large German industrial town, 33 children with ADHD were compared with 33 members of a combined group of children with major depressive disorder, anxiety disorders, oppositional defiant disorder, or conduct disorder, and 33 children without any psychiatric disorder with respect to their performances in a stop-signal task. The children received continuous feedback under high-or low-incentive conditions. The children's performance was compared in terms of qualitative (inhibition rate) and quantitative (reaction time) measures. There were no indications of deficits in sustained attention in children with ADHD. Under conditions of low incentives, children with ADHD were less able to inhibit their reactions and had longer stop-signal reaction times. But when given high incentives, children with ADHD performed the task as well as both other groups. Supposed deficits in children with ADHD should be regarded from a perspective that differentiates performance from ability. Furthermore, the findings support a motivational explanation of the origins of lowered inhibitory control in children with ADHD.
Citation: Slusarek, M., Velling, S., Bunk, D., & Eggers, C. (2001). Motivational effects on inhibitory control in children with ADHD. Journal Of The American Academy Of Child & Adolescent Psychiatry, 40(3), 355-363.
NPR broadcast “A peek at brain connections may reveal attention deficits”
TEDx talk “Not wrong, just different: ADHD as innovators”
 Evans, W. N., Morrill, M. S., & Parente S. T. (2010). Measuring inappropriate medical diagnosis and treatment in survey data: The case of ADHD among school-age children.Journal of Health Economics, 29(5), 657-673.
 Berger, A., Kofman, O., Livneh, U., & Henik, A. (2007). Multidisciplinary perspectives on attention and the development of self-regulation. Progress in Neurobiology, 82(5), 256-286.
 Humphreys, K. L., Katz, S. J., Lee, S. S., Hammen, C., Brennan, P. A., & Najman, J. M. (2013). The association of ADHD and depression: Mediation by peer problems and parent-child difficulties in two complementary samples. Journal of Abnormal Psychology, 122(3), 854-867.
 Pliszka, S. R., Liotti, M., & Woldorff, M. G. (2000). Inhibitory control in children with attention-deficit/hyperactivity disorder: Event-related potentials identify the processing component and timing of an impaired right-frontal response-inhibition mechanism. Biological Psychiatry, 48(3), 238-246.
 Uzefovsky, F., Allison, C., Smith, P., & Baron-Cohen, S. (2016). Brief report: The go/no-go task online: Inhibitory control deficits in autism in a large sample. Journal of Autism and Developmental Disorders, 46, 2774-2779.
 Liddle, E. B., Hollis, C., Batty, M. J., Groom, M. J., Totman, J. J., …& Liddle, P. F. (2011). Task-related default mode network modulation and inhibitory control in ADHD: Effects of motivation and methylphenidate. Journal of Child Psychology and Psychiatry, 52(7), 761-771.
 Slusarek, M., Velling, S., Bunk, D., & Eggers, C. (2001). Motivational effects on inhibitory control in children with ADHD. Journal Of The American Academy Of Child & Adolescent Psychiatry, 40(3), 355-363.
 Kollins, S. H., McClernon, F. J., & Van Voorhees, E. E. (2010). Monetary incentives promote smoking abstinence in adults with attention deficit hyperactivity disorder (ADHD). Experimental and Clinical Psychopharmacology, 18(3), 221-228.
 Prevatt, F., Smith, S. M., Diers, S., Marshall, D., Colman, J., … & Miller, N. (2017). ADHD coaching with college students: Exploring the processes involved in motivation and goal completion. Journal of College Student Psychotherapy, 31(2), 93-111.
Contributor: Brooke Herd- Azusa Pacific University, Department of Clinical Psychology, Psy.D. Student
Agenesis of the corpus callosum (AgCC) is a rare congenital condition resulting from the complete absence (cAgCC) or hypogenesis (partial absence; pAgCC) of the corpus callosum [1-2]. The corpus callosum is the main commissure connecting the two cerebral hemispheres, and is composed of about 200 million axonal connections . A typically developing corpus callosum serves to provide connections primarily among homologous cortical areas and has numerous intra-and interhemispheric axonal projections [4-5]. AgCC results from the lack of these axonal fibers forming, and causes disrupted integration between the cerebral hemispheres [1-2]. In AgCC, the integration of information is often dependent upon the smaller subcortical commissures, including both the anterior and hippocampal commissures .
