Neuropsychiatric symptoms and brain morphology in patients with mild cognitive impairment, cerebrovascular disease and Parkinson disease: A cross sectional and longitudinal study.

OBJECTIVES: Neuropsychiatric symptoms (NPS) increase risk of developing dementia and are linked to various neurodegenerative conditions, including mild cognitive impairment (MCI due to Alzheimer's disease [AD]), cerebrovascular disease (CVD), and Parkinson's disease (PD). We explored the structural neural correlates of NPS cross-sectionally and longitudinally across various neurodegenerative diagnoses. METHODS: The study included individuals with MCI due to AD, (n = 74), CVD (n = 143), and PD (n = 137) at baseline, and at 2-years follow-up (MCI due to AD, n = 37, CVD n = 103, and PD n = 84). We assessed the severity of NPS using the Neuropsychiatric Inventory Questionnaire. For brain structure we included cortical thickness and subcortical volume of predefined regions of interest associated with corticolimbic and frontal-executive circuits. RESULTS: Cross-sectional analysis revealed significant negative correlations between appetite with both circuits in the MCI and CVD groups, while apathy was associated with these circuits in both the MCI and PD groups. Longitudinally, changes in apathy scores in the MCI group were negatively linked to the changes of the frontal-executive circuit. In the CVD group, changes in agitation and nighttime behavior were negatively associated with the corticolimbic and frontal-executive circuits, respectively. In the PD group, changes in disinhibition and apathy were positively associated with the corticolimbic and frontal-executive circuits, respectively. CONCLUSIONS: The observed correlations suggest that underlying pathological changes in the brain may contribute to alterations in neural activity associated with MBI. Notably, the difference between cross-sectional and longitudinal results indicates the necessity of conducting longitudinal studies for reproducible findings and drawing robust inferences.

White matter hyperintensities and smaller cortical thickness are associated with neuropsychiatric symptoms in neurodegenerative and cerebrovascular diseases.

BACKGROUND: Neuropsychiatric symptoms (NPS) are a core feature of most neurodegenerative and cerebrovascular diseases. White matter hyperintensities and brain atrophy have been implicated in NPS. We aimed to investigate the relative contribution of white matter hyperintensities and cortical thickness to NPS in participants across neurodegenerative and cerebrovascular diseases. METHODS: Five hundred thirteen participants with one of these conditions, i.e. Alzheimer's Disease/Mild Cognitive Impairment, Amyotrophic Lateral Sclerosis, Frontotemporal Dementia, Parkinson's Disease, or Cerebrovascular Disease, were included in the study. NPS were assessed using the Neuropsychiatric Inventory - Questionnaire and grouped into hyperactivity, psychotic, affective, and apathy subsyndromes. White matter hyperintensities were quantified using a semi-automatic segmentation technique and FreeSurfer cortical thickness was used to measure regional grey matter loss. RESULTS: Although NPS were frequent across the five disease groups, participants with frontotemporal dementia had the highest frequency of hyperactivity, apathy, and affective subsyndromes compared to other groups, whilst psychotic subsyndrome was high in both frontotemporal dementia and Parkinson's disease. Results from univariate and multivariate results showed that various predictors were associated with neuropsychiatric subsyndromes, especially cortical thickness in the inferior frontal, cingulate, and insula regions, sex(female), global cognition, and basal ganglia-thalamus white matter hyperintensities. CONCLUSIONS: In participants with neurodegenerative and cerebrovascular diseases, our results suggest that smaller cortical thickness and white matter hyperintensity burden in several cortical-subcortical structures may contribute to the development of NPS. Further studies investigating the mechanisms that determine the progression of NPS in various neurodegenerative and cerebrovascular diseases are needed.

Cognitive correlates of antisaccade behaviour across multiple neurodegenerative diseases.

