Neuropathology and morphometry of dentate nucleus neurons in DYT1 brains: Cerebellar abnormalities in isolated dystonia.

Brain lesions exclusive to dystonia, or specific forms of it, such as isolated dystonia, have been rarely described. While the identification of distinctive intra- or extraneuronal abnormalities in childhood-onset generalized dystonia (DYT1) brains remains lacking, recent stereology-based findings demonstrated hypertrophy of neurons in the substantia nigra (SN) of DYT1-carriers manifesting dystonia (DYT1-manif) versus DYT1-carriers nonmanifesting dystonia (DYT1-nonmanif), and age-matched control subjects (C). Because other brain regions including the cerebellum (CRB) have been implicated in the pathomechanisms of dystonia, we investigated neurons of the dentate nucleus (DN), the "door-out" nucleus of the CRB. We performed systematic neuropathologic assessments and stereology-based measurements of 7 DN from DYT1-carriers (DYT1-DN; 4 DYT1-manif and 3 DYT1-nonmanif), and 5 age-matched control (C-DN) subjects. Data demonstrated larger cell body (+14.1%), nuclear (+10.6%), and nucleolar (+48.3%) volumes of DYT1-DN versus C-DN neurons. No differences in intra- and extracellular pathological indicators (ß-amyloid, pTau, α-synuclein, Torsin1A, Negri, Bunina, Hirano, Marinesco, Nissl bodies, Buscaino bodies, granulovacuolar degeneration, or cerebrovascular lesions) were detected in DYT1-DN versus C-DN. Astroglial reactivity (GFAP) and microglial activation (IBA1) were observed in some DYT1-DNs. These novel findings confirm involvement of the DN and CRB in the pathogenesis of DYT1 and perhaps of other forms of isolated dystonia.

Hypertrophy of nigral neurons in Torsin1A deletion (DYT1) carriers manifesting dystonia.

OBJECTIVE: To individuate morphometric changes and prevalent types of intraneuronal inclusions in nigral neurons of DYT1 dystonia autopsy-brains. METHODS: Using precise methods of quantification, such as unbiased stereology, we measured cellular and subcellular volumes of neuromelanin-containing (pigmented) neurons in the substantia nigra (SN) of DYT1 carriers with and without manifestation of generalized dystonia (manif-DYT1 and non-manif-DYT1, respectively), non-DYT1 carriers manifesting generalized dystonia (manif-non-DYT1) patients, and age-matched control subjects (controls). A total of four DYT1 carriers (two manif-DYT1 and two non-manif-DYT1), six manif-non-DYT1 carriers, and six controls autopsy-brains were available for these neuropathological-morphometric analyses. The search of brain lesions was performed for: tau neurofibrillary tangles and neurites, extracellular ß-amyloid deposits, Lewy bodies and neurites, TorsinA, Laminin A + C, Ubiquitin, p62, pTDP43 intraneuronal inclusions; and Negri, Bunina, Hirano, Marinesco, Nissl, and Buscaino bodies. RESULTS: An increased mean cell body, nuclear, and nucleolar volume of nigral neurons in manif-DYT1 vs. non-manif-DYT1 (p < 0.0001), manif-non-DYT1 (p < 0.0001), and controls (p < 0.00001) was found. Increased nuclear and nucleolar volumes in manif-non-DYT1 vs. controls were also found. None of the considered possible intraneuronal lesions were more frequent or prevalent in nigral neurons of manif-DYT1 vs. all the other groups. CONCLUSIONS: Unbiased stereology-based measurements of nigral neurons enlargement in manif-DYT1 in the absence of intraneuronal inclusions or neurodegenerative processes, is novel. These findings suggest distinct pathogenetic mechanisms between manif-DYT1 vs. non-manif-DYT1 and manif-non-DYT1 dystonia, especially in terms of possible nigral dopaminergic abnormalities. These data could open new pathophysiologic views on specific dopamino-associated pathomechanisms related to the clinical manifestation of generalized dystonia.

Postural, Bone, and Joint Disorders in Parkinson's Disease.