AgCC occurs in 1:4000 individuals and seems to arise from a variety of causes that reflect errors during any of the stages of callosal development [1, 6]. The formation of the corpus callosum includes midline patterning and the development of the cerebral hemispheres, as well as the birth and correct specification of commissural neurons, and accurate guidance for the axons of these neurons across the midline to reach the appropriate destination on the contralateral hemisphere . Research in this area shows that these issues in callosal development may arise in humans due to genetic causes, including single gene inherited and sporadic mutations, as well as a complex combination of inherited and sporadic mutations [1, 7]. Environmental factors are less understood but also may be a contributing cause of AgCC, such as is seen in Fetal Alcohol Syndrome (FAS) and the impact it has on callosal development . AgCC is present in 3-5% of all neurodevelopmental disorders [8-9]. It can be detected prenatally through high resolution ultrasound or magnetic resonance imaging . Although genetic causes have been identified, only about 30-45% of all cases of AgCC can be attributed to specific genetic syndromes or chromosomal abnormalities, while the remaining 55-70% of cases appear to be an isolated instance with no identifiable cause for callosal agenesis . Given that it can be comorbid with different genetic and prenatal conditions but also can occur in isolation, AgCC has a widely heterogeneous clinical presentation [1, 10]. Behavioral symptoms can be highly variable, but AgCC is typically accompanied by neuropsychological and social deficits . AgCC can appear similar to that of an autism spectrum disorder (ASD), and corpus callosum abnormalities present at birth are a major risk factor for developing autism .
Generally, individuals with isolated AgCC are capable of simple behaviors but more complex behaviors are often impacted. These individuals may present with intact intellectual functioning but have shown to have difficulties solving complex problems , specifically demonstrating delayed processing speed with complex information [12-14]. They also show difficulties with verbal and visual learning and memory [10-11], as well as sensory deficits in the integration of complex visual information . Social deficits are also apparent in this population, including a reduced theory of mind , as well as challenges with understanding higher level facets of communication such as non-literal language, affective prosody, and humor [10, 16-18]. When compared to their peers however, deficits in the comprehension of nonliteral language have shown to be more clearly pronounced in adults with AgCC than in children with AgCC . There is also impaired facial scanning in individuals with AgCC, leading to deficits in one’s ability to recognize facial emotions [10, 19].
Much of what is understood about AgCC comes from the study of animal models. One well known animal model for studying AgCC is the BTBR T+tf/J (BTBR) inbred mouse strain . The BTBR strain is documented as having a 100% total absence of the corpus callosum as well as a severely reduced hippocampal commissure in nearly every animal . This strain is commonly tested against the control mouse strain C57BL/6J (B6), which has normal commissural fibers. Research on the BTBR strain has helped to better understand genes that may be involved in human AgCC . The BTBR strain has been utilized in different paradigms within autism research for its reduced social behaviors [ 21-23], but the use of this strain for ASD research has been questioned for lacking construct validity . Although much research has been done on the social behaviors of the BTBR strain, little research has been conducted on the cognitive functioning of BTBR mice for further knowledge on AgCC. Testing BTBR mice within different paradigms represents an area of potential research for better understanding the social and cognitive functioning in those with AgCC.
Abstract: Clinical Characterization, Genetics, and Long-Term Follow-up of a Large Cohort of Patients With Agenesis of the Corpus Callosum (2017)
To gain a better understanding of the clinical and genetic features associated with agenesis of corpus callosum, we enrolled and characterized 162 patients with complete or partial agenesis of corpus callosum. Clinical and genetic protocols allowed us to categorize patients as syndromic subjects, affected by complex extra-brain malformations, and nonsyndromic subjects without any additional anomalies. We observed slight differences in sex ratio (56% males) and agenesis type (52% complete). Syndromic agenesis of corpus callosum subjects were prevalent (69%). We detected associated cerebral malformations in 48% of patients. Neuromotor impairment, cognitive and language disorders, and epilepsy were frequently present, regardless of the agenesis of corpus callosum subtype. Long-term follow-up allowed us to define additional indicators: syndromic agenesis of corpus callosum plus patients showed the most severe clinical features while isolated complete agenesis of corpus callosum patients had the mildest symptoms, although we observed intellectual disability (64%) and epilepsy (15%) in both categories. We achieved a definitive (clinical and/or genetic) diagnosis in 42% of subjects.
Romaniello, R., Marelli, S., Giorda, R., Bedeschi, M. F., Bonaglia, M. C., Arrigoni, F., & ... Borgatti, R. (2017). Clinical characterization, genetics, and long-term follow-up of a large cohort of patients with agenesis of the corpus callosum. Journal of Child Neurology, 32(1), 60-71.