Oculomotor tasks generate a potential wealth of behavioural biomarkers for neurodegenerative diseases. Overlap between oculomotor and disease-impaired circuitry reveals the location and severity of disease processes via saccade parameters measured from eye movement tasks such as prosaccade and antisaccade. Existing studies typically examine few saccade parameters in single diseases, using multiple separate neuropsychological test scores to relate oculomotor behaviour to cognition; however, this approach produces inconsistent, ungeneralizable results and fails to consider the cognitive heterogeneity of these diseases. Comprehensive cognitive assessment and direct inter-disease comparison are crucial to accurately reveal potential saccade biomarkers. We remediate these issues by characterizing 12 behavioural parameters, selected to robustly describe saccade behaviour, derived from an interleaved prosaccade and antisaccade task in a large cross-sectional data set comprising five disease cohorts (Alzheimer's disease/mild cognitive impairment, amyotrophic lateral sclerosis, frontotemporal dementia, Parkinson's disease, and cerebrovascular disease; n = 391, age 40-87) and healthy controls (n = 149, age 42-87). These participants additionally completed an extensive neuropsychological test battery. We further subdivided each cohort by diagnostic subgroup (for Alzheimer's disease/mild cognitive impairment and frontotemporal dementia) or degree of cognitive impairment based on neuropsychological testing (all other cohorts). We sought to understand links between oculomotor parameters, their relationships to robust cognitive measures, and their alterations in disease. We performed a factor analysis evaluating interrelationships among the 12 oculomotor parameters and examined correlations of the four resultant factors to five neuropsychology-based cognitive domain scores. We then compared behaviour between the abovementioned disease subgroups and controls at the individual parameter level. We theorized that each underlying factor measured the integrity of a distinct task-relevant brain process. Notably, Factor 3 (voluntary saccade generation) and Factor 1 (task disengagements) significantly correlated with attention/working memory and executive function scores. Factor 3 also correlated with memory and visuospatial function scores. Factor 2 (pre-emptive global inhibition) correlated only with attention/working memory scores, and Factor 4 (saccade metrics) correlated with no cognitive domain scores. Impairment on several mostly antisaccade-related individual parameters scaled with cognitive impairment across disease cohorts, while few subgroups differed from controls on prosaccade parameters. The interleaved prosaccade and antisaccade task detects cognitive impairment, and subsets of parameters likely index disparate underlying processes related to different cognitive domains. This suggests that the task represents a sensitive paradigm that can simultaneously evaluate a variety of clinically relevant cognitive constructs in neurodegenerative and cerebrovascular diseases and could be developed into a screening tool applicable to multiple diagnoses.

Neuropsychiatric Symptom Burden across Neurodegenerative Disorders and its Association with Function.

OBJECTIVE: Neuropsychiatric symptoms (NPS) are prevalent in neurodegenerative disorders, however, their frequency and impact on function across different disorders is not well understood. We compared the frequency and severity of NPS across Alzheimer's disease (AD) (either with mild cognitive impairment or dementia), Cerebrovascular disease (CVD), Parkinson's disease (PD), frontotemporal dementia (FTD), and amyotrophic lateral sclerosis (ALS), and explored the association between NPS burden and function. METHODS: We obtained data from Ontario Neurodegenerative Disease Research Initiative (ONDRI) that included following cohorts: AD (N = 111), CVD (N = 148), PD (N = 136), FTD (N = 50) and ALS (N = 36). We compared the frequency and severity of individual NPS (assessed by the neuropsychiatric inventory questionnaire) across cohorts using generalized estimating equations and analysis of variance. Second, we assessed the relationship of NPS burden with instrumental (iADLs) and basic (ADLs) activities of living across cohorts using multivariate linear regression while adjusting for relevant demographic and clinical covariates. RESULTS: Frequency of NPS varied across cohorts (χ2(4) = 34.4, p < .001), with post-hoc tests showing that FTD had the greatest frequency as compared to all other cohorts. The FTD cohort also had the greatest severity of NPS (H(4) = 34.5, p < .001). Further, there were differences among cohorts in terms of the association between NPS burden and ADLs (F(4,461) = 3.1, p = 0.02). Post-hoc comparisons suggested that this finding was driven by the FTD group, however, the differences did not remain significant following Bonferroni correction. There were no differences among cohorts in terms of the association between NPS burden and IADLs. CONCLUSIONS: NPS frequency and severity are markedly greater in FTD as compared to other neurodegenerative diseases. Further, NPS burden appears to be associated differently with function across neurodegenerative disorders, highlighting the need for individualized clinical interventions.

Targeted copy number variant identification across the neurodegenerative disease spectrum.

BACKGROUND: Although genetic factors are known to contribute to neurodegenerative disease susceptibility, there remains a large amount of heritability unaccounted for across the diagnoses. Copy number variants (CNVs) contribute to these phenotypes, but their presence and influence on disease state remains relatively understudied. METHODS: Here, we applied a depth of coverage approach to detect CNVs in 80 genes previously associated with neurodegenerative disease within participants of the Ontario Neurodegenerative Disease Research Initiative (n = 519). RESULTS: In total, we identified and validated four CNVs in the cohort, including: (1) a heterozygous deletion of exon 5 in OPTN in an Alzheimer's disease participant; (2) a duplication of exons 1-5 in PARK7 in an amyotrophic lateral sclerosis participant; (3) a duplication of >3 Mb, which encompassed ABCC6, in a cerebrovascular disease (CVD) participant; and (4) a duplication of exons 7-11 in SAMHD1 in a mild cognitive impairment participant. We also identified 43 additional CNVs that may be candidates for future replication studies. CONCLUSION: The identification of the CNVs suggests a portion of the apparent missing heritability of the phenotypes may be due to these structural variants, and their assessment is imperative for a thorough understanding of the genetic spectrum of neurodegeneration.

Investigating the contribution of white matter hyperintensities and cortical thickness to empathy in neurodegenerative and cerebrovascular diseases.

Change in empathy is an increasingly recognised symptom of neurodegenerative diseases and contributes to caregiver burden and patient distress. Empathy impairment has been associated with brain atrophy but its relationship to white matter hyperintensities (WMH) is unknown. We aimed to investigate the relationships amongst WMH, brain atrophy, and empathy deficits in neurodegenerative and cerebrovascular diseases. Five hundred thirteen participants with Alzheimer's disease/mild cognitive impairment, amyotrophic lateral sclerosis, frontotemporal dementia (FTD), Parkinson's disease, or cerebrovascular disease (CVD) were included. Empathy was assessed using the Interpersonal Reactivity Index. WMH were measured using a semi-automatic segmentation and FreeSurfer was used to measure cortical thickness. A heterogeneous pattern of cortical thinning was found between groups, with FTD showing thinning in frontotemporal regions and CVD in left superior parietal, left insula, and left postcentral. Results from both univariate and multivariate analyses revealed that several variables were associated with empathy, particularly cortical thickness in the fronto-insulo-temporal and cingulate regions, sex (female), global cognition, and right parietal and occipital WMH. Our results suggest that cortical atrophy and WMH may be associated with empathy deficits in neurodegenerative and cerebrovascular diseases. Future work should consider investigating the longitudinal effects of WMH and atrophy on empathy deficits in neurodegenerative and cerebrovascular diseases.

Contribution of rare variant associations to neurodegenerative disease presentation.

Genetic factors contribute to neurodegenerative diseases, with high heritability estimates across diagnoses; however, a large portion of the genetic influence remains poorly understood. Many previous studies have attempted to fill the gaps by performing linkage analyses and association studies in individual disease cohorts, but have failed to consider the clinical and pathological overlap observed across neurodegenerative diseases and the potential for genetic overlap between the phenotypes. Here, we leveraged rare variant association analyses (RVAAs) to elucidate the genetic overlap among multiple neurodegenerative diagnoses, including Alzheimer's disease, amyotrophic lateral sclerosis, frontotemporal dementia (FTD), mild cognitive impairment, and Parkinson's disease (PD), as well as cerebrovascular disease, using the data generated with a custom-designed neurodegenerative disease gene panel in the Ontario Neurodegenerative Disease Research Initiative (ONDRI). As expected, only ~3% of ONDRI participants harboured a monogenic variant likely driving their disease presentation. Yet, when genes were binned based on previous disease associations, we observed an enrichment of putative loss of function variants in PD genes across all ONDRI cohorts. Further, individual gene-based RVAA identified significant enrichment of rare, nonsynonymous variants in PARK2 in the FTD cohort, and in NOTCH3 in the PD cohort. The results indicate that there may be greater heterogeneity in the genetic factors contributing to neurodegeneration than previously appreciated. Although the mechanisms by which these genes contribute to disease presentation must be further explored, we hypothesize they may be a result of rare variants of moderate phenotypic effect contributing to overlapping pathology and clinical features observed across neurodegenerative diagnoses.

The prevalence of Parkinson's disease: a systematic review and meta-analysis.

Parkinson's Disease (PD) is a common neurodegenerative disorder. We sought to synthesize studies on the prevalence of PD to obtain an overall view of how the prevalence of this disease varies by age, by sex, and by geographic location. We searched MEDLINE and EMBASE for epidemiological studies of PD from 1985 to 2010. Data were analyzed by age group, geographic location, and sex. Geographic location was stratified by the following groups: 1) Asia, 2) Africa, 3) South America, and 4) Europe/North America/Australia. Meta-regression was used to determine whether a significant difference was present between groups. Forty-seven studies were included in the analysis. Meta-analysis of the worldwide data showed a rising prevalence of PD with age (all per 100,000): 41 in 40 to 49 years; 107 in 50 to 59 years; 173 in 55 to 64 years; 428 in 60 to 69 years; 425 in 65 to 74 years; 1087 in 70 to 79 years; and 1903 in older than age 80. A significant difference was seen in prevalence by geographic location only for individuals 70 to 79 years old, with a prevalence of 1,601 in individuals from North America, Europe, and Australia, compared with 646 in individuals from Asia (P < 0.05). A significant difference in prevalence by sex was found only for individuals 50 to 59 years old, with a prevalence of 41 in females and 134 in males (P < 0.05). PD prevalence increases steadily with age. Some differences in prevalence by geographic location and sex can be detected.

Extrastriatal dopaminergic dysfunction in tourette syndrome.

OBJECTIVE: Tourette syndrome (TS) is a neuropsychiatric disorder presenting with tics and a constellation of nonmotor symptoms that includes attention deficit hyperactivity disorder, obsessive-compulsive disorder, and impulse control disorders. Accumulated evidence from pharmacological trials and postmortem analyses suggests that abnormalities of dopaminergic neurotransmission play a key role in the pathogenesis of TS. A substantial body of evidence has also accrued to implicate regions outside the striatum in the generation of tics. METHODS: We initiated an [11C]FLB 457 positron emission tomography study in conjunction with an amphetamine challenge to evaluate extrastriatal dopamine (DA) D2/D3 receptor binding and DA release in a group of treatment-naive, adult TS patients compared with a group of age- and sex-matched controls. RESULTS: At baseline, TS patients showed decreased [11C]FLB 457 binding potentials bilaterally in cortical and subcortical regions outside the striatum, including the cingulate gyrus, middle and superior temporal gyrus, occipital cortex, insula, and thalamus. Amphetamine challenge induced DA release in both control and TS subjects bilaterally in many cortical regions; however, in TS patients, regions of increased DA release were significantly more widespread and extended more anteriorly to involve anterior cingulate and medial frontal gyri. Conversely, and in contrast to healthy controls, no significant DA release was noted in the thalami of TS patients. INTERPRETATION: These abnormalities of dopaminergic function localize to brain regions previously implicated in TS and suggest a mechanism for the hyperexcitability of thalamocortical circuits that has been documented in the disorder.

Neurobiological basis of serotonin-dopamine antagonists in the treatment of Gilles de la Tourette syndrome.

Tourette syndrome (TS) is a heritable neuropsychiatric disorder that presents in childhood with a constellation of motor and non-motor symptoms. The defining feature of the disorder is the presence of brief, stereotyped, motor or vocal behaviours called tics. Although tics are themselves voluntary, they are typically performed secondary to involuntary sensory symptoms or irresistible urges. TS is therefore said to be a disorder of human volition that likely represents a general failure of inhibition. It shares many features with obsessive compulsive disorder (OCD), attention deficit hyperactivity disorder (ADHD) and impulse control disorder with which it is also commonly associated. Much of the anatomic substrate for TS probably lies in the circuits that connect multiple areas of cortex with the basal ganglia and thalamus to subserve motivation, inhibition of behaviour, planning of motor acts and detection of threats. To date, pathological studies of TS have been very few and the number of subjects evaluated too small to reliably elucidate the nature and significance of several reported abnormalities. However, evidence derived from both pharmacological trials and selected functional imaging studies suggests that disturbances of the dopaminergic and serotonergic neurotransmitter systems play a key role in the pathogenesis of TS. At the same time, multiple studies have demonstrated reciprocal interactions between the serotonin and dopamine systems of the brain. This information, when placed in the context of the observed functional imaging abnormalities, may generate further insights into the pathophysiology of TS.

EEG changes in a patient with steroid-responsive encephalopathy associated with antibodies to thyroperoxidase (SREAT, Hashimoto's encephalopathy).

A 56-year-old woman presented with an acute confusional state and moderate global aphasia. Thyroperoxidase antibody level was elevated (3,890 IU/mL) and SREAT was diagnosed. MRI findings were normal. Cerebrospinal fluid examination revealed only a mildly increased protein. The initial electroencephalogram EEG showed slowing and markedly decreased amplitude over the left hemisphere and left temporal sharp waves. An EEG performed after treatment with intravenous steroids showed a significant improvement of the background slowing, which correlated with clinical improvement. One week later, the patient had an episode of forced head-turning and fencing posture to the right. The EEG shortly afterward showed slowing and a decreased amplitude over the right hemisphere. Continuous EEG monitoring was performed at the time of steroid treatment. Again, there was a significant improvement of the EEG after this treatment that correlated with the clinical condition. SREAT is characterized by fluctuations in mental status and variable EEG findings. These patients often show an excellent clinical improvement to immunosuppressive therapy, including corticosteroids. This case report documents the dramatic clinical and EEG improvement with steroid therapy.

Coital hemorrhage of an arteriovenous malformation after premedication with tadalafil (Cialis).

Phosphodiesterase type 5 (PDE 5) inhibitors are widely used in the treatment of erectile dysfunction. However, the results on the cerebral vasculature are unknown. Several cases of intraparenchymal hemorrhage in the setting of PDE 5 inhibitor use have been reported. The effect of these agents on the risk of arteriovenous malformation (AVM) hemorrhage is speculative. This report illustrates a possible association between tadalafil (Cialis, Lilly ICOS, Indianapolis, IN), a new long-acting PDE 5 inhibitor, and AVM hemorrhage during coitus. A 59-year-old male suffered a coital intraparenchymal hemorrhage after premedication with tadalafil. Angiography and magnetic resonance imaging demonstrated an underlying right temporoparital AVM. The AVM was excised, and the patient made an uneventful recovery. AVMs are felt to be dynamic lesions that evolve in response to changes in blood flow. Repeated use of PDE 5 inhibitors could induce changes in an AVM that would make it more likely to hemorrhage, particularly in the setting of additional stress from coitus and elevated blood pressure. The potential for risk of devastating neurovascular complications related to PDE 5 inhibitors should be monitored.