BACKGROUND: Stooped posture was mentioned in the original description of the characteristic features of Parkinson's disease (PD). Since then, a variety of postural, bone, and joint problems have become recognized as common aspects of the illness and deserve attention. METHODS: A Medline literature search for the period from 1970 to 2016 was performed to identify articles relevant to this topic. Keywords for the search included posture, spine, bone disorders, fractures, joint disorders, kyphosis, scoliosis, stooping, camptocormia, Pisa syndrome, frozen shoulder, anterocollis, dropped head syndrome, and pain in combination with PD. The articles were then reviewed to summarize clinical features, frequency, impact, pathophysiology, and treatment options for these conditions. RESULTS: Postural disorders (kyphoscoliosis, camptocormia, Pisa syndrome, dropped head syndrome), bone mineralization disorders (osteoporosis, bone fractures), and joint disorders (frozen shoulder, dystonia involving joints, joint pain) are often seen in association with PD. Treatment options for these conditions are varied and may include medications, physical therapy, or surgical interventions. CONCLUSIONS: Posture, bone, and joint disorders are common in patients with PD; they often produce added disability, and they may be treatable.

Parkinson disease and incidental Lewy body disease: Just a question of time?

OBJECTIVE: To quantify the loss of pigmented neurons in the substantia nigra (SN) of autopsy-confirmed Parkinson disease (PD) and incidental Lewy body disease (ILBD) vs age-matched controls (C). METHODS: Unbiased stereology methods were used to rigorously count number and measure volumes of nigral pigmented neurons in PD, ILBD, and C brains. The obtained stereologic results were correlated with Lewy body (LB), amyloid plaque (AP), neurofibrillary tangle (NFT), and vascular pathology loads assessed in nigral and extranigral regions of each PD, ILBD, and C brain. The stereologic measurements were also correlated to predeath motor and cognitive scores as available for each participant. RESULTS: A marked nigral neuronal loss (NNL) in PD (-82%) and ILBD (-40%) compared to C (p < 0.0001) was found. While there was significant correlation between NNL and LB in some cortical areas of PD (i.e., olfactory bulb), there were no correlations between NNL and LB, AP, or NFT loads or cerebral infarct volumes in any other examined regions for PD and ILBD brains. CONCLUSIONS: Using unbiased stereology methods, we show that there is a significant loss and absence of hypertrophic changes in nigral pigmented neurons of ILBD in comparison to C brains. Intriguingly, no significant correlations were found between NNL and LB loads in the SN of both PD and ILBD brains. These autopsy-verified stereologically based findings are novel and support ILBD as a pathologic condition. These results suggest possible new and alternative pathophysiologic hypotheses on the actual relationship between NNL and LB pathology.

Tremor and Klinefelter's Syndrome.

BACKGROUND: Klinefelter's syndrome (KS) has been associated with tremor, but reports on tremor phenomenology and treatment are limited. CASE REPORTS: Patient 1 is a 17-year-old male with a dystonic tremor treated with deep brain stimulation (DBS). Patient 2 is a 57-year-old male with a predominant left hand resting tremor and dystonic features. DISCUSSION: Our cases suggest that the tremor in patients with KS may be dystonic in nature. Patient 1 is also the third reported case of successful treatment with DBS. These cases have implications for elucidating the underlying neurobiological mechanism of tremor and identifying treatment options.

Reduced Number of Pigmented Neurons in the Substantia Nigra of Dystonia Patients? Findings from Extensive Neuropathologic, Immunohistochemistry, and Quantitative Analyses.

BACKGROUND: Dystonias (Dys) represent the third most common movement disorder after essential tremor (ET) and Parkinson's disease (PD). While some pathogenetic mechanisms and genetic causes of Dys have been identified, little is known about their neuropathologic features. Previous neuropathologic studies have reported generically defined neuronal loss in various cerebral regions of Dys brains, mostly in the basal ganglia (BG), and specifically in the substantia nigra (SN). Enlarged pigmented neurons in the SN of Dys patients with and without specific genetic mutations (e.g., GAG deletions in DYT1 dystonia) have also been described. Whether or not Dys brains are associated with decreased numbers or other morphometric changes of specific neuronal types is unknown and has never been addressed with quantitative methodologies. METHODS: Quantitative immunohistochemistry protocols were used to estimate neuronal counts and volumes of nigral pigmented neurons in 13 SN of Dys patients and 13 SN of age-matched control subjects (C). RESULTS: We observed a significant reduction (∼20%) of pigmented neurons in the SN of Dys compared to C (p<0.01). Neither significant volumetric changes nor evident neurodegenerative signs were observed in the remaining pool of nigral pigmented neurons in Dys brains. These novel quantitative findings were confirmed after exclusion of possible co-occurring SN pathologies including Lewy pathology, tau-neurofibrillary tangles, ß-amyloid deposits, ubiquitin (ubiq), and phosphorylated-TAR DNA-binding protein 43 (pTDP43)-positive inclusions. DISCUSSION: A reduced number of nigral pigmented neurons in the absence of evident neurodegenerative signs in Dys brains could indicate previously unconsidered pathogenetic mechanisms of Dys such as neurodevelopmental defects in the SN.

Complementary Therapies for Parkinson's Disease: What's Promoted, Rationale, Potential Risks and Benefits.

BACKGROUND: Nearly half of all patients with Parkinson's disease (PD) utilize some form of complementary therapy often identified on the Internet and frequently not reported to their physicians. Treating physicians are sometimes unaware of such treatments, including their rationale, mechanisms, potential efficacy, and potential adverse effects. METHODS: Methods for this study included systematic Internet search of products recommended for PD, medical literature review to determine scientific rationale, any evidence of efficacy, and potential risks. RESULTS: A large number of complementary therapies are recommended for patients with PD, generally falling into the following categories: dietary and nutritional; chelation; and physical. Most have reasonable justifications based on mechanism of action and current theories on causes of neurodegeneration in PD, but few have documented evidence of benefit. Fortunately, most have few risks and side effects, although some are very expensive. The protein redistribution diet has substantial evidence of symptomatic benefit. Some antioxidative or -inflammatory supplements, aerobic exercise, Tai chi, and dance and music therapy have preliminary evidence of symptomatic benefit or potential neuroprotective effects, but more research is needed to establish efficacy. CONCLUSIONS: Patients with PD are faced with many recommendations for complementary therapies. Physicians should know about these in order to have informed discussions with their patients. Some deserve further study.

Movement disorders in women: a review.

The field of women's health developed based on the recognition that there are important sex-based differences regarding several aspects of medical illnesses. We performed a literature review to obtain information about differences between women and men for neurological movement disorders. We identified important differences in prevalence, genetics, clinical expression, course, and treatment responses. In addition, we found that female life events, including menstruation, pregnancy, breast feeding, menopause, and medications prescribed to women (such as oral contraceptives and hormone-replacement therapy), have significant implications for women with movement disorders. Understanding this biological sex-specific information can help improve the quality and individualization of care for women with movement disorders and may provide insights into neurobiological mechanisms.

Functional MRI predicts post-surgical memory following temporal lobectomy.

Temporal lobectomy is an effective therapy for medically refractory temporal lobe epilepsy (TLE), but may be complicated by amnestic syndromes. Therefore, pre-surgical evaluation to assess the risk/benefit ratio for surgery is required. Intracarotid amobarbital testing (IAT) is currently the most widely used method for assessing pre-surgical memory lateralization, but is relatively invasive. Over the past decade functional MRI (fMRI) has been shown to correlate with IAT for language lateralization, and also for memory lateralization in a small number of patients. This study was carried out to compare fMRI during memory encoding with IAT testing for memory lateralization, and to assess the predictive value of fMRI during memory encoding for post-surgical memory outcome. Thirty-five patients with refractory TLE undergoing pre-surgical evaluation for temporal lobectomy and 30 normal subjects performed a complex visual scene-encoding task during fMRI scanning at 1.5 T using a 10-min protocol. Encoding performance was evaluated with subsequent recognition testing. Twenty-three patients also completed the same task again outside the scanner, an average of 6.9 months following surgery. A region of interest (ROI) analysis was used to quantify activation within hippocampal and a larger mesial temporal lobe ROI consisting of hippocampus, parahippocampus and fusiform gyrus (HPF) as defined by a published template. Normal subjects showed almost symmetrical activation within these ROI. TLE patients showed greater asymmetry. Asymmetry ratios (ARs) from the HPF ROI correlated significantly with memory lateralization by intracarotid amobarbital testing. HPF ARs also correlated significantly with memory outcome, as determined by a change in scene recognition between pre-surgical and post-surgical trials. When absolute activation within the HPF ROI was considered, a significant inverse correlation between activation ipsilateral to temporal lobectomy and memory outcome was observed, with no significant correlation in the contralateral HPF ROI. Although further technical improvements and prospective clinical validation are required, these results suggest that mesial temporal memory activation detected by fMRI during complex visual scene encoding correlates with post-surgical memory outcome and supports the notion that this approach will ultimately contribute to patient management.

Age-related total gray matter and white matter changes in normal adult brain. Part I: volumetric MR imaging analysis.

BACKGROUND AND PURPOSE: A technique of segmenting total gray matter (GM) and total white matter (WM) in human brain is now available. We investigated the effects of age and sex on total fractional GM (%GM) and total fractional WM (%WM) volumes by using volumetric MR imaging in healthy adults. METHODS: Fifty-four healthy volunteers (22 men, 32 women) aged 20-86 years underwent dual-echo fast spin-echo MR imaging. Total GM, total WM, and intracranial space volumes were segmented by using MR image-based computerized semiautomated software. Volumes were normalized as a percentage of intracranial volume (%GM and %WM) to adjust for variations in head size. Age and sex effects were then assessed. RESULTS: Both %GM and %WM in the intracranial space were significantly less in older subjects (> or =50 years) than in younger subjects (<50 years) (P <.0001 and P =.02, respectively). Consistently, %GM decreased linearly with age, beginning in the youngest subjects. %WM decreased in a quadratic fashion, with a greater rate beginning only in adult midlife. Although larger GM volumes were observed in men before adjustments for cranium size, no significant differences in %GM or %WM were observed between the sexes. CONCLUSION: GM volume loss appears to be a constant, linear function of age throughout adult life, whereas WM volume loss seems to be delayed until middle adult life. Both appear to be independent of sex. Quantitative analysis of %GM and %WM volumes can improve our understanding of brain atrophy due to normal aging; this knowledge may be valuable in distinguishing atrophy of disease patterns from characteristics of the normal aging process.

Age-related total gray matter and white matter changes in normal adult brain. Part II: quantitative magnetization transfer ratio histogram analysis.

BACKGROUND AND PURPOSE: The magnetization transfer ratio (MTR) is a sensitive and quantitative identifier of underlying structural changes in the brain. We quantitatively evaluated age- and sex-related MTR changes in global gray matter (GM) and global white matter (WM) in healthy adults. METHODS: Fifty-two healthy volunteers (21 men, 31 women) aged 20-86 years underwent dual-echo fast spin-echo and magnetization transfer imaging performed with and then without a saturation pulse. GM and WM were distinguished by using a computer-assisted semiautomated segmentation technique. MTR histograms were generated for each segmented tissue in each subject and compared among age and sex groups. RESULTS: The mean, median, first quartile, and peak height of the MTR histogram were significantly lower in the older group (> or =50 years) than those in the younger group (<50 years) for both GM and WM. The age dependency of these values can be expressed in a quadratic fashion over the entire span of adulthood. The MTRs started to decline only after the age of approximately 40 years in both tissues. No statistically significant differences in MTR histogram measurements between the sexes were observed. CONCLUSION: The different MTR values for both GM and WM in the two age groups suggest that notable microscopic changes occur in GM and WM with advancing age, yet no significant sex-related variations in MTR measurements were found in these neurologically healthy adults. Such normative data based on the inherent contrast in MTRs are essential in studies of specific disorders of aging, and they may have implications for our understanding of the gross structural changes in both GM and WM in the aging brain.