Other Media and Resources
Website- National Organization for Disorders of the Corpus Callosum (NODCC)
Documentary- Curious: Mind, Brain, Machine (AgCC Segment: 21:42-35:10)
Description (taken directly from nodcc.org)
CURIOUS, a PBS documentary on selected California Institute of Technology scientists, was produced by WNET in New York with funding from TIAA-CREF and has been aired by PBS stations throughout the U.S. over the last few months. The episode Mind, Brain, Machine features a segment in which Dr. Lynn K. Paul discusses agenesis of the corpus callosum (AgCC).
Lynn K. Paul, PhD is the head of the Corpus Callosum Research Program at Caltech. This program represents the hub of the AgCC Research Consortium, a multisite collaborative effort whose other members include the Fuller Graduate School of Psychology/Travis Research Institute and the University of California in San Francisco.
Podcast- ACC Research and Progress
Speakers (Titles taken directly from nodcc.org)
Elliott Sherr, MD, PhD is an Assistant Professor in Neurology and Pediatrics at UCSF. He directs the Brain Development Research Program. Warren S. Brown, PhD is Professor of Psychology at the Graduate School of Psychology at Fuller Theological Seminary, where he is Director of the Lee Travis Research Institute. Lynn K. Paul, PhD (Past President of the NODCC) is currently serving as Senior Research Fellow at California Institute of Technology, where she is directing an ACC research program.
Lecture Abstract (Taken directly from nodcc.org):
Professionals conducting on-going research studies related to agenesis of the corpus callosum and other callosal disorders presented a brief overview of the current status on genetic, neuropsychological and behavior research relative to disorders of the corpus callosum. Presentation compiled by Warren S. Brown PhD, Lynn K. Paul, PhD, Elliott Sherr, MD, PhD.
Podcast- DCC and Autism Spectrum Behaviors
Mary Gavin, MEd is a teacher in the Natick Public School District for students with severe special needs and sensory impairments. In this podcast, she presents as a speaker at the 2014 Disorders of the Corpus Callosum (DCC) Conference.
Lecture Abstract (Taken directly from nodcc.org)
Children diagnosed with a DCC can exhibit behaviors similar to those exemplified in autism spectrum disorders (ASD), attention deficit disorder (ADD) and attentive deficit hyperactive disorder (ADHD). As a result they have many challenges in being able to meet academic and social expectations in school. They also often have difficulty functioning successfully within their family and in the community. Lecture will focus on causes of difficult behavior, means of intervention, modification strategies and tools necessary to plan for success in order to help children achieve their potential.
DCC and Autism Spectrum Behaviors Podcast
Agenesis of the Corpus Callosum: Genetic, Developmental and Functional Aspects of Connectivity. Paul, L. K., Brown, W. S., Adolphs, R., Tyszka, J. M., Richards, L. J., Mukherjee, P., & Sherr, E. H. (2007). Agenesis of the corpus callosum: Genetic, developmental and functional aspects of connectivity. Nature reviews. Neuroscience, 8(4), 287.
Agenesis of the Corpus Callosum and Autism: A Comprehensive Comparison. Paul, L. K., Corsello, C., Kennedy, D. P., & Adolphs, R. (2014). Agenesis of the corpus callosum and autism: A comprehensive comparison. Brain: A Journal of Neurology, 137(6), 1813-1829. doi:10.1093/brain/awu070
Counseling in Fetal Medicine: Agenesis of the Corpus Callosum. Santo, S., D'antonio, F., Homfray, T., Rich, P., Pilu, G., Bhide, A., ... & Papageorghiou, A. T. (2012). Counseling in fetal medicine: Agenesis of the corpus callosum. Ultrasound in Obstetrics & Gynecology, 40(5), 513-521.
Processing Speed Delays Contribute to Executive Function Deficits in Individuals with Agenesis of the Corpus Callosum. Marco, E. J., Harrell, K. M., Brown, W. S., Hill, S. S., Jeremy, R. J., Kramer, J. H., & ... Paul, L. K. (2012). Processing speed delays contribute to executive function deficits in individuals with agenesis of the corpus callosum.Journal of The International Neuropsychological Society, 18(3), 521-529. doi:10.1017/S1355617712000045
Verbal Learning and Memory in Agenesis of the Corpus Callosum. Erickson, R. L., Paul, L. K., & Brown, W. S. (2014). Verbal learning and memory in agenesis of the corpus callosum. Neuropsychologia, 60, 121-130.